By Jude Webber

NAZCA, Peru (Reuters) – A tiny, hand-painted sign mounted
on a flimsy barbed wire fence warns visitors to Peru’s Nazca
lines: “No entry. Area off-limits.”

It’s not much of a deterrent.

The latest threat to the vast U.N. World Heritage site
where the enigmatic shapes and lines, stylized figures of birds
and animals were etched in the desert some 2,000 years ago, is
a camp of around 30 shacks that appeared in August.

The rudimentary straw-matting huts are pitched in the dry
earth on the fringe of a protected area that covers 111,200
acres — roughly 2-1/2 times the size of Washington, D.C.
Directly below them is an ancient burial site still pitted by
long-ago scars of tomb raiders hunting for priceless textiles,
pottery or jewels to steal.

The lines — one of Peru’s top tourist attractions and only
properly visible from the air — were made by clearing away
surface shale or piling it up onto other stones when the Roman
Empire still existed. But there are signs modern vandals have
been at work.

One giant trapezoid, which is not on the usual tourist
aerial overview, has graffiti scrawled all over it.

Nearby, someone has also drawn a penis — a recent
addition, judging by how the newly disturbed earth stands out
brightly against the gray of the plain.

“Everyone thinks we’re exaggerating when we say the lines
are being irreparably damaged, but I’d like them to see the
amount of graffiti on these lines,” said Eduardo Herran, chief
pilot at Aerocondor, who flies over Nazca almost daily.

The squatters — who have been reported to the police but
say they have nowhere else to go — have invaded the edge of
the Nazca no-go area, next to an older shanty town on protected
land that is so established it has a concrete sports field.

Ironically, they are just over the road from the house of
Maria Reiche, the German mathematician dubbed the “Lady of the
lines,” who devoted her life to studying and protecting them.

Although the shacks are far from Nazca’s most emblematic
figures, like the monkey with the spiral tail, archeologists
fear they will spread unless people are evicted.

“Look around: all this is off-limits … it’s full of
excrement, rubbish, (old) signs of looting,” said squatter
Maximiliano Tenorio.

EVER MORE URGENT

Tomb raiders remain one of Nazca’s top threats. From the
air, it looks like some areas have been machine gunned because
of the clusters of craters dug over the decades.

Herran said a textile from the Paracas civilization, when
archeologists say the earliest lines in Nazca and those in
neighboring Palpa were made, could fetch $1 million. The
Paracas culture ran from about 500 B.C. to 200 B.C. and Nazca
from about 100 B.C. to 650 A.D.

Among other dangers, Herran said he had seen goat tracks 10
yards (meters) from the head of the famous hummingbird figure.

Protection is increasingly urgent as the area — whose
baffling lines have variously been interpreted as landing
strips for alien astronauts, astronomical charts, an agrarian
calendar; or linked to fertility, rituals or water — reveals
more treasures.

For example several largely unknown Paracas-era figures on
the Nazca plain, including one like two monkeys and another
like a fish or snake, came to light in September.

“Everything that has been preserved by the desert is being
destroyed now by man — by agriculture, expansion of housing
and destruction of archeological sites,” warned Guiseppe
Orefici, an Italian archeologist excavating the Nazca
ceremonial site and pyramids of Cahuachi.

TREASURES WHEREVER YOU TREAD

The Nazca lines were declared a U.N. heritage site in 1994
— six decades after a lizard figure was chopped in two by the
construction of the Pan-American highway.

Further damage occurred later when electricity towers were
installed, close to at least one figure.

“Wherever you tread in Nazca there are archeological
remains, evidence of cemeteries as well as lines,” said
historian Josue Lancho.

And just treading is trouble. The plain is partly covered
by scree but the earth underneath is peculiarly spongy, making
even the faintest footprints or marks virtually indelible.

That is why the Nazca and Palpa lines have survived
virtually intact for some 2,000 years. But it is also why
half-century-old tire tracks are now part of the scenery.

Helaine Silverman, an authority on Nazca at the University
of Illinois, said more should be done. The authorities “plead a
lack of funds but it’s really a lack of will,” she said.

Only a couple of watchmen on motorbikes patrol Nazca, one
of Peru’s top tourist attractions. One, Humberto Cancho, said
he had found people dumping a truckload of trash inside the
protected area, and said long-distance buses routinely chucked
refuse sacks out of windows as they sped by.

Leading archeologist Johny Isla said people seemed to be
waking up, as damage in Nazca has fallen in recent years.

But he said things were critical in Palpa, which does not
yet share Nazca’s protected status. The lines there are on
desert hillsides, with a shanty town creeping closer, and some
have been damaged by curious people clambering up for a look.

“The classic thing is to write their names. There aren’t
many untouched hillsides left now, he said.

By Oliver Bullough

POLUKARPOVO, Russia (Reuters) – On Moscow’s crowded streets
you would never sense Russia had a population crisis. But go to
Polukarpovo — or thousands of villages like it — and the
emptiness hits you.

As the mobile shop made its twice-weekly visit, the
village’s inhabitants gathered — three pensioners, a young
woman and two boys — on a dirt track lined with boarded-up log
cabins.

The faint calls of a giant V of geese flying south high
overhead and the rustle of falling leaves barely disturbed the
silence.

“There used to be a family in every house, probably 30
families. Now there’s just us. No one helps us. No one pays
attention to us any more,” said Vera Malchanova, 58, wrapped up
against the autumn chill as she came to buy bread.

Villages such as Polukarpovo, which is halfway between
Moscow and St Petersburg, line Russia’s country roads — mute
and rotting witnesses to a population collapse that is eating
out the heart of the world’s biggest country.

In particular, a rising death rate among adult males is
hitting both the pool of army conscripts and the size of the
workforce, forcing a revision of military and economic planning
in decades to come.

A climbing mortality rate will see Russia’s population fall
by some 790,000 — the number of people in Cyprus or South
Dakota — out of 143 million total over the next year.

DEMOGRAPHIC CRISIS

Many Western nations are seeing declining populations as
well, but the Russian population is falling much faster. It is
driven above all by a high death rate, rather than fewer births
or emigration, said Anatoly Vishnevsky, head of Russia’s Center
of Demography and Human Ecology.

His institute, based in a tower block in southern Moscow,
has a Web site that keeps a running total of Russia’s
population. Refresh www.demoscope.ru every few minutes and you
can watch the population fall in real time.

“One of the main reasons is the high mortality of adult
men,” he told Reuters. “Child mortality is higher than in the
West but the trend is positive. But adult mortality is rising.
And in recent times the level of female mortality has started
rising faster than for men.”

“If you look at how long a 30-year-old man can be expected
to live, there is basically no change since the beginning of
the 20th century.”

Russian consumption of vodka is legendary and alcohol
poisoning killed 39,000 Russians last year. Additionally, it is
seen as a key cause of the 39,000 deaths in traffic accidents,
the 36,000 murders and the 46,000 suicides.

“You have to ask why people drink so much. Here there are
cultural and historical roots, but in general it comes from the
unfortunate social situation,” said Vishnevsky.

“A major difference (between Russia and the West) is death
from external causes — murder, accidents, and so on. These are
healthy people, but often they are drunk and they are not
showing care for their own life.”

Some officials have suggested payments to young mothers and
tighter control on alcohol sales as measures to halt the
crisis, but analysts say their response will necessarily be
limited by ordinary Russians’ opposition to living healthily.

“Above all, of course, we need to think of ensuring social
and economic stability in the country,” said President Vladimir
Putin in an address to the nation last month, in which he
stressed the need to reduce deaths among working-age adults.

“Drunkenness, drugs, deaths at work, traffic accidents, a
health system not being organized the way it should be … all
of this together creates our problems.”

CONSCRIPTION AGE

The population collapse must drastically alter military and
economic planning, since the rise in deaths has gone together
with a fall in births as experienced in the rest of Europe.

The number of Russian men of conscription age will fall by
nearly 40 percent to 1.4 million in 20 years.

Forecasters predict Russia’s lengthy borders will have
fewer than a million young men to defend them by 2050 — less
than half those eligible for conscription now.

The work force will peak in the next few years and then
drop by 20 million from the present 85 million by the middle of
the century.

Vishnevsky said there was little the government could do
about it because of the lack of pressure for healthy living,
citing the case of former Soviet President Mikhail Gorbachev,
whose attempt to ban alcohol was a major cause of his
unpopularity.

“Fighting against drinking and smoking is not happening
here as it is in the West. No politician will do this because
the people will not support such a campaign,” he said.

And in Polukarpovo, the villagers doubted their demoralized

and impoverished neighbors had the resources to drag
themselves up from the general depression on their own.

“When the men do not work, they begin to drink. And when
they drink, they can’t work,” said Boris Andreyev, 60, as he
gloomily watched a kitten playing in the dust of the road.

“That is our younger generation. There it is see, playing
with that leaf,” he said with a sad smile, before tucking his
loaf of bread under his arm and returning to his nine sheep.

By Tim Gaynor

SASABE, Mexico (Reuters) – For decades, residents of this
Mexican desert village on the border with the United States
baked bricks and ranched cattle to make a meager living. Sasabe
was barren and isolated then.

Now it is a boomtown studded with bars, flophouses and taco
stands as that isolation has made it a popular and thriving hub
for smugglers hauling undocumented migrants north into America,
authorities say.

The U.S. Border Patrol said more than 165,000 illegal
immigrants were picked up last year in a scrub- and
cactus-strewn corridor near this sun-baked community, nearly an
eighth of the total 1.2 million arrested for the whole
2,000-mile (3,200-km) Mexican border.

A crackdown on security in the border cities of San Diego,
California, to the west and Nogales, Arizona, to the east in
recent years has forced immigrants to seek more out-of-the way
spots like Sasabe to sneak across the border.

Each afternoon hundreds of weary looking travelers, many
hefting gallon jugs of water for the journey ahead, gather on
benches outside cheap restaurants in Sasabe as they wait to
cross into Arizona, led by guides dubbed “polleros” or
“coyotes.”

“It all started when the U.S. authorities closed the border
around the cities, and people started to cross in the most
inhospitable areas,” town administrator Jose Alejandro Leyva
said in the one-story office building he shares with the
community’s three police officers.

“At one time there were no undocumented migrants here …
and now the town is growing out of control … driven by the
influx of migrants passing through here on their way north,” he
added.

BORDER BOOMTOWN

Two coyotes, dressed like immigrants in well-worn jeans,
T-shirts and baseball caps so as to blend in if nabbed by U.S.
border police after crossing into the United States, bluntly
refused to be interviewed for this story and accused the
reporter of being a policeman.

Mexican state migrant welfare organization Grupo Beta
estimates up to 1,000 people — mainly from poverty-wracked
southern states such as Veracruz, Oaxaca and Chiapas — stream
north through Sasabe each day headed for the United States
either on foot or in trucks.

The village has doubled in size to some 4,000 people in
just four years as a result, with criminals and entrepreneurs
from across Mexico flocking in to make money on the back of the
illicit cross-border trade.

The most obvious beneficiaries are the coyotes, who earn a
fat cut from fees of up to $2,000 that U.S. border police say
immigrants must pay to be taken over the border and north to
Arizona cities Tucson and Phoenix.

The money is spent building new cinder-block homes in the
dusty village, as well as on things like late-model pickup
trucks, many of which are fitted with tinted windows. These
trucks ride the dusty main street blaring out thumping
accordion ballads.

Secondary businesses have also sprung up to cater to the
migrants including general stores, flophouse hotels that charge
just $3 a night, as well as restaurants and cantinas — one
cheekily named ‘El Coyote’ by its owners.

Locals say many businesses have been set up by people from
outside the community to take advantage of the easy money,
including one cook from the eastern state of Veracruz who
opened a taco stall early in October.

“We figured there was a chance to make something out of the
passing trade,” cook Mariano Oliver said as he stirred a vat of
simmering ox bones for a group of migrants in his dirt-floor
diner.

A DANGEROUS BUSINESS

The trade can be deadly. The U.S. Border Patrol in Tucson
said 145 migrants died in the year to October crossing the
western desert area that includes Sasabe. Most perished of
dehydration during the brutal summer heat.

The cross-border trade also has a downside for Sasabe and
surrounding areas, as cinder-block buildings are thrown up
regardless of planning regulations, and added demand is placed
on already hard-pressed water supplies, Leyva said.

Some ranchers near the town also complained that immigrants
snip through the five-strand barbed wire border fence marking
the northern limit of their land, letting their cattle out to
roam into the United States.

Sasabe’s namesake twin just across the cactus-studded
border in Arizona, has also been marked by the migration, as
pristine desert trails are littered with empty water bottles,
plastic bags and discarded clothing.

Residents say the roadway through the tiny village, which
includes a primary school and a general store, has become a
racetrack as Border Patrol units chase after smugglers fleeing
back to Mexico in vans packed with migrants.

“One time they were going so fast through here that they
spun off the road at the hairpin bend and through a neighbor’s
wall,” said long-suffering store owner Deborah Grider.

“We have a school here, and we are very concerned that
someone could get killed,” she added.

By Ahmed, Aftab

Injury of any sort to the breast can cause localized pain and may last for weeks or months.

Mastalgia, or breast pain, is a necessary part and consequence of reproductive life. Like breast swelling, it waxes and wanes during the menstrual cycle and is one of the first symptoms of pregnancy. It is understandable then that many women expect that breast pain will be a thing of the past with the onset of menopause. When that does not happen, they may fear that they have breast cancer. The good news is that breast pain is rarely a symptom of malignancy, irrespective of age. The possibility, however, should be considered along with a number of benign conditions that affect the breasts.

Broadly speaking, breast pain is either cyclical or non- cyclical. Cyclical breast pain correlates with menstruation and results from monthly fluctuations of estrogen and progesterone. While no hormonal abnormality has been linked with cyclical breast pain, it is known that estrogen and progesterone affect the breast, increasing the size and number of ducts and milk glands and causing the breast to retain water.

Just prior to the onset of menstruation, both breasts may swell and become tender, painful and lumpy. The pain may extend to the upper and outer portions of the breast and into the arm. The symptoms may subside when the menstrual cycle is completed. Cyclic pain may worsen during perimenopause, when hormones can surge and drop erratically, and linger into menopause, especially in women taking oral contraceptives or on hormone replacement therapy (HRT).

Non-cyclical breast pain, on the other hand, does not obviously track menstruation and does not follow any predictable pattern. It may be persistent or intermittent, may affect one breast or both, and may involve the whole breast or a cross-section of it. Ordinarily, non-cyclical pain is a symptom of a specific problem- such as a cyst, benign growth, or trauma. Conditions that affect the chest wall, esophagus, neck, upper back, and even the heart can produce symptoms that are felt as breast pain.

Tentative evidence suggests that an imbalance in fatty acid metabolism might play a role in breast pain by sensitizing the breast tissue to hormonal changes. Importantly, fibrocystic changes in the breast tissue may cause cyclical or noncyclical pain in one or both breasts. Women with this rather common condition have thickened tissue or an increased number of cysts in otherwise normal breasts.

Breast pain may be caused by several other factors, however, which are not related to menstrual cycle. Thus, infection of the breast tissue (mastitis) or a rare abscess can cause severe pain. Mastitis is most common in lactating women but can occur at any age. Nursing or chafing from clothing can irritate the skin overlying the nipple, possibly allowing bacteria to enter and infect the breast. Mastitis can cause fever and breast swelling, redness and tenderness. For a more detailed description of disorders of the breast, visit www. bioaginginc. com.

Injury of any sort to the breast can cause localized pain and may last for weeks or months. Trauma does potentially lead to inflammation and a clot in the superficial vein of a breast (thromobophlebitis) that results in pain and swelling, but it rarely progresses to serious outcomes. Some prescription medications can underlie breast pain as well. Aside from hormones, cardiovascular and psychiatric drugs may be the root cause of persistent pain. Also, support problems should be adequately addressed. Heavy, pendulous breasts may stretch ligaments and tissue resulting in pain in the shoulders, back, neck, and breasts.

It should be emphasized here that breast pain is rarely a symptom of malignancy. Thus, a minuscule number of women receive a diagnosis of malignancy in the breast. Other conditions unrelated to the breast, however, could precipitate pain in the tissue. For example, strain in the pectoralis major muscle, which lies directly beneath and around the mammary girth, may be discerned as pain coming from the interior of the breast. Likewise, inflammation of the cartilage joining the ribs to the breastbone (costochondritis) causes a burning sensation in the breast. Furthermore, maladies of connective tissue, shingles, heart disease, gastroesophageal reflux disease (GERD), and, among others, arthritis in the neck or upper back may also manifest as breast pain.

It is indispensable to seek competent professional advice for pain in the breast, especially in light of individual clinical history. This will help to rule out any festering malignancy. Numerous treatment strategies can then be implemented to alleviate acute and severe pain. Thus, pain on account of pectoral muscle strain, costochondritis, or arthritis may necessitate a short course of non-steroidal anti-inflammatory drugs (NSAIDs), along with stretching, yoga, or neck rotation exercises. Mastitis, however, may require antibiotics, as does an abscess, which must also be drained.

Inside the Breast

Breast pain unrelated to menstrual cycle may be caused by conditions that affect the pectoralis major muscle, structures within the breast, and the ribs or sternum.

An increasingly popular approach is lifestyle modification. Ordinarily, a snugly fitting, supportive brassiere should help. For exercise, and if the pain is severe during sleep as well, a sports brassiere may be recommended. While there is no evidence to that effect yet, many women report that abstention from caffeine and nicotine helps mitigate the severity of the pain. By the same token, limited data suggests that the consumption of an extremely low-fat diet (15-20 percent of daily calories from fat) can reduce breast tenderness and swelling.

Even though the data are scant and not entirely reliable, apparently both cyclical and non-cyclical breast pain is somewhat mitigated by evening primrose oil, which contains gamma-linolenic acid, an essential fatty acid. Equally, some reports indicate that fish oil supplements might be helpful as well.

Three rather powerful drugs-danazol, tamoxifen, and bromocriptine- relieve breast pain. These pharmaceuticals usually cause serious side effects and, breast pain. These pharmaceuticals usually cause serious side effects and, therefore, are only reluctantly prescribed to manage severe, unremitting pain that has proven refractory to other options. In addition, there is increasing restiveness among women about using such drugs. Thus, one recent study reported that a mere 18 percent of women at risk for breast cancer opt for using tamoxifen to prevent malignancy. The overwhelming majority is content to hedge its bets. Combined with the recent “scare” associated with NSAIDS-and their molecular cousins COX-2 inhibitors- the reluctance to use powerful medications is not surprising at all. Given its preponderance, however, it is imperative to develop remedies that correct the underlying causes of mastalgia.

Inflammatory response figures prominently in mastalgia, irrespective of the origin of the pain. Inflammation kicks into high gear with infection, and is persistent if pain is presented with concomitant conditions, such as strained muscle, costochondritis, or arthritis. Therefore, resolution of the inflammatory response is an essential factor in any corrective approach to manage mastalgia and related breast maladies. While NSAIDs and COX-2 inhibitors may be helpful under clinical supervision over short terms, these drugs are imminently inadequate to resolve the latent inflammatory response.

How so? Inflammatory response is comprised of a complex cascade of reactions and interactions of many different substances. The most important of these molecular actors are cytokines-proteins that can both precipitate inflammation and help resolve it when the offending stimulus dissipates. Ordinarily, there is a tight balance between anti- and pro-inflammatory cytokines. When a pain stimulus is given- say, an infection, a grazed knee, or hormonal fluctuations during the menstrual cycle-the levels of pro-inflammatory cytokines are increased, causing redness, pain and swelling of the affected area. Thus, a corrective remedy should strive to restore the balance in favor of anti-inflammatory cytokines. Systemic enzymes do precisely that. By re-balancing the immune response to a stimulus, systemic enzymes mitigate the sensations of discomfort and irritation.

Glossary of Breast Disorders

MASTALGIA

Breast pain and tenderness women feel typically during the menstrual cycle. In most cases, breast pain is not a symptom of malignancy. Occasionally, cysts in the breasts cause pain.

CYSTS

Fluid-filled sacs that may develop in the breast and that are easily felt and cause pain.

FIBROCYSTIC BREAST DISEASE

(FBD): A common condition in which breast pain, cysts, and non- cancerous lumpiness occur together. Although termed a disease, FBD is not a disease, since most women have some general lumpiness in the breasts, usually in the upper, outer quadrants.

FIBROUS BREAST LUMPS

Small, non-cancerous, solid lumps composed of fibrous and glandular tissue. Also, known as fibroadenomas. Other types of solid breast lumps include a hardening of glandular tissue (sclerosing adenosis) and scar tissue replacing injured fatty tissues (fat necrosis).

BREAST INFECTION AND ABSCESS

Variously known as mastitis, breast infections are rare, except around the time of childbirth orafter an injury. A breast abscess, which is more rare, is a collection of pus in the breast, and may develop if a breast infection is not treated.

For additional breast disorders and further details, visit www.bioaginginc.com.

Aftab Ahmed, Ph.D.

Copyright Total Health Communications Aug 2005

By Anonymous

Moducare is a patented blend of plant sterols and sterolins, and the only sterol/sterolin product clinically proven to be effective in immune modulation. Moducare can be considered an adjunct to help shift immune responses to a more balanced state. It enhances the activity of various immune cells and increases the killing ability of specialized cells, called natural killer cells, responsible for immune surveillance. Moducare also has anti-inflammatory properties and helps reduce the effects of stress on the immune system by managingthe release of cortisol, a stress hormone. Moducare is well- tolerated, with no known interactions with either prescribed medications or natural supplements. Plus, long-term studies have found that it has no significant negative side effects.

Human Research Proves Plant Sterols Action

We call sterols the forgotten nutrient because although thousands of research studies have been preformed on this nutrient, it has not been given the recognition it deserves.

Over 4,000 published studies to date have examined phytosterols and 140 of these studies are double-blind, placebocontrolled human trials. Rheumatoid arthritis, cervical cancer, diabetes, immune function, prostate problems, HIV, herpes, hepatitis C, allergies, stressinduced immune suppression, chronic fatigue, tuberculosis, breast cancer, and high cholesterol are only some of the diseases where sterols and sterolins have been shown to be extremely effective.

Plant sterols and sterolins are essential for modulating (balancing) the immune system, enhancing it if it is under active, and reducing it when it is over stimulated. They perform the balancing act very effectively. Patrick J.D. Bouic, Ph.D., has shown in his research that plant sterols and sterolins are effective in enhancing an under active immune system and/or decreasing an overactive one. This happens without the side effects associated with pharmaceutica substances such as interferon, prednisone or methotrexate. Sterols and sterolins have been evaluated in a 25,ooo- person safety study and found to have no side effects, no drug interactions, and no toxicity. It is safe for children, as well as pregnant and nursing mothers. Only those who have had an organ transplant cannot take plant sterols because they may stimulate rejection.

Plant sterols and sterolins also increase the number and action of natural killer cells (our cancer fighters) and increase our DHEA levels naturally. They are also able to reduce the stress hormone cortisol and the proinflammatory immune factor, interleukin-6 (IL- 6), and tumor necrosis factor alpha (TNF-a). Interleukin-6 and TNF- a are increased in autoimmune disorders, osteoporosis over exercising, fibromyalgia, and osteoarthritis. Reduction ofthis inflammatory agent is the key to halting symptoms and pain. This is exactly what plant sterols and sterolins do.

Sterols-Great Stress Busters

Chronic stress is so negative that it can promote and exacerbate most disease. Numerous studies have linked our ability to deal with stress to our susceptibility to the common cold as well as more serious diseases such as cancer. Adults who have recently lost a loved one or have been divorced or separated tend to have the highest cancer rates. Unrelieved stress gradually weakens and suppresses our immune system, causing disease. Stressful situations promote the release of cortisol, the stress hormone which in turn causes the secretion of a negative immune factor interleukin-6. Abnormal levels of IL-6 are associated with osteoporosis, autoimmune disease, asthma, inflammatorydiseases including arthritis, and more. We know that phytosterols are effective in reducing IL-6, cortisol and other negative immune factors. They also improve DHEA, a hormone known to help fight the effects of stress.

An overview follows of a few of the outstanding studies published to date.

Sterols Lower Cholesterol

The rapid cholesterol-lowering effects of phytosterols have been reported in over 400 studies. Beta-sitosterol is very similar in structure to cholesterol except that it has an extra ethyl group on the side chain. Due to this similarity, it interferes with the absorption ofthe cholesterol found in our foods as well as the cholesterol produced by the body. By including phytosterol-rich foods or supplements containing sterols, we can normalize cholesterol much fasterthan with the common cholesterollowering drugs.

Sterols Halt Hepatitis C

Hepatitis C is now occurring in epidemic proportions. Over four million North Americans are infected with hepatitis C. Liver specialists are overwhelmed as they struggle to deal with the increase in the incidence of this disease. Hepatitis C is the leading cause of liver transplants in North America, Physicians using sterols and sterolins to treat hepatitis C have already shown that with 90 days of the sterols and sterolins treatment liver enzymes and viral load normalize.

Sterols, Heart Disease and DHEA

A team of Canadian researchers discovered that an error in the regulation of certain immune cells that fight bacterial infections may be implicated in heart attacks and strokes. In a study published in the International Journal of Immunopharmacology, plant sterols and sterolins are shown to improve the ability of the immune system to fight bacterial infections. Sterols and sterolins, not antibiotics, may be the way to treat bacterialinduced heart disease.

Prostate Problems Eliminated

Urologists in Germany have been using plant sterols and sterolins for over two decades for the treatment of enlarged prostate. In one double-blind, placebo controlled study of 200 patients with an average age of 65 and with BPH, subjects were given sterols and sterolins for six months. The treatment group showed a rapid reduction of the symptoms mentioned above and an increase in peak urinary flow and a decrease in inflammation. When does a health food product become mainstream? Do 4,000 medical studies constitute good scientific evidence of a nutrient’s effectiveness? We believe plant sterols and sterolins will change the way we treat disease in the future. Instead of treating symptoms, we will get directly to the source of the symptoms and repair the cause of the disease.

Consider Moducare your daily secret weapon in supporting immune system health.

by totalhealth editors

Copyright Total Health Communications Aug 2005

By MARTYN HALLE

SCIENTISTS have developed a treatment that could save the lives of hundreds of people needing liver transplants – they have discovered how patients can ‘regrow’ their own livers.

During the new procedure, doctors remove healthy cells from a patient’s own liver, grow them for up to a week in a laboratory – and then infuse them back into the liver. There, they continue to multiply.

At present, there is no way of keeping alive critically ill liver patients for long enough to receive a transplant if one is not available immediately.

There is also an enormous demand for livers, and doctors say that is likely to increase dramatically because of rising rates of obesity, heart disease and hepatitis C.

Doctors have struggled for years to grow enough liver cells in the laboratory to save seriously ill patients.

But researchers have employed a relatively new surgical technique that allows the new liver cells to grow rapidly when put back into the liver.

The method, embolisation, has already been used to help patients with liver cancer grow more liver cells after surgery to remove their tumours.

Surgeons cut off some of the blood supply of the liver where the cells are infused, and this forces that part of the liver to work rapidly to make new cells.

So far, only animal trials have taken place, involving the removal of cells.

But human trials are expected to start in the next few weeks on new-born babies with major liver failure who might otherwise die.

Results of the research were reported yesterday at the conference of the United European Gastroenterology Conference in Copenhagen by doctors from the Hospital St Antoine in Paris.

Dr Andrew Burroughs, a liver specialist at London’s Royal Free Hospital, said: ‘This is a really exciting development which opens up the possibility that soon the majority of patients will not need a donor liver transplant.

‘We are desperately short of donor livers and often lose patients because an organ cannot be found in time.

‘There are also patients we would like to put on the transplant list but cannot because of the shortage of organs. So patients are prioritised for transplant.’ The number of donor organs becoming available in the UK is less than half the rate of many other European countries. Italy and Spain have among the highest donor liver rates.

A growing number of patients developing liver failure suffer from obesity and heart disease. The damage is caused by a build-up of cholesterol.

Dr Burroughs says: ‘The popular misconception is that the majority of patients with liver failure are alcoholics. Patients with diseased and damaged livers due to alcohol abuse form a large number of those needing transplant, but they are in a minority.

‘The benefit of using a patient’s own liver cells to regrow their liver is that they not only avoid transplant, but also would not need to spend the rest of their lives on anti-rejection drugs.

‘We also know that even those who have successful liver transplants may – after 15 or 20 years – need a new liver. Growing and infusing liver cells would get round those difficulties.’

Healthy cells are removed from the patient’s liver to be grown in laboratory 2. Cells returned a week later but only after surgeons cut off some of liver’s blood supply, tricking it into reproducing cells rapidly so it regenerates itself

TOKYO (Reuters) – The percentage of Japanese who smoke hit
a record low in June, but this is still high compared with
other industrialized nations, according to a survey published
on Tuesday.

Japan has long been relatively smoker-friendly, but a
growing awareness of the health risks associated with smoking,
and increasing limitations on where smoking is permitted, have
begun to whittle away at the number of people who still smoke.

According to the survey, which was conducted by Japan
Tobacco Inc, the world’s third-biggest tobacco company and a
former state monopoly, the number of Japanese who smoke edged
down to 29.2 percent from 29.4 percent in 2004.

By comparison, some 21.6 percent of U.S. citizens smoke,
according to a study by the Centers for Disease Control and
Prevention.

The rate of male smokers dipped by 1.1 percentage point to
45.8 percent — still the highest among industrialized nations
— while the percentage of female smokers actually rose by 0.6
point to 13.8 percent.

Japan Tobacco said the overall decline was due to Japan’s
aging population as well as a rising awareness of the health
risks and stricter smoking regulations.

Japan recently started requiring stronger warning messages
on cigarette packs. Since July, all cigarette packets have
carried warnings such as “Smoking can cause lung cancer and
increases the risk of cardiac problems, strokes and emphysema.”

Prior to that, packages carried warning labels that said
“Smoking may damage your health.”

WOODCLIFF LAKE, N.J., Oct. 18 /PRNewswire-FirstCall/ — Duramed Pharmaceuticals, Inc., a subsidiary of Barr Pharmaceuticals, Inc. , today announced that it has signed a definitive agreement to acquire FEI Women’s Health, LLC, for $281.5 million in a strategic transaction that will expand the Company’s presence into the non-hormone contraceptive product marketplace. FEI owns the New Drug Application (NDA) for the ParaGard(R) T 380A (Intrauterine Copper Contraceptive) IUD, which is approved for continuous use for the prevention of pregnancy for up to 10 years. ParaGard(R) was approved in 1984 and has been marketed in the United States since 1988. Sales of ParaGard(R) in the United States and internationally were approximately $48 million for calendar year 2004.

This transaction is subject to the satisfaction of certain conditions, including Hart-Scott-Rodino antitrust filings. Barr said it expects to close the transaction before December 31, 2005.

“With this transaction, we will expand our commitment to contraception beyond oral contraceptive products into a new arena for the Company,” said Bruce L. Downey, Barr’s Chairman and Chief Executive Officer. “IUDs represent an under-utilized contraceptive option for women in the United States, and we believe that we are well positioned to grow this category through consumer and professional education and marketing. Adding ParaGard(R) to our portfolio of products will provide new opportunities for our Specialty Sales Force, which we anticipate increasing substantially from the current 40-person level as a result of this transaction. In addition, this transaction further strengthens our commitment to leadership in female healthcare by offering enhanced contraceptive options, particularly given that ParaGard(R) is the only hormone-free IUD, and the only product approved for continuous use for a 10- year period.”

“More than 76 million women worldwide have safely utilized ParaGard(R) over the past 17 years,” Downey continued. “We believe that the uniqueness of this safe and effective product, combined with our position in the contraceptive marketplace, and our targeted female healthcare sales and marketing capabilities, will enable us to realize significant value from this acquisition.”

FEI is a women’s health care company that manufactures, sells and markets the ParaGard(R) T 380A. ParaGard(R) is the only contraceptive approved for 10 years of continuous use and is more than 99% effective at preventing pregnancy.

FEI currently promotes ParaGard(R) in the United States to female healthcare practitioners and public health institutions with its 50-person Specialized Sales Force established in late 2004. ParaGard(R) is known as the Copper T Model TCu 380A outside the United States.

Financial Impact

Excluding charges associated with the acquisition, including amortization charges related to an inventory write-up, Barr anticipates that the transaction will be neutral to earnings in fiscal 2006 and accretive for fiscal 2007 and thereafter.

Safety Information on ParaGard(R)

ParaGard(R) does not protect against HIV/AIDS or other sexually transmitted diseases. A woman must not use ParaGard(R) if she currently has acute Pelvic Inflammatory Disease (PID) or engages in current behavior suggesting a high risk for PID. ParaGard(R) is also not an option for women who might be pregnant, have had a post-pregnancy or post-abortion uterine infection in the past 3 months, have cancer of the uterus or cervix, have an infection in the cervix, have an allergy to any component of ParaGard(R), or have Wilson’s disease.

The most common side effects of ParaGard(R) are heavier and longer periods for a few months after placement; some women have spotting between periods. For most women, this typically subsides after a few months. If you ever miss a period, call your healthcare professional without delay, as you might be pregnant.

Some possible serious complications that have been associated with intrauterine contraceptives, including ParaGard(R), are pelvic inflammatory disease (PID), perforation of the uterus, and expulsion (where the contraceptive falls completely or partially out of the uterus).

Barr Pharmaceuticals, Inc. is a holding company whose principal subsidiaries, Barr Laboratories, Inc. and Duramed Pharmaceuticals, Inc., develop, manufacture and market generic and proprietary pharmaceuticals.

Forward-Looking Statements

Except for the historical information contained herein, the statements made in this press release constitute forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Forward-looking statements can be identified by their use of words such as “expects,””plans,””projects,””will,””may,””anticipates,””believes,””should,””intends,””estimates” and other words of similar meaning. Because such statements inherently involve risks and uncertainties that cannot be predicted or quantified, actual results may differ materially from those expressed or implied by such forward-looking statements depending upon a number of factors affecting the Company’s business. These factors include, among others: the difficulty in predicting the timing and outcome of legal proceedings, including patent-related matters such as patent challenge settlements and patent infringement cases; the outcome of litigation arising from challenging the validity or non- infringement of patents covering our products; the difficulty of predicting the timing of FDA approvals; court and FDA decisions on exclusivity periods; the ability of competitors to extend exclusivity periods for their products; our ability to complete product development activities in the timeframes and for the costs we expect; market and customer acceptance and demand for our pharmaceutical products; our dependence on revenues from significant customers; reimbursement policies of third party payors; our dependence on revenues from significant products; the use of estimates in the preparation of our financial statements; the impact of competitive products and pricing on products, including the launch of authorized generics; the ability to launch new products in the timeframes we expect; the availability of raw materials; the availability of any product we purchase and sell as a distributor; the regulatory environment; our exposure to product liability and other lawsuits and contingencies; the increasing cost of insurance and the availability of product liability insurance coverage; our timely and successful completion of strategic initiatives, including integrating companies and products we acquire and implementing our new enterprise resource planning system; fluctuations in operating results, including the effects on such results from spending for research and development, sales and marketing activities and patent challenge activities; the inherent uncertainty associated with financial projections; changes in generally accepted accounting principles; and other risks detailed from time-to-time in our filings with the Securities and Exchange Commission, including in our Annual Report on Form 10-K for the fiscal year ended June 30, 2005.

The forward-looking statements contained in this press release speak only as of the date the statement was made. The Company undertakes no obligation (nor does it intend) to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except to the extent required under applicable law.

Barr Pharmaceuticals, Inc.

CONTACT: Carol A. Cox of Barr Pharmaceuticals, +1-201-930-3720,[email protected]

Web site: http://www.barrlabs.com/

Company News On-Call: http://www.prnewswire.com/comp/089750.html

By Patrick Markey

LAS CLARITAS, Venezuela (Reuters) – His face blistered with
red burns from an accident, Venezuelan miner Ronald Guillen
massages a silvery ball of fine gold he hopes would feed his
wife and three children for a while.

The sliver of malleable metal culled after a day in an open
mining pit should fetch around $30, a lucky day for unlicensed
miners like Guillen who carve out a hardscrabble existence in
deforested clearings in Venezuela’s Bolivar state.

“Sometimes we get nothing, sometimes four grams. Gold is
all about luck,” Guillen said as his children darted around his
shack of plastic sheets and wooden poles. “It’s not the life
for everyone.”

Tens of thousands of poor, mostly unlicensed miners are
drawn to quarries in southern Venezuela hoping the precious
yellow metal can bring them quick riches or at least a source
of income in a remote region where jobs are scarce.

In camps hacked from dense jungle, miners slog waist-deep
in sludge with generators and water hoses to wash down the
earth and suck it onto raised pallets. Then it is dried and
panned with mercury for small pieces of gold.

The sweltering jungle here is scarred by huge open pits,
blasted by jets of water into bright red and gray moonscapes
tangled with a mess of pipes, motor parts, muddy pools and
skeletal wooden frames used to dry earth.

Mining became a political issue last month when hundreds of
unlicensed miners blocked a highway leading to Brazil to demand
jobs and permits. Troops battling protesters protected the
nearby Las Cristinas concession, where Canadian miner
Crystallex has an operating contract.

Soon after, President Hugo Chavez’s government warned that
it would revoke contracts and concessions judged inactive after
a sector review and hand the blocks over to small mining
cooperatives supported by the state.

The announcement was the latest to rattle investors in
Venezuela, where left-winger Chavez has promised to introduce
sweeping reforms as part of his socialist revolution to fight
poverty in the world’s No. 5 oil exporter.

JUST MORE PROMISES?

The Las Cristinas deposit is set in miles (km) of jungle
framed by Venezuela’s famous Gran Sabana, where the beauty of
the region’s flat-topped mountains inspired Sir Arthur Conan
Doyle to write his novel “The Lost World.”

But the beauty fades in the nearby town of Las Claritas,
where many seethe over the lack of development. Wooden shacks
cram dusty streets selling mining equipment, clothes, food,
music and liquor. In alleys, merchants equipped with small
scales offer to ply their trade in gold and rough diamonds.

Community leaders say most people have no formal employment
and about 70 percent live directly or indirectly through
illegal mining. Prostitution is common and HIV infections and
poisoning from mercury contamination are problems, they say.

Small-scale miners use mercury to extract gold amalgam but
often pollute riverways and earth with waste from the recovery
process.

Crystallex says it has invested more than $2 million in a
local clinic, water treatment plants, housing and roadways as
part of its infrastructure investment in the area. But the
problems at Las Claritas are complex.

Deputy Environmental Minister Nora Delgado said officials
are working to create an alternative employment plan for miners
while reorganizing and supporting those who will get licenses
and continue working in the area.

Authorities say they are slowly trying to shift unlicensed
miners away from the River Caroni, where mining work threatens
the environment of a waterway that provides huge amounts of
hydroelectric power.

“We have a plan of action … (with) alternative options
for the mining zone, and regulating and putting order in the
areas where people will stay on working the mines,” she said.

But for miners working in unlicensed encampments like those
that pockmark the ground near and inside the Las Cristinas,
such announcements sound like just more hollow promises.

Most say their illegal status forces them to pay high
prices to transport contraband food and gasoline to their camps
and they complain about abuses by National Guard troops trying
to keep them off official mining sites.

“The government? We don’t get help from anyone here,” said
Simon Hernandez, a life-long miner who sat resting in a shack
inside one camp, his skin caked in mud from work.

“The president says the permits are on the way,” he said.
“But local officials here never deliver.”

By Looney, W J

ABSTRACT

Stenotrophomonas maltophilia (previously Pseudomonas maltophilia, Xanthomonas maltophilia) is highly resistant to antibiotics. It causes infections that result in increased morbidity, but not usually mortality, in patients with weakened host defences. The increase in S. maltophilia nosocomial infections is due to the changing nature of the hospital patient population and to changes in antibiotic usage. Detection, identification and susceptibility testing methods require improvement, and this complicates the comparison of published data. Susceptibility testing should be reserved for those isolates that are clearly associated with disease. Treatment can be difficult and may be complicated by biofilm formation. S. maltophilia can both acquire and transfer resistance to antibiotics. Future therapeutic development may be directed against biofilms and efflux mechanisms, in order to render the organism more susceptible to available antimicrobial agents.

KEY WORDS: Bacterial infections.

Drug resistance, bacterial.

Intensive care.

Stenotrophomonas maltophilia.

Introduction

Hospital-acquired infections, otherwise known as nosocomial infections, pose a threat to patient well-being and to the efficient operation of hospitals. The policies used to limit the spread of such infections can lead to the temporary closure of certain facilities, the need to destroy equipment that cannot be sterilised and to extra duties for personnel. This can place significant burdens on hospital resources, reducing their capacity to provide care. Hospitals employ a variety of measures to try to prevent nosocomial infections; however, increasing healthcare costs mean that preventive strategies must show that they are effective in reducing nosocomial infections and also that they are cost effective. Clearly, the key to success lies in the use of current knowledge of nosocomial pathogens.

Nosocomial infection remains the most common type of complication affecting hospital patients. It is caused by a wide variety of microorganisms and, in most developed countries, 6-10% of patients who go into hospital acquire such an infection.1 Furthermore, more than 20% of patients admitted to European intensive care units (ICUs) develop an ICU-acquired infection.2 American surveillance data found that 27% of all nosocomial infections in American medical ICUs were due to pneumonia, with 86% of nosocomial pneumonia associated with mechanical ventilation and primarily due to Gram- negative aerobic organisms.3 Nosocomial pneumonia has been found to increase hospital stay by as much as 14 days.3

A patient who has acquired a nosocomial infection will usually require treatment. The optimal treatment of nosocomial infection requires that antimicrobial therapy be started early in the course of infection, using the correct agent, at the most appropriate dose, and for an adequate duration. Such antibiotic prescribing has been shown to significantly reduce mortality, length of ICU and hospital stay and overall costs.4

Choice of appropriate antimicrobial therapy is complicated by a number of factors, particularly use of antibiotics prior to hospitalisation and to resistant pathogens. Resistance to antimicrobial agents is emerging in a wide variety of pathogens, particularly those that cause nosocomial infection.4 As a consequence of this, increasing resistance, morbidity and mortality due to nosocomial infection is also increasing.4 One reason for the administration of inappropriate therapy is the presence of Gram- negative bacteria that are resistant to the newer cephalosporins.

The ubiquitous Gram-negative bacillus Stenotrophomonas maltophilia is intrinsically resistant to many classes of antibiotic and is a significant nosocomial pathogen, particularly in debilitated patients.5,6 In a survey of 20 British medical microbiologists conducted in 2000, S. maltophilia was voted the ninth most important multidrug-resistant pathogen.7 Among the Gramnegative bacilli, only Pseudomonas aeruginosa, Acinetobacter spp. and Klebsiella spp. were judged a greater problem.7 In the fight against S. maltophilia nosocomial infections, the relationship between virulence, transmissibility and antibiotic resistance must first be understood.”

Stenotrophomonas maltophilia

Nomenclature

In 1961, S. maltophilia was designated P maltophilia on the basis of its flagellar characteristics.5 In 1983, the new name Xanthomonas maltophilia was proposed on the strength of ribosomal RNA (rRNA) homology data,5 but in 1993 it was moved to the newly formed genus Stenotrophomonas, due to the inconsistencies it showed with Xanthomonas.5

Occurrence

S. maltophilia is an environmental organism found in water, soil and on plants such as fruits, vegetables, flowers and wheat.5,9 Like P. aeruginosa, it is ubiquitous in aqueous environments and can be cultured readily from water sources in homes and hospitals.5 It has been isolated from well water, river water, raw milk, frozen fish, raw sewage, human and rabbit faeces,10 and also colonises the gastrointestinal tract.11

It has been found as a contaminant of ambulance oxygen humidifier water reservoirs, brushes used for preoperative shaving, chlorhexidine-cetramide disinfectant, EDTA anticoagulant in vacuum blood collection tubes, transducer dome and calibration devices, a cardiopulmonary bypass pump, in ice-making machines, tracheal suction catheters, breathing circuits, ‘sterile’ water and on the hands of staff.10

S. maltophilia has been isolated from various clinical settings, including meningitis,12 septicaemia,12 endocarditis,12 pneumonia,12,13 peritonitis,13 urinary tract infection,12 ocular infection,12 epididymitis,12 mastoiditis,12 soft-tissue and wound infections,13 cholangitis,13 osteochondritis,13 bursitis13 and paranasal sinusitis.13

Culture and identification

S. maltophilia grows on nutrient agar, although most strains require methionine (or cysteine plus glycine) for growth.14 Isolation from normally sterile body sites is straightforward, and bacteraemia and septicaemia can be detected using standard blood- culture techniques.5 However, Klrner et al. pointed out that problems may occur when using automated blood-culture systems.15 It should be borne in mind, however, that the data they presented for S. maltophilia was drawn from experimental work, and during their one-year clinical study they did not recover a single isolate of S. maltophilia from a patient.

The problem, however, has more to do with the isolation of the bacterium from specimens taken from body sites with a normal flora. Denton et al. were able to show that the use of a selective medium improved the sensitivity of culturing for S. maltophilia, when compared to an established procedure that did not use a selective medium.16

Their group used a mannitol agar base supplemented with vancomycin (5 mg/L), imipenem (32 mg/L), amphotericin-B (4 mg/L) and bromthymol blue as the pH indicator. S. maltophilia does not produce acid from mannitol and could be distinguished clearly from other Gram-negative carbapenam-resistant bacilli isolated on the medium during the study.

Graff and colleagues demonstrated a direct correlation between the frequency of S. maltophilia isolation and its density in the sputum of CF patients.17 Thus, under-reporting of S. maltophilia from respiratory specimens of CF patients can occur if inappropriate culture techniques are applied.17

Colonies of S. maltophilia resemble those of P. aeruginosa, being opaque and flat with rugose surfaces and uneven borders. In addition, a yellow or brown diffusible pigment may be produced.14 They develop a characteristic faint lavender-green colour and strong odour of ammonia when grown on a blood agar medium.14

S. maltophilia produces haemolysins that are active against horse and sheep erythrocytes;18 however, the haemolysis may take three days to appear and may be confined to the area under the colonies. Indophenol oxidase is usually not detected.” A partially thermostabile DNase is produced14,18 and aesculin is hydrolysed.14 It should be remembered that media used to detect enzymatic activities of non-fermenters, including S. maltophilia, should be incubated at 30C.14

S. maltophilia is motile, and cultures to test for motility should be incubated at room temperature, as the synthesis of flagellar proteins is favoured by low temperature.14 S. maltophilia produces acid from maltose but not always from glucose.5,19,20

Misidentification of a range of Gram-negative non-fermenters, including S. maltophilia, Achromobacter xylosoxidans and the Burkholderia cepacia-complex presents a challenge to effective infection control in CF.21 The misidentification of S. maltophilia as B. cepacia-complex has been documented.22,23 The interpretation of DNase tests requires particular attention.5 Kiska et al.,24 van Pelt et al.,25 Rhoden et al.26 and Otto et al.27 showed that commercial systems used to identify S. maltophilia are not equally accurate. S. maltophilia can be identified by the Api 20NE system (bioMrieux, Marcy l’Etoile, France).16,25

Whitby and colleagues addressed this problem and developed a species-specific rRNA-directed polymerase chain reaction (PCR) technique for the identification of S. maltophilia.9 When used for identification, the method showed a sensitivity and specificity of 100%.9 They also indicated its potential for detecting S. maltophilia in clinical specimens, although this r\equires more extensive evaluation, particularly with regard to the usefulness of the information generated.9

Reference facilities, such as the Laboratory of HealthCare- Associated Infection (LHCAI) in England, are available in certain countries. The LHCAI offers molecular comparison of epidemiologically related isolates using pulsed-field gel electrophoresis (PFGE). It also offers identification of S. maltophilia by multiplex PCR.

Susceptibility testing

Susceptibility testing of S. maltophilia poses certain problems. These are related to the methods used and the differing results that they produce.28 Disc diffusion testing is not recommended.5 Automated susceptibility testing methods have also been shown to have limitations.29,30 The E-test method or minimum inhibitory concentration (MIC) broth micro-dilution tests may be more useful.5 No gold-standard or true reference method can be established without a correlative clinical investigation.30 Such work has not been conducted on S. maltophilia. The American NCCLS has a subcommittee that is looking into this problem.5

Given these disparate results, Carroll et al. contended that all susceptibility testing techniques are inaccurate with S. maltophilia.30 As a result of this situation it can be difficult, if not impossible, to compare published resistance rates if the methods used are not identical. Thus, it is important to follow locally/ nationally accepted procedures. In the UK, the methodology of the BSAC is generally followed. It should be noted that King published a supplement to this method, which describes the modifications to standard procedures required when testing S. maltophilia.31 Essentially, the modifications seem to require MIC determination and incubation at 30C.31

Testing should be reserved for those isolates that are clearly associated with disease, and it may be prudent for laboratories that test these organisms to add an interpretive comment to the effect that susceptibility testing may determine in vitro resistance, but may not predict therapeutic efficacy.30

Owing to the limited choice of antimicrobials available to treat S. maltophililia infections, the emergence of resistance should be monitored carefully.

Resistance mechanisms

S. maltophilia shows high-level intrinsic resistance to a variety of structurally unrelated antibiotics, including β-lactams, quinalones and aminoglycosides.32

Multidrug efflux pumps and the impermeable outer membrane contribute to the intrinsic antibiotic resistance of S. maltophilia.33 Some of the multidrug efflux pumps appear to be homologous with those already described in P. aeruginosa,32 while others are different.34 Alonso and colleagues have shown that S. maltophilia strains, in which over- expression of the multidrug efflux pump SmeDEF occurs, are less environmentally ‘fit’ and are possibly less virulent than wild-type strains.35 This observation may also apply to the SmeABC multidrug efflux pump.

Most Gram-negative bacilli are quite sensitive to aminoglycoside antibiotics, but S. maltophilia is not.36 Aminoglycoside resistance in S. maltophilia is mediated by efflux pumps and enzyme inactivation. The aminoglycoside-modifying enzyme AAC(6′)-Iz acetyltransferase confers resistance to tobramycin, netilmicin, sisiomicin and neomycin.36 The temperature-dependent variation in susceptibility to aminoglycosides and polymixin B, but not to quinolones, β-lactams and chloramphenicol, is linked to outer membrane lipopolysaccharide characteristics.33 S. maltophilia shows greater resistance to aminoglycosides and polymixin B at 30C than at 37C.

Resistance to β-lactam agents is primarily intrinsic and mediated by at least two inducible β-lactamases (L1, an Ambler class-B metallo-β-lactamase [penicillinase], and L2, an Ambler class-A active site serine β-lactamase [cephalosporinase]).19,37 These two β-lactamases are induced when cells are exposed to β-lactams, and can hydrolyse almost all classes of β-lactam antibiotic.19,38 Avison et al. have recently shown that the production of these two β-lactamases is not coordinated, a finding based on mutant studies that goes against the previously accepted hypothesis.38

The results of Valdezate et al. suggest that, for quinolones, both permeability and topoisomerase targets in S. maltophilia may differ from those in other Gram-negative bacteria.28

S. maltophilia can acquire and transfer resistance to antibiotics. Alonso and colleagues have documented the transfer of DNA from Gram-positive bacteria to S. maltophilia.39 They provided evidence that S. maltophilia D457 has acquired a cluster of antibiotic and heavy-metal resistance genes from Gram-positive bacteria. Most of these genes are isoforms of genes previously found in Staphylococcus aureus plasmids.39 Furthermore, Barbolla and colleagues have demonstrated the spread of class-1 integrons coding for sulfamethoxazole/trimethoprim resistance in Stenotrophomonas maltophilia.40 Chang et al. have suggested that integrons and plasmids do not play a major role in the resistance of S. maltophilia.41

Pathogenicity

S. maltophilia is distinguished by a high degree of antibiotic resistance, rather than by invasiveness and tissue destruction, and is a major concern, primarily in immunocompromised patients.2

S. maltophilia produces DNase, RNase, arbutinase, acetase, esterases, lipases, mucinase, acid and alkaline phosphatases, phosphoamidase, leucine arylamidase and β-glucosidase.18 Some strains may produce elastase and hyaluronidase.18 The production of proteases and elastase plays a significant role in bacterial pathogenesis, participating in invasion, tissue damage and host defence evasion.42 Production of lipases seems to contribute to the virulence of some species associated with pulmonary infections, either by hydrolysing lipid-rich pulmonary tissue components or by triggering an intense inflammatory response.42

The spgM gene codes for the production of a hexose phosphate mutase, which is required for alginate and thus lipopolysaccharide production.33 Using a rat lung model, McKay and colleagues showed that a functional spgM gene is required for colonisation by S. maltophilia, and leads to histopathological changes in the lung.33 No histopathological changes were observed for mutants lacking a functional spgM gene. The gene also confers resistance to complement- mediated cell killing.33 Thus, outer membrane lipopolysaccharide is an important virulence determinant in S. maltophilia and SpgM is important for the maintenance of the lipopolysaccharide structure.

Adherence to epithelial cells is central to the initiation of colonisation or invasion of host tissues by many bacteria. This event is often mediated by fibrillar structures called fimbriae or pili. Fimbrial adhesins may mediate direct binding of the bacteria to the host target cell, or may mediate indirect binding by forming cross-link liaisons between bacteria that favour colonisation. All 46 clinical isolates of S. maltophilia studied by de Oliveira- Garcia et al. produced peritrichous semiflexible fimbriae,43 which enabled S. maltophilia to adhere to cultured epithelial cells and inert materials, resulting in biofilm formation.43

Biofilms are composed of a surface-associated community of cells that is enclosed in an extracellular matrix composed of polysaccharides and proteins.43 Bacterial biofilms are frequently found in persistent infections such as those associated with cystic fibrosis and foreign-body-associated infection.8 Bacteria growing in biofilms are more resistant to the action of phagocytic cells’ antibacterial activity, as well as to the action of antibiotics, than are those that have a planktonic way of life.8

Adhesion of S. maltophilia to abiotic surfaces, such as medical implants and catheters, results in line-related colonisation and infection.43 In this way, endotracheal tubes, for example, can contribute to pneumonia pathogenesis by allowing direct entry of bacteria into the lung and by providing a surface along the inside of the tube for the formation of a bacterial biofilm.3 Organisms that reach the inside of the tube can proliferate easily because this site is not protected by host defences, and antibiotics do not penetrate there.3 More than three-quarters of endotracheal tubes studied had a biofilm that contained bacteria.3

Hanes et al. noted that the clinical presentation (temperature, WBC count, presence of purulent aspirates, ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen) of S. maltophilia pneumonia was no different to that of pneumonia caused by other Gram-negative bacteria, which indicates that the severity of illness is similar.44

During the study of tobramycin solution inhalation therapy (TSI) in CF patients reported by Graff et al., the use of TSI to suppress P. aeruginosa improved lung function, regardless of S. maltophilia culture frequency.17 However, improvement was not as marked among patients who were persistently co-infected with S. maltophilia,17 indicating that it played an active role in the disease process.

Generalised S. maltophilia infection has now been documented,45 which shows the ability of the organism to disseminate within the body, even if this manifestation is exceptional at this point in time.

Finally, S. maltophilia also has the potential for indirect pathogenicity, as it can aid other pathogens. Katayoka et al. have shown that β-lactamases produced by S. maltophilia can increase the survival of P. aeruginosa that are normally susceptible to imipenem when the two organisms grow in culture together.19

S. maltophilia infection

Risk factors

The single most important predisposing factor for infection with S. maltophilia is the presence of a compromised immune system.2 Previous broad-spectrum antimicrobial treatment, prolonged hospitalisation, instrumentation, ICU exposure and significant under\lying disease are associated with an increased risk of developing S. maltophilia infection,46 which must always be suspected in patients who develop a superinfection while receiving carbapenems.2

Previous antibiotic treatment promotes colonisation and infection by antibiotic-resistant bacteria that otherwise may not be able to compete effectively with indigenous microflora. In this way, antibiotic resistance is a relevant colonisation factor when the microorganisms interact with the treated patient. Epidemiological studies have demonstrated that antibiotic therapy is a relevant risk factor for colonisation by S. maltophilia.8

Sanyal et al. showed that a sustained increase in the use of carbapenems in a hospital environment might play a more important role in the acquisition of an S. maltophilia infection than previous therapy of the individual patient with a carbapenem.47 Their data also suggested that third-generation cephalosporins are much less effective in promoting S. maltophilia nosocomial infections than are carbapenems.47

The work of Schaumann and colleagues supported the finding that pretreatment with a carbapenem is no longer an unequivocal risk factor for S. maltophilia infection.48 They did find that the length of hospital stay proved to be an independent risk factor for acquiring an S. maltophilia infection and that its isolation in clinical specimens is associated with longer hospitalisation of patients.48

Friedman et al. reported that the mean duration of stay prior to bacteraemia was 19 days.6 S. maltophilia pneumonia usually occurs as late-onset nosocomial pneumonia (i.e., beginning after more than five days’ hospitalisation).3 Cefepime exposure and the presence of a tracheostomy were identified as the most significant risk factors for development of S. maltophilia ventilator-associatedpneumonia in the retrospective study of trauma patients conducted by Hanes and colleagues.44

Nosocomial pneumonia often occurs by aspiration of oropharyngeal flora, and the nature of this changes with time in the hospital but not with duration of mechanical ventilation.3 The role of endogenous ICU flora, with a high incidence of endemic resistant bacteria, is important in determining the bacteriology of early- or late-onset nosocomial pneumonia, reiterating the importance of detailed knowledge of local ICU microbiology in planning accurate empiric therapy.3

Diabetics serve as an example of patients who have underlying disease. Diabetic patients with foot ulcers are often exposed to high levels of antibiotic selective pressure and may develop multiresistant S. maltophilia infections for which limb amputation may be the only remaining therapeutic measure.46

The compromised immune system of human immunodeficiency virus (HIV) patients increases their risk of acquiring infections, and S. maltophilia infection is no exception to this rule. S. maltophilia infection is usually associated with an advanced HIV infection, occurring in patients with a previous or concurrent acquired immune deficiency syndrome (AIDS) diagnosis.49 Therefore, these bacterial infections are related to a concurrent, severe immunodeficiency stage, which was characterised in the study of Calza et al. by a mean CD4+ lymphocyte count (SD) of 7225.2 cells/μL, while the mean CD4+ cell count (SD) in the HIV control group without S. maltophilia infection was 448211 cells/μL.49

Graff et al. found the systemic administration of steroids to be a risk factor for S. maltophilia acquisition in CF patients, although inhaled steroids posed no increased risk.17 The study of Talmaciu and colleagues confirmed this difference.50

Patients with CF are infected by a predictable cascade of pathogens, and chronic lung disease is the most common cause of morbidity and mortality.51 In efforts to treat pulmonary exacerbations and slow the progression of lung disease, CF patients receive multiple courses of oral, intravenous and aerosolised antibiotics. As the life expectancy of CF patients has increased, newly emerging pathogens, such as S. maltophilia, have been detected.51 During the study of CF patients reported by Graff et al., inhalation therapy with tobramycin solution (TSI) did not result in a greater risk for isolation of S. maltophilia than that seen with standard care alone.17 In contrast, oral quinolone antibiotic use during the trial was associated with a 2.7-fold increased risk of having a culture positive for S. maltophilia.17

Colonisation versus infection

Antibiotic treatment should not be started at the colonisation stage to eradicate carriage of S. maltophilia, and antibiotics should only be used if clinical and laboratory signs of infection appear.52 Patients with S. maltophilia infection have elevated C- reactive protein values and may have a slightly elevated white blood cell count.48

The microbiological diagnosis of pneumonia can be made non- invasively by quantitative or qualitative culture of sputum, tracheal aspirate or invasively by isolation of organisms via bronchoscopy.3 It must be remembered, however, that oropharyngeal contamination and colonisation may result in positive sputum cultures in the absence of infection.3 Bronchoscopy techniques include bronchoalveolar lavage (BAL) or protected specimen brushes (PSB), with quantitative cultures, specifically using ≥ 10^sup 3^/mL for PSB and ≥ 10^sup 4^/mL for BAL, to help differentiate infection from colonisation.3 However, it has been found that guiding management by the results of invasive diagnostic methods led to no improvement in mortality, compared with management guided by non-invasive quantitative culture methods.3

Graff et al. noted in their study of CF patients that it appeared that a substantial portion of intermittently culturepositive patients in the trial were transiently re-infected with different isolates at different visits and, thus, were not continuously colonised with S. maltophilia.17 It is also possible that the culture-positive patients were being infected with multiple S. maltophilia genotypes and that they isolated different genotypes as a result of their culturing techniques.17 Thus, it is unclear whether any of the factors identified as risks for S. maltophilia isolation do, in fact, predispose patients to colonisation/ infection or that colonisation is a common, transient and recurring phenomenon among CF patients.17

Infection

Although S. maltophilia may cause a wide spectrum of human disease, the respiratory tract is the most common site of S. maltophilia infection, especially in patients with compromised lung function.53 In the five continent multicentre study reported by Gales et al., the largest number of isolates came from the respiratory tract, followed by the bloodstream, wounds and the urinary tract, in a decreasing frequency of isolation.53 However, wound and urinary tract isolates remain relatively rare.53

Senol et al. showed that the attributable mortality rate for S. maltophilia bacteraemia is similar to the attributable mortality rate for other nosocomial bloodstream infections.54 Friedman et al. reported that S. maltophilia was cultured from at least one other site in 38% of the episodes of bacteraemia studied, and the most common sites were sputum and central vascular catheters (CVC).6

Crispino et al. reported that the lower respiratory tract was the only site from which S. maltophilia was isolated from their adult ICU patients and that isolation always indicated infection in these patients.55 In the study by Calza et al., most episodes of S. maltophilia infection in HIV patients were represented by bacteraemia/sepsis (48/61, 78.7%), followed by pneumonia (five cases, 8.2%) and urinary tract infection (four cases, 6.6% ).49

Isolation of this organism from a blood culture should prompt a careful review of the patient, with particular emphasis on removal of indwelling CVCs and the commencement of appropriate antibiotic therapy.6 Friedman et al. found the most common characteristics in cases of bacteraemia were the presence of an indwelling CVC and previous antibiotic therapy, and a significant correlation was found between deaths and a failure to remove the CVC or treat with appropriate antimicrobials.6

Adherence to the guidelines on CVC use published by O’Grady and colleagues should help to reduce CVC-related infections to a minimum.56 These guidelines are based on use of appropriate measures and materials, and the education of all those involved in CVC management.56 It should be noted that the different types of CVC carry different risks of infection.56 Generally speaking, the mechanical removal of the focus of infection is beneficial in cases of S. maltophilia infection.46

Cystic fibrosis is characterised by the presence of a chronic endobronchial infection that leads to progressive suppurative obstructive lung disease, which is the primary cause of death in >90% of patients.17 Optimising antibiotic therapy, against the major CF pathogens, and antiinflammatory therapy is of the highest priority, as lung disease has a major impact on prognosis.21

P. aeruginosa is the most common bacterial pathogen isolated from the CF respiratory tract.17 However, the microbiological flora of CF lung disease is evolving and S. maltophilia is being isolated with increasing frequency from CF respiratory tract secretions.17 S. maltophilia prevalence rates vary considerably between CF centres, with a mean prevalence rate of 4.3-6.4%, but up to 10-25% in single centres.21 Unlike the pathogenic roles of P. aeruginosa and B. cepacia in CF, that of S. maltophilia, and thus the implications for acquiring the organism, is uncertain.17,21

The cohort study of Goss et al., in which 1673 CF patients from whom S. maltophilia had been isolated were studied, showed that detection of S. maltophilia does not affect shortterm (three-year) survival.57 Nonetheless, the problematic antimicrobial resistance patterns of S. maltophili\a and the pathogenic role of the organism in non-CF disease make the increasing frequency of S. maltophilia isolation in CF patients a cause for concern.17

Antimicrobial therapy

Treatment of infections caused by S. maltophilia can be difficult because it is intrinsically resistant to most antipseudomonal β- lactam antibiotics, the older quinolones and aminoglycoside agents.2 S. maltophilia is routinely resistant to imipenem and meropenem.58 Trimethoprim/ sulfamethoxazole or β-lactam/β-lactamase inhibitor combinations, mainly aztreonam plus clavulanic acid, remain the most accepted therapy for S. maltophilia infection.28 The most active single drugs in vitro against S. maltophilia are ticarcillin/clavulanate and trimethoprim/ sulfamethoxazole, and the most active combination in synergy studies is ticarcillin/ clavulanate plus aztreonam.58 Trimethoprim-sulfamethoxazole is not bactericidal and resistance may emerge during treatment.51

For almost three decades trimethoprim/sulfamethoxazole has been, and remains, the therapy of choice for S. maltophilia infection.2,59 Late-generation cephalosporins and antipseudomonal penicillins may also be useful.6 Sanyal et al. found all the isolates included in the five-year surveillance of their hospital S. maltophilia population, between 1993 and 1997, to be sensitive to trimethoprim/ sulfamethoxazole and ciprofloxacin.47 Betriu et al. reported a decrease in the percentage of strains resistant to trimethoprim/ sulfamethoxazole, but slight rise in the percentage of strains resistant to ciprofloxacin at their hospital in Madrid, Spain, during the period 1995 to 1999.59 The significant decrease in trimethoprim/sulfamethoxazole resistance corresponded to a decrease in the use of the drug over the five-year period.59

Noteworthy is the observation of Tsiodras and colleagues when examining their cohort of 40 patients with infections due to trimethoprim-sulphamethoxazole-resistant S. maltophilia. They concluded that such infection was not associated with an increased risk of death.46 Antibiotic monotherapy and invasive procedures usually resulted in cure.46

The results of the study of S. maltophilia nosocomial pneumonia in trauma patients conducted by Haynes et al. confirmed that high mortality is associated with inadequate empiric antibiotic therapy.44 However, S. maltophilia pneumonia once again was associated with increased morbidity, but not increased mortality.44

Few therapeutic interventions have been successful in affecting the incidence of late-onset ventilator-associated pneumonia (VAP), which carries a higher mortality than early- onset VAP.3 In patients diagnosed with VAP on the basis of clinical criteria and positive BAL cultures, it has been shown that appropriate treatment given immediately after a clinical diagnosis of nosocomial pneumonia was associated with a significantly lower mortality, compared to inadequate or delayed treatment.3

On the basis of currently available information, it would be difficult to recommend withholding antibiotics pending the results of cultures obtained by bronchoscopy if there is a high clinical suspicion of pneumonia.3 This implies that the laboratory’s major role is to provide up-to-date information about the frequency of isolation and resistance levels of local ICU bacteria, in order to provide the best possible basis for selection of empiric therapy. European ICU physicians favoured using invasive microbiological diagnosis only to guide and adjust initial empiric therapy, but not to decide whether or not a ventilated patient has pneumonia, which they felt could be made on clinical grounds.3 Furthermore, the majority agreed that they would start broad-spectrum antibiotics in a patient with VAP, irrespective of the initial Gram stain, until the results of culture became available.3

Increasing resistance to trimethoprim/sulfamethoxazole may prompt the use of newer quinolones, either alone or in combination with other agents.6 However, there are few data comparing the activity of new and old quinolones.28 Weiss et al. have reported significantly better in vitro activity of the newer quinolones trovafloxacin, clinafloxacin and moxifloxacin against 326 clinical isolates of S. maltophilia, compared to ciprofloxacin and levofloxacin.60 The newer quinolones can reach a lung concentration five times their serum concentration, and quinolones exert concentration-dependent killing.60 They suggested that this improved availability and activity make the newer quinolones an interesting therapeutic option for respiratory tract infections.60

Valdezate et al. reported the MIC^sub 90^ of the new fluoroquinolones grepafloxacin, trovafloxacin, and moxifloxacin (0.5 mg/mL) to be eight-fold lower than those of ofloxacin and ciprofloxacin (4 mg/mL), and 16- to 128-fold lower than those of pefloxacin, norfloxacin and nalidixic acid (8-64 mg/mL), and concluded that these agents might be considered for treating S. maltophilia infections.28

In serious infections, triple therapy with either trimethoprim/ sulphamethoxazole, carbenicillin and rifampicin or trimethoprim/ sulphamethoxazole, minocycline and ticarcillin/clavulanate are said to be synergistic regimens.6 Prolonged administration of antimicrobial agent may be required in patients with septicaemia.47

The multi-centre study of Gales et al. showed that among the 842 strains of S. maltophilia collected from 43 centres on five continents, resistance to antimicrobials varied with geographical region.53 Trimethoprim-sulphamethoxazole resistance varied from 2% to 10%, ticarcillin/clavulanate resistance from 10% to 29%, gatifloxacin resistance from 2% to 15% and trovafloxacin resistance from 2% to 13%.53 Of the 69 strains found to be resistant to trimethoprim-sulphamethoxazole, 77% came from the US and Europe.53 However, it should be borne in mind that these figures are now five years out of date.

Hanberger et al. reported S. maltophilia resistance rates for strains isolated from ICU patients in different European countries over the period 1990 to 1995.2 Gentamycin resistance varied from 46% to 89%, imipenem resistance from 94% to 100%, ceftriaxone resistance from 72% to 100%, ceftazidime resistance from 11% to 61%, piperacillin resistance from 45% to 83% and ciprofloxacin resistance from 28% to 100%.2

In general, treatment strategies for S. maltophilia in CF patients are similar to those used for P. aeruginosa or B. cepacia- complex, whereby high doses of two or more parenteral agents with different mechanisms of action are used to manage a pulmonary exacerbation.51 Multi-resistant S. maltophilia poses a major problem for optimal antibiotic therapy of CF patients.21 Combination therapy with antibiotics, shown to be active as single agents in vitro, given in two- to four-week courses, is recommended.21 If the initial therapy for early colonisation/infection of a CF patient does not eradicate the organism, another treatment regimen, including intravenous antibiotics, should be administered.21

It is unclear how many different treatment regimens should be used before it is considered impossible to eradicate the organism in a given patient.21 However, more studies are needed to optimise therapy.21 While aerosolised high doses of tobramycin or colistin have proved beneficial as suppressive therapy in CF patients chronically infected with P. aeruginosa, there are no clinical data to support the use of these treatment modalities for S. maltophilia.51

In the six-year study (1996-2001) reported by San Gabriel et al., in which approximately 14% of all S. maltophilia isolates from US CF patients were included, doxycycline was shown to be the most active antibiotic tested (80% of isolates sensitive in vitro).51 Trimethoprim-sulfamethoxazole inhibited only 16% of isolates, but 65% of isolates were inhibited when this was paired with ticarcillin- clavulanate.51 Ticarcillin-clavulanate alone inhibited 27% of isolates, and ciprofloxacin and piperacillin both inhibited less than 4% of strains each. The authors cautioned that the interpretation of their in vitro results into therapeutic measures may well be complicated by factors such as biofilm formation and the effects of stationary-phase growth, which may occur in CF patients’ lungs.

Epidemiology

It must be remembered that S. maltophilia infection may either be nosocomial or community-acquired.45,48 Friedman et al. reported that 80% of cases of S. maltophilia bacteraemia in their tertiary care hospital were nosocomial in origin,6 and Calza et al. reported 77% of infections from their 10-year study of HIV patients as being nosocomial in origin.49 Thus, the majority of serious S. maltophilia infections are nosocomial. A total of 400 cases of bacteraemia from England and Wales were reported to the Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre (CDSC) in 2000.61 The study of Caylan et al. showed that the same strains of S. maltophilia may have survived in the hospital environment for a period of 12 months.62

Unravelling the transmission routes of microorganisms is generally difficult, as multiple routes are possible, including direct patient-to-patient contact, contact between patients and healthy carriers of the bacterium (e.g., hospital personnel) who acquired colonisation from other patients or from the environment, and direct contact between the patient and environmental sources.

Among US children under two years of age suffering from CF, S. maltophilia is already found in throat, sputum and bronchoscopy cultures in 7% of cases.63 This compares with a general rate of recovery from the sputum of US CF patients of more than 10%.64 As bacterial strains may undergo substantial phenotypic change during the course of chronic infection, most bacterial organisms in CF patients are typed by genetic methods.21 Genotyping of S. maltophilia in CF centres has not yet indicated transmissibility as a major probl\em.21 Dring et al. considered normal hygienic precautions to be sufficient for preventing cross-infection with S. maltophilia in CF patients, and that placing patients in cohorts is not necessary for preventing transmission of S. maltophilia.21

Identification of sources, typing of the microorganism in question and case-control studies are used to investigate the epidemiology of a transmission route.21 Reliable and highly discriminatory typing methods are essential to any microbiological surveillance programme or investigation of transmission routes.21 ‘Fingerprinting’ of chromosomal DNA using PFGE or random amplified polymorphic DNA (RAPD) analysis is often used.21 Reference laboratories are essential to assure the quality standards for species identification and strain typing and to perform techniques not available at the local level, and also facilitate the identification of the spread of epidemic strains at the national and international level.21

Laing and colleagues studied S. maltophilia isolates from three hospitals for their genetic relatedness and epidemiology.65 They used PFGE to characterise 80 isolates and demonstrated that each of the nosocomial and community-acquired isolates in two acute-care hospitals were different, making nosocomial transmission very unlikely.65 However, in the ICU of the third hospital, isolates from six patients had identical profiles, suggesting that spread between patients was occurring, or that a common source of infection was present.65

Travassos and colleagues were able to demonstrate probable patient-to-patient transmission of S. maltophilia in two different cases.42 They used RAPD-PCR to establish the relatedness of the isolates.42 Valdezate et al. were able to demonstrate nosocomial transmission of S. maltophilia in five separate instances.66 They used PFGE to analyse the relatedness of their 139 isolates, all of which came from non-CF patients at the same hospital. Both Valdezate et al. and Travassos et al. found a high degree of genetic diversity among strains.42,66

Countermeasures

The anti-infectious repertoire includes hygienic measures, epidemiological controls, vaccines and antibiotics.8 Vaccines are not relevant to the control of opportunistic infection, and antibiotics have been dealt with above.

All those concerned with anything that comes into contact with patients should adhere to hospital hygiene regulations, which must be critically reviewed should the level of nosocomial infection attain unacceptable levels. One reported outbreak of S. maltophilia nosocomial infection was traced to the incorrect preparation of a biocide.67 A review and change of preparation procedures led to the resolution of the outbreak.

The equipment used during instrumentation procedures is particularly worthy of attention. Rogues and colleagues reported an outbreak of S. maltophilia colonisation/infection on a surgical ICU, which was resolved by improved disinfection of the temperature sensors used in the servo-controlled humidifiers of the mechanical ventilators when they were serviced between patients.68

The study of Denton and colleagues into the role of nebulisers in the colonisation of CF patients by S. maltophilia raises a number of interesting points. They showed that 10% of hospital nubulisers yielded cultures of S. maltophilia.64 Almost a quarter of ward environmental sites also yielded cultures of S. maltophilia; however, the environmental isolates were genetically distinct from the nebuliser isolates.64 Furthermore, none of the patients using the contaminated nubulisers had S. maltophilia isolated from their sputum during the study period.64

The contamination rate of home-use nebulisers has been reported to be similar.64 The retrospective nature of the study and the environmental sampling at only one point in time may explain the failure to isolate matching strains.64 None of the patients with contaminated equipment in the study had positive sputum cultures for the bacterium. However, routine sputum culture did not use a selective medium to isolate S. maltophilia, whereas a selective medium was used to ascertain the presence of nebuliser and environmental contamination, so the presence of low numbers of S. maltophilia in sputum samples may have been missed.64 Thus the clinical significance of the frequent colonisation of nebuliser equipment by S. maltophilia remains uncertain64. However, if nebuliser equipment is rinsed in tap water between uses, it is of primary importance that it should be dried thoroughly afterwards.64

The results of the study by Lemmen and colleagues showed that written treatment guidelines for nosocomial infections, combined with a bedside infectious disease consulting service, resulted in a reduction in antibiotic administration.69 Antimicrobial expenditure was reduced by 44.8% without compromising patient outcome or length of stay in the ICU.69 The implementation of the infectious disease service was extremely cost-effective, saving a total of 24,113 euros in one year.69 In addition, it contributed to an overall reduction in problematic and multi-resistant pathogens, with a significant decrease in isolation of S. maltophilia. The marked reduction in isolation of S. maltophilia was associated with a 75% reduction of carbapenem usage during the study period.69

Lannotte and colleagues reported on the usefulness of their systematic monitoring of intubated and ventilated paediatric ICU patients.52 They tested for tracheal bacterial colonisation twice a week and found five patients colonised with S. maltophilia over a four- month period.52 Molecular typing (RAPD, PFGE) showed that four of the five strains were related.52 Strict isolation of patients and improved application of hygiene procedures stopped the spread of S. maltophilia within two months.52

In order to avoid decline in the lung function of CF patients, it has also been suggested that regular microbiological monitoring, early intensive therapy and also perhaps anti-inflammatory therapy is warranted.21 Although it may not be possible to eradicate bacterial pathogens from airways of patients with CF, it is important to try to remove pathogens such as S. maltophilia using antibiotics based on individual sensitivity tests.21

Conclusions

S. maltophilia is a highly resistant, ubiquitous environmental bacterium that can cause infections that result in increased morbidity, but not usually mortality, in patients with weakened host defences. The increased occurrence of S. maltophilia nosocomial infection is due to the changing nature of the hospital patient population and the changing pressure placed on the hospital microbiological flora due to changes in antibiotic usage.

There is a certain amount of information available to physicians and other healthcare professionals confronted with S. maltophilia infection. However, the completeness and comparability of this information is called into question when such factors as the sensitivity of detection methods, accuracy of identification and the meaning of susceptibility testing results are borne in mind.

Hospital hygiene remains a cornerstone in the fight against nosocomial infection. Thoughtful examination of procedures can lead to the reduction or elimination of sources of infection. Systematic surveillance, using appropriate techniques, of patients at risk can lead to timely intervention against, and the containment of, nosocomial S. maltophilia infection. Surveillance of antibiotic resistance rates, both locally and regionally, should be used to formulate up-to-date empirical antibiotic therapy guidelines.

In the future, efforts to eliminate biofilm formation may be valuable and could include using new adhesion-resistant materials. Effective antibiotic therapy may require the targeting of efflux mechanisms, in order to render the organism more susceptible to available antimicrobial agents. Information is the key to achieving efficient reduction in the frequency and impact of S. maltophilia infection, and the diagnostic medical microbiology laboratory will play a key role in extending our knowledge of this opportunistic pathogen.

JOURNAL-BASED LEARNING – BJBS

REGULATIONS

* To obtain credits for journal-based learning (JBL), you must be registered on the Institute of Biomedical Science CPD scheme. A CPD registration form is available from the CPD section at the IBMS office.

* Deadline for submission of a completed answer card: Monday 3 October 2005

* The pass mark will be 17 questions answered correctly out of 20.

* 5 CPD credits in the ‘Vocational’ category will be awarded for each set of questions passed.

BRIEF INSTRUCTIONS

* Use a pencil or black/blue pen.

* Enter your membership number and the assessment number as indicated.

* For each question (A-T), mark either T (true) or F (false).

* Use a new card if you make a mistake.

* Enter your name and address, and affix a postage stamp for return of the results.

* Post the card in an envelope addressed to the CPD Department, Institute of Biomedical Science, 12 Coldbath Square, London EC1R 5HL.

* This activity is also available online at www.ibms.org.

Role of Stenotrophomonas maltophilia in hospital-acquired infection

Role of Stenotrophomonas maltophilia in hospital-acquired infection

References

1 Department of Health. Towards cleaner hospitals and lower rates of infection. DoH: London, July 2004.

2 Hanberger H, Diekema D, Fluit A et al. Surveillance of antibiotic resistance in European ICUs J Hosp Infect 2001; 48: 161- 76.

3 Mehta RM, Niederman MS. Nosocomial pneumonia in the intensive care unit: controversies and dilemmas. J Intensive Care Med 2003; 18: 175-88.

4 Masterton R, Drusano G, Paterson DL, Park G. Appropriate antimicrobial treatment in nosocomial infections: the clinical challenges. J Hosp Infect 2003; 55: 1-12.

5 Gilligan PH, Lum G, Vandamme PAR, Whittier S. Burkholderia, Stenotrophomonas, Ralstonia, Brevundimonas, Comamonas, Delftia, Pandoraea and Aci\dovorax In: Manual of clinical microbiology (8th edn). Washington: ASM Press, 2003: 729-48.

6 Friedman ND, Korman TM, Fairley CK, Franklin JC, Spelman DW. Bacteraemia due to Stenotrophomonas maltophilia: an analysis of 45 episodes. J Infect 2002; 45: 47-53.

7 Bywater RJ, Casewell MW. An assessment of the impact of antibiotic resistance in different bacterial species and of the contribution of animal sources to resistance in human infections J Antimicrob Chemother 2000; 46: 639-45.

8 Martinez JL, Baquero F. Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity and antibiotic resistance. Clin Microbiol Rev 2002; 15: 647-79.

9 Whitby PW, Carter KB, Burns JL, Royall JA, LiPuma JA, Stull TL. Identification and detection of Stenotrophomonas maltophilia by rRNA- directed PCR. J Clin Microbiol 2000; 38: 4305-9.

10 Spencer RC. The emergence of epidemic, multiple-antibiotic- resistant Stenotrophomonas (Xanthomonas) maltophilia and Burkholderia (Pseudomonas) cepacia. J Hosp Infect 1995; 30: 453-64.

11 Apisarnthanarak A, Fraser VJ, Dunne WM et al. Stenotrophomonas maltophilia intestinal colonisation in hospitalised oncology patients with diarrhea. Clin Infect Dis 2003; 37: 1131-5.

12 Morrison AJ, Hoffmann KK, Wenzel RP Associated mortality and clinical characteristics of nosocomial Pseudomonas maltophilia in a university hospital. J Clin Microbiol 1986; 24: 52-5.

13 Sattler CA, Mason EO, Kaplan SL. Non-respiratory Stenotrophomonas maltophilia infection at a children’s hospital. Clin Infect Dis 2000; 31: 1321-30.

14 Gilardi GL. Pseudomonas and related genera. In: Manual of clinical microbiology (5th edn). Washington: ASM Press, 1991: 429- 41.

15 Klrner HG, Eschenbach U, Kamereck K, Lehn N, Wagner H, Miethke T. Failure of an automated blood culture system to detect non- fermentative Gram-negative bacteria. J Clin Microbiol 2000; 38: 1036- 41.

16 Denton M, Hall MJ, Todd NJ, Kerr KG, Littlewood JM. Improved isolation of Stenotrophomonas maltophilia from the sputa of patients with cystic fibrosis using a selective medium. Clin Microbiol Infect 2000; 6: 385-95.

17 Graff GR, Burns JL. Factors affecting the incidence of Stenotrophomonas maltophilia isolation in cystic fibrosis. Chest 2002; 121: 1754-60.

18 O’Brien M, Davis GHG. Enzymatic profile of Pseudomonas maltophilia. J Clin Microbiol 1982; 16: 417-21.

19 Kataoka D, Fujiwara H, Kawakami T et al. The indirect pathogenicity of Stenotrophomonas maltophilia Int J Antimicrob Agents 2003; 22: 601-6.

20 Barrow GI, RKA Feltham, eds. Cowin and Steel’s Manual for the identification of medical bacteria. Cambridge: Cambridge University Press, 1993.

21 Dring G, Hoiby N. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cystic Fibrosis 2004; 3: 67-91.

22 Burdge DR, Noble MA, Campbell ME, Krell VL, Speert DP Xanthomonas maltophilia misidentified as Pseudomonas cepacia in cultures of sputum from patients with cystic fibrosis: a diagnostic pitfall with major clinical implications. Clin Infect Dis 1995; 20: 445-8.

23 McMenamin JD, Zaccone TM, Coenye T, Vandamme P, LiPuma JJ. Misidentification of Burkholderia cepacia in US cystic fibrosis treatment centers: an analysis of 1,051 recent sputum isolates. Chest 2000; 117: 1661-5.

24 Kiska DL, Kerr A, Jones MC et al. Accuracy of four commercial systems for identification of Burkholderia cepacia and other Gram- negative non-fermenting bacilli recovered from patients with cystic fibrosis. J Clin Microbiol 1996; 34: 886-91.

25 Van Pelt C, Verduin CM, Goessens HF et al. Identification of Burkholderia spp. in the clinical microbiology laboratory: comparison of conventional and molecular methods. J Clin Microbiol 1999; 37: 2158-64.

26 Rhoden DL, Schable B, Smith PB. Evaluation of PASCO MIC-ID system for identifying Gram-negative bacilli. J Clin Microbiol 1987; 25: 2363-6.

27 Otto LA, Blachman U. Non-fermentative bacilli: evaluation of three systems for identification. J Clin Microbiol 1979; 10: 147- 54.

28 Valdezate S, Vindel A, Baquero F, Canton R. Comparative in vitro activity of quinolones against Stenotrophomonas maltophilia. Eur J Clin Microbiol Infect Dis 1999; 18: 908-11.

29 Stefaniuk E, Baraniak A, Gniadkowski M, Hryniewiez W. Evaluation of the BD Phoenix automated identification and susceptibility testing system in clinical microbiology laboratory practice. Eur J Clin Microbiol Infect Dis 2003; 22: 479-85.

30 Carroll KC, Cohen S, Nelson R et al. Comparison of various in vitro susceptibility methods for testing Stenotrophomonas maltophilia. Diag Microbiol Infect Dis 1998; 32: 229-35.

31 King A. Recommendations for susceptibility tests on fastidious organisms and those requiring special handling. J Antimicrob Chemother 2001; 48 (Suppl S1): 77-80.

32 Zhang L, Li XZ, Poole K. Multiple antibiotic resistance in Stenotrophomonas maltophilia: involvement of a multidrug efflux system. Antimicrob Agents Chemother 2000; 44: 287-93.

33 McKay GA, Woods DE, MacDonald KL, Poole K. Role of phosphoglucomutase of Stenotrophomonas maltophilia in lipopolysaccharide biosynthesis, virulence and antibiotic resistance. Infect Immun 2003; 71: 3068-75.

34 Li XZ, Zhang L, Poole K. SmeC, an outer membrane multidrug efflux protein of Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2002; 46: 333-43.

35 Alonso A, Morales G, Escalante R, Campanario E, Sastre L, Martinez JL. Overexpression of the multidrug efflux pump SmeDEF impairs Stenotrophomonas maltophilia physiology. J Antimicrob Chemother 2004; 53: 432-4.

36 Li XZ, Zhang L, McKay GA, Poole K. Role of the acetyltransferase AAC(6′)-Iz modifying enzyme in aminoglycoside resistance in Stenotrophomonas maltophilia. J Antibicrob Chemother 2003; 51: 803-11.

37 Saino Y, Kobayashi F, Inoue M, Mitsuhashi S. Purification and properties of inducible penicillin beta-lactamase isolated from Pseudomonas maltophilia. Antimicrob Agents Chemother 1982; 22: 564- 70.

38 Avison MB, Higgins CS, Ford PJ, von Heldreich CJ, Walsh TR, Bennett PM. Differential regulation of L1 and L2 beta-lactamase expression in Stenotrophomonas maltophilia. J Antimicrob Chemother 2002; 49: 387-9.

39 Alonso A, Sanchez P, Martinez JL. Stenotrophomonas maltophilia D457R contains a cluster of genes from Gram-positive bacteria involved in antibiotic and heavy-metal resistance Antimicrob Agents Chemother 2000; 44: 1778-82.

40 Barbolla R, Catalano M, Orman BE et al. Class 1 integrons increase trimethoprim-sulfamethoxazole MICs against epidemiologically unrelated Stenotrophomonas maltophilia isolates Antimicrob Agents Chemother 2004; 48: 666-9.

41 Chang LL, Chen HF, Chang CY, Lee TM, Wu WJ. Contribution of integrons, and SmeABC and SmeDEF efflux pumps, to multidrug resistance in clinical isolates of Stenotrophomonas maltophilia. J Antimicrob Chemother 2004; 53: 518-21.

42 Travassos LH, Pinheiro MN, Coelho FS, Sampaio JLM, Merquior VLC, Marques EA. Phenotypic properties, drug susceptibility and genetic relatedness of Stenotrophomonas maltophilia clinical strains from seven hospitals in Rio de Janeiro, Brazil. J Appl Microbiol 2004; 96: 1143-50.

43 de Oliveira-Garcia D, Dall’Agnol M, Rosales M et al. Fimbriae and adherence of Stenotrophomonas maltophilia to epithelial cells and to abiotic surfaces. Cell Microbiol 2003; 5: 625-36.

44 Hanes SD, Demirkan K, Tolley E et al. Risk factors for late- onset nosocomial pneumonia caused by Stenotrophomonas maltophilia in critically ill trauma patients. Clin Infect Dis 2002; 35: 228-35.

45 Platsouka E, Routsi C, Chalkis A, Dimitriadou E, Paniara O, Roussos C. Stenotrophomonas maltophilia meningitis, bacteraemia and respiratory infection. Scand J Infect Dis 2002; 34: 391-2.

46 Tsiodras S, Pittet D, Carmeli I, Eliopoulos G, Boucher H, Harbarth S Clinical implications of Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole : a study of 69 patients at 2 university hospitals. Scand J Infect Dis 2000; 32: 651-6

47 Sanyal SC, Mokaddas EM. The increase in carbapenem use and emergence of Stenotrophomonas maltophilia as an important nosocomial pathogen J Chemother 1999; 11: 28-33.

48 Schaumann R, Stein K, Eckhardt C, Ackermann G, Rodloff AC. Infections caused by Stenotrophomonas maltophilia: a prospective study. Infection 2001; 29: 205-8.

49 Calza L, Manfredi R, Chiodo F. Stenotrophomonas (Xanthomonas) maltophilia as an emerging opportunistic pathogen in association with HIV infection: a 10-year surveillance study. Infection 2003; 31: 155-61.

50 Talmaciu I, Varlotta L, Mortensen J, Schidlow DV. Risk factors for emergence of Stenotrophomonas maltophilia in cystic fibrosis Pediatr Pulmonol 2000; 30: 10-5

51 San Gabriel P, Zhou J, Tabibi S, Chen Y, Trauzzi M, Saiman L. Antimicrobial susceptibility and synergy studies of Stenotrophomonas maltophilia isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 2004; 48: 168-71.

52 Lanotte P, Cantagrel S, Mereghetti M et al. Spread of Stenotrophomonas maltophilia colonisation in a pediatric intensive care unit detected by monitoring tracheal bacterial carriage and molecular typing. Clin Microbiol Infect 2003; 9: 1142-7.

53 Gales AC, Jones RN, Forward KR, Linares J, Sader HS, Verhoef J. Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features and trends in the SENTRY antimicrobial surveillance program (1997-1999). Clin Infect Dis 2001; 32(Suppl 2): 104-13.

54 Senol E, DesJardin J, Stark PC, Barefoot L, Snydman DR. Attributable mortality of Stenotrophomonas maltophilia bacteremia. Clin Infect Dis 2002; 34: 1653-6.

55 Crispino M, Boccia MC, Bagattini M, Villari P, Triassi M, Zarrilli R. Molecular epidemiology of Stenotrophomonas maltophilia in a university hospital. J Hosp Infect 2002; 52: 88-92.

56 O’Grady NP, Alexander M, Dellinger EP et al. Guidelines for the prevention of intravascular catheter-related infections. Cli\n Infect Dis 2002; 35: 1281-307.

57 Goss CH, Otto K, Aitken ML, Rubenfeld GD. Detecting Stenotrophomonas maltophilia does not reduce survival of patients with cystic fibrosis. Am J Respir Crit Care Med 2002; 166: 356-61.

58 Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918-51.

59 Betriu C, Sanchez A, Palau ML, Gomez M, Picazo JJ. Antibiotic resistance surveillance of Stenotrophomonas maltophilia, 1993-1999. J Antimicrob Chemother 2001; 48: 152-4.

60 Weiss K, Restieri C, De Carolis E, Laverdire M, Guay H. Comparative acitivity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia. J Antimicrob Chemother 2000; 45: 363-5.

61 Communicable Disease Surveillance Centre. Antimicrobial resistance in 2000: England and Wales. www. hpa. org.uk/infections/ topics_az/antimicrobial_resistance/a mr.pdf.

62 Caylan R, Kaklikkaya N, Aydin K et al. An epidemiological analysis of Stenotrophomonas maltophilia strains in a university hospital Jpn J Infect Dis 2004; 57: 37-40.

63 Saiman L. Microbiology of early CF lung disease. Pediat Respir Reviews 2004; 5(Suppl A): S367-S369.

64 Denton M, Rajgopal A, Mooney L et al. Stenotrophomonas maltophilia contamination of nebulizers used to deliver aerosolized therapy to inpatients with cystic fibrosis. J Hosp Infect 2003; 55: 180-3.

65 Laing FPY, Ramotar K, Read RR et al. Molecular epidemiology of Xanthomonas maltophilia colonization and infection in the hospital environment. J Clin Microbiol 1995; 33: 513-8.

66 Valdezate S, Vindel A, Martin-Davila P, Del Saz S, Baquero F, Canton R. High genetic diversity among Stenotrophomonas maltophilia strains despite their originating at a single hospital. J Clin Microbiol 2004; 42: 693-9.

67 Wishart MM, Riley TV. Infection with Pseudomonas maltophilia: hospital outbreak due to contaminated disinfectant. Med J Aust 1976; 19: 710-2.

68 Rogues AM, Maugein J, Allery A et al. Electronic ventilator temperature sensors as a potential source of respiratory tract colonisation with Stenotrophomonas maltophilia. J Hosp Infect 2001; 49: 289-92.

69 Lemmen SW, Hfner H, Kotterik S, Ltticken R, Tpper R. Influence of an infectious disease service on antibiotic prescription behaviour and selection of multiresistent pathogens. Infection 2000; 28:384-7.

W. J. LOONEY

Department of Clinical Microbiology, Institute for Infectious Diseases, University of Bern, Friedbhlstrasse 51, CH-3010 Bern, Switzerland

Accepted: 18 July 2005

Correspondence to: Mr W. J. Looney Email: [email protected]

Copyright Step Publishing Ltd. 2005

By Gibbs, G J

Diagnosis of haematological malignancy relies on the assessment of cellular morphology and immunophenotype (having largely replaced cytochemistry), cytogenetic, molecular, and clinical features. Usually, however, an abnormal full blood count (FBC) is the first laboratory indication that haematological malignancy may be present.

Modern haematology analysers measure an increasing number of parameters in addition to traditional indices in a variety of different ways, depending on the manufacturer. Awareness of these parameters on front-line laboratory instruments, and their ability to offer additional diagnostic clues, is a growing area of interest. The Advia 120 haematology analyser (Bayer Diagnostics, Newbury, UK) uses a combination of cytochemistry and light-scatter measurements to derive its peroxidase activity (PA) and nuclear density (ND) analysis (PANDA) cytograms.

Peroxidase activity is measured using the peroxidase channel. In a heated reaction chamber, red blood cells are lysed with a surfactant, and the white blood cells are fixed using formaldehyde. In the presence of hydrogen peroxide and the chromogen 4-chloro-1- naphthol, cells containing myeloperoxidase form a dark precipitate and are characterised by their light-scatter and light-absorption properties.

Nuclear density is derived from the basophil/nuclear lobularity channel. In a heated reaction chamber, phthalic acid strips the cytoplasm from white blood cells (except basophils). Two-angle light scatter is then used to determine cell size and nuclear density. Together, PA and ND are used to derive the white blood cell (WBC) count and the WBC differential.

In a recent study by d’Onofrio,1 PA and ND cytograms were used to assess the utility of these parameters to assist in the diagnosis and classification of haematological malignancy, leading to the construction of a PANDA preclassification grid comprising seven PA and two ND categories (Fig. 1). One hundred and eighty cases were studied, including examples of acute leukaemia, chronic lymphoproliferative and myeloproliferative disorders, as well as cases of infectious mononucleosis and peroxidasedeficient neutrophils (both of which also have abnormal cytograms). With some variation in respective categories, overall accuracy of classification using the PANDA grid was reported to be 91.1%.

Use of pattern-recognition software on the next generation of laboratory computer systems seems increasingly likely. Rather than using relatively simple analyser flagging, future computer systems may integrate and assess parameters such as the PANDA profiles, and even alert the operator to possible diagnoses for further investigation.

Fig. 1. Examples of peroxidase activity (PA) cytograms P0-P6 and nuclear density (ND) cytograms D0-D1. Peroxidase activity in the predominant cell population varies from absent (P) to intense (P6). D0 represents a normal ND profile whilst the mononuclear cell population in D1 is shifted down and to the left, signifying the presence of blasts.

Bayer (Tarrytown, NY, USA) has developed an artificial neural network capable of assessing multiple Advia 120 parameters. The system was ‘trained’ using FBC data from 1000 patients. Initial results are reported to be promising and there are plans to extend the system to include the classification of other disorders such as anaemia.2

In the present study, the performance of the PANDA pre- classification grid was assessed retrospectively on 140 randomly selected Advia 120 FBC printouts with abnormal PA and ND cytograms (Table 1) using d’Onofrio’s criteria.1 With the exception of peroxidase-deficient neutrophil (PDN) and infectious mononucleosis (IM) cases, which were validated by biomedical scientists, all diagnoses were made by consultant haematologists.

Of the 18 acute myeloid leukaemia (AML) cases studied, 17 (94.4%) were correctly classified as AML, which compared well with d’Onofrio’s results (95.2%). Of the AML cases with a French- American-British (FAB) subtype, all except the two M1 cases were classified correctly. Both Ml subtypes were categorised as probably being either M2 or M4 (P3/D1) using the grid (Table 2).

Importantly, although only one case of M3 AML was present in this study, the characteristic PANDA profile (P6/D1) was displayed. None of the remaining 17 cases of AML exhibited this profile. Indeed, the only haematological malignancy allocated to the P6/D1 category is M3 AML. In view of the response of this disorder to all-frans retinoic acid (ATRA), the potential importance of this as an initial screen is highlighted, and has also been noted by others.3 Unfortunately, d’Onofrio did not subgroup his AML cases according to FAB type, although his pre-classification grid does.

There is some (often considerable) duplication of the FAB subtypes of AML across the pre-classification grid, with, for example, M2 being allocated to P1, P2, P3 and P4 (+D1). Similarly, M5a is allocated to P0, P1 and P2 (+D1). This is not unexpected and reflects the heterogeneity of the disease. Realistically, with the possible exception of M3 AML, the PANDA classification system has the most value as an indicator of a possible case of AML, rather than attempting to pinpoint the FAB classification.

d’Onofrio studied cases of high-grade non-Hodgkin’s lymphoma (HG- NHL). The eight NHL cases included in this study were all low-grade (LG), and six had a chronic lymphoproliferative disease (LPD) profile (P0/D0). Clearly, more cases are required to determine whether or not LG-NHL should be allocated to the P0/D0 category of the preclassification grid.

Table 1. Summary of patients and Advia 120 PANDA results (n=140).

Table 2. Listing of FAB classification of AML patients (n=18).

The two remaining cases both had a P0/D1 profile. One of these was a case of mantle-cell lymphoma (MCL). Although classified as low- grade, MCL has a broad clinical spectrum, from indolent to aggressive. Examples of the latter often require treatment as for HG- NHL. This case progressed rapidly, despite treatment, and resulted in the death of the patient.

Much variability was noted with the myelodysplasia (MDS), chronic myelomonocytic leukaemia (CMML), myeloproliferative disease (MPD) and myelofibrosis (MF) cases, using P5/D0 for classification. If the pre-classification categories P3 and P4 (+D0) were extended to include the probability of MDS/CMML/MPD/MF in addition to CML, then 64.7% of the cases in this study would have been grouped into these categories. Notably, four of the CMML/MPD/MF cases showed an excess of blasts and the ND cytograms of each had a D1, rather than D0, profile. An excess of blasts can indicate transformation to acute leukaemia and may signify the need for more frequent patient monitoring.

Using the P0/D2 category initially proposed by d’Onofrio, 12 (80%) of the 15 IM cases were classified correctly (compared with 88.2% by d’Onofrio). The D2 profile is not included in the PANDA templates currently issued by Bayer and so these 12 cases would have been excluded from having a high probability of haematological malignancy, as they did not match any of the other pre- classification grid categories. Each was morphologically typical of IM and positive with the Paul Bunnell test. On further investigation, the three remaining cases (P0/D0) were each morphologically typical of IM and positive with the Paul-Bunnell test.

Three of the FBC printouts used in the study were from myeloma patients in the leukaemic phase (circulating neoplastic plasma cells in the peripheral blood) and each had a P0/D1 profile. A limitation of the pre-classification grid in its current form is that it does not include this disease entity as a possible diagnosis. More cases are required to assess whether or not leukaemic-phase myeloma should also be assigned to the P0/D1 profile.

In the present study, which included all patient categories, the pre-classification grid was 77.8% accurate, compared to 91.1% in the study by d’Onofrio. By removing cases that do not fall within the current scope of the grid (LG-NHL, MPD, MF, CMML and leukaemic- phase myeloma), overall accuracy increased to 93.8%. Clearly, the pre-classification grid is not exhaustive in its current coverage of haematological malignancy, although more patient data may allow future revision.

In summary, this study supports the findings of d’Onofrio. Furthermore, for cases of acute and chronic leukaemia, the PANDA classification system does appear to have value as a preliminary guide that may allow a more focused approach towards subsequent diagnosis.

The author thanks Teresa Bromidge and Denise Howe for reading the manuscript and suggesting improvements.

References

1 d’Onofrio G. PANDA – Innovative classification of hematopoietic malignancies. Bloodline Reviews 2001; 2-R: 3-6.

2 Zini G, d’Onofrio G. Neural network in hematopoietic malignancies. Clin Chim Acta 2003; 333: 195-201.

3 Lock RJ, Virgo PF, Kitchen C, Evely RS. Rapid diagnosis and characterization of acute promyelocytic leukaemia in routine laboratory practice. Clin Lab Haem 2004; 26: 101-6.

G. J. GIBBS

Department of Haematology, Taunton and Somerset Hospital, Musgrove Park, Taunton, Somerset TA1 5DA, UK

Correspondence to: Graham Gibbs

Email: [email protected]

Copyright Step Publishing Ltd. 2005

By Bernd Debusmann

CARACAS, Venezuela (Reuters) – It has been labeled a weapon
against “cultural imperialism,” the voice of Venezuelan
President Hugo Chavez, a threat to U.S. influence in Latin
America, and “poison for the minds of people longing to be
free.”

The object of such diverse descriptions is Telesur, a
Caracas-based Spanish-language TV channel which became part of
a war of words between Venezuela and the United States even
before Chavez formally launched it on July 24 and said the
network was vital to his vision of Latin American integration.

Telesur was conceived as a Latin American alternative to
international networks like CNN, the BBC, TVE of Spain and
Germany’s Deutsche Welle, all of which broadcast to Latin
America in Spanish.

“We want to show Latin America through Latin American
eyes,” said Aram Aharonian, Telesur’s director general. “The
United States and Europe have dominated information beamed to
our continent for decades. It is time to change that. They
portray us in black and white. We are a region in Technicolor.”

Judging from Telesur’s programming in the first weeks of
October, those colors are pink or red. So far, the new network
resembles more a History Channel for left-wing intellectuals
than a serious challenge to round-the-clock news broadcasts
from the United States and Europe.

There were documentaries on the last days of Marxist
revolutionary Che Guevara, the victory of the Sandinistas over
Nicaraguan dictator Anastasio Somoza, and the unsuccessful
fight of the Montoneros movement against Argentine governments
in the 1970s.

Rounding out the offer: documentaries on the harsh living
conditions of miners in Bolivia and the situation in the
Western Sahara, a former Spanish colony where the Polisario
Front and Morocco fought a 16-year war over a desolate desert
region.

Such high-brow fare contrasts sharply with local TV
programming in most of Latin America, where ratings are
determined by light entertainment and telenovelas, soap operas
that command huge audiences.

“We don’t have a way of measuring our audience yet,” said
Aharonian, a Uruguayan journalist who is 59, wears his gray
hair tied in a ponytail and speaks with the enthusiasm of a
20-year-old. “We estimate our present viewership at between two
and seven million and we aim for 30 million.”

Telesur broadcasts expanded from an hour a day in the pilot
phase to four hours by the time of the launch and six hours at
present, re-broadcast four times each 24 hours.

By the end of the month, it is scheduled to go to 24 hours
a day, with 10-minute newscasts at the top of the hour and two
one-hour news programs during the day.

U.S. HOSTILITY PIQUES INTEREST

According to Aharonian, interest in Telesur surged after
the U.S. House of Representatives adopted an amendment that
authorized the U.S. government to counter the new network with
broadcasts of its own.

The amendment was introduced by Connie Mack, a conservative
Republican congressman from Florida who described Chavez as “an
enemy of freedom” and said he wanted to use Telesur to “poison
the mind of people longing to be free.”

“Mack did us a favor,” said Aharonian. “People from all
over Latin America and the U.S. called us asking how they could
get Telesur. He couldn’t have done better if he had worked for
us.”

Broadcast over satellite, Telesur is a joint project of the
governments of Venezuela, which provided 51 percent of the $10
million start-up capital, Argentina (20 percent), Cuba (19
percent) and Uruguay (10 percent). The partners agreed to share
programming, such as documentaries, classic movies and films
made by up-and-coming Latin directors.

Telesur is not the first attempt to produce television by
Latin Americans for Latin Americans, though it is the first
joint venture between governments.

In 1994, Reuters, Argentina’s Artear, Spain’s Antena 3 and
the Miami-based network Telemundo joined up to form
Telenoticias, a 24-hour news channel transmitted via satellite
to cable and broadcast outlets in Latin America, Spain and the
United States. It failed to capture a large audience and faded
away after changing ownership twice.

Mexico’s television giant, Televisa, ran a 24-hour
international service called ECO, compiled from correspondents
around the world, for many years. ECO ended in 2001 when
Televisa fired 400 employees.

Like its unsuccessful predecessors, Telesur is partly based
on the premise that Latin Americans know little about each
other but would like to know more, given the chance. One of the
promotional trailers which now take up a good part of the
network’s air time highlights the thinking.

The trailer shows a reporter asking six people in the
street, apparently picked at random, to name the capital of
France. They all have the right reply: Paris. The reporter then
asks the same people to name the capital of Honduras.

“Guatemala,” says one. “Nicaragua,” says another. Others
just shrug their shoulders. Only one has the right answer:
Tegucigalpa. The trailer ends with the exhortation: “Lets get
to know each other.”

NEW YORK — In patients experiencing an episode of highly elevated blood pressure, also known as acute hypertensive crisis, without organ damage, antianxiety treatment effectively lowers blood pressure (BP) and may be considered as a first step in therapy, researchers from Israel suggest in a report in the American Journal of Hypertension.

Many patients who have hypertension that is normally controlled with medication may have an episode of highly elevated blood pressure “sometimes accompanied with headache and other non-specific complaints,” Dr. Ehud Grossman from The Chaim Sheba Medical Center in Tel-Hashomer noted in comments to Reuters Health. “In many cases, these hypertensive crises are related to anxiety or panic attacks.”

Therefore, Grossman’s team designed a study to compare the effectiveness and safety of the antianxiety drug diazepam (Valium) with the antihypertension drug captopril (Capoten), administered under the tongue, in 36 adults seen in the emergency room in hypertensive crisis.

The subjects had a BP greater than 190 over 100 mm Hg without evidence of acute target organ damage. (The normal cut-off for a diagnosis of hypertension is 140 over 80 mm Hg.) Neither the nurses who measured the BP nor the physicians who assessed the response were told which treatment was being administered.

The researchers randomly assigned 19 subjects to 5 mg oral diazepam and 17 subjects to 25 mg sublingual captopril. The researchers monitored BP and heart rate hourly for 3 hours.

According to the authors, both treatments decreased BP significantly and similarly. BP fell from 213 over 105 to 170 over 88 mm Hg in the diazepam group and from 208 over 107 to 181 over 95 mm Hg in the captopril group.

Both treatments were well tolerated and no abrupt decrease in BP was observed.

“The take home message from our study,” Grossman said, “is that anti-anxiety treatment is effective in lowering blood pressure in most patients with acute elevation of blood pressure and it may be worthwhile to try this treatment at home. Only when this treatment does not work one should search for medical help.”

These results, the researchers say, justify performing a larger trial to confirm the benefits of antianxiety drugs for treatment of patient with hypertensive crisis without organ damage.

SOURCE: American Journal of Hypertension, September 2005.

1. What is diabetes?

Diabetes is a disease that affects the way your body uses blood sugar, or glucose, which is your body’s main source of fuel. Most of what we eat turns into glucose, and our body uses it for energy. A hormone called insulin helps glucose enter into the body’s cells. When you have diabetes, your body does not produce or properly use insulin, causing a buildup of the sugars in your blood.

2. Who’s at risk of getting diabetes?

Take the test below to see if you are at risk.

3. What are the common symptoms of diabetes?

_ Frequent urination

_ Excessive thirst

_ Unexplained weight loss

_ Extreme hunger

_ Sudden vision changes

_ Tingling or numbness in hands or feet

_ Excessive fatigue

_ Very dry skin

_ Cuts and bruises that are slow to heal

_ Recurring skin, gum or bladder infections

A person with type 2 diabetes may not have any of these symptoms. That is why it is often called the “silent killer.”

4. Is diabetes contagious?

Unlike the cold or flu, diabetes is not caused by a germ or virus and is not contagious. The cause of diabetes continues to be a mystery; scientists believe that autoimmune, genetic and environmental factors are involved in the development of this disease.

5. Can you die from diabetes?

According to the American Diabetes Association, diabetes is the fifth-leading cause of death in the United States.

6. What is insulin?

Insulin is a hormone released from the pancreas. It is the primary substance responsible for stabilizing your blood-sugar levels. Insulin allows glucose to be transported into cells so the body can create energy. The rise in blood-sugar levels after eating or drinking stimulates the pancreas to produce insulin, causing blood-sugar levels to fall gradually. Someone with diabetes does not use insulin properly to maintain normal blood-sugar levels.

7. How do you check your blood-sugar levels?

Blood-sugar levels are often checked at a routine physical examination. A blood sample is usually taken after you have fasted for about eight hours. Some elevation of blood-sugar levels after eating is normal, but even then, the levels shouldn’t be very high.

8. Is there more than one type of diabetes?

There are three types of diabetes characterized by high levels of blood glucose as a result of improper insulin production: type 1, type 2 and gestational. Each type is associated with serious complications.

9. Who is at greater risk for type 1 diabetes?

Type 1 diabetes was previously called insulin-dependent diabetes or juvenile-onset diabetes. According to the ADA, this type may account for 5 percent to 10 percent of all diagnosed cases. People with type 1 diabetes produce little or no insulin at all. Most develop the disease before age 30.

10. Who is at greater risk for type 2 diabetes?

Type 2 diabetes was previously called non-insulin-dependent diabetes, or adult-onset. The pancreas continues to manufacture insulin, sometimes at higher than normal levels. But the body develops a resistance to its effects, resulting in an insulin deficiency.

This disease commonly begins after the age of 30 and becomes more common with age. However, the disease can strike a person of any age. The ADA reports that there are a growing number of people under the age of 21 that are diagnosed with type 2 diabetes each year, and many experts believe that there is a relationship between this trend and the increasing problem of juvenile obesity.

People with type 2 account for 90 percent to 95 percent of the cases. Risk factors for type 2 include: older age, obesity, a family history of diabetes, prior history of gestational diabetes, impaired glucose tolerance, physical inactivity and race/ethnicity. African-Americans, Hispanics, American Indians and some Asian-Americans and Pacific Islanders are at particularly high risk.

11. What is gestational diabetes?

This type of diabetes develops in 2 percent to 5 percent of all pregnancies but usually disappears when the pregnancy is over. During pregnancy, gestational diabetes requires treatment to normalize maternal blood-glucose levels to avoid complications in the infant. African-Americans, Hispanics and American Indians are at higher risk of developing gestational diabetes. After pregnancy, 5 percent to 10 percent of women with gestational diabetes are found to have type 2 diabetes.

12. What is pre-diabetes?

Before individuals develop type 2 diabetes, they almost always have pre-diabetes. In such cases, the blood-glucose levels are higher than normal but are not yet high enough to be diagnosed as diabetes. The ADA estimates that 41 million people in the United States ages 40 to 74 have pre-diabetes. Research has shown that some long-term damage to the body, especially heart and circulatory problems, may already be occurring during this stage.

If you have pre-diabetes and take action to manage your blood-glucose levels through changes in your diet and increased exercise, research has shown that you can delay or prevent developing type 2 diabetes.

13. What treatments are available for diabetes?

Managing blood-glucose levels should be planned with a qualified health care team. Treatments and prevention strategies change frequently. The main goal is to keep blood-sugar levels within a normal range. Treatment requires constant attention to weight control, exercise and diet. In type 1 diabetes, insulin-replacement therapy must be used. Insulin can be administered via injections (given by the patient or the patient’s parent) or via an insulin pump that patients wear around the clock. Because insulin is destroyed in the stomach, it cannot be taken by mouth.

14. Is there a cure for diabetes?

Diabetes is a chronic disease that has no cure.

15. What are the complications of diabetes?

Many people first become aware that they are diabetic after developing one of the following life-threatening complications:

_Heart disease

_Blindness

_Kidney failure

_Need for amputation of a lower extremity

Other complications can include poor healing and deep infections caused by poor circulation.

16. Can diabetes be prevented?

Researchers are working to identify the exact genetics and triggers that predispose some people to develop type 1 diabetes. A number of studies have shown that regular physical activity and proper nutrition can significantly reduce the risk of developing type 2 diabetes.

17. How often should you be screened for diabetes?

If you have any of the symptoms listed in question 3 or are in an at-risk category, you should contact your health care professional to assess your risks.

18. Can a person who’s diabetic still have foods that contain sugar?

Foods that contain sugar are not off-limits to a person with diabetes. But your diet should be reviewed with a medical professional and sugar should be consumed with great moderation. Again, careful monitoring of the blood-glucose levels must be done.

19. What is the ADA?

The ADA is the nation’s leading nonprofit health organization providing diabetes information and advocacy. Its mission is to prevent and cure diabetes and to improve the lives of all people affected by the disease. To help raise the money needed for diabetes research, the ADA supports fundraisers, including America’s Walk for Diabetes, Tour de Cure, School Walk for Diabetes and Kiss-A-Pig. For more information, call (800) DIABETES (342-2383) or visit the Web site at www.diabetes.org.

20. Are there any support groups?

For information about support groups or ADA-recognized diabetes treatment programs or providers in your area, call (800) DIABETES (342-2383) or visit www.diabetes.org.

___

(c) 2005, Fort Worth Star-Telegram.

Visit the Star-Telegram on the World Wide Web at http://www.star-telegram.com.

Distributed by Knight Ridder/Tribune Information Services.

_____

KRT OnePages Elements offers editors the content from our paginated spot OnePages, but in a text-only format.

___

TO PURCHASE ONEPAGES ELEMENTS

Items offered as ONEPAGES ELEMENTS are not included in your KRT News Service subscription. You can purchase the items on KRT Direct at www.krtdirect.com. For details or pricing information, please contact Rick DeChantal at Tribune Media Services at (800) 245-6536 or [email protected]. Outside the United States, call Tribune Media Services International at +1-213-237-7987 or e-mail [email protected].

___

ARCHIVE PHOTOS on KRT Direct (from KRT Photo Service, 202-383-6099):

diabetes

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail [email protected].

By DeVinney, David J; Tansey, Timothy N; Ferrin, James M; Pruett, Steven R

Abstract – With an aging workforce, the likelihood of persons applying for services with undiagnosed dementias or other substantial cognitive impairments are likely to increase. Identifying persons that may require additional evaluation prior to plan development will promote individual plans for employment that are consistent with individual needs. The focus of this article is to explain the benefits of incorporating the assessment of mental status into vocational evaluation systems. Specifically, the authors describe the benefits of using the Mini-Mental Status Examination (MMSE) in rehabilitation counseling and vocational evaluation. Suggestions as to how to incorporate this assessment instrument into rehabilitation services and the psychometric properties of the MMSE are reviewed.

The demographics of the workforce in the United States are changing in a way not previously seen (Griffiths, 1999). One example of this transformation is the age of the average person in the workforce. Two factors, the aging of the workforce and the finding that individuals are remaining in the workforce longer (Griffiths), have combined to increase in the age of the average worker. While changes in the average age, in and of itself, should not be particularly troubling to rehabilitation counselors, being able to identify those individuals with dementia and other cognitive disorders is of interest. Specifically, while certain changes in cognitive functioning are anticipated with age (Tansey, Tschopp, Lee, Ferrin, & Mizelle, 2004), being able to identify those individuals experiencing atypical cognitive deficits will allow rehabilitation counselors to adjust services accordingly.

Rehabilitation counselors are entrusted with assisting their clients in developing Individual Plans for Employment (IPE) that are consistent with their clients’ informed choice and likely to result in successful vocational outcomes. During both eligibility and IPE development, exploring factors that may affect the likelihood that applicants will benefit from rehabilitation services is both a legal and an ethical requirement. For instance, the co-occurrence of dementia or other age-related cognitive complaints should not prevent an individual from being found eligible for services. However, information regarding the severity, chronicity, and progressiveness of disabilities such as dementias may affect IPE development. Knowledge of these secondary disabilities will allow counselors to assist their client in making informed choices regarding rehabilitation services required for successful closure (Tansey et al., 2004). Specifically, the indication that a secondary disability such as a dementia exists will require expanding the focus of evaluation in the rehabilitation plan to include a neuropsychological evaluation.

While the number of individuals experiencing atypical cognitive impairment or dementias is expected to increase proportionally with age (Griffiths, 1999), requiring all applicants for rehabilitations services to undergo a complete neuropsychological evaluation would be inappropriate and expensive. Therefore, using a screening instrument in “high-risk” cases, or those cases that dementia or other cognitive concerns are a factor, will minimize burden to client and counselor while streamlining referrals for neuropsychological evaluations. In keeping with trends in psychiatric medicine, the use of a short screening instrument such as one commonly used by psychiatrists and psychologists would be appropriate (Gregory, 1999)

The Mini-Mental Status Examination (Folstein, Folstein, & McHugh, 1975: MMSE) is a short, structured interview that is designed to offer a rapid screen of an individual’s mental state. The MMSE is a shortened version of the comprehensive mental status examination (MSE) that a psychiatrist or psychologist might perform before any other psychological, psychiatric or neuropsychological assessment (Gregory, 1999). Whereas a MSE takes a considerable amount of time to administer, the MMSE consists of only 11 items, takes approximately 15 minutes to administer, and does not require extensive training on the part of the administrator. Because the MMSE is a rapid and highly structured assessment, it is used by primary care physicians and their staff to screen for signs of dementia such as Alzheimer’s disease and other cognitive deficits (Gregory).

However, the MMSE is seldom used in vocational assessment even though it offers useful information that will benefit planning efforts for individuals with cognitive deficits (Tansey et al., 2004). The purpose of this article is to introduce the MMSE as a valuable tool for rehabilitation counselors and vocational evaluators. The MMSE can provide crucial and timely assessment information on the mental status of rehabilitation clients. Rehabilitation counselors and vocational evaluators can benefit both from understanding the basic principles of the MMSE and incorporating this instrument into eligibility determination and employment planning aspects of rehabilitation services.

Mental Status Examinations in Rehabilitation Counseling

Rehabilitation counselors may not be directly familiar with the use of the MMSE, but many practitioners are probably familiar with the brief notations found in medical reporting forwarded with a referral for evaluation such as: “patient alert and a good historian,” or “patient alert and oriented times three.” These, and similar statements are essentially medical shorthand for the results of a MMSE which is often reduced to a single phrase, owing to the severe time constraints placed on medical reporting. This is regrettable since underlying these concise statements of mental status findings are a pool of data that could be useful to readers of these reports, including rehabilitation counselors.

While the prospect of adding another assessment instrument to the responsibilities of rehabilitation counselors and vocational evaluators may seem burdensome, the time expenditure is minimal in comparison to an in-depth vocational assessment. Vocational assessments may take several days and involve the evaluation of a host of behaviors and functions beyond those cognitive functions and behaviors that are assessed in a MSE (Chan et al., 1997). However, the implementation of an MMSE as a screening device may provide information that will affect rehabilitation planning and vocational evaluation strategies.

MMSE and Vocational Evaluation

It is generally not the purpose of vocational evaluation to diagnose specific mental or physical disorders. However, the symptoms and behaviors observed with certain psychiatric disorders and mental status disorders resulting from medical conditions are of particular importance in vocational evaluation, especially those symptoms/behaviors that present limitations in terms of an individual’s ability to successfully participate in vocational evaluation.

The administration of a MMSE as a screening instrument in vocational evaluation has several benefits. First, the MMSE can alert the evaluator to problem areas that need further study. second, the MMSE can indicate whether the client’s general level of functioning was adequate for standard adult assessment techniques (Lezak, 1995). If the MMSE revealed that an individual was disoriented, unaware of the concept of time, and was experiencing a general slowing of thought processes and bodily movement, proceeding with a full battery of tests and other evaluation procedures would provide little benefit to the client and the evaluator. The appropriate course of action may be to return the case to the referral source with a recommendation for further medical work-up or diagnostic testing. Otherwise, an unremarkable outcome on a MMSE would provide confidence that subsequent assessment results would be accurate indicators of the individual’s usual functioning (Gregory, 1999).

MMSE and Rehabilitation Counseling

Chan et al. (1997) described a three-level model of rehabilitation assessment: screening, clinical case study, and vocational evaluation. We suggest a fourth level be added, prescreening, where the MMSE would be administered at the onset of rehabilitation counseling services. MMSE results would provide important data about the necessity of obtaining additional information regarding a consumer’s abilities as well as his or her ability to participate in subsequent levels of assessment. For example, a deficit in registration or delayed verbal memory could make it difficult for a client to take a test where the directions are presented orally. A deficit in visual construction may affect a client’s ability to participate in a test of spatial perception that utilized geometric design formats, or construct a work sample from plans.

The MMSE should be restricted to use in cases where there is a significant probability of a limitation in cognitive functioning. Examples of client referrals where the MMSE could be of benefit include: (a) referrals for individuals who had experienced brain injury (including stroke), (b) referrals for individuals in which there was documented or suspected dementia of any type (possibly including HIV-1 and MS), (c) referrals for individuals with a primary diagnosis of a psychiatric disord\er with features of cognitive impairment (e.g., major depression), (d) referral for individuals with learning disorders, and (e) referral for individuals with a history of chronic substance abuse where the substance may have a neurotoxic effect (e.g., alcohol and inhalants). While history of these disabilities should be of primary concern, a number of other treatments and disabilities may create short and long-term cognitive concerns that may require further examination. In each of the categories found in Table 1, research suggests that individuals with disabilities or with exposure to the listed toxic or pharmaceutical agents may be experiencing cognitive impairment, including stable and progressive dementias.

Table 1 – Disabilities Associated with Cognitive Compliants

Technical Aspects of the MMSE

The MMSE is designed to be a brief checklist, or clinical aid, to serve as a rapid cognitive screen (Folstein, Anthony, Parhad, Duffy, & Gruenberg, 1985). The MMSE attempts to provide an accurate description of an individual’s current functioning in the realms of memory, thought, language, feeling, and judgment. Important descriptors include physical appearance, attitudes, and motor behaviors. Lezak (1995) identified nine aspects of individual behavior that are assessed in mental status examinations. Specifically, the nine areas are: (a) appearance, (b) orientation, (c) speech, (d) thinking, (e) attention, concentration, and memory, (f) cognitive functioning, (g) emotional state, (h) special preoccupations and experiences, and (i) insight and judgment (Lezak, p. 737).

As with any psychometric instrument, it is important that the rehabilitation counselor have an understanding of the technical aspects of the MMSE, including reliability and validity. Also valuable is an understanding of the influence of demographic and social variables on the total scores of the MMSE. Crum, Anthony, Bassett, and Folstein (1993) and Spreen and Strauss (1998) provide an extensive and thorough review of the MMSE, from which the following is extrapolated.

Reliability

Internal consistency estimates for the MMSE range from .31 for a community-based sample to .96 for a mixed group of medical patients. There is an association between alpha levels and years of education: the alpha level for a sample with a primary education (.65) was higher than a sample with 8 or more years of education (.54; Crum et al., 1993).

Although scoring of some items is subjective, the inter-rater reliability of the MMSE remains above .65 (Spreen & Strauss, 1998). This may be improved with greater attention to administration and scoring. The test-retest reliability estimates for the MMSE for intervals of less than two months range from .80 to .95. These estimates were for both individuals who were cognitively intact and individuals who had cognitive impairments. After one to two years the retest correlations with normal individuals were about .80. This translates to a fluctuation in scores of about two points. Recall and attention subtests tend to be the least reliable. Overall, these reliability estimates are consistent with those reported for other brief cognitive screening tests (Crum et al., 1993).

Validity

The validity of the MMSE has been generally reported in terms of the sensitivity of the test to correctly identify those individuals who have been classified as cognitively impaired (true positives) according to accepted standards (e.g., Diagnostic and Statistical Manual of the American Psychiatric Association), and the specificity of the MMSE to identify those individuals who have previously been classified as cognitively intact (true negatives; Spreen & Strauss, 1998).

The sensitivity of the MMSE to identify individuals with dementia across 25 studies is approximately 75% (Crum et al., 1973). The sensitivity of the MMSE to identify neurological and psychiatric patients ranges from 21% to 76% (Spreen & Strauss, 1998). This substantial range is attributed to the bias of the MMSE toward verbal items, which makes it relatively insensitive to damage in the right hemisphere of the brain (Spreen & Strauss).

Construct validity for the MMSE is established by a modest to high correlations (-0.66 to -0.93) that it has with other brief screening tests (e.g., the Blessed Test and the Dementia Rating Scale). The MMSE was initially designed to assess the construct of general cognitive ability, and this appears to be corroborated by reported correlations of .78 with the Verbal scale and .66 with the Performance scale of the Wechsler Adult Intelligence Scales (Spreen & Strauss, 1998). The MMSE also demonstrates modest to high correlations with neuropsychological tests such as Trails B, Wechsler Memory Scales, and digit span. The correlations of the MMSE with scales of activities of daily living range from .40 to .75. Lower MMSE scores are related to decreased independence (Crum et al., 1973).

Assets and Limitations of MMSEs

The MMSE is often integrated into the introductory interview, is brief, non-demanding, and may allow the client to experience initial success. The MMSE has several assets that allow for effective and efficient incorporation into rehabilitation counseling settings. First, as many of the items are not common to other assessments used in vocational assessment, there is a minimal practice effect (Mitrushina & Altman-Fuld, 1996). Regardless of the extent of testing prior to administration, evaluees are unlikely to receive specific preparation that will affect test scores. Next, the uniformity in administration and scoring allow for reliable results. Due to the minimal formal training required for administration, scoring, and interpretation, rehabilitation counselors can quickly incorporate this assessment into their “toolbox.” Another asset is that the MMSE focuses on constructs familiar to most health professionals. Thus, in discussing clients’ needs or test results with other professionals, rehabilitation counselors will be able to communicate relevant information with limited confusion. Finally, the MMSE provides quantified results that facilitate service decisions, as well as allow comparison over time (Mitrushina & Altman-Fuld). Specifically, rehabilitation counselors will be able to make appropriate referrals for extended evaluations as well as be in a position to recognize decompensation of cognitive abilities should they occur.

Limitations of the MMSE

Despite these assets, the MMSE has limitations that may affect broad use of the instrument in rehabilitation settings. Limitations of the MMSE include: (a) the potential for false-negatives; (b) difficulty distinguishing between acute and chronic organic conditions; and (c) its results are affected by a number of demographic variables (Mitrushina & Altman-Fuld, 1996). Further, the data obtained in the MMSE are “impressionistic and tend to be coarse- grained, compared with the fine scaling of psychometric tests [and do] not substitute for formal testing” (Lezak 1995, p. 737).

Potential for false negatives. The MMSE has been associated with reporting false negatives for evaluees (Spreen & Strauss, 1998). The language items found on the MMSE are fairly simple and may not detect mild impairments. Further, the heterogeneity of neurological patients makes it difficult to identify cognitive impairment. Thus, the cutoff scores for “impairment” are set in an attempt to reduce the number of false positives.

Organic versus functional conditions. The overlapping of symptoms between organic and functional conditions is particularly troubling and is a reason for not using a brief MSE for diagnostic purposes. For individuals with organic brain disease, the first symptoms observed are often emotional and behavioral changes. Of these, the most common emotional change seen is the onset of depression, which in-turn leads to a misdiagnosis of, and treatment for, an adjustment disorder with depressed mood (Strub & Black, 1993). In a study of 2,090 psychiatric outpatients, 18% of the patients had symptoms that were directly attributable to organic disease (Hall, Popkin, DeVaul, Faillace, & Stickney, as cited in Taylor, 1990).

Differentiating dementia from depression can be so difficult in older persons that 5% to 15% of thoroughly evaluated individuals with a diagnosis of dementia will be diagnosed with depression at follow-up (Feinberg & Goodman, 1984; Tansey et al. 2004). It would take an evaluation far beyond the extent of a MMSE to sort out whether or not the individual’s memory deficit was the result of depression or an organic disorder. For example, both conditions can result in a deficit in immediate recall, although the rate of forgetting in individuals with mild Alzheimer’s disease is strikingly higher than that for depressed individuals (see Hart, Kwentus, Taylor, & Harkins, 1987). Other emotional states that may result from either a psychological disorder or from a neurological disorder include anxiety and euphoria (Starratt, 1998).

Demographic variables. Three important demographic and social variables to consider when using the MMSE are: (a) intelligence and educational achievement; (b) race/ethnicity; and (c) age.

MMSE scores are related to premorbid intelligence and educational achievement. Individuals with higher intelligence and more extensive formal education score higher than those with lower intelligence and less education (Spreen & Strauss, 1998). Evidence shows that low educational levels increase the likelihood of misclassifying normal individuals as cognitively impaired (false-positive), particularly when individuals have fewer than nine years of education (Spreen & Strauss).

MMSE scores are reported to be affected by race and ethnicity. MMSE scores tend to decrease in individuals of non-Caucasian ethnicity. The findings regarding lower scores by race/ethnicity are consistent within different educational levels (Spreen & Strauss, 1998).

With the aging of the work\force and with people remaining in the workforce longer (Griffiths, 1999), the effect of age on MMSE findings is a concern. Cognitive decline with advancing age is normal, yet the effect of normal aging increases the risk of diagnosis of organic mental disorders (Tansey et al., 2004). For example, Spar and LaRue (1990), in reviewing research on the MMSE, indicate that 21 percent of individuals over the age of 60 will score below the typical cutoff for cognitive impairment, yet most were found to be without a diagnosable disorder on detailed neuropsychological evaluation. Thus, MMSE scores appear to decrease with advancing age. Most age-related changes in MMSE scores tend to begin about age 55 or 60 and then accelerates over the age range of 75 or 80 (Spar & LaRue). These age effects are stable across educational levels.

Summary and Recommendations

The intent of this article was to provide the rehabilitation counselors and vocational evaluators with an introduction to a brief mental status examination that would be useful as a first-line cognitive screening instrument in the initial stages of rehabilitation services and vocational evaluation. The scores obtained by the MMSE should not be used for diagnosis, classification, or as the basis for vocational planning. Instead, MMSE scores may be helpful in determining whether or not an individual requires more extensive evaluation services and as to whether they are capable of proceeding with an informative evaluation. In the appropriate circumstances, MMSE scores may be useful markers of cognitive function warranting further exploration and evaluation.

Rehabilitation counselors must prepare for this source of referrals and incorporate the MMSE into the initial interview and treatment plan. For instance, seeing diagnoses such as Huntington’s or Parkinson’s disease on a referral form should prompt the counselor to incorporate the MMSE into the interview to determine what type of further evaluation, if any, is warranted. Referring counselors from agencies may overlook the potential limitations created by the wide variety of conditions listed in Table 1. Information gained through the use of the MMSE, the time and resources such a screening instrument would save, and the effect this information would have on developing future rehabilitation plans all create potential benefits for not only the referring agency, but the client as well. In developing their own referral and assessment plans, rehabilitation counselors and evaluators should review the references listed in Table 1 for the potential cognitive concerns associated with various disabling conditions and incorporate that information in the planning process.

The authors caution that care must be taken in selecting individuals for whom the MMSE is appropriate. The MMSE is designed as a cognitive function screen and should only be administered to those individuals in high-risk categories for experiencing cogntive limitations. The MMSE is associated with a high false negative rate and should not be the sole evidence collected to determine if there is a deficit in an area of neuropsychological functioning (Schwamm, Van Dyke, Kiernan, Merrin, & Mueller, 1987). Rather, rehabilitation counselors and vocational evaluators should consider positive results as a prompt for further investigation and possibly referral to a neuropsychologist. Finally, readers are encouraged to consult this article for suggestions regarding the appropriate clientele for the MMSE and to consult the reference materials used by the authors.

References

Abate, G., Ferrari-Ramondo, V., & Dilorio, A. (1998). Risk factors for cognitive disorders in the elderly: A review. Archives of Gerontology and Geriatrics, Suppl, 6, 1-15.

Ahles, T. A., Silberfarb, P. M., Rundle, A. C., Holland, J. C., & et al. (1994). Quality of life in patients with limited small-cell carcinoma of the lung receiving chemotherapy with or without radiation therapy, for cancer and leukemia group B. Psychotherapy & Psychosomatics, 62, 193-199.

Akiskal, H. S., & Akiskal, K. (1994). Mental status examination: The art and science of the clinical interview. In M. Hersen & S.M. Turner (Eds.), Diagnostic interviewing (2nd Ed.) (pp. 25-51). New York: Plenum Press. Alien, J. G.

Console, D. A., & Lewis, L. (1999). Dissociative detachment and memory impairment: Reversible amnesia or encoding failure? Comprehensive Psychiatry, 40, 160-171.

Ayd, F. J. (1990). The future of anxiolytic drug therapy. International Review of Psychiatry, 2, 385-398.

Barnes, T. R. E., & McPhillips, M. A. (1996). Antipsychotic- induced extrapyramidal symptoms: Role of anticholinergic drugs in treatment. CNS Drugs, 6, 315-330.

Benati, G., Cilia, D., Cirillo, G., & Pedone, V. (1998). Relations between protein-calorie malnutrition and cognitive impairment. Archives of Gerontology & Geriatrics, 39-41.

Blanchard, J. J., & Neale, J. M. (1992). Medication effects: Conceptual and methodological issues in schizophrenia research. Clinical Psychology Review, 12, 345-361.

Boivin, M. J., & Giordani, B. (1995). A risk evaluation of the neuropsychological effects of childhood lead toxicity. Developmental Neuropsychology, 11, 157-180.

Boone, K. B., & Lu, P. H. (1999). Impact of somatoform symptomatology on credibility of cognitive performance. Clinical Neuropsychologist, 13, 414-419.

Bowler, J. V., & Hachinski, V. (1995). Vascular cognitive impairment: A new approach to vascular dementia. Baillieres Clinical Neurology, 4, 357-376.

Breitbart, W., Rosenfeld, B., Roth, A., Smith, M. J., Cohen, K., & Passik, S. (1997). The Memorial Delirium Assessment Scale. Journal of Pain & Symptom Management, 13, 128-137.

Broman, S. H., & Grafman, J. Eds. (1994). Atypical cognitive deficits in developmental disorders: Implications for brain function. Hillsdale, NJ: Lawrence Erlbaum Associates, Inc.

Brown, S. W. (1989). Cognitive impairment in epilepsy. Educational & Child Psychology, 6, 25-32.

Bruera, E., Macmillan, K., Hanson, J., & MacDonald, R. N. (1989). The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain, 39, 13-16.

Byrne, J. M., Backman, J. E., Gates, R. D., & Clark-Touesnard, M. (1986). Interpretation of the Personality Inventory for Children- Revised PIC-R: Influence of cognitive impairment. Journal of Abnormal Child Psychology, 14, 287-296.

Calev, A., Nigal, D., Shapira, B., Tubi, N., & et al. (1991). Early and long-term effects of electroconvulsive therapy and depression on memory and other cognitive functions. Journal of Nervous & Mental Disease, J 79, 526-533.

Capruso, D.X., Hamsher, K. deS., & Benton, A. (1998). Clinical evaluation of visual perception and constructional ability. In P.J. Snyder & P.D., Nussbaum (Eds.), Clinical neuropsychology: A pocket handbook for assessment (pp. 521-540). Washington, D.C.: American Psychological Association.

Chabrol, H., Peresson, G., & Bonnet, D. (1999). Cognitive deficits in adolescents with schizophrenia undergoing antipsychotic treatment. American Journal of Psychiatry, 156, 497-498.

Chan, F., Reid, C., Roldan, G., Kaskel, L., Rahimi, M., & Mpofu, E. (1997). Vocational assessment and evaluation of people with disabilities. Physical Medicine and Rehabilitation Clinics of North American, 8, 311-325.

Conn, D. K. (1996). Other dementias and mental disorders due to general medical conditions. In J. Sadavoy, L. W. Lazarus & et al. Eds., Comprehensive review of geriatric psychiatry-//2nd d., pp. 497- 528. Washington, DC: American Psychiatric Press, Inc.

Crawford, J. R., & Parker, D. M. Eds. (1989). Developments in clinical and experimental neuropsychology. New York, NY: Plenum Press.

Crenshaw, B. (1991). The complexities of cognitive impairment and the process of aging. In P. A. Wisocki Ed., Handbook of clinical behavior therapy with the elderly client pp. 141-165. New York, NY: Plenum Press.

Crum, R.M., Anthony, J.C., Bassett, S.S., & Folstein, M.F. (1993). Population-based norms for the Mini-Mental State Examination by age and educational level. Journal of the American Medical Association, 269, 2386-2391.

Cull, A. (1990). Invited review: Psychological aspects of cancer and chemotherapy. Journal of Psychosomatic Research, 34, 129-140.

Curran, S., & Wrigley, M. (1997). Lewy bodies. American Journal of Psychiatry, 154, 1322-1323.

de Vries, P. J., Honer, W. G., Kemp, P. M., & McKenna, P. J. (2001). Dementia as a complication of schizophrenia. Journal of Neurology, Neurosurgery & Psychiatry, 70, 588-596.

Dorahy, M. J. (2001). Dissociative identity disorder and memory dysfunction: The current state of experimental research and its future directions. Clinical Psychology Review, 21, 771-795.

Feinberg, T., & Goodman, B. (1984). Affective illness, dementia and pseudodementia. Journal of Clinical Psychiatry, 45,100-103.

Ferrin, J.M. (1994). Drug efficacy in the treatment of Wernicke and Korsakoff syndromes: A Review for rehabilitation professionals. Journal of Applied Rehabilitation Counseling, 25, 32-36.

Fleminger, S. (1998). What do psychiatrists need to know about Prion disease? Forum, The Harvard Mental Health Letter, 8, 2.

Folstein, M.F., Anthony, J.C., Parhad, I., Duffy, B., & Gruenberg, E.M. (1985). The meaning of cognitive impairment in the elderly. Journal of the American Geriatrics Society, 33, 228-235.

Folstein, M.F., Folstein, S.E., & McHugh, P.R. (1975). “Mini- Mental State:” A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189- 198.

Franulic, A., Horta, E., Maturana, R., Scherpenisse, J., & Carbonell, C. (2000). Organic personality disorder after traumatic brain injury: cognitive, anatomic and psychosocial factors: A 6 month follow-up. Brain Injury, 14, 431-439.

Garcia, J.H., & Brown, G.G. (1992). Vascular dementia neuropathological alterations and metabolic brain changes. Journal of Neurologic Science, 109, 121-131.

Gibb, W.R.G., Luthert, P.T., & Ma\rsden, C.D. (1989). Corticofaasal degeneration. Brain, 112, 1171-1192.

Gregory, RJ. (1999). Foundations of intellectual assessment. Boston: Allyn & Bacon.

Griffiths, A. (1999). Work design and management: The older worker. Experimental Aging Research, 25, 411-420.

Hardy, J. (1999). Pathways to primary neurodegenerative disease. Mayo Clinical Proceedings, 74, 835-837.

Hart, R.P., Kwentus, J.A., Taylor, J.R., & Harkins, S.W. (1987). Rate of forgetting in dementia and depression. Journal of Consulting and Clinical Psychology, 55, 101-105.

Harvey, P. D., & Dahlman, K. L. (1999). Neuropsychological assessment in dementing conditions. In A. Calev Ed., Assessment of neuropsychological functions in psychiatric disorders, pp. 329-372. Washington, DC: American Psychiatric Press, Inc.

Kerns, K., Don, A., Mateer, C. A., & Streissguth, A. P. (1997). Cognitive deficits in nonretarded adults with fetal alcohol syndrome, Journal of Learning Disabilities, 30, 685-693.

Kessler, H.R. (1998). The beside neuropsychological examination. In PJ. Snyder & P.O. Nussbaum (Eds.), Clinical Neuropsychology: A pocket handbook for assessment (pp. 54-75). Washington, D.C.: American Psychological Association.

Kiernan, R.J., Mueller, J., Langston, J.W., & Van Dyke, C. (1987). The neurobehavioral cognitive status examination: A brief but differentiated approach to cognitive assessment. Annals of Internal Medicine, 707,481-485.

Knight, R. G., & Longmore, B. E. (1994). Clinical neuropsychology of alcoholism. Hillsdale, NJ: Lawrence Erlbaum Associates, Inc.

Kotler, M., Iancu, I., Efroni, R., & Amir, M. (2001). Anger, impulsivity, social support, and suicide risk in patients with posttraumatic stress disorder. Journal of Nervous & Mental Disease, 189, 162-167.

Kurtz, M. M., Moberg, P. J., Mozley, L. H., Hickey, T., Arnold, S. E., Bilker, W. B., et al. (2001). Cognitive impairment and functional status in elderly institutionalized patients with schizophrenia. International Journal of Geriatric Psychiatry, 16, 631-638.

Lennox, G., Lowe, E.J., & Landon, M. (1989). Diffuse Lewy body disease: Clinical features in 15 cases. Journal of neurology, neurosurgery and psychiatry, 52, 709-719.

Lezak, M.D. (1995). Neuropsychological assessment (3rd Ed.). New York: Oxford University Press.

Levy, M. L., & Uncapher, H. (2000). Basic psychopharmacology in the nursing home. In V. Molinari Ed., Professional psychology in long term care: A comprehensive guide pp. 279-297. New York, NY: Hatherleigh Press.

Lo, P. C. (2001). Cognitive functioning in a homeless population: The relationship of multiple traumatic brain injuries to neuropsychological test scores. Dissertation Abstracts International: section B: The Sciences & Engineering, 62, 1586.

Marquis, P., Palmer, F. B., Mahoney, W. J., & Capute, A. J. (1982). Extrapyramidal cerebral palsy: A changing view. Journal of Developmental & Behavioral Pediatrics, 3, 65-68.

Matthews, W.B. (1988). Creutzfeldt-Jakob disease. In J.A.M. Frederiks (Ed.) Handbook of clinical neurology (pp. 289-299). Amsterdam: Elsevier Science.

McElroy, S. L., Keck, P. E., & Friedman, L. M. 1995. Minimizing and managing antidepressant side effects. Journal of Clinical Psychiatry, 56, 49-55.

Mitrushina, M., & Altman-Fuld, P. (1996). Cognitive screening methods. In I. Grant & K.M. Adams (Eds.), Neuropsychological assessment of neuropsychiatrie disorders (2nd Ed.) (pp. 118-138). New York: Oxford University Press.

Morgan, S. B. (1990). Early childhood autism: Current perspectives on definition, assessment, and treatment. In S. B. Morgan & T. M. Okwumabua (Eds.), Child and adolescent disorders: Developmental and health psychology perspectives (pp. 3-45). Hillsdale, NJ: Lawrence Erlbaum Associates, Inc.

Morriss, R. K., Schaerf, F., Brandt, J., McArthur, J. C., & et al. (1992). AIDS and multiple sclerosis: Neural and mental features. Acta Psychiatrica Scandinavica, 85, 331-336.

Murphy, F. C., Rubinsztein, J. S., Michael, A., Rogers, R. D., Robbins, T. W., Paykel, E. S., et al. (2001). Decision-making cognition in mania and depression. Psychological Medicine, 31, 679- 693.

Murphy, F. C., & Sahakian, B. J. (2001). Neuropsychology of bipolar disorder. British Journal of Psychiatry, 178, 120-127.

Myers, G. J., Davidson, P. W., Weitzman, M., & Lanphear, B. P. (1997). Contribution of heavy metals to developmental disabilities in children. Mental Retardation & Developmental Disabilities Research Reviews, 3, 239-245.

Neary, D. (1999). Classification of the dementias. Reviews in Clinical Gerontology, 9, 55-64.

Neylan, T. C., Canick, J. D., Hall, S. E., Reus, V. I., Sapolsky, R. M., & Wolkowitz, O. M. (2001). Cortisol levels predict cognitive impairment induced by electroconvulsive therapy. Biological Psychiatry, 50, 331-336.

Oxman, T. E. (1996). Antidepressants and cognitive impairment in the elderly. Journal of Clinical Psychiatry, 57, 38-44.

Paraherakis, A., Charney, D. A., & Gill, K. (2001). Neuropsychological functioning in substance-dependent patients. Substance Use & Misuse, 36,251-211.

Payne, H. C. (2000). Traumatic brain injury, depression and cannabis use-assessing their effects on a cognitive performance. Brain Injury, 14, 479-489.

Polanski, P. J., & Hinkle, J. S. (2000). The mental status examination: Its use by professional counselors. Journal of Counseling and Development, 78, 357-364.

Pulsifer, M. B. (1996). The neuropsychology of mental retardation. Journal of the International Neuropsychological Society, 2, 159-176.

Rabkin, J. G., Ferrando, S. J., van Gorp, W., Rieppi, R., McElhiney, M., & Sewell, M. (2000). Relationships among apathy, depression, and cognitive impairment in HIV/AIDS. Journal of Neuropsychiatry & Clinical Neurosciences, 12, 451-457.

Ramsay, S. G., & Stott, D. J. (2000). Cerebral rnulti-infarct states. Reviews in Clinical Gerontology, JO, 109-122.

Ratti, M. T., Soragna, D., Sibilla, L., Giardini, A., Albergati, A., Savoldi, F., et al. (1999). Cognitive impairment and cerebral atrophy in “heavy drinkers”. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 23, 243-258.

Roebuck, T. M., Mattson, S. N., & Riley, E. P. (1999). Behavioral and psychosocial profiles of alcohol-exposed children. Alcoholism: Clinical & Experimental Research, 23, 1070-1076.

Sabbadini, M., Bonanni, R., Carlesimo, G. A., & Caltagirone, C. (2001). Neuropsychological assessment of patients with severe neuromotor and verbal disabilities. Journal of Intellectual Disability Research, 45, 169-179.

Sakurai, Y., Hashida, H., Uesugi, H., Arima, K., & et al. (1996). A clinical profile of corticobasal degeneration presenting as primary progressive aphasia. European Neurology, 36, 134-137.

Schwamm, L.H., Van Dyke, C., Kiernan, R.J., Merrin, E.L., & Mueller, J. (1987). The Neurobehavioral Cognitive Status Examination: comparison with the Cognitive Capacity Screening Examination and the Mini-Mental State Examination in a neurosurgical population. Annals of Internal Medicine,107, 486-491.

Scott, T.F. (1998). The neurological examination. In PJ. Snyder & P.D. Nussbaum (Eds.), Clinical Neuropsychology: A pocket handbookfor assessment (pp. 11-28). Washington, D.C.: American Psychological Association.

Settle Jr, E. C. (1998). Antidepressant drugs: Disturbing and potentially dangerous adverse effects. Journal of Clinical Psychiatry, 59, 25-30.

Snowdon, D.A., Greiner, L.H., Mortimer, J.A., Riley, K.P., Greiner, P.A., & Markesbery, W.R. (1997). Brin infarction and the clinical expression of Alzheimer Disease: The Nun Study. JAMA, 277, 813-817.

Spar, J.E., & LaRue, A. (1990). Geriatric psychiatry. Washington, D.C.: American Psychiatric Press.

Spreen, A., & Strauss, E. (1998). A Compendium of neuropsychological tests: Administration, norms, and commentary (2nd Ed.). New York: Oxford University Press.

Starratt, C. (1998). Emotional disorders associated with neurological diseases. In P.J. Snyder and P.O. Nussbaum (Eds.), Clinical neuropsychology: A pocket handbook for assessment (pp. 613- 628). Washington, D.C.: American Psychological Association.

Steinhausen, H. C., Willms, J., & Spohr, H.L. (1993). Long-term psychopathological and cognitive outcome of children with fetal alcohol syndrome. Journal of the American Academy of Child & Adolescent Psychiatry, 32, 990-994.

Strub, R.L., & Black, F. W. (1993). The mental status examination in neurology (3rd Ed.). Philadelphia: F. A. Davis.

Strupp, B. J., & Levitsky, D. A. (1983). Early brain insult and cognition: A comparison of malnutrition and hypothyroidism. Developmental Psychobiology, 16, 535-549.

Sussman, N., & Chou, J. C. (1988). Current issues in benzodiazepine use for anxiety disorders. Psychiatric Annals, 18, 139-145.

Szatmari, P., Jones, M. B., Tuff, L., Bartolucci, G., & et al. (1993). Lack of cognitive impairment in first-degree relatives of children with pervasive developmental disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 32, 1264-1273.

Tansey, T. N., Tschopp, M. K., Lee, G. K., Ferrin, J. M., & Mizelle, N.D. (2004). Cognitive assessment issues with older persons. Vocational Evaluation and Career Assessment Personnel Journal, 7(1), 5-23.

Taylor, R.L. (1990). Distinguishing psychologic from organic disorders: Screening for psychological masquerade. New York: Springer.

Testa, J. A., Brumback, R. A., Baik, T.-K., Leech, R. W., & Cannon, T. C. (1998). Neuropathology and memory dysfunction in neurodegenerative disease. In A. I. Troester Ed., Memory in neurodegenerative disease: Biological, cognitive, and clinical perspectives pp. 36-86. New York, NY: Cambridge University Press.

Tueth, M.J., & Cheong, J.A. (1993). Delirium: Diagnosis and treatment in the older patient. Geriatrics, 48, 75-81.

Troester, A. I. Ed. (1998). Memory in neurodegenerative disease: Biological, cognitive, and clinical perspectives . New York, NY: Cambridge University Press.

Victor, M., Adams, R.D., & Collins, G.H. (1971). The Wernicke- Korsakoff syndrome. Oxford: Blackwell.

Vig, S., & Jed\rysek, E. (1999). Autistic features in young children with significant cognitive impairment: Autism or mental retardation? Journal of Autism & Developmental Disorders, 29, 235- 248.

Walkup, J. (1991). Increased antichoiinergic levels, memory and judgement. Human Psychopharmacology Clinical & Experimental, 6, 189- 196.

Wieneke, M. H., & Dienst, E. R. (1995). Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psycho-Oncology, 4, 61-66.

Williamson, D. J.G., Scott, J.G., & Adams, R.L. (1996). Traumatic brain injury. In R.L. Adams, O.A. Parsons, J.L. Culbertson, & SJ. Nixon (Eds.), Neuropsychology for clinical practice: Etiology, assessment, and treatment of common neurological disorders (pp. 9- 64). Washington, D.C.: American Psychological Association.

Wiscott, R., Kopera-Frye, K., & Seifert, L. (2001). Issues in neuropsychological assessment: Older adults with mental retardation. Clinical Gerontologist, 22, 71-86.

Wise, M.G., & Gray, K.F. (1996). Delirium, dementia and amnestic disorders. In R.E. Hales & S.C. Yudofsky (Eds.), The American psychiatric press synopsis of psychiatry, pp. 681-699. Washington, DC: American Psychiatric Press.

Yamauchi, H., Fukuyama, H., Nagahama, Y., Anonymous, Dong, Y., Hayashi, T., et al. (1998). Atrophy of the corpus callosum, cortical hypometabolism, and cognitive impairment in corticobasal degeneration. Archives of Neurology, 55, 609-614.

Zanello, A., & Huguelet, P. (2001). Relationship between subjective cognitive symptoms and frontal executive abilities in chronic schizophrenia outpatients. Psychopathology, 34, 153-158.

David J. DeVinney, Ph.D., works as a rehabilitation psychologist on the central inpatient medical unit, Dodge Correctional Institution, Wisconsin Department of Corrections, Waupun, Wl.

Timothy N. Tansey, Ph.D., is an assistant professor in the Department of Counselor Education, Psychology, and Special Education, Michigan State University.

James M. Ferrin, Ph.D, is an assistant professor in the Rehabilitation Counseling Program, University of South Carolina.

Steven R. Pruett, Ph.D., is an assistant professor in the Rehabilitation Counseling Department, University of Florida.

Copyright National Rehabilitation Counseling Association Fall 2005

By Ansbach, Robert K; Dybus, Karen; Bergeson, Rachel

Abstract.

Treatment of uncomplicated urinary tract infections (UTIs) has changed in the past few years with researchers advocating empiric treatment for shorter periods of time without the use of cultures. Researchers report that antibiotic resistance of Escherichia coli (E coli) to commonly prescribed antibiotics in uncomplicated UTIs has been increasing. Trimethoprim/sulfamethoxazole (TMP/SMX) is 1 of these antibiotics. Researchers also report that resistance patterns may differ depending on the geographic area of the United States. In this study, the authors present the results of a 7-month retrospective chart analysis of 98 E coli sensitivities to commonly prescribed antibiotics in the treatment of uncomplicated UTIs at a college health service. They examined the more common antibiotic choices and analyzed their in vitro responses. Of these antibiotics, ciprofloxacin, nitrofurantoin, amoxicillin/clavulanate, and TMP/SMX had the highest sensitivity rates. The authors compared the results with a previous study that they performed at the same institution in 1993. The results of this study show a sensitivity rate of 86% for TMP/SMX. When compared with the previous result of 87%, this represented a 1% change. Because of this slight decrease in sensitivity and the increasing concern over resistance, the authors suggest that they will continue to reevaluate the resistance pattern in their population on a regular basis. This will help determine if there is a need for modifying choices of empiric therapy for UTIs.

Key Words: antibiotics, bacterial resistance, E coli, trimethoprim/sulfamethoxazole, urinary tract infections

Escherichia coli (E coli) still remains the most common causative pathogen in uncomplicated urinary tract infection (UTI). It is the predominant organism in approximately 70% to 95% of cases of uncomplicated UTIs.1 In the past few years, practitioners and medical facilities began to change the way they managed uncomplicated UTIs because researchers advocated empiric treatment of UTIs for shorter periods of time without cultures. The reason for this was to increase patient compliance and decrease serious adverse drug reactions. By cutting down on the number of days to treat a patient, the patient, the practitioner, or medical facility realize a cost savings. Researchers recommended single dose and 3-day regimens of medications such as trimethoprim/sulfamethoxazole (TMP/ SMX), ciprofloxacin, and others. With this change, a new emerging problem developed: antibiotic resistance.

Antibiotic resistance is now becoming a major factor in uncomplicated community-acquired UTI. Resistance was traditionally a problem only in nosocomial complicated UTI. Because of this emerging resistance problem, relying on the empiric treatment of infections is more challenging for practitioners in the outpatient setting. The prevalence of resistance to TMP/SMX, the current drug of choice in the United States for empiric therapy of uncomplicated UTIs in women, now approaches 18% to 22% in some regions of the United States.2 Not only is there an increase in resistance to TMP/SMX, but within the past 10 years, resistance to ampicillin and cephalothin increased from approximately 20% to between 30% and 40%.2,3

Fortunately, resistance to other agents, such as nitrofurantoin or fluoroquinolone therapies, remains low.4 In the United States, E coli resistance to nitrofurantoin and ciprofloxacin are approximately 2% and 3%, respectively. In Europe, the resistance rate to ciprofloxacin is approximately 2%.5 Although sensitivity rates to various antibiotics have changed, it is important to note that these resistance patterns are not the same across the United States. This is especially true of TMP/SMX. Depending on the area of the country, the sensitivity rate may vary significantly, with the lowest E coli TMP/SMZ susceptibility occuring in the southern and western regions of the United States and a higher susceptibility occurring in the northeastern region.6

In addition to regional predictors, a 1999 study by Wright et al7 suggests that TMP/SMX resistance may be higher in certain identified outpatient populations. Although researchers need to conduct further studies, it appears that current or recent (within the past 3 months) use of TMP/SMX or any antimicrobials increases the risk of having a TMP/SMX-resistant uncomplicated UTI.2

In this study, we report on the results of a retrospective analysis of E coli sensitivities to commonly prescribed antibiotics in the treatment of uncomplicated UTIs at a college health service. We examined the more common antibiotic choices and analyzed their in vitro responses. We compared these results with a previous study we performed in 1993. We sought to determine if there was a change in sensitivity rates of E coli to the more commonly prescribed antibiotics.

METHOD

For this study, we used women who presented to the Stony Brook University Student Health Service with symptoms of uncomplicated UTIs and who had a urine culture and sensitivities showing a colony count greater than 105 colonyforming units per millimeter (cfu/mL) for E coli. We collected specimens by standard clean catch method. We tested susceptibility using the Kirby Bauer disk diffusion method.

From June through December 2003, we performed a retrospective chart review. Using charts and laboratory records, we found 98 female patients to have an uncomplicated E coli infection. We recorded the patients’ ages (range- 18-32 years; M- 22.1 years), E coli sensitivities, and the initially prescribed antibiotic therapy. According to standard laboratory practice, we reported sensitivities to ampicillin, nitrofurantoin, TMP/SMX, cephalothin, ciprofloxacin, tetracycline, doxycycline, and amoxicillin/clavulanate potassium as sensitive, intermediate, or resistant.

FIGURE 1. Percentage of sensitivity of E coli oragnisms to varioius antibiotics used in the treatment of uncomplicated urinary tract infection.

RESULTS

We found great variation in sensitivities of E coli to each of the antibiotics that we studied (see Figure 1). Ciprofloxacin, nitrofurantoin, amoxicillin/clavulanate, and TMP/SMX had the highest sensitivity rates. Ampicillin had the highest resistance rate, followed by tetracycline and doxycycline. Figure 2 shows the initial prescribing trends in the cases of presumptive uncomplicated UTIs at the Stony Brook University Student Health Service. TMP/SMX is the most commonly prescribed antibiotic for the initial treatment of an uncomplicated UTI at the student health service.

COMMENT

Geographic Variation

Presently, there is no systematic surveillance system for monitoring susceptibility profiles of community-acquired UTI isolates in the United States.2 Practitioners have few sources of information about resistance rates in their specific practice areas. Many studies suggest that practitioners should consider local resistance patterns when choosing a first-line agent for treatment of an uncomplicated UTI. The Infectious Diseases Society of America (IDSA) recommends that local communities establish methods to evaluate the susceptibility of urinary tract pathogens in their areas. Our study is a way of becoming vigilant about resistance patterns in a local community.

FIGURE 2. Initial antibiotic prescribed for the treatment of presumptive uncomplicated urinary tract infection.

Treatment Guidelines

Once practitioners establish that empiric treatment is appropriate, they must make a decision regarding the choice of which first-line antibiotic agent to prescribe. As discussed earlier, practitioners should consider the local rate of resistance to antibiotics in making their decision. The 1999 IDSA guidelines for uncomplicated UTI treatment advises that practitioners should consider the empiric use of a 3-day course of TMP/SMX as the current standard therapy. This is particularly true in communities with a TMP/SMX resistance pattern of 10% to 20%. If resistance is less than 10%, practitioners should consider an alternative drug.2 Two agents that the IDSA recommends are fluoroquinolone and nitrofurantoin. Even in areas of relatively higher resistance, practitioners may consider TMP/SMX if the patient has no other risk factors for resistance. If practitioners choose TMP/SMX in this situation, they may need to follow up more closely than they would if they give an alternative therapy.

Summary

Although diagnosis of an uncomplicated UTI remains relatively simple, treatment continues to grow more complex as patterns of local resistance continue to change. For practitioners in community settings to prescribe empiric antimicrobial therapy for patients presenting with UTI symptoms, they must be aware of the local patterns of antimicrobial resistance. This requires that practitioners establish a methodology for examining resistance patterns within the community. Periodic reexamination is desirable, considering the emergence of and changes in resistance patterns over the past several decades. In addition, history taking will reveal additional risk factors for resistance, such as recent or current antimicrobial use.

In this study,our analysis revealed a TMP/SMX sensitivity rate of 86%. We believe that this indicates that, although we may still consider TMP/SMX as a first-line agent in our population, fluoroquinolone or nitrofurantoin may also be reasonable, especially in patients who have an additional risk factor for resistance.

When we compared the results from this study with the results from our 1993 study, in which the sensitivity rate was 87%,8 we found that there was a 1% change over a 10-year period. Given the concern of increasing resistance of E coli to TMP/SMX, we were expecting a more significant increase in resistance in our population. We observed this trend in increasing resistance only slightly in this study. Data related to the prescribing habits of our practitioners in cases of UTIs showed that TMP/SMX was the most prescribed antibiotic.

Because TMP/SMX is the most commonly prescribed antibiotic at Stony Brook University, and because we are concerned with the increasing resistance of E coli to commonly used antibiotics, we will continue to reevaluate the resistance pattern in our population on a regular basis. This will help us determine if there is the need for modifying our initial antibiotic choice of empiric therapy for UTI.

NOTE

For comments and further information, please address correspondence to Robert K. Ansbach, Associate Director/Physician Assistant, Stony Book University Student Health Service, 1 Stadium Road, Stony Brook, NY 11794-3191 (e-mail: ransbach@ notes.cc.sunysb.edu).

REFERENCES

1. Hooton TM. The current management strategies for community acquired urinary tract infection. Infect Dis Clin North Am. 2003;49:303-332.

2. Gupta K. Addressing antibiotic resistance. Dis Mon. 2003;49:99- 110.

3. Gupta K. Emerging antibiotic resistance in urinary tract pathogens. Inf Dis Clin North Am. 2003;17:243-259.

4. Nicolle LE. Urinary tract infection: traditional pharmacologie therapies. Dis Mon. 2003;49:111-128.

5. Hooton TM. Optimizing treatment for acute uncomplicated cystitis-factors that influence antibiotic selection. Available at: http://www.jobsoneducation.com/clinicianscme/index.asp?show=les son&page=courses/2925/lesson.htm&lsn_id=2925. Accessed 2004.

6. Gupta K, Sahm DF, Mayfield D, Stamm WE. Antimicrobial resistance among uropathogens that cause community-acquired urinary tract infections in women: a nationwide analysis. Clin Infect Dis. 2001;33:89-94.

7. Wright SW, Wren KD, Haynes ML. Trimethoprimsulfamethoxazole resistance among urinary coliform isolates. J Gen Intern Med. 1999;14:606-609.

8. Ansbach RK, Dybus, KR, Bergeson RA. Uncomplicated E coli urinary tract infection in college women: a retrospective study of E coli sensitivities to commonly prescribed antibiotics. J Am Coll Health. 1995;43:183-185.

9. Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am. 1997;11:551-581.

10. Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Dis Mon. 2003;49:71-82.

11. Bent S. The optimal use of diagnostic testing in woman with acute uncomplicated cystitis. Dis Mon. 2003;49:83-98.

Robert K. Ansbach, MA, RPA-C; Karen Dybus, MS, RPA-C; Rachel Bergeson, MD

The authors are with the Stony Brook University Student Health Service, NY, where Robert K. Ansbach is the associate director and a physician assistant, Karen Dybus is a physician assistant, and Rachel Bergeson is the medical director.

Copyright HELDREF PUBLICATIONS Sep/Oct 2005

By Rosenwasser, Lanny J; O’Brien, Terrence; Weyne, Jonathan

Key words: Anti-histamines * Mast cell stabilizer * Olopatadine * Ocular allergy

ABSTRACT

Background: Histamine receptor activation and degranulation of mast cells are the mechanisms by which the ocular itching, hyperemia, chemosis, eyelid swelling, and tearing of seasonal allergic conjunctivitis are induced. Some of the topical solutions available as anti-allergy therapies are intended to interfere with these mechanisms, and the body of research regarding the capabilities of these therapeutic molecules continues to expand.

Objective.-Jo review the currently available literature regarding one topical ophthalmic antiallergy agent, olopatadine (Patanol*), and its antihistaminic and mast cell stabilizing actions, both in pre-clinical and clinical settings.

Design and methods: Relevant research of laboratory, animal model, and clinical trial studies performed using olopatadine was reviewed. MEDLINE literature searches were conducted and supplemented by additional reports which furthered relevant discussion or were necessary to verify the information resulting from original searches.

Results: Olopatadine demonstrates unique properties both pre- clinically and clinically which differentiate it from other therapeutic molecules in its class of dual action mast cell stabilizer/antihistamine. Its non-perturbation of cell membranes, human conjunctival mast cell stabilization in vivo and in vitro, and superior efficacy as compared to other topical anti-allergic medications including mast cell stabilizers, anti-histamines, and dual action agents, all contribute to olopatadine’s profile.

Conclusions: Peer-reviewed literature suggests that Olopatadine is clinically superior to the other anti-allergic molecules because of its strong antihistaminic qualities and its unique ocular mast cell stabilizing properties.

Introduction

Since the discovery of histamine in 19101, and the development of the first anti-histamine compound in 19372, much has been learned about the complex nature of the allergic reaction. The evolution of anti-histamines has provided medicine with agents that act more specifically and for a longer duration, such as levocabastine and emadastine.

However, advances in immunology have demonstrated that blocking the action of histamine alone does not completely suppress the allergic reaction, as it is released from the mast cell along with numerous other allergic mediators3. This realization led to the birth of a new class of drugs: the mast cell stabilizers. The original mast cell stabilizer molecules, such as cromolyn sodium, were at first tested in allergic models, based on non-ocular tissues, not representative of the clinical pharmacology of the allergic eye. These compounds, also including nedocromil, pemirolast, and lodoxamide in addition to cromolyn, have for the most part been supplanted in ocular allergy therapy by newer therapeutic molecules.

The most recently developed class is that of the dual action agents, which are more precisely aimed at the mast cell. Though there are also several less-frequently prescribed anti-allergy options available including products such as corticosteroids (loteprednol etabonate) and non-steroidal anti-inflammatory drugs (ketorolac), the dual action molecules have become the standard therapy of use for seasonal allergic conjunctivitis. Dual action molecules are classified as such based upon pharmacological testing which revealed their inhibition of H^sub 1^-receptors as well as ability to stabilize mast cells. Drugs included in this class are olopatadine, ketotifen, epinastine, and azelastine, though olopatadine is the only one of this class to have shown human conjunctival mast cell stabilization in vitro and in vivo.

The present review asks how pre-clinical findings correspond to the clinical effects, thus discussing a possible pre-clinical rationale which explains olopatadine’s clinical effects, as seen across many peer-reviewed studies. These include evaluations of allergic mediators at the molecular level, as well as clinical comparisons with other anti-allergy medications, including topical eye drops of various mechanisms, as well as systemic and nasal spray anti-allergy therapies. The distinctiveness of olopatadine, both clinically and pharmacologically, with respect to the other drugs in this class will also be discussed.

Design and methods

Database searches of the literature were conducted from 1966- June 2005. Searches for in vitro, cell membrane, and clinical study of the olopatadine molecule were conducted using the search terms Olopatadine and in vitro’, Olopatadine and cell membrane’, and Olopatadine and clinical’ on the MEDLINE online searchable database. From the results of literature searches, articles were selected for inclusion based upon their applicability to the central question of this review: that of determining the relationship between olopatadine’s effects at the molecular level and those observed clinically. Additional original reports were referenced at the authors’ discretion if it was determined that the data presented was relevant to the discussion on the topics of this review or if further support was necessary to verify the information resulting from original searches.

Results

Initial in vitro and in vivo characterization of Olopatadine

Olopatadine hydrochloride is the active ingredient in the currently marketed anti-allergy treatment, Patanol (Alcon Laboratories Inc, Fort Worth, TX, USA). The molecule is a selective H1-receptor antagonist and human conjunctival mast cell stabilizer. In the ophthalmic solution currently available, olopatadine exists as an aqueous solution containing 0.1% olopatadine.

Olopatadine was the focus of many in vitro and in vivo animal studies designed initially to identify its potential clinical value. It was shown in various screening models to both inhibit the binding of histamine to H!-receptors4″6 and to stabilize mast cells in the conjunctiva and other tissues7″9. The exceptionally high binding affinity of olopatadine for H^sub 1^-receptors was first demonstrated in rodent brain homogenates; affinities for H2 and H3 receptors were also observed9. The high selectivity of olopatadine has been proposed as being due to a unique binding pocket containing the aspartate residue and other sites within the H^receptor10. Studies have since demonstrated that the H j-receptor selectivity of olopatadine is superior to other anti-histamines formulated for use in the eye such as levocabastine, pheniramine, and antazoline3, as determined through histamine receptor subtype binding assays as well as assays for non-histamine receptors. Olopatadine’s high level of selectivity is further defined by its lack of interaction with alpha- adrenergic, muscarinic, dopaminergic and numerous other receptors. Taken together, the authors of these studies noted that these findings indicate olopatadine as having a relatively high affinity, high potency antagonism, specifically of the H ^receptor, which suggests that this compound has advantages over other topical ocular antiallergic medications5,9.

Olopatadine was shown to inhibit, in a dose-dependent fashion, the immunologically-stimulated release of histamine from rat basophilic leukemia cells and from human conjunctival mast cells in vitro4. Greater than 90% inhibition was achieved without observable histamine release even at 10 times the clinically maximally effective dose. Results obtained with the comparative drug, ketotifen, gave a first glimpse at the divergent activity of olopatadine compared to other drugs in this class. Ketotifen elicited a clearly biphasic response: at low concentrations, exhibiting suppression of histamine release, but as concentration was increased, histamine release was stimulated4. This disparity was an early indication that olopatadine has a potentially broader margin of efficacy and safety than ketotifen.

Two in vivo models of passive conjunctival anaphylaxis confirmed these in vitro findings. Olopatadine elicited an 80% inhibition of allergic conjunctivitis in passively sensitized guinea pigs, with significant activity noted after 8 hours. Its anti-histaminic properties were then defined in vivo by measuring changes in histamineinduced conjunctival vascular permeability. This activity was of rapid onset and prolonged duration, evident from 5 minutes to 24 hours after drug administration4.

With regard to determining mast cell stabilizing activity, it is first important to understand the heterogeneity of mast cell populations. This heterogeneity translates into variability in mast cell properties, such as differences in reactivity to pharmaceutical molecules, among species, and even among tissues within the same species”’12. It is of note that olopatadine was shown to be specifically effective at the cellular level in human conjunctival mast cells. One study was aimed at defining and comparing the effects of nedocromil, olopatadine, and pemirolast on mediator release from human conjunctival mast cell cultures and comparing these effects with those obtained with cromolyn sodium as an historical point of reference8. The affinity of these compounds for the Hj-receptor was also investigated. Interestingly, findings indicated that cromolyn and pemirolast failed to significantly inhibit histaminerelease from human conjunctival mast cells while nedocromil elicited only a 28% inhibition of histamine release even at higher than customary doses8. In this study, only olopatadine inhibited histamine release from human conjunctival mast cells in a dose-dependent fashion, as well as inhibiting H^sub 1^-receptor binding at clinically relevant concentrations. The lack of efficacy of the other antiallergic agents to act on human conjunctival mast cells, after they had been shown to exert efficacy in rodent models, underscores the importance of evaluating these drugs in the appropriate model and species.

Further definition of the mechanisms of olopatadine activity

The role of conjunctival epithelial cells in allergy has gained interest in recent years, and these cells are considered a potential site for pharmacological intervention. Epithelial cells produce cytokines following a number of stimuli13; and are known to have functional Hj-receptors14. Exposure of human conjunctival epithelial cells (HCEC) to histamine has been shown to stimulate interleukin (IL)-G and IL-8 production, and treatment with H^sub 1^ antagonists prevents this stimulus15. Blocking these effects of histamine on the epithelium accounts, in large part, for the anti-inflammatory effects of many common anti-histaminic agents15,16.

Olopatadine has been shown to significantly downregulate the effects of mast cell-mediated intercellular adhesion molecule-1 (ICAM-1) on HCEC after anti-immunoglobulin E (IgE) antibody challenge, although it did not decrease ICAM-1 directly. ICAM-1, a mediator important to promotion of the allergic reaction, contributes to the recruitment of migrating pro-inflammatory mediators. It is not known if this effect is related to H^sub 1^ antagonism, though it is known that ICAM-1 expression is upregulated by mediators released from the mast cell. Inhibition of mast cell tumor necrosis factor-alpha (TNF-α) and epithelial cell ICAM-1 by olopatadine is a measure which contributes to limiting the attraction of migrating cells such as eosinophils to the site of allergic reaction17’18. The long duration of action of olopatadine has been proposed by some to be at least in part due to shutting down of this ripple effect: a blocking of TNF-α-mediated upregulation of inflammatory marker expression on conjunctival epithelial cells may lead to generalized suppression of inflammatory cell migration and recruitment on the ocular surface18. This supporting anti-inflammatory role of olopatadine may render it appropriate therapy to use, as an adjunct to the primary therapy of steroids, for chronic inflammatory diseases such as allergic keratoconjunctivitis or vernal keratoconjunctivitis, where a damaging cellular infiltrate is a significant component of the disease.

Cell membrane effects of anti-allergic agents: pre-clinical differences and clinical implications

Marked differences in the mast cell stabilization capabilities of ketotifen and olopatadine have been demonstrated4, yet there is still an incomplete knowledge of how these compounds behave transcellularly. Recent research has focused on the interaction of these drugs with model and biological membranes19. Surface activity can regulate the biological activity of a drug, as well as a drug’s tendency to first stabilize and then permeabilize biological membranes. One study evaluated the functional consequences of these interactions using several assessments: natural membranes by leakage of 6-carboxyfluorescein (small molecules) and hemoglobin (large molecules) from intact erythrocytes and ghosts, and by lactate dehydrogenase (LDH) (i.e. cytoplasmic) and histamine release (i.e. intracellular granules) from human conjunctival mast cells (HCMC) and corneal epithelial cells. Compounds tested were: desloratadine, clemastine, azelastine, ketotifen, diphenhydramine, pyrilamine, emedastine, epinastine, and olopatadine19.

Results of this set of tests indicated that all anti-histamines except olopatadine had a negative impact on mast cell surface membranes. Intrinsic surface activity, as measured using an argon- buffer interface, resulted in measurements of surface activity ranging from highly surface active to weakly surface active in the following order: desloratadine > clemastine > azelastine = ketotifen > diphenhydramine > pyrilamine > emedastine > epinastine ≥ olopatadine. In further tests assessing the functional consequences of these surface activities, olopatadine showed the lowest intrinsic surface activity, as measured by cell-based assays (hemoglobin leakage from erythrocytes, LDH release from HCMC, 6- carboxyfluorescein release from erythrocyte ghosts), and was the only compound tested to inhibit release of histamine from the human mast cell at the marketed concentration.

In natural membranes, olopatadine was the only agent that did not promote membrane perturbation. Assessment of the degranulation potential of marketed concentrations of ketotifen (0.025%), azelastine (0.05%), and epinastine (0.05%) revealed significant membrane perturbation of HCMC and, importantly, human corneal epithelial cells. This was in contrast to the marketed concentration of olopatadine (0.1%), which maintained normal mast cell and corneal epithelial cell membrane function. Thus, ketotifen, azelastine, and epinastine, the other dual action drugs approved for use in the eye, all behave similarly: the suppression of histamine release at low concentrations is followed by membrane perturbation and histamine release after achieving a threshold concentration. This effect was seen at the marketed concentrations, was independent of histamine receptor antagonism, and was a direct consequence of interaction of these agents with the human conjunctival mast cell membrane. Thus, we suggest that these data contribute to explaining how these compounds can demonstrate a certain level of clinical efficacy (via anti-histaminic activity) while actually causing mast cell degranulation after an initial mast cell stabilization. An illustration of the divergent effects of the commercially available compounds on histamine release can be seen in Figure 1. Olopatadine’s restricted interaction with membrane phospholipids, limiting membrane perturbation and release of intracellular constituents, including histamine, LDH and hemoglobin19, represent a novel property of this molecule, which we hypothesize may contribute to the superior efficacy and patient tolerability that have been observed with its use in clinical trials.

Figure 1. Effects of the commercially available concentrations of olopatadine, ketotifen, azelastine and epinastine ophthalmic solutions on histamine release from immunologically stimulated human conjunctival mast cells in vitro. Only olopatadine did not elicit a biphasic reaction (i.e. initial inhibition at low concentrations/ stimulation of response at marketed concentrations)19

Clinical experience with olopatadine

Placebo-controlled trials

The clinical efficacy of anti-allergic compounds is ideally evaluated in the conjunctival allergen challenge model (CAC), which has been accepted as a valid clinical model for drug registration trials in the United States20. The CAC model controls allergen exposure, inducing an ocular allergic reaction in a reproducible manner and has been used for the standardized evaluation of criteria including ocular itching, redness, hyperemia, chemosis, and eyelid swelling. Signs and symptoms are graded on standardized scales and the onset and duration of action of drugs can be accurately determined by modifying the time of drug administration in relation to the time of challenge. The standard CAC design can also be modified to induce a clinically evident late phase of allergy in a subgroup of predisposed patients by challenging with high doses of allergen.

A combined analysis of two CAC placebocontrolled trials evaluated the efficacy, safety, optimal concentration, onset and duration of action of olopatadine (n = 169)21. The onset of action was determined to be within five minutes of challenge, and the duration of action over 8 hours. Both 0.5% and 0.1% concentrations of olopatadine were the strongest candidates for drug formulation, significantly inhibiting peak ocular itching and hyperemia (p

A human clinical trial has researched olopatadine’s effects on specific cellular mediators involved in the ocular allergic reaction. This study was performed in a subset of patients who experienced a late phase of allergy when challenged with high doses of allergen22. Contralateral olopatadine and placebo treatment in challenged allergic patients (n = 10) verified the mast cell stabilizing effects previously observed in vitro with olopatadine. In olopatadine-treated eyes, itching and hyperemia were significantly reduced as compared to placebo (p

The significant effects of olopatadine against both ocular itching and hyperemia have been comprehensively researched and validated21-30. In addition, the effects of olopatadine on the recalcitrant sign of eyelid swelling have also been investigated. Eyelid swelling is difficult to treat since it is a lingering, residual consequence of the vascular permeability changes wrought by mediator release. In a single visit, randomized placebo-controlled CAC trial, an ocular allergic reaction was induced and only those patients who experienced lid swelling as a component of the allergic reaction were continued in the study (n = 56). In addition to the usual subjective measurement of eyelid swelling provided by the patient, scanning and imaging technology was used to objectively measure pre- and post-challenge changes in the volume of the skin around the eyes with a sensitivity of 0.5 mm. The imager indicated that 15 minutes after challenge, lid swelling was 5.65 times greater, and after 30 minutes, 1.76 times greater in placebo- versus olopatadine-treated eyes23. These changes were statistically and clinically significant (p

An additional study has evaluated the effect of olopatadine on chemosis of the conjunctiva which, like eyelid swelling, results from the increases in vascular permeability induced by histamine and other vasoactive mediators during an ocular allergic reaction. This randomized, double-masked study evaluated the effects of olopatadine on chemosis in 20 individuals with a history of allergic conjunctivitis. There was significantly less chemosis evident in olopatadine treated eyes at 3, 10, and 20 minutes following allergen challenge as compared to placebo treated eyes (p

Comparative trials

Olopatadine has been compared to many anti-allergic/ anti- inflammatory agents: topical anti-histamines, mast cell stabilizers, and corticosteroids, in controlled, randomized, masked clinical studies. Olopatadine has also been paired with nasal corticosteroids and with systemic anti-histamines in CAC studies to identify appropriate modalities for multi-allergy sufferers. In the clinical comparisons reviewed here, olopatadine consistently performs significantly more favorably than its comparators in terms of both efficacy and comfort.

One of the first comparative trials evaluated olopatadine versus ketorolac 0.5%, a nonsteroidal anti-inflammatory eye drop approved for the relief of ocular itching associated with seasonal allergic conjunctivitis24. This was a randomized, double-masked, contralaterally placebo controlled, crossover design, CAC study which evaluated ocular itching, hyperemia, and comfort in allergic conjunctivitis patients (n = 36). Medication dosing took place 27 minutes prior to allergen challenge. Evaluations of ocular itching and hyperemia were performed at 3, 10, and 20 minutes following allergen challenge. Patients evaluated comfort, using a standardized discomfort scale immediately following instillation. Olopatadine significantly reduced ocular itching and hyperemia versus placebo at all three evaluation time points, both statistically (p

Subsequently, in separate studies, olopatadine was demonstrated to be superior to nedocromil25 and ketotifen26,32-34 in the CAC model. One study compared olopatadine to ketotifen in a prospective, doublemasked, contralaterally controlled design (n = 32)26. The primary efficacy variables were ocular itching and subject satisfaction. Drop comfort was assessed immediately after eye drop instillation, efficacy at 12 hours duration (i.e. medication dosing occurred at 12 hours prior to CAC), and satisfaction following the efficacy analysis.

In a more recent comparative study of olopatadine and ketotifen, in which 100 patients used both medications over a two week period, 81% of patients with seasonal or perennial allergic conjunctivitis preferred olopatadine based on its comfort and superior efficacy (p

In a single-center, randomized, double-masked, contralaterally controlled, CAC model evaluation of olopatadine and nedocromil, comfort and efficacy were evaluated (n = 49). One drop of olopatadine was shown to be statistically and clinically, significantly more effective in controlling itching than a 2-week (29 drop) load of nedocromil (p

A comparison of cromolyn with olopatadine was also carried out in a parallel group seasonal allergic conjunctivitis study (n = 185; mean age 35, range 4-77), confirming the superiority of olopatadine in controlling itching and hyperemia, as well as better local tolerability in children less than 11 years of age; specifically the ocular hyperemia scores were two times lower in pediatric subjects who received olopatadine as compared to those who received cromolyn (p = 0.002)27.

Azelastine, a compound approved for the relief of itching due to allergic conjunctivitis, was interestingly compared to olopatadine as both of these compounds are dual-action anti-histamine/mast cell stabilizers28. Olopatadine was found to be more effective in this controlled, randomized, double-masked study (n = 111), in the management of itching (p

Corticosteroids such as loteprednol etabonate 0.2% are potent anti-inflammatory agents. Since steroids are known to have a longer onset of action, a 14-day loading period was incorporated into the study for loteprednol (n = 50). Results demonstrated that one drop of olopatadine was significantly more effective than a 57 drop, 2- week loading of loteprednol for the relief of ocular allergic itching and hyperemia (p

A recent comparative trial investigated epinastine, an agent that was originally approved for rhinitis, in comparison to olopatadine in the CAC model in a placebo controlled, randomized, double-masked study (n = 66). Olopatadine was shown to be superior to epinastine in inhibition of itching, hyperemia, and chemosis. In this study, epinastine was statistically equivalent to placebo in the ocular redness assessment at 20 minutes post challenge, suggesting initial mast cell stabilization is followed later by mast cell degranulation and the release of histamine30. This relates to the preclinical data on the non-specific degranulation effects of epinastine on cell membranes19. This may also suggest the reason epinastine received an indication for ocular itching only, rather than for all signs and symptoms of allergic conjunctivitis, as had been originally requested.

A careful review of the evidence provided by preclinical studies has been confirmed in clinical trials, and is summarized in Table 1. Comparative clinical studies against cromolyn\, nedocromil, levocabastine, ketorolac, epinastine, ketotifen, azelastine and loteprednol concluded that olopatadine had superior efficacy and greater tolerability.

Table 1. Olopatadine: relationship of pre-clinical to clinical data

Population subsets

A portion of overlap exists between the contact lens wearing population, which is estimated to be at 36 million in the United States33, and ocular allergy sufferers, who comprise approximately 20% of the general population36.

In a CAC model evaluation of comfort and efficacy in contact lens wearers37, olopatadine was revealed to be significantly more efficacious in managing the signs and symptoms of allergy (n = 20, p

Multiple sites of allergic sensitivity are known to be more the rule than the exception in the clinical manifestations of allergy, providing a challenge for its treatment by the health care professional. Systemic anti-histamines may be a treatment option prescribed by clinicians or self-selected by patients in an attempt to control ocular allergies. However, clinical studies have shown that a topical anti-allergy therapy often provides superior alleviation of ocular allergy as compared to systemic agents. In two original reports, the oral antihistamine, loratadine 10mg was compared to topical olopatadine using the CAC model (n = 14; n = 29)40,41. Results showed that the itch associated with ocular allergy was controlled by olopatadine and not systemic loratadine (p

Further study of olopatadine combined it with other types of treatment, evaluating the combined efficacy of fluticasone propionate nasal spray and olopatadine eye drops (i.e. an entirely local regimen) as compared to fluticasone and the oral anti- histamine fexofenadine, a regimen with a systemic component (n = 80)44. In this study, the primary efficacy variables were ocular itching and hyperemia, as well as nasal symptoms (itching of the nose and palate, rhinorrhea, and sneezing). Results indicated that olopatadine treated eyes had less ocular itching and hyperemia (p

The effects of ophthalmic olopatadine drops on rhinitis spurred subsequent studies to better define the effects of this drug in the commonly observed allergic combination of conjunctivitis and rhinitis. Olopatadine dosed ocularly was shown to attenuate nasal symptoms in 131 rhinoconjunctivitis patients in a seasonal environmental study (rhinorrhea: p

A recent study with an environmental, crossover design enrolled rhinitis patients being treated on a steady regimen for their rhinitis with a systemic antihistamine and/or a nasal spray47. These patients were then separated into two groups. For the first 2 weeks of study, Group A (n = 97) received 2 weeks of olopatadine therapy added to their systemic or nasal regimen; Group B (n = 103) did not receive additional ophthalmic therapy. Cross-over took place after 2 weeks, with Group A ceasing olopatadine use, and Group B commencing twice-daily administration of olopatadine for two weeks. All patients were administered two quality of life questionnaires (Allergic Conjunctivitis Quality of Life Questionnaire; Rhinitis Quality of Life Questionnaire) at baseline, at the 2-week cross- over, and at 4 weeks when the study concluded. Results indicated that significant improvements in quality of life were evident when an eye drop was added to patients’ existing rhinitis regimens (p

Finally, a highly favorable comfort and tolerability profile of an ophthalmic eye drop formulation might be regarded as a relatively important attribute for effective usage and compliance particularly in the pediatric population. Pediatric data was retrospectively extracted from two studies (n = 30; n = 22) assessing olopatadine treatment, as well as 2% cromolyn sodium and 0.05% levocabastine. The mean ages of pediatric patients were 7.2 years (male) and 8.5 (female) in the olopatadine versus cromolyn study, and 8.3 (male) and 8.8 (female) in the comparison to levocabastine. The results of these two studies revealed that all three treatments were well tolerated, however olopatadine exhibited superior efficacy in relief of itching and hyperemia as compared to cromolyn and levocabastine (p

Discussion

Many of the anti-histamine/mast cell stabilizer agents currently available, with the exception of olopatadine, cause significant degranulation of human mast cells due to their high non-specific surface activity (Figure 1)19. This effect leads to a release of histamine from ruptured human mast cells and corneal epithelial cell membranes. Notably, these degranulation effects occur at commercially available concentrations of ketotifen, azelastine and epinastine. The degranulationinducing nature of these compounds may contribute to high ocular surface irritability and/or lesser patient acceptance and lesser efficacy.

Based upon the body of research summarized here, it appears that the pharmacology of olopatadine is unique, even compared to other ophthalmic antiallergic agents in its category, including epinastine, azelastine, and ketotifen19. While the pharmacological effects of many of the currently available topical ocular anti- allergic products block histamine receptors, peer-reviewed literature to date demonstrates a nonspecific degranulation effect on human conjunctival mast cells for epinastine, azelastine, and ketotifen at marketed concentrations. This is in contrast to the mast cell stabilization effects of olopatadine at marketed concentrations and across all other concentrations (i.e. lesser and greater) tested19. Therefore, careful review of the data suggests that this point of preclinical differentiation contributes to the observed clinical effects of olopatadine and its ability to offer the complete range of relief across all signs and symptoms (including itching, chemosis, hyperemia, tearing, and eyelid swelling). These pre-clinical data may also suggest a component of the molecule’s behavior that explains the consistent results generated by the myriad clinical studies supporting the clinical efficacy of olopatadine.

Conclusions

Analysis of the peer-reviewed literature indicatesthat olopatadine is a potent, selective, and longacting anti-allergic molecule. The combined antihistaminic and mast cell stabilizing properties across varying concentrations are unique to olopatadine and differentiate this molecule from all comparators in control of all the signs and symptoms associated with allergic conjunctivitis.

Acknowledgments

Declaration of interest: The publication of this review article has been supported by Alcon Laboratories, Inc., Fort Worth, TX (the manufacturers of olopatadine).

* Patanol is a registered trade name of Alcon Laboratories Inc, Fort Worth, TX, USA

References

1. Dale HH, Laidlaw PP. The physiologic action of beta- imidazolethyamine. J Physiology 1910;41:318

2. Staub AM, Bovet D. Action de la thymoxyethyl-diethylamine (929F) et des ethers phenoliques sur le choc anaphylactique du cobaye. CR Soc Biol 1937;125:818

3. Abelson MB, Katelaris C, Slugg AP, et al. Ocular Immunology in Allergie Diseases of the Eye. Abelson M, editor. Philadelphia: WB Saunders Co. 2000, pp. 20-7

4. Yanni JM, Stephens DJ, Miller ST, et al. The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther 1996; 12:389-400

5. Sharif NA, Xu SX, Miller ST, et al. Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL- 4943A), a novel drug for treating ocular allergic diseases. J Pharmacol Exp Ther 1996;278:1252-61

6. Nonaka H, Ishii A, Kase H. Effect of KW-4679, a novel antiallergic agent, on histamine Hl receptor. Jpn J Pharmacol 1993;61(suppl):87P

7. Ishii H, Kitamura S, Ohmoti K. Inhibitory effect of KW-4679 on allergic models in rats. Jpn J Pharmacol 1991;55(suppl): 375P

8. Yanni JM, Miller ST, Gamache DA, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol 1997;79:541-5

9. Sharif NA, Xu SX, Yanni JM. Olopatadine (AL-4943A): Ligand binding and functional studies on a novel, long acting Hlselective histamine antagonist and anti-allergic agent for use in allergie conjunctivitis. J Ocul Pharmacol Ther 1996; 12: 401-7

10. Nonaka H, Otaki S, Ohshima E, et al. Unique binding pocket for KW-4679 in the histamine Hl receptor. Eur J Pharmacol 1998)345:111-7

11. Katz HR, Stevens RL, Austen KF. Heterogeneity of mammalian mast cells differentiated in vivo and in vitro. J Allergy CHn Immunol 1985)76:250-9

12. Irani AMA, Schwartz LB. Mast cell heterogeneity. Clin Exp Allergy 1989)19:143-55

13. Hingorani M, Calder V, Buckley RJ, et al. The role of conjunctival epithelial cells in chronic ocular allergic disease. Exp Eye Res 1998)67:491-500

14. Sharif NA, Xu SX, Magnino PE, et al. Human conjunctival epithelial cells express histamine-1 receptors coupled to phosphoinositide turnover and intracellular calcium mobilization: Role in ocular allergic diseases. Exp Eye Res 1996)63:169-78

15. Yanni JM, Sharif NA, Gamache DA, et al. A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs. Acta Ophthalmol Scand 1999)77:33-7

16. Yanni JM, Weimer LK, Sharif NA, et al. Inhibition of histamineinduced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol 1999)117:643-7

17. Cook EB, Stahl JL, Barney NP, et al. Olopatadine inhibits antiimmunoglobulin E-stimulated conjunctival mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells. Ann Allergy Asthma Immunol 2001)87:424-9

18. Cook EB, Stahl JL, Barney NP, et al. Olopatadine inhibits TNF- a release from human conjunctival mast cells. Ann Allergy Asthma Immunol 2000)84:504-8

19. Brockman HL, Momsen MM, Knudtson JR, et al. Interactions of olopatadine and selected antihistamines with model and natural membranes. Ocular Immunol Inflamm 2003)2:247-68

20. Abelson MB, Chambers WA, Smith LM. Conjunctival Allergen Challenge: A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990)108:84-8

21. Abelson MB, Spitalny L. Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am J Ophthalmol 1998)125:797-804

22. Leonardi AA, Abelson MB. Double-masked, randomized, placebo- controlled controlled clinical study of the mast cell stabilizing effect of treatment with olopatadine in the conjunctival allergen challenge model in humans. Clin Ther 2003)25: 2539-52

23. Abelson MB, Pratt S, Mussoline JF, et al. One-visit, randomized, placebo-controlled, conjunctival allergen challenge study of scanning and imaging technology for objective quantification of eyelid swelling in the allergic reaction with contralateral use of olopatadine and artificial tears. Clin Ther 2003)25:2070-84

24. Deschenes J, Discepola M, Abelson MB. Comparative evaluation of olopatadine ophthalmic solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using the provocative antigen challenge model. Acta Ophthalmol Scand Suppl 1999)228:47-52

25. Butrus S, Greiner JV, Discepola M, et al. Comparison of the clinical efficacy and comfort of olopatadine hydrochloride 0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model. Clin Ther 2000)22:1462-72

26. Berdy GJ, Spangler DL, Bensch G, et al. A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther 2000)22:826-33

27. Katelaris CH, Ciprandi G, Missotten L, et al. International Olopatadine Study Group. A comparison of the efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and cromolyn sodium 2% ophthalmic solution in seasonal allergic conjunctivitis. CHn Ther 2002)24:1561-75

28. Spangler DL, Bensch G, Berdy GJ. Evaluation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochloride 0.5% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther 2001 ;23: 1272-80

29. Berdy GJ, Stoppel JO, Epstein AB. Comparison of the clinical efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension in the conjunctival allergen challenge model. Clin Ther 2002;24:918-29

30. Lanier BQ, Finegold I, D’Arienzo P, et al. Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival challenge model. Curr Med Res Opinion 2004;20:1227-33

31. Abelson MB, Spangler D, Giovanoni A, et al. Chemosis is an important diagnostic tool for evaluating new ophthalmic antiallergic agents using the conjunctival allergen challenge model. American College of Allergy, Asthma and Immunology meeting: Nov 7-12, 1997; San Diego, CA [abstract]

32. Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Acta Ophthalmol Scand Suppl 2000)230:52-5

33. Artal MN, Luna JD, Discepola M. A forced choice comfort study of olopatadine hydrochloride 0.1% versus ketotifen fumarate 0.05%. Acta Opthalmol Scand Suppl 2000; 78:64-5

34. Leonardl A, Zafirakis P. Efficacy and comfort of olopatadine versus ketotifen ophthalmic solutions: a double-masked environmental study of patient preference. Curr Med Res Opinion 2004;20:1167-73

35. Bausch & Lomb. Annual report to vision care professionals. Available from http://www.optistock.com/trends_contact_ lenses_2001_dec.pdf [Accessed 14 Dec 2001] pp. 8-11

36. Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr Allergy 1987;21:1-20

37. Brodsky M, Berger WE, Butrus S, et al. Evaluation of comfort using olopatadine hydrochloride 0.1% ophthalmic solution in the treatment of allergic conjunctivitis in contact lens wearers compared to placebo using the conjunctival allergen-challenge model. Eye Contact Lens 2003;29:113-6

38. Brodsky M. Allergic conjunctivitis and contact lenses: experience with olopatadine hydrochloride 0.1% therapy. Acta Ophthalmol Scand Suppl 2000;230:56-9

39. Dassanayake NL, Carey TC, Owen GR. A laboratory model to determine the uptake and release of olopatadine by soft contact lenses. Acta Ophthalmol Scand 2000;78:16-7

40. Abelson MB, Lanier RQ. The added benefit of local patanol therapy when combined with systemic Claritin for the inhibition of ocular itching in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl 1999;228:53-6

41. Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to Claritin (loratadine lOmg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl 2000; 230:60-3

42. Ousler GW, Wilcox KA, Gupta G, et al. An evaluation of the ocular drying effects of 2 systemic antihistamines: loratadine and cetirizine hydrochloride. Ann All Asth Immunol 2004;93: 460-464

43. Welch D, Ousler GW, Nally LA, et al. Ocular drying associated with oral antihistamines (loratadine) in the normal population – an evaluation of exaggerated dose effect. Adv Exp Med Biol 2002;506:1051-55

44. Lanier RQ, Abelson MB, Berger WE, et al. Comparison of the efficacy of combined fluticasone propionate and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by conjunctival allergen challenge. Clin Ther 2002;24:1161-74

45. Spangler DL, Abelson MB, Ober A, et al. Randomized, doublemasked comparison of olopatadine ophthalmic solution, mometasone furoate monohydrate nasal spray, and fexofenadine hydrochloride tablets using the conjunctival and nasal allergen challenge models. Clin Ther 2003;25:2245-67

46. Abelson MB, Turner D. A randomized, double-blind\, parallelgroup comparison of olopatadine 0.1% ophthalmic solution versus placebo for controlling the signs and symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Clin Ther 2003;25:931-47

47. Berger WE, Beck M, Kimura S, et al. Effects of adjuvant therapy with 0.1% olopatadine hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using systemic or nasal therapy. Ann All Asth Immunol 2005;95 [in press]

48. Ciprandi G, Turner D, Gross RD. Double-masked, randomized, parallel-group study comparing olopatadine 0.1% ophthalmic solution with cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in children with seasonal allergic conjunctivitis. Curr Ther Res 2004;65:186-99

49. Bertin D, Fedrigo A, Cano-Parra J. Efficacy and safety of olopatadine (Patanol) eye drops 0.1% compared to levocabastine 0.05% in seasonal allergic conjunctivitis. European Association for Vision and Eye Research meeting, In: Ophthal Res 2001,’33 (suppl 1) [abstract]

50. Cook EB, Stahl JL, Sedgwick JB, et al. The promotion of eosinophil degranulation and adhesion to conjunctival epithelial cells by IgE-activated conjunctival mast cells. Ann Allergy Asthma Immunol 2004;92:65-72

51. Fukuishi N, Matsuhisa M, Shimono T, et al. Inhibitory effect of olopatadine on antigen-induced eosinophil infiltration and the LFA-I and Mac-1 expression in eosinophils. Jpn J Pharmacol 2002;88:46

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3068_5, Accepted for publication: 28 June 2005

Published Online: 03 August 2005

doi: 10.1185/030079905X56547

Lanny J. Rosenwasser(a), Terrence O’Brien(b) and Jonathan Weyne(c)

a Marjorie and Stephen Raphael Chair in Asthma Research, and Professor of Allergy and Immunology, National Jewish Medical and Research Center, Denver, CO, USA

b Professor of Ophthalmology, External Diseases and Cornea, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

c Clinical Assistant Professor, NYU Department of Ophthalmology, School of Medicine, New York, NY, USA

Address for correspondence: Jonathan S. Weyne, MD, 178 East 71st Street, New York, NY 10021, USA. Tel.: +1-212-650-0400; Fax: +1-212- 288-4223; email: [email protected]

Copyright Librapharm Sep 2005

By Combest, Wendell; Newton, Marian; Combest, Austin; Kosier, June Hannay

A recent and frequently cited survey of alternative medicine revealed that 42% of Americans use alternative therapies, with 12% of these therapies being the use of herbal supplements at a cost of $5 billion annually. Furthermore, 60% of people using alternative therapy do not report this information to their health care providers (Eisenberg, Davis, & Ettner, 1999). One problem with dietary supplement use is lack of consistent requirements for rigorous safety, efficacy, and purity testing resulting in varying amounts of active constituents from batch to batch.

Although herbal medicine use continues to grow in many disease conditions, the risk from use may over shadow potential benefit, especially in the renal compromised patient population (Foote & Cohen, 1998; Isnard et al., 2004). Vulnerable times for the renally compromised patient include predialysis, dialysis, and the post- renal transplant periods. They may also be confronting co-morbid dis ease states such as hypertension or diabetes. Renal patients may reach for additional therapy in the form of herbal dietary supplements because they experience adverse side effects or lack of efficacy from conventional medicines.

Plants with Known Direct Renal Toxicity

The most dramatic and highest profile case of herbal nephrotoxicity occurred from 1990-1992 in over 100 people in Belgium who ingested a Chinese weight loss/slimming remedy containing aristolochic acid principally from the plant Aristolochia fangchi (Vanherweghem et al., 1993). Seventy of these patients required renal transplants or dialysis and 30 subsequently developed urothelial carcinoma. In 2000, the FDA identified two new cases of interstitial renal fibrosis from aristocholic-containing herbal products. The resulting nephropathy is referred to as “aristolochic acid nephropathy” or less accurately “Chinese herb nephropathy.” Aristolochic acid is a nitrophenanthrene carboxylic acid which forms DNA adducts in renal as well as other tissues after metabolic activation (Volker, Stiborova, & Schmeister, 2002). The DNA adducts result in genotoxic mutations resulting in urothelial carcinoma as well as the characteristic renal interstitial fibrosis and extensive loss of cortical tubules. Aristolochic acid is found in several other plants particularly in the Asarum and Bragantia genera. Hundreds of additional cases have been reported in several European and Asian countries since these early reports in Belgium. The FDA has imposed strict guidelines to prevent any Chinese herbal products containing aristolochic acid from entering the U.S. market.

A similar type of nephropathy has been reported in the Balkans and has been termed “Balkan endemic nephropathy” (Tatu, Oren, Finkelman, & Feder, 1998). The causative agent in this type of nephropathy is plant products contaminated by the fungal mycotoxin ochratoxin A. It also forms mutagenic DNA adducts in renal tissue which likely underlies the observed pathology.

Many traditional medicines and foods especially in the tropical regions of Africa and Asia contain renal toxic plants. One such food/ medicine is the djenkol bean, a pungent smelling edible fruit of the hardwood tree Pithecellobium labatum (Areekul, Kirdudom, & Chaovanapricha, 1976). A 70% ethanol extract of the djenkol bean containing the toxic compound djenkolic acid was fed to monkeys, rats, and mice. Histologie examination of their kidneys showed severe tubular necrosis with a lesser degree of glomerular cell necrosis. A traditional remedy in South Africa called “Impila” is made from the roots of the plant Callilepis laureola. It is used to treat a number of conditions and has marked hepatic and renal toxicity. The renal damage caused is characterized by acute proximal convoluted tubule and loop of Henle necrosis which can lead to kidney failure (Stewart, Steenkamp, van der Merwe, Zuckerman, & Crowther, 2002).

There have been reports of acute renal failure in individuals ingesting wild mushrooms containing the nephrotoxin orellanine (Mount, Harris, Sinclair, Finlay, & Becker, 2002). Renal biopsy showed marked tubular interstitial nephritis and fibrosis. There has been one case report of acute renal failure in a patient with systemic lupus erythematosus taking the popular Peruvian herb cat’s claw (Uncaria tomentosa) (Hileps, Bellucci, & Mossey, 1997).

Herbs That May Alter Serum Potassium Or Contain Oxalic Acid

Several medicinal plants have the potential to alter plasma levels of potassium resulting in either hypokalemia or hyperkalemia. Licorice root (Glycyrrhiza glabra), especially when used at high doses and for prolonged periods, has a well-known pseudoaldosterone- like effect on the reabsorption of sodium and potassium (Stewart et al., 1987). Sodium retention is increased, potentially increasing blood pressure with a corresponding decrease in K+ leading to hypokalemia. Hypokalemia may in turn increase the toxicity of drugs such as digoxin by increasing its binding to cardiac membranes. The mechanism of this effect relates to glycyrrhizic acid in licorice root being hydrolyzed to glycyrrhetenic acid which is an inhibitor of renal 11-hydroxysteroid dehydrogenase. This enzyme catalyzes the inactivation of cortisol to cortisone. Cortisol accumulates in the kidney and stimulates the aldosterone receptors in cells of the cortical collecting duct thus increasing Na^sup +^ reabsorption (Funder, Pearce, Smith, & Smith, 1988).

Several herbal remedies taken as laxatives contain active compounds called anthraquinones. The laxative herbs senna (Senna alexandria), cascara sagrada (Rhamnus purshiana), and rhubarb (Rheum officinale) can lead to electrolyte imbalance especially hypokalemia (Westendorf, 1993). Another herbal supplement of possible concern to the renal patient is noni juice. Juice made from the noni fruit (Morinda citrifolia) could contribute to the development of hyperkalemia due to its high content of potassium (56.3 mEq/L) (Mueller, Scott, Sowinski, & Prag, 2000). Dandelion (Taraxacum officinale), stinging nettle (Urtica dioica), horsetail (Equisetum arvense), and alfalfa (Medicago sativa) are also high in potassium (Leung & Foster, 1996). Plants high in oxalic acid such as rhubarb (Rheum officinale) may increase the formation of kidney stones (Leung & Foster, 1996). There has also been a report of acute oxalate nephropathy following ingestion of star fruit (Averrhoa carambola) (Chen, Fang, Chou, Wang, & Chung, 2001).

Medicinal Plants with Diuretic Activity

These herbs may be of particular interest to patients pre- dialysis who believe that they may be able to stimulate their declining kidney function and thus delay the need for dialysis. The following herbs have traditional use as diuretics: juniper berry (Juniperus communis), parsley (Petroselinum crispum), dandelion (Taraxacum officinale), horsetail (Equisetum arvense), asparagus root (.Asparagus officinalis), lovage root (Levisticum officinale), goldenrod (Solidago virgaurea), uva ursi (Arctostaphylos uva ursi), stinging nettle leaf (Urtica dioica), and alfalfa (Medicago sativa) (Fetrow & Avila, 1999). These herbs with varying degrees of diuretic activity require caution even in healthy individuals but should be especially a concern for the renalcompromised patient. Most of these herbs should more accurately be called “aquaretics” in that they increase glomemlar filtration rate and urine output but do not stimulate electrolyte secretion. Some act as direct tubular cell irritants and others may alter serum electrolytes with resultant cardiovascular consequences.

Juniper berries contain terpine-4-ol in the volatile oil fraction which may cause kidney irritation and damage in excess (Newall, Anderson, & Pbillipson, 1996). In Germany, parsley and goldenrod are indicated for systemic irrigation of the urinary tract and for preventing kidney stones. The diuretic effect of parsley leaf and root is due to its volatile oil components myristicin and apiole (Newall et al., 1996). Also in Germany, dandelion, horsetail, and uva ursi are licensed as standard medicinal teas to stimulate diuresis.

Herbal Products Adulterated with Drugs And Heavy Metals

There have been many reports especially of Chinese and Ayurvedic herbal products containing nephrotoxic heavy metals such as lead, mercury, cadmium, and arsenic (Espinosa, Mann, & Bleasdell, 1995; Keen, Deacon, Delves, Moreton, & Frost, 1994; Wu, Hong, Lin, Yang, & Chien, 1996). To add to the complication, many heavy metals are considered medicinal in these medical systems but their presence in some imported formulations are not revealed on their labels. In addition some of these same herbal products contain pharmaceutical drugs. Formulations containing nonsteroidal anti-inflammatory drugs (NSAIDs) may lead to renal failure via changes in intrarenal blood flow. Another example is a case where a Chinese herbal formula contained the drug phenylbutazone which caused analgesic nephropathy (Segasothy & Samad, 1991). The California Department of Health Services recently screened 260 imported Asian patent medicines and found that 83 contained undeclared drugs or heavy metals (Marcus & Grollman, 2002).

Herbs and the Transplant Patient

The transplant patient is also at risk for complications from herbal remedies such as Echinacea (Echinacea purpurea), which is promoted as an immune system stimulant (Combest & Nemecz, 1997). This ef\fect could endanger the transplant patient taking immunosuppressant drugs. Furthermore, St. John’s wort (Hypericum perforation) causes a decrease in cyclosporine, an immunosuppressant, serum levels thus compromising the success of the organ transplant (Mandelbaum, Pertzborn, Martin-Facklam, & Wiesel, 2000). Although not yet demonstrated, many other herbal supplements may have a similar effect on the metabolism of cyclosporine as well as other drugs used to treat the transplant patient (see Table 1).

Table 1.

Nephro-Toxic Herbs and Dietary Supplements

Nephro-Protective Herbs and Dietary Supplements

Milk thistle (Silybum marianum) seeds containing several potent antioxidant flavonolignans collectively called silymarin have both hepatic and renal protective effects in rodent models (Combest, 1998). The main constituents composing silymarin are silibinin, silicristin, isosilibinin, and silidianin. Silibinin and silicristin, aside from their antioxidant effects against damaging free radicals, also stimulate RNA and protein synthesis which is important for renal and hepatic repair mechanisms. In addition these same flavonolignans protect kidney cells in culture from the renal toxic effects of the drugs paracetamol, cisplatin, and vincristine (Sonnenbichler, Scalera, Sonnenbichler, & Weyhenmeyer, 1999). Another study in rats demonstrated that silibinin protected renal tubular cells from the oxidative damage from cisplatin (Gaedeke, Pels Bokemeyer, Mengs, Stolte, & Lentzen, 1996). Silibinin also protects against experimental cyclosporine nephrotoxicity (Zima et al., 1998).

Table 2.

Nephro-Protective Herbs and Dietary Supplements

Another potentially useful nephro-protective medicinal herb popular in Ayurvedic medicine is picroliv (Picrorhiza kurrooa). Extracts from the roots and rhizomes offer protection against various hepatic and renal toxins. Picroliv protects the kidney in a renal ischemia-reperfusion induced injury (IRI) model in rats (Seth et al., 2000). Pretreatment of rats orally with picroliv for 7 days before initiation of experimental IRI lowered renal lipid peroxidation, reduced apoptosis, and generally increased the viability of renal cells. Another study in rats found that oral administration of picroliv to rats exposed to the carcinogen 1,2 dimethylhydrazine decreased the extent of renal necrosis [Rajeshkumar & Kutton, 2003). As with milk thistle animal studies using picroliv support their potential clinical benefit as nephro- protectants. However, human clinical studies are needed to confirm these results in cell culture and animal models.

Astragalus (Astragalus membranaceus), a popular herb used in Chinese traditional medicine, is effective against experimentally induced glomerulonephritis in rats, especially in reducing proteinuria (Su et al., 2000). Several clinical studies also showed a reduction in proteinuria in patients with chronic glomerulonephritis by Astragalus (Shi et al., 2002). Cordyceps (Cordyceps sinensis), a fungus found growing in caterpillar larvae of certain moths, has long been valued as a kidney tonic in China (Zhu, Halpern, & Jones, 1998). One study in 61 patients with lupus nephritis showed that a combination of 2 g to 4 g of cordyceps powder together with 0.6 grams of artemisinin from the plant Artemisia annua for 3 years improved kidney function as measured by creatinine clearance (Lu, 2002). Another study found that cordyceps lessened the nephrotoxicity of cyclosporine in kidney transplant patients (Xu, Huang, Jiang, Xu, & Mi, 1995). An antioxidant protective mechanism was postulated for this protective effect. The Japanese traditional remedy Sairei-to, a 12 herb mixture, has shown in human and animal studies to protect the kidney in gentamicin renal toxicity, IgA nephropathy, and lupus nephritis (Ohno et al., 1993). Another study in rats showed that extracts from the root of the plant Salvia miltiorriza (Danshen) along with fructose 1-6 diphosphate prevented the decline of renal cortical Na-K-ATPase activity induced by ischemia and gentamicin (Lu & Li, 1989). Further, extracts of the plant Herniaria hirsute inhibit calcium oxalate crystal aggregation and thus could be useful in preventing kidney stone formation (Atmani & Khan, 2000). In summary, there seems to be many potentially protective medicinal plants and supplements that may protect the kidney perhaps via acting primarily as anti-oxidants (see Table 2).

Nursing Care

The nurse may be one of the first members of the health care team to be approached by the patient using or contemplating the use of an herbal product for renal failure symptoms. The nurse should establish dialogue with patients regarding use of herbal supplements which affect the kidney. The nurse should be armed with information and legitimate Internet sources regarding the effect of dietary supplements on the kidney. As nurses, we want to be proactive during the routine history and physical and include questions such as “Tell me about any herbal supplements you may be using because we want to provide the safest care possible for you and need to know all medications and supplements you take. Some prescribed medications may interact with the supplements and some may affect kidney function.” The nurse should also have evidencebased herbal dietary supplement references to share with patients such as the Professional’s Handbook of Complementary and Alternative Medicines published by Amazon Books and the Natural Medicines Comprehensive Database available online and in print (Barrett, 2000). Table 3 lists interventions to facilitate safe care for renal patients using herbal dietary supplements.

Table 3.

Approaches to Facilitate Safe Care for Renal Patients Using Herbal Dietary Supplements

Conclusion

The increased patient use of alternative medicine requires the nurse to be aware of potential risks and benefits that alternative medicines may offer. Nephrotoxic plants containing aristolochic acid and djenkol bean must be avoided in all patients but especially in renal-compromised patients. Other herbal remedies such as licorice root, senna, cascara, and rhubarb may alter serum potassium values or increase the risk of kidney stones high in oxalic acid. Transplant patients must be made aware of the potential risk of complications from Echinacea and St. John’s wort as these medicinal plants may cause a decrease in the effect of immunosuppressant drugs. In summary, the nurse plays a vital role in monitoring the ingestion and effects of herbal supplements in the renal- compromised patient.

References

Areekul, S., Kirdudom, P., & Chaovanapricha, K. (1976). Studies on djenkol bean poisoning (djenkolism) in experimental animals. Southeast Asian Journal of Tropical Medicine and Public Health, 7(4), 551-558.

Atmani, F., & Khan, S.R. (2000). Effects of an extract from Herniaria hirsuta on calcium oxalate crystallization in vitro. BJU International, 85(6), 621.

Barrett, S. (2000). The herbal minefield. Retrieved June 17, 2005, from http://quackwatch.com/OlQuackeryRelatedTopics/ herbs.html

Chen, C.L., Fang, H.C., Chou, K.J., Wang, J.S., & Chung, H.M. (2001). Acute oxalate nephropathy after ingestion of star fruit. American Journal of Kidney Disease, 37(2), 418-422.

Cingliano, M., & Sun, A. (1998). Keeping safe with herbs: The 12 commandments. JAMA, 280, 1565-1566.

Combest, W.L., & Nemecz, G. (1997, October). Echinacea: This rediscovered American herb has shown efficacy as an important natural-immune-stimulator. US Pharmacist, 126-132.

Combest, W.L. (1998, October). Milk thistle. US Pharmacist, 86- 94.

Eisenberg, D.M., Davis, R.B., & Ettner, S.L. (1999). Trends in alternative medicine use in the United States. JAMA, 280, 1569- 1575.

Espinosa, E.O., Mann, MJ., & Bleasdell, B. (1995). Arsenic and mercury in traditional Chinese herbal balls. New England Journal of Medicine, 333, 803-804.

Fetrow, C.W., & Avila, J.R. (1999). Complementary and alternative medicine. Springhouse, PA: Lippincott Williams, & Wilkins.

Foote, J., & Cohen, B., (1998). Medicinal herb use and the renal patient. Journal of Renal Nutrition, 8(1), 40- 42.

Funder, J.W., Pearce, P.T., Smith, R., & Smith, A. (1988). Mineralocorticoid action: Target tissue specificity is enzyme, not receptor mediated. Science, 242(4878), 583-585.

Gaedeke, J., Pels, L.M., Bokemeyer, C., Mengs, U., Stolte, H., & Lentzen, H. (1996). Cisplatin nephrotoxicity and protection by silibinin. Nephrology, Dialysis, Transplantation, 11(1), 55-62.

Hileps, J., Bellucci, A., & Mossey, R. (1997). Acute renal failure caused by “cat’s claw” herbal remedy in a patient with systemic lupus erythematosus. Nephron, 77, 361.

Isnard Bagnis, C., Deray, G., Baumelou, A., Le Quintrec, M., & Vanherweghem, J.L. (2004). Herbs and the kidney. American Journal of Kidney Disease, 44(1), 1-11.

Keen, R.W., Deacon, A.C., Delves, H.T., Moreton, J.A., & Frost, P.G. (1994). Indian herbal remedies for diabetes as a cause of lead poisoning. Postgraduate Medical Journal, 70(820), 113-114.

Leung, A.Y., & Foster, S. (1996). Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York: John Wiley & Sons.

Lu, L. (2002). Study on the effect of cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis. Chinese Journal of Integrated Traditional and Western Medicine, 22, 169- 171.

Lu, P.M., & Li, S.Y. (1989). Effects of ADP and Danshen on renal cortical Na-K-ATPase activity in rats after treatment with renal ischemia and gentamicin. Chinese Medical Journal, 102(7), 516-523.

Marcus, D., & Grollman, A. (2002). Botanical medicines: The need for new regulations. New England Journal of Medicine, 347, 2073- 2076.

Mandelbaum, A., Pertzborn, F., Martin-Facklam, M., & Wiesel, M. (2000). Unexplained decrease of cyclosporine trough levels in a compliant renal transplant patient. Nephrology, Dialysis, Transplantation, 25(9), 1473-1474.

Mount, P., Harris, G., Sinclair, R., Finlay, M., & Becker, G.J. (2002). Acuterenal failure following ingestion of wild mushrooms. Internal Medicine Journal, 32(4), 187-190.

Mueller, B, Scott, M., Sowinski, K., & Prag, K.A. (2000). Noni juice (Morinda citrifolia): Hidden potential for hyperkalemia? American Journal of Kidney Disease, 35(2), 310-312.

Newall, C.A., Anderson, L.A., & Phillipson, A. (1996). Herbal medicines: A guide for health-care professional. London: The Pharmaceutical Press.

Ohno, I., Shibasaki, T., Nakano, H., Matsuda, H., Matsumoto, H., Misawa, T., et al. (1993). Effect of Sairei-to on gentamicin nephrotoxicity in rats. Archives of Toxicology, 67(2), 145-147.

Rajeshkumar, N.V. & Kutton, R. (2003). Modulation of carcinogenic response and antioxidant enzymes of rats administered 1,2 dimethylhydrazino by Picroliv. Cancer Letters, 191(2), 137-143.

Segasothy, M., & Samad, S. (1991). Illicit herbal preparation containing phenylbutazone causing analgesic nephropathy. Nephron, 59, 166-167.

Seth, P., Kumari, R., Madhavan, S., Singh, A.K., Mani, H., Banaudha, K.K., et al. (2000). Prevention of renal ischemiareperfusion-induced injury in rats by picroliv. Biochemical Pharmacology, 59(10), 1315-1322.

Shi, J.F., Zhu, H.W. Zhang, C., et al. (2002). Therapeutic effect of astragalus on patients with chronic glomerulonephritis. Acta Medicinalis secondae Shanghai, 22, 245-248.

Sonnenbichler, J., Scalera, F., Sonnenbichler, L, & Weyhenmeyer, R. (1999). Stimulating effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. Journal of Pharmacology and Experimental Therapeutics, 290(3), 1375-1383.

Stewart, P.M., Wallace, A.M., Valentino, R., Burt, D., Shackleton, C.H., & Edwards, C.R. (1987). Mineralocorticoid activity of licorice: 11 Beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet, 2(8563), 821-824.

Stewart, M.J., Steenkamp, V., van der Merwe, S., Zuckerman, M., & Crowther, NJ. (2002). The cytotoxic effects of a traditional Zulu remedy, irnpila (Callilepis laureola). Human & Experimental Toxicology, 21(12), 643-647.

Su, L., Chen, Y.C., Hu, J.D., et al. (2000). Comparisons between different doses of Astragalus membranaceus and Salvia miltiorrhiza in rats proteinuria. Chinese Journal of New Drugs and Clinical Remedies, 19, 205-208.

Tatu, C.A., Oren, W.H., Finkelman, R.B., & Feder, G.L. (1998). The etiology of Balkan endemic nephropathy: Sill more questions than answers. Environment Health Perspectives, 106(11), 689-700.

Vanherweghem, J.L., Depierreux, M., Tielemans, C., Abramowicz, D., Dratwa, M., Jadoul, M., et al. (1993). Rapidly progressive interstitial renal fibrosis in young women: Asociations with slimming regimen including Chinese herbs. Lancet, 342(8842), 387- 391.

Volker, M.A., Stiborova, M., & Schmeister, H. H. (2002). Aristolochic acid as a probable human cancer hazard in herbal remedies: A review. Mutagenesis, 17, 265-277.

Westendorf, J. (1993). Anthranoid derivatives in: Adverse effects of herbal drugs II (p. 105-118). Berlin, Heidelberg, Germany: Springer-Veerlag.

Wu, M.S., Hong, JJ., Lin, J.L., Yang, C.W., & Chien, H.C. (1996). Multiple tubular dysfunction induced by mixed Chinese herbal medicines containing cadmium. Nephrology, Dialysis, Transplantation, 22(5), 867-870.

Xu, R, Huang, J.B., Jiang, L., Xu, J., & Mi, J. (1995). Amelioration of cyclosporine nephrotoxicity by Cordyceps sinensis in kidney-transplanted recipients. Nephrology, Dialysis, Transplantation, 20(1), 142-143.

Zhu, J.S., Halpern.G.M., & Jones, K. (1998). The scientific rediscovery of an ancient Chinese herbal medicine: Cordyceps sinensis: Part I. Journal of Alternative and Complementary Medicine, 4, 289-303.

Zima, T., Kamenikova, L., Janebova, M., Buchar, E., Crkovska, J., & Tesar, V. (1998). The effect of silibinin on experimental cyclosporine nephrotoxicity. Renal Failure, 20(3), 471-479.

Wendell Combest, PhD, is a Professor of Pharmacology, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA.

Marian Newton, PhD, RN, PMHNP, is a Professor, Division of Nursing, and Adjunct Professor, Pharmacy, Shenandoah University and PMHNP, Northwestern Community Services, Winchester, VA.

Austin Combest, BS, is a Member of the Department of Biology, East Carolina University, Greenville, NC, and a Doctor of Pharmacy Student, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA.

June Hannay Kosier, MS, RN, CNN, is a Clinic Manager, Albany Regional Kidney Center, Albany, NY.

Copyright Anthony J. Jannetti, Inc. Oct 2005

NEW YORK (Reuters Health) – For children with kidney
failure who require dialysis, performing it at home at
nighttime seems to improve their overall sense of well-being, a
study shows.

Dialysis is a process by which waste products are removed
from the bloodstream when the kidneys are incapable of doing
so. Traditionally, patients requiring dialysis travel several
times per week to a clinic where the process can take upwards
of 5 hours.

The use of home nighttime dialysis was developed for adults
in 1994 and the use of this treatment has expanded in the adult
renal failure population, in whom it reportedly improves
dialysis delivery and patient well-being at reduced cost.

The current study suggests it’s a worthwhile option for
adolescents who require dialysis as well.

In the September issue of the Journal of Pediatrics,
Canadian researchers report on four teenagers who successfully
underwent dialysis at home for 8 hours, 6 to 7 nights per week.

The introduction of home nighttime dialysis to a patient’s
home is “a huge undertaking,” Dr. Denis F. Geary and colleagues
from the University of Toronto emphasize in their report.

“However, the improvement in clinical status, school
attendance and performance, which we have noted, and the small
but consistent improvement in quality of life reported by our
patients suggest that the outcomes justify the psychosocial
burden that (it) accompanies.”

The annual cost of home nighttime dialysis per patient was
$64,000 Canadian. This represents a 27 percent savings compared
with hemodialysis performed in a clinic three times per week.

SOURCE: Journal of Pediatrics, September 2005.

By Dr. Allen Douma

Q: Over the last few months I’ve become aware that my husband’s legs shake all night long. I think you wrote an article about this subject sometime in the past. If you did, would you send it to me by e-mail? I would be most appreciative.

— J.L.

A: Because of the large volume of letters and e-mails, I am unable to respond to readers individually. But because the problem you describe occurs often — more often than I think the medical profession realizes — I will write about it again now.

Your husband may have one of two syndromes: nocturnal (at night) myoclonus syndrome (NMS) or restless legs syndrome (RLS). In both, the major problem is not the leg movement but the impact on quality of life caused by lack of sleep for him and you.

Myoclonus is the medical term for the sudden contraction of a muscle or group of muscles. This is a neuromuscular problem. It can happen anywhere but is quite common in the legs.

Myoclonus may indicate an underlying seizure disorder like epilepsy.

Treatment begins by identifying a cause and eliminating it or treating it directly. When no definite cause is found, treatment is directed at reducing muscle activity just before going to bed.

Your husband can get some relief from mild stretching, hot baths, massage or tryptophan (as a supplement or in warm milk) just before bedtime.

Restless leg syndrome is one of a group of sleep disorders known as parasomnias. It affects up to one in six people over the age of 50. Often the symptoms are brought out when someone is under more stress.

The symptoms are jerky leg movements that may be preceded by creepy-crawly or electric current sensations. They worsen when someone is sitting or lying down and also worsen at night.

The primary cause is unknown, but many with the syndrome also have a family history of it. Secondary causes include iron deficiency anemia and peripheral neuropathy.

Pergolide has been used successfully for short-term treatment of restless leg syndrome.

Treatment of both these syndromes may require additional medications. For some, anticonvulsant medications, especially valproic acid, helps. For others, benzodiazepines (the family of drugs that contains Valium) are helpful. One of these, clonazepam, seems to be particularly helpful.

I recommend that you talk with your husband about his “shaky” legs and consider seeking advice from your doctor or a specialist (neurologist).

Update on significance: I am frequently frustrated by reporting in the medical press, even in the best medical journals, about treatments that are said to be significant.

As an example, consider a recent report in the Annals of Internal Medicine, one of the best medical journals. The study concluded that a drug called tiotropium reduces flare-ups in people with chronic lung disease.

However, the study actually found that 28 percent of men who used the drug daily for six months had flare-ups, while 32 percent of those using a placebo had flare-ups. Although this difference was judged unlikely to happen by chance alone (that is, the difference is “statistically significant”), the benefit to patients is certainly underwhelming.

Write to Allen Douma in care of Tribune Media Services, 2225 Kenmore Ave., Suite 114, Buffalo, NY 14207; or contact him at DRFamily(AT)aol.com. This column is not intended to take the place of consultation with a health-care provider.

BATON ROUGE, La., Oct. 13 /U.S. Newswire/ — Louisiana State University today announced that patient medical record data at Charity and University Hospitals was not destroyed during Hurricane Katrina and has been captured and stored electronically on a system called CLincal InQuiry, CLIQ.

CLIQ patient records, which contain a major subset of clinical information on many patients, can serve as clinically valuable information to assist providers who are now caring for displaced patients of Hurricane Katrina.

The LSU Health Care Services Division, which operates Louisiana’s public hospital system, is concerned about the health and continuity of care of its patients as they seek medical services elsewhere in Louisiana and other parts of the nation

“It is very important that the doctors at other facilities who have graciously taken in our patients know that these patient records are accessible,” said Dr. Dwayne Thomas, CEO of the Medical Center of LA in New Orleans. “We want to do everything we can to ensure continuity of care for our patients as they seek medical services in other areas of Louisiana.”

If you are a licensed medical provider seeing patients previously receiving care at the Medical Center of Louisiana in New Orleans, and for whom historical medical record information would be helpful in managing their care, please contact our patient medical record representative at 1-800-735-1185.

For more information please contact Marvin McGraw at 225-922- 1424.

——

The LSU Health Care Services Division hospital and clinic system is the largest provider of health care in Louisiana, with more than 1.2 million patient visits annually to 350 outpatient clinics, and 46,000 admissions to nine hospitals.

http://www.usnewswire.com

By Tewari, Mallika; Shukla, H S

The significance of breast tuberculosis is due to rare occurrence and mistaken identity with breast cancer and pyogenic breast abscess. Breast tuberculosis was scarcely reported even from endemic areas until lately when several reports have come up from South Africa and India. The incidence of tubercular mastitis although decreasing in the West, could show a resurgence with the global pandemic of AIDS. Breast tuberculosis has no defined clinical features. Radiological imaging is not diagnostic. Diagnosis is based on identification of typical histological features or the tubercle bacilli under microscopy or culture. Antitubercular therapy for 6 months with or without minimal surgical intervention forms the mainstay of treatment today. Over the years since the first description of tubercular mastitis in 1829, the incidence, clinical presentation, diagnostic and treatment methodology of breast tuberculosis has gradually changed. This review discusses the important issues relating to the diagnosis, clinical features, and management of breast tuberculosis.

Key words Breast tuberculosis – clinical presentation – diagnosis – treatment

Breast tuberculosis is a rare form of tuberculosis1,2. The first case of mammary tuberculosis was recorded by Sir Astley Cooper in 1829 who called it ‘scrofulous swelling of the bosom’3. A literature review by Morgan in 1931(4), revealed 439 cases of tubercular mastitis with the incidence between 0.5 and 1.04 per cent. In 1944, Klossner5 reported 50 cases of breast tuberculosis in women, out of 75,000 women with pulmonary tuberculosis with lung involvement. Of approximately 8,000 breast specimens studied, Haagensen6 reported only five cases of breast tuberculosis between 1938 and 1967. Only 500 cases were documented from the world literature by Hamit and Ragsdale in 19827. Since then, case reports and reviews have been published at infrequent intervals mostly in western literature.

Breast tuberculosis is rare in the western countries, incidence being

The incidence of tuberculosis, in general, is still quite high in India and so is expected of the breast tuberculosis. But the disease is often overlooked and misdiagnosed as carcinoma or pyogenic abscess12. Thus, reports on breast tuberculosis from India have been few. Less than 100 cases of breast tuberculosis were reported from India till 198713. The first 13 cases of breast tuberculosis from India were reported by Chaudhury in 195714 from 433 breast lesions studied by her. This was followed by several reports from different parts of India15-19. Several Indian series reported the incidence of breast tuberculosis amongst the total number of mammary conditions to vary between 0.64 and 3.59 per cent16,18. In our own series (unpublished data), we have found 30 cases of breast tuberculosis of the 1180 breast lesions examined in the past 20 yr giving an overall incidence of 2.5 per cent (Table I).

Routes of infection: Breast tissue is remarkably resistant to tuberculosis. This is due to the fact that, like skeletal muscles and spleen, it provides infertile environment for the survival and multiplication of tubercle bacilli18. The theory of secondary involvement of the breast from a tuberculous lesion at some other site, was supported by Raw20 and Morgan4. But, Mckeown and Wilkinson21 classified breast tuberculosis as primary when the breast lesion was the only manifestation of tuberculosis, and secondary when there was a demonstrable focus of tuberculosis elsewhere in the body. However, Vassilakos22 stated that primary breast tuberculosis was probably quite rare and was diagnosed because the clinician was unable to detect the true focus of the disease. Later on, breast tuberculosis was considered invariably secondary to a lesion elsewhere in the body. Primary form may rarely result from infection of the breast through abrasions or through openings of the ducts in the nipple.

The breast may become infected in a variety of ways21 e.g., (i) haematogenous, (ii) lymphatic, (iii) spread from contiguous structures, (iv) direct inoculation, and (v) ductal infection. Of these, the most accepted view for spread of infection is centripetal lymphatic spread18. The path of spread of the disease from lungs to breast tissue was traced via tracheobronchial, paratracheal, mediastinal lymph trunk and internal mammary nodes21. According to the Cooper’s theory, communication between the axillary glands and the breast results in secondary involvement of the breast by retrograde lymphatic extension23. Supporting this hypothesis was the fact that axillary node involvement was shown to occur in 50 to 75 per cent of cases of tubercular mastitis24. In our own series, ipsilateral axillary nodal involvement was present in 18 cases (60%) (Table I).

Table I. Cases of breast tuberculosis (n=30) of the 1180 breast lesions examined (between 1983 and 2003) in the Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Breast is resistant to tuberculous infection by blood stream, even in debilitated patients of tuberculosis21. Occasionally, direct extension from contiguous structures such as infected rib, costochondral cartilage, sternum, shoulder joint and even through the chest wall from a tuberculous pleurisy or via abrasions in the skin can occur5,26.

Coincidental tuberculosis of the faucial tonsils of suckling infants has been suggested as one of the common routes of spread of breast tuberculosis from the suckling infant to the nipple, and in turn, to the lactating breast via lacticiferous ducts19,27. In all cases, bacilli infected the ducts and spared the lobules. This may be the sole example of primary breast tuberculosis relevant even today.

Clinical presentation: The history of the presenting symptoms in breast tuberculosis is usually less than a year but varies from few months to several years17,18. Breast tuberculosis commonly affects women in their reproductive age group28, between 21-30 yr, similar to the highest incidence of pulmonary tuberculosis reported in the same age group of females29. This may be because the female breast undergoes frequent changes during the period of activity and is more liable to trauma and infection18. In pregnant and lactating women, the breast is vascular with dilated ducts, predisposed to trauma making it more susceptible to tubercular infection13,28. It is uncommon in prepubescent females and elderly women7. Breast tuberculosis is rare in males30 and is reported in about 4 per cent of cases4. Bilateral involvement is uncommon (3%)13.

Breast tuberculosis most commonly presents as a lump19,31 in the central or upper outer quadrant of the breast29. It is probably due to frequent extension of tuberculosis from axillary nodes to the breast. Multiple lumps are less frequent16. The lump is often indistinguishable from carcinoma breast being irregular, hard and at times, fixed to either skin or muscle or even chest wall28. But the lump is usually painful. Breast remains mobile unless involvement is secondary to tuberculosis of the underlying chest wall13.

Tubercular ulcer over the breast skin and tubercular breast abscess with or without discharging sinuses are other common forms of clinical presentation of breast tuberculosis29. Peau d’ orange is often seen in patients with extensive axillary nodal tuberculosis. Purulent nipple discharge or persistent discharging sinus may be the rare presenting feature. Twenty two of the 30 patients in our present series presented with lump in the breast, 11 of these had tubercular ulcer and 4 had multiple discharging sinuses in the overlying breast skin (Table I).

Classification of breast tuberculosis: Breast tuberculosis was first classified into five different types by Mckeown and Wilkinson21: (i) Nodular tubercular mastitis, (ii) Disseminated or confluent tubercular mastitis, (iii) Sclerosing tubercular mastitis, (iv) Tuberculous mastitis obliterans, and (v) Acute miliary tubercular mastitis. Since then this classification has been followed though the clinical scenario of breast tuberculosis lias gradually changed over the years.

The nodulocaseous form of breast tuberculosis presents as a well circumscribed, slowly growing painless mass (es) that progresses to involve the overlying skin, may ulcerate, form sinuses and may become painful. In early stage it is difficult to differentiate from a fibroadenoma, while at later stages it mimics a carcinoma32,33. Sixteen of 20 patients of Dubey and Agarwal17 were found to have nodular tubercular mastitis and only 2 had sclerosing tuberculous mastitis. All four cases reported by Dharkar et al16 had nodular variety. Similarly, Mukerjee et al.18 found 9 of the 14 cases with nodulocaseous variety and 3 had sclerosing tuberculous mastitis. Other reports also indicated that the nodulocaseous variety was still the commonest form of breast tuberculosis24,28,34.

Few reports described disseminated form of breast tuberculosis2428. It is characterized by multiple foci throughout the breast that later caseate leading to sinus formation. The overlying skin is thickenedand stretched with or without painful ulcers. The breast may be tense and tender. The draining axillary lymph nodes are enlarged and matted28. The sclerosing variety finds mention in old literature usually affecting involuting breasts of older females. Excessive fibrosis rather than caseation is the dominating feature. There is a hard painless slow growing lump with nipple retraction. Suppuration is rare. It may be misdiagnosed as a scirrhotic carcinoma28. Often the entire breast becomes hard because of dense fibrous tissue.

Tuberculous mastitis obliterans as described by Mckeown and Wilkinson21 is characterized by duct infection producing proliferation of lining epithelium and marked epithelial and periductal fibrosis. The ducts are occluded and cystic spaces are produced resembling ‘cystic mastitis’. In acute miliary tubercular mastitis breast disease is a part of a generalized miliary tuberculosis. However, no case of breast tuberculosis was found in a post-mortem series of 34 patients with miliary tuberculosis18 and is of little clinical significance21.

With the changes seen in presentation of tuberculosis over the period of time, miliary tuberculosis is rare today. Moreover, there are hardly enough reports in the past two decades to merit the sclerosing tubercular mastitis, tuberculous mastitis obliterans and acute miliary tubercular mastitis in the classification of breast tuberculosis.

Table II. New proposed classification of breast tuberculosis

Tubercular breast abscess is often a common mode of presentation of breast tuberculosis, especially in young women. In a review of benign breast disorders in India, Shukla and Kumar29 found tubercular breast abscess to be a common presentation of breast tuberculosis. In our series we found eight patients presented with a fluctuant breast abscess (Table I).

Thus at present, breast tuberculosis may be reclassified as nodular, disseminated and abscess varieties. The sclerosing type, mastitis obliterans and miliary variety are of historical importance only (Table II).

Diagnosis: Breast tuberculosis is mostly misdiagnosed and the patient is often subjected to numerous investigations before a definitive diagnosis is made. It warrants a high index of suspicion on clinical examination and pathological or microbiological confirmation of all suspected lesions.

(i) Mantoux test – This test is usually positive in adults in endemic area for tuberculosis. It simply demonstrates that at some point of time the person was exposed to tubercle bacilli. It is, therefore of no diagnostic value for breast tuberculosis and today stands obsolete.

(ii) Radiological investigations – The modern radiological investigations help in defining the extent of the lesion rather than in diagnosis. Sophisticated radiological tools like mammography, computed tomography (CT-scan) and magnetic resonance imaging (MRI) of the breast have been extensively explored for the diagnosis of breast tuberculosis but of no avail. The chest X-ray may show evidence of active or healed tuberculous lesion in the lungs in a few cases18, and may also reveal clustered calcifications in the axilla suggesting the possibility of lymph node tuberculosis in suspected patients29.

The mammogram in breast tuberculosis is of limited value as the findings are often indistinguishable from carcinoma breast28,34. The mammographie picture of nodular tuberculosis is usually of a dense round area with indistinct margins seen without the classic halo sign found in fibroadenoma34. The mammographie size of the tuberculous lesion correlates well with its clinical size, unlike that of a carcinoma28. Disseminated variety mimics inflammatory carcinoma and the radiographs show dense breast with thickened skin34. Sclerosing tubercular mastitis reveals a homogenous dense mass with fibrous septa and nipple retraction13,28,35,36. However, as breast tuberculosis is found in young women of 20-40 yr of age, dense breasts makes interpretation of mammogram difficult. Moreover, this facility might not be available and economical to many patients from the less developed world where the disease is very common.

Ultrasonography of the breast is cheap, easily accessible and helps in characterizing the lesion better (especially cystic from solid lesions) without exposure to radiation34. In nodular form of the disease, lesions are either hypoechoic with ill-defined margins or complex cystic masses. In diffuse breast tuberculosis, ill- defined hypoechoic masses are seen whereas in patients with sclerosing breast tuberculosis, increased echogenecity of the breast parenchyma often with no definite mass is seen3437. At times, a beak like fistulous connection between retromammary abscess and thoracic wall is seen in sonogram36. Ultrasound-guided fine needle aspiration decreases the failure rate and obviates the need for multiple punctures34,35. The mammographic and sonographic features of tubercular mastitis as stated by a recent study38 include a mass lesion mimicking malignant tumours (30%), smooth bordered masses (40%), axillary or intramammary adenopathy (40%), asymmetric density and duct ectasia (30%), skin thickening and nipple retraction, macrocalcification (20% each), and skin sinus ( 10%). On ultrasound, 60 per cent had hypoechoic masses, 40 per cent focal or sectorial duct ectasia, and 50 per cent axillary adenopathy38.

CT scan seldom adds to the diagnostic yield other than in defining the involvement of thoracic wall in patients presenting with deeply adhered breast lump39. Tubercular breast abscess may be seen as smoothly marginated, non homogeneous, hypodense lesion with surrounding rim on contrast CT. A direct fistulous tract with the pleura or a destroyed rib fragment in the abscess can also be seen40. Percutaneous drainage of a tubercular breast abscess under CT guidance is feasible39. CT can show area(s) of lung destruction beneath the pleural disease39,41, and is a valuable tool in demonstrating the extent of disease, in planning of surgery and also in assessment of response to treatment.

MRI of the breast may reveal a smooth or irregular bright signal intensity lesion on T2-weighted images suggesting a breast abscess. Again the findings are non specific and reports on MRl of the breast suggest its usefulness only in demonstrating the extramammary extent of the lesion37,40,41.

(iii) Fine needle aspiration cytology – Fine needle aspiration cytology (FNAC) from the breast lesion continues to remain an important diagnostic tool of breast tuberculosis2. Approximately 73 per cent cases of breast tuberculosis can be diagnosed on FNAC when both epitheloid cell granulomas and necrosis are present2. Failure to demonstrate necrosis on FNAC does not exclude tuberculosis in view of small quantity of the sample harvested and examined. The demonstration of acid-fast bacilli (AFB) on FNAC is not mandatory, since for AFB to be seen microscopically, their number must be 10,000-100,000/ml of material42. In tubercular breast abscess, FNAC may be inconclusive and the FNA picture may be dominated by acute inflammatory exudates. AFB-negative breast abscess that fail to heal despite adequate drainage and antibiotic therapy, and those with persistent discharging sinuses should raise suspicion of underlying tuberculosis. Biopsy of the abscess wall and demonstration of characteristic histological features or culture are essential to confirm the diagnosis of breast tuberculosis2,24.

(iv) Culture – Though mycobacterial culture remains the gold standard for diagnosis of tuberculosis, the time required and frequent negative results’ in paucibacillary specimens are important limitations. Moreover, culture is not always helpful in the diagnosis of breast tuberculosis431. During the last two decades several rapid techniques for detection of early mycobacterial growth (5-14 days as compared to 2-8 wk with conventional methods) have been described43 which helped in obtaining the culture and sensitivity reports relatively early. Prominent among such methods are BACTEC, mycobacterial growth indicator tube (MGIT), Septi-chek, MB/BacT systems43.

(v) Polymerase chain reaction (PCR) – Gene amplification methods (PCR as well as isothermal) developed for the diagnosis of tuberculosis are highly sensitive especially in culture-negative specimens from paucibacillary forms of disease. A variety of PCR techniques have been developed for detection of specific sequences of Mycobacleriiiin tuberculosis and other mycobacteria. PCR has positivity rates ranging from 40 to 90 per cent in diagnosing tubercular lymphadenitis43. PCR in the diagnosis of breast tuberculosis is less often reported, mostly as a tool to distinguish tubercular mastitis from other forms of granulomatous mastitis in selected reports44. However, PCR is by no means absolute in diagnosing tubercular infection and false negative reports are still a possibility43.

Most of these new techniques are too expensive and sophisticated to be of any practical benefit to the vast majority of TB patients living in underdeveloped countries like India for whom an early and inexpensive diagnosis remains as elusive as ever.

(vi) Histopathology of the specimen – Histological findings include epithcloid cell granulomas with caseous necrosis in the specimen. Core needle biopsy yields a good sample often yielding a positive diagnosis. However, open biopsy (incision or excision) of breast lump, ulcer, sinus or from the wall of a suspected tubercular breast abscess cavity almost always confirms breast tuberculosis2,28.

Histologically, tubercular mastitis is a form of granulomatous inflammation. There are many other conditions that are characterized histologically by a tuberculoid type of tissue reaction. These conditions include sarcoidosis, various fungal infections, and granulomatous reactions to altered fatty material. Sometimes the microscopical picture is indistinguishable from that of tuberculosis25.

Bre\ast tuberculosis versus carcinoma breast: Clinical examination often fails to differentiate carcinoma breast from tuberculosis and high index of suspicion is necessary. Factors predictive but not diagnostic of breast tuberculosis include constitutional symptoms, mobile breast lump, multiple sinuses, and an intact nipple and areola13 in young, multiparous or lactating females28. Nipple retraction, peau d’orange, and involvement of axillary lymph nodes are more common in malignancy than in tuberculosis. Mammography is not of much help as the findings in carcinoma in advanced stage are similar to that of tubercular lesion28,36.

Carcinoma and tuberculosis of the breast occasionally co-exist. Similar finding in the axillary lymph nodes may also be seen6,10. In assessing diagnosis it is therefore important to remember that recognition of tuberculosis does not exclude concomitant breast cancer.

Treatment: The treatment of breast tuberculosis consists of anti- tubercular chemotherapy (ATT) and surgery with specific indications.

ATT is the backbone of treatment of breast tuberculosis45. No specific guidelines are available for the chemotherapy of breast tuberculosis per se. The regimen generally followed in the treatment of breast tuberculosis is similar to that used in pulmonary tuberculosis1,27. Extrapulmonary tuberculosis except for tubercular meningitis, can be treated with 6 months regimens comprising two months of intensive phase treatment (with 4-drug combination) followed by a continuation phase of 4 months (with 2-drug combination). The first line drugs being ethambutol (E) 1200 mg; streptomycin (S) 750 mg, rifampicin (R) 450 mg, isoniazid (H) 600 mg and pyrazinamide (Z) 1500 mg. The Revised National Tuberculosis Control Programme (RNTCP) of India recommends category III regimen (2HRZ/4HR) for less serious forms of extrapulmonary tuberculosis viz., lymph node tuberculosis, cutaneous tuberculosis, unilateral pleural effusion, and category I regimen (2EHRZ/4HR) for more severe forms of extrapulmonary tuberculosis. Drugs are administered thrice weekly46. The World Health Organization has recommended a 4-drug intensive phase (2EHRZ) in category III iegimen as well. Patients resistant to standard 4-drug ATT will require second-line ATT drugs47. Local streptomycin has been claimed to be useful16. The overall prognosis is good with adequate medical treatment13.

Multilating surgey like simple mastectomy for breast tuberculosis was in vogue in the past with the belief that the lesion tends to persist and reappear with conservative treatment even with chemotherapy27. However, today minimal surgical intervention is required for drainage of breast abscess or biopsy from the abscess wall, scraping of sinuses in the breast, incisional or excisional biopsy13,19,28. Small lesions are eminently treatable by an excision biopsy followed by a full course of ATT28. Residual lump following ATT may require surgical removal. Simple mastectomy with or without axillary clearance is rarely required for extensive disease comprising large, painful ulcerated mass involving the entire breast and draining axillary lymph nodes rendering organ preservation impossible28. For concomitant breast cancer, the form of surgery is dependant upon the stage of breast cancer.

In our series, FNAC was positive in 11 patients, core needle biopsy in 2, and an open biopsy was required in 17 patients. All 8 patients of tubercular breast abscess responded to repeat aspiration in conjunction with ATT. All patients were treated with ATT (2EHRZ/ 7HR) for a total of 9 months, and were free of recurrence in 12 to 200 months of follow up. Simple mastectomy was performed in one patient who defaulted after initial diagnosis and returned with a large ulcerated breast lesion and matted axillary nodes (Table I).

Conclusion

Extrapulmonary tuberculosis occurring in the breast is extremely rare. Breast tuberculosis is uncommon even in countries where the incidence of pulmonary and extrapulmonary tuberculosis is high. In the abscence of well-defined clinical features, the true nature of the disease remains obscure and it is often mistaken for carcinoma or pyogenic breast abscess. It also presents a diagnostic problem on radiological and microbiological investigations and thus high index of suspicion acquires an important position. Caseating epitheloid cell granulomas in the tissue samples are diagnostic of tuberculosis. The disease is eminently curable with the modern antitubercular cliemotherapeutic drugs with surgery playing a role in the background only.

References

1. Kalac N, Ozkan B, Bayiz H, Dursun AB, Demirag F. Breast tuberculosis. Breast 2002; 11 : 346-9.

2. Kakkar S. Kapila K, Singh MK, Verma K. Tuberculosis of the breast. A cytomorphologic study. Ada Cytol 2000; 44 : 292-6.

3. Cooper A. Illustrations of the diseases of the breast. Part I. London: Longman, Rees, Orme, Brown and Green; 1829 p.73

4. Morgan M. Tuberculosis of the breast. Surg Gynecol Obstet 1931; 53 : 593-605.

5. Klossner AR. Uber die Brustdrusentuberculose. Eine pathologisch-anatomische und klinische studie. Acta Chir Scand 1944; 90 (Suppl 85) : 1-181.

6. Haagensen CD. Infections in the breast. In: Haagensen CD, (ed). Diseases of the breast. 3rd ed. Philadelphia: WB Saunders; 1986 p. 384-93.

7. Hamit HF, Ragsdale TH. Mammary tuberculosis. JR Soc Med 1982; 75 : 764-5.

8. O’Reilly M, Patel KR, Cummins R. Tuberculosis of the breast presenting as carcinoma. Mil Med 2000; 165 : 800-2.

9. O-Marri MR, Almosleh A, Almoslmani Y. Primary tuberculosis of the breast in Qatar: ten year experience and review of the literature. Eur J Surg 2000; 166 : 687-90.

10. Fujii T, Kimura M, Yanagita Y, Koida T, Kuwano H. Tuberculosis of axillary lymph nodes with primary breast cancer. Breast Cancer 2003; 10 : 175-8.

11. Verfaillie G, Goosscns A, Lamotc J. Atypical mycobacterium breast infection. Breast J 2004; 10 : 60.

12. Green RM, Ormerod LP. Mammary tuberculosis: rare but still present in the United Kingdom. Int J Tuberc Lung Dis 2000; 4 : 788- 90.

13. Banerjee SN, Ananthakrishnan N, Mehta RD, Prakash S. Tuberculous mastitis: a continuing problem. World J Surg 1987; 11 : 105-9.

14. Chaudhary M. Tuberculosis of the breast. Br J Dis Chest 1957; 51 : 195-9.

15. Gupta RS, Roy R. Tuberculous disease of the breast. Indian J Surg 1960; 22 : 576-9.

16. Dharkar RS, Kanhere MH, Vaishya ND, Baisarya AK. Tuberculosis of the breast. J Indian Med Assoc 1968; 50 : 207-9.

17. Dubey MM, Agravval S. Tuberculosis of the breast. J Indian Med Assoc 1968; 51 : 358-9.

18. Mukerjee P, George M, Maheshwari HB, Rao CP. Tuberculosis of the breast. J Indian Med Assoc 1974; 62 : 410-2.

19. Gupta R, Gupta AS, Duggal N. Tubercular Mastitis. Int Surg 1982; 67 : 422-4.

20. Raw N. Tuberculosis of the breast. Br Med J 1924; J : 657-8.

21. Mckeown KC, Wilkinson KW. Tuberculous diseases of the breast. Br J Surg 1952; 39 : 420.

22. Vassilakos P. Tuberculosis of the breast: cytological findings with fine-needle aspiration. A case clinically and radiologically minicking carcinoma. Acta Cytol 1973; 17 : 160-5.

23. Domingo C, Ruiz J, Roig J, Texido A, Aguilar X, Morera J. Tuberculosis of the breast: a rare modern disease. Tubercle 1990; 71 : 221-3.

24. Sharma PK, Babel AL, Yadav SS. Tuberculosis of breast (study of 7 cases). J Postgrad Med 1991; 37 : 24-6.

25. Symmers St. WC. The Breasts. In: W St C Symmers, editor. Systemic pathology. 2nd ed. vol. 4. New York: Churchill Livingstone; 1978 p. 1759-1861.

26. Hale JA, Peters GN, Cheek JH. Tuberculosis of the breast: rare but still exist. Review of the literature and report of an additional case. Am J Surg 1985; 150 ; 620-4.

27. Wilson TS, MacGregor JW. The diagnosis and treatment of tuberculosis of the breast. Can Med Assoc J 1963; 89 : 1118-24.

28. Shinde SR, Chandawarkar RY, Deshmukh SP. Tuberculosis of the breast masquerading as carcinoma: a study of 100 patients. World J Surg 1995; 19 : 379-81.

29. Shukla US. Kumar S. Benign breast disorders in nonwestern populations: Part U – Benign breast disorders in India. World J Surg 1989; 13 : 746-9.

30. Jaideep C, Kumar M. Klianna AK. Male breast tuberculosis. Postgrad Med J 1997; 73 : 428-9.

31. Alagaratnam TT, Ong GB. Tuberculosis of the breast. Br J Surg 1980: 67: 125-6.

32. Graunsman RI, Goldman ML. Tuberculosis of the breast-report of nine cases including two cases of co-existing carcinoma and tuberculosis. Am J Surg 1945; 67 : 48.

33. Inoue Y, Nishi M, Hirose T. Tuberculosis of the breast – a case which could not be mammographically distinguished from breast cancer. Rinsho Hoshasen 1986; 31 : 321-2.

34. Popli MB. Pictorial essay: tuberculosis of the breast. Indian J Radiol Imag 1999; 9 : 127-32.

35. Schnarkowski P, Schmidt D. Kessler M, Reiser MF. Tuberculosis of the breast: US, mammographic, and CT findings. J Comput Assist Tomogr 1994; 18 : 970-1.

36. Makanjuola D. Murshid K, Al Sulaimani S, Al Saleh M. Mammographic features of breast tuberculosis: the skin bulge and sinus tract sign. Clin Radiol 1996; 51 : 354-8.

37. Oh KK, Kim JH, Kook SH. Imaging of tuberculous disease involving breast. Eur Radiol 1998; 8 : 1475-80.

38. Sakr AA, Fawzy RK, Fadaly G, Baky MA. Mammographie and sonographic features of tuberculous mastitis. Eur J Radial 2004; 51 : 54-60.

39. Romero C, Carreira C, Cereceda C, Pinto J, Lopez R, Bolanos F;. Mammary tuberculosis: percutaneous treatment of a mammary tuberculous abscess. Eur Radiol 2000; 10: 531-3.

40. Bhatt GM, Austin HM. CT demonstration of empyema necessitates. J Coinput Assist Tomogr 1985; 9 : 1108-09.

41. Chung SY, Yang I, Bae SH, Lee Y, Park HJ, Kim HH, et al. Tuberculous abscess in rctromammary region: CT findings. J Comput Assist Tomogr 1996; 20 : 766-9.

42. Pagel W, Simmonds FAH, Macdonald J, Nassau E. Pulmonary Tuberculosis. 4th ed. London: Oxford University Press; 1964 p. 245.

43. Katoch VM. Newer diagnostic techniques for tuberculosis. Indian J Med Res 2004; 120 : 418-28.

44. Tse GM, Poo\n CS, Ramachandram K, Ma TK, Pang LM, Law BK, et al. Granulomatous mastitis: a clinicopathological review of 26 cases. Pathology 2004; 36: 254-7.

45. Elmrabet F, Ferhati D, Amenssag L, Kharbach A, Chaoui A. Breast tuberculosis. Med Trop (Mars) 2002; 62 : 77-80.

46. Jawahar MS. Current trends in chemotherapy of tuberculosis. Indian J Med Res 2004; 120 : 398-417.

47. Kumar P, Sharma N. Primary MDR- TB of the breast. Indian J Chest Dis Allied Sci 2003; 45 : 63-5.

Mallika Tewari & H.S. Shukla

Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Received November 22, 2004

Reprint requests: Dr H.S. Shukla, 7 SKG Colony, Lanka, Varanasi 222005, India

e-mail: [email protected]

Copyright Indian Council of Medical Research Aug 2005

By Chawadee Nualkhair

SUNGAI KOLOK, Thailand (Reuters) – Along with the
ubiquitous cans of soda and packets of noodles, the mom-and-pop
stores of violence-plagued southern Thailand are selling
tickets to a new life.

For 5 baht, the stubs of paper buy a 30-second boat ride
across a narrow river to Malaysia — the land of opportunity
for young Muslims wanting to escape 21 months of unrest in
Thailand’s three southernmost provinces.

As the death toll climbs above 900 and the local economy
collapses, young Muslims see little point in staying behind to
get caught up in an increasingly dirty guerrilla conflict
between separatist militants and more than 30,000 soldiers and
police.

“People here worry about three things. Where will the
authorities arrest me? When should I leave? How will I die?”
said Abdulrahman Abdulsahad, president of the Islamic Council
of Narathiwat province, 750 miles south of Bangkok.

The fear is taking its toll on youngsters in Narathiwat and
the neighboring provinces of Yala and Pattani, once an
independent sultanate where Muslims now say they feel like
second-class citizens.

“I am definitely going to move,” said Sobri, a 22-year-old
Muslim university student in Pattani who wants to further his
studies in Malaysia. “If you don’t agree with the government,
you are their enemy.”

The mainly Buddhist administration in Bangkok has poured
troops into the region, where 80 percent of the 1.8 million
population are Muslim, ethnic Malay and non-Thai speaking, but
has failed to halt the daily bombings and shootings.

The presence of so many Buddhist troops is also fueling
local Muslim resentment, leading to fears they are actually
exacerbating the situation, rather than calming it.

“It’s like the government has two kids: one who is good in
school and one who has been naughty,” said Fakhruddin Boto, a
Muslim senator in Narathiwat.

“If you constantly reprimand the naughty boy, tell him he
is worthless, what will that naughty boy turn out to be when he
grows up?”

SLIPPING ABROAD

For many Muslims, the rules to staying alive are simple but
stifling — do not eat at a restaurant or tea shop frequented
by the police or soldiers; be wary of venturing out at night
after evening prayers; arrange weddings and funerals for
daylight hours.

For some, however, such precautions are not enough.

Last month, a group of 131 Muslims, half of them women and
children, sparked a diplomatic row with Kuala Lumpur when they
fled to northern Malaysia seeking refuge from what they said
was persecution by Thai security forces.

Bangkok denies its army or police would ever intimidate
Muslims, but such a large exodus exposed the reality that some
southern Muslims feel scared enough to seek political asylum.

No one knows how many others have slipped quietly over the
notoriously porous border to a new life in Malaysia, but the
problem appears widespread.

“Many of my students are leaving,” said Abdulrahman, the
Narathiwat religious leader.

SINGING A NEW TUNE

Sobri, an economics major who used to live in Bangkok, play
in a rock band and drink alcohol, felt his world turning upside
down the day he visited the grieving relatives of dozens of
Muslims who died in army custody last year.

It was one of the bloodiest incidents in the conflict.
Security forces fired on Muslim protesters, killing seven
people and detaining hundreds more, stacking them like logs in
the back of army trucks for the long journey to an army base.
During the trip, 78 Muslims died of suffocation.

Since then, Sobri has cut his hair and is singing a new
tune.

“If I didn’t have my education, my schooling to fall back
on, yes, absolutely, I would pick up a gun and fight,” he said
during a night out with friends at a tea shop on the outskirts
of Pattani, a provincial capital.

“If they’re pointing a gun at me and threatening to shoot,
do you think I should give them flowers? That’s crazy.”

Like many of his peers, Sobri, who would not give his full
name for fear of persecution by police, says leaving is the
only option in a society that is slowly but surely falling
apart.

“The rift is not between Buddhists and Muslims,” said
27-year-old Amin, who helps run a youth development program in
Pattani. “It’s more of a lack of trust between authorities and
the people who live here.”

Patchiya Pimanman, who runs an Islamic school in
Narathiwat, is more blunt: “Do you want to stop the unrest? Get
rid of the soldiers.”

Others, however, are determined to stay. Fah, a 21-year-old
Muslim university student, wants to become a civil servant.

“I do get frustrated sometimes. When I watch the news, I
want to scream. They are always exaggerating and reporting
propaganda,” she said. “But Pattani is my home, regardless of
what happens.”

By Cotton, Ann Beemer

Wounds in patients on dialysis require specific nutrition for proper healing and to control the effects of kidney failure. Nutrients, such as zinc, arginine, and vitamins A and C, are important to wound healing but undergo altered metabolism from kidney failure, dialysis and/or dialysis-related medications. A team approach that provides appropriate nutrition as well as infection control and pressure relief is required to achieve wound healing in the patient on dialysis.

Patients on dialysis acquire wounds from the longterm effects of diabetes and vascular disease, surgical procedures, and with the loss of skin integrity from immobility. Chronic foot and leg ulcers are common and often difficult to heal. Malnutrition is frequently observed and, coupled with the inflammation of wound healing; specific needs arise where the renal diet and nutrition related to wound healing must be meshed. Adequate calories and protein are needed but certain nutrients, vitamins A and C as well as zinc and arginine, although important to wound healing, require special consideration in the patient on dialysis.

A team approach that uses nutrition, pressure relief, and infection control is essential to the wound healing process. An initial wound evaluation should be done with periodic reassessment. Good communication between the RN, RD, MD, and social worker is critical to achieve healing and improve quality of life for the patient.

Vitamin A

Retinoic acid, a form of vitamin A, mediates the DNA transcription of several growth factors essential to the wound healing process (Wicke, Halliday, Alien, & Roche, 2000). Vitamin A also assists with collagen crosslinking and re-epithelization. In renal failure vitamin A metabolism changes as retinol binding protein (RBP), the carrier for vitamin A or retinol, is no longer degraded by the kidney. Normally serum retinol rises as binding sites increase, however, inflammatory states such as wound healing can also depress RBR Osteolytic activity with hypercalcemia may occur if available binding sites are exceeded with the use of supplemental vitamin A (Farrington, Miller, Varghese, Baillod, & Moorhhead, 1981; Fishbane, Frei, Finger, Dressier, & Silbiger, 1995). No vitamin A other than that provided in diet should be given unless the usual intake is less than two-thirds of the Dietary Reference Intake (DRI) (Chazot & Kopple, 1997), or the serum retinol:serum RBP ratio is less than 0.4 (Cundy, Earnshaw, Heynen, & Kanis, 1983). Then, vitamin A should be supplemented at the level of the DRI, 900 meg per day for 7 to 10 days (Chazot & Kopple, 1997).

Vitamin C

The hydroxylation of prolyl and lysyl hydrolases in collagen crosslinking during wound healing is vitamin C dependent. Doses of 1000 to 2000 mg of vitamin C per day are frequently given to support this activity, however, the recommendation for the patient on dialysis is not to exceed 150 mg (Costello, Sadovnic, & Cottingham 1991). Most renal vitamins supply 60 to 100 mg of vitamin C.

The dose of vitamin C in renal vitamins was established to correct for dialysis losses and limit oxalate generation. Vitamin C is an oxalate precursor that is excreted in the urine with normal renal function but is retained in the dialysis patient, increasing the likelihood of soft tissue calcification (Ono, 1986; Pru, Eaton, & Kjellstrand, 1985). The short-term risk of calcification with higher doses of vitamin C must be weighed against the needs of wound healing.

Although usually considered an antioxidant, vitamin C also has pro-oxidant activity that presents another issue with its use in dialysis patients. When provided at high doses, vitamin C will penetrate the ferritin molecule. Iron is then reduced to its ferrous state and lost as free or redox iron into the serum (Herbert, Shaw, & Jayatileke, 1995). This has been used in EPO blockade with 300 mg or more of vitamin C given intravenously during dialysis (Gastadello, Vereerstraeten, Nzame-Nze, Vanherweghem, & Tielemens, 1995; Tarng & Huang, 1998). Iron is freed with an improvement in hematocrit, but a rise in oxidative stress parameters has also been noted. Vitamin E provided orally or incorporated into the dialyzer membrane can alleviate oxidative stress in the dialysis patient receiving IV iron (Handelman, 2003; Roob et al., 2000). Perhaps a more appropriate dose of vitamin C is 250 mg to support wound healing while adding 200 to 400 IU of vitamin E to control for oxidative stress effects.

Zinc

Cellular immunity is dependent on zinc and essential to wound infection control. Metallothionein is a zinc-binding protein produced on wound edges as a zinc reservoir to support the synthesis of the over 200 zinc-dependent enzymes within the wound matrix (Lansdowne, 2002, Ravanti & Kahari, 2000). With an abundance of zinc- containing enzymes in wound fluid, it can be expected that high drainage wounds incur significant zinc losses.Those dialysis patients with high output ostomies and/or enterocutaneous fistulas will incur zinc losses in addition to that from wound drainage.

Zinc is greater than 90% protein bound in the serum, primarily to albumin. Therefore, serum zinc is not a good indicator of zinc status when inflammatory conditions such as wounds are present (Galloway, McMillan & Sattar, 2000). A better measure is an assessment of dietary intake in conjunction with the consideration to any wound and/or gastrointestinal losses. Most high protein foods are good sources of zinc so if protein intake has been poor, then zinc status is likely poor. Zinc sulfate provides 50 mg of elemental zinc in 220 mg and should be provided for 2 to 3 weeks for repletion then returning to an intake in the DRI range of 8 to 11 mg/day.

Arginine

In stress, such as wound healing, the amino acid arginine becomes semi-essential with demand out running supply (Witte & Barbul, 2003). Arginine is not directly a building block in tissue synthesis but rather a precursor. Via nitric oxide synthase and arginase, arginine is metabolized to nitric oxide, polyamines, and proline which facilitate wound healing (Frank, Kampfer, Wetzler, & Pfeilschifter, 2002).

Dietary intake is the primary source of arginine, amounting to 5 to 6 grams per day in a well-tolerated diet. The intestinal-renal axis, the only route for de novo arginine synthesis, is lost in dialysis dependency worsening the potential arginine deficit. However, hyperkalemia has been noted in the patient on dialysis with intakes of 30 grams or more of arginine per day (Zaloga, Siddiqui, Terry, & Marik, 2004). A safe dose achieved from diet and arginine- enhanced oral or enterai feedings appears to be about 20 grams per day in the patient on dialysis. The available arginine-enhanced products also contain supplemental vitamin A and C that needs to be accounted for in the cumulative intake of these vitamins.

Calories and Protein

The nitrogen needs of wound healing can be met with a protein intake of 1.2 to 2.0 grams per day. Higher protein intakes should be used for more serious stage 3 and 4 wounds. Current dialysis technology can provide the clearance to match the potential urea generation from a higher protein intake. An adequate energy intake in the range of 30 to 35 kcal/kg will also provide protein-sparing effect and promote positive nitrogen balance (Kopple, 2001).

Achieving a sufficient intake of calories and protein may require more than one feeding route. When the dietary intake consumed fails to meet calorie and protein needs, supplemental enterai feedings may be indicated. Persistent gastrointestinal symptoms such as vomiting and/or diarrhea that do not respond to pharmaceutical and/or diet intervention may require parenteral nutrition.

Conclusion

Wounds can be a debilitating, lifestyle limiting morbidity for the patient on dialysis. Treatment requires attention to nutrition, pressure relief, and infection control. Failure to address one or more of these three areas will result in chronic, nonhealing wounds. However, the expertise in these areas is available from the patient’s dialysis team and should be used to heal and rehabilitate the patient.

References

Chazot, C. & Kopple, J. (1997). Vitamin metabolism and requirements in renal disease and renal failure. In Kopple, J. & Massry, S.G. (Eds.), Nutritional management of renal disease. Baltimore, MD: Williams and Wilkens.

Costello, J.F., Sadovnic, MJ. & Cottingham, E.M. (1991). Plasma oxalate levels rise in hemodialysis patients despite increased oxalate removal. Journal of the American Society of Nephrology, 1, 1289-1298.

Cundy, T., Earnshaw, M., Heynen, G., & Kanis, J.A. (1983). Vitamin A and hyperparathyroid bone disease in uremia. American Journal of Clinical Nutrition, 38, 914-920.

Farrington, K., Miller, P., Varghese, Z., Baillod, R.A., & Moorhead, J.F. (1981). Vitamin A toxicity and hypercalcemia in chronic renal failure. British Medical Journal, 282, 1999-2002.

Fishbane, S., Frei, G.L., Finger, M., Dressler, R., & Silbiger, S. (1995). Hypervitaminosis A in two healthy hemodialysis patients. American Journal of Kidney Disease, 25, 346-349.

Galloway, P., McMillian, D.C., & Sattar, N. (2000). Effect of inflammatory response on trace element and vitamin status. Annals of Clinical Biochemistry, 37, 289-297.

Gastadello, K., Vereerstraeten, A., Nzame-Nze, T., Vanherweghem, J.L., & Tielemans, C. (1995). Resistance to erythropo\ietin in iron- overloaded hemodialysis patients can be overcome by asacorbic acid administration. Nephrology Dialysis Transplantation, W, 44-47.

Handelman, GJ. (2003). Current studies on oxidant stress in dialysis. Blood Purification, 21, 46-51.

Herbert, V, Shaw, S., &Jayatileke, E. (1995). Vitamin C driven free radical generation from iron. Journal of Nutrition, 126, 1213- 1218.

Lansdown, A.B. (2002). Metallothioneins: Potential therapeutic agents aids for wound healing in the skin. Wound Repair and Regeneration, 10, 130-132.

Ono, K. (1986). secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clinical Nephrology, 26, 239-243.

Pru, C., Eaton, J. & Kjellstrand, C. (1985). Vitamin C and hyperoxalemia in chronic hemodialysis patients. Nephron, 39, 112- 116.

Raventi, L. & Kahari, VM. (2000). Matrix metalloproteinases in wound repair, International Journal of Molecular Medicine, 6, 391- 407.

Roob, J.M., Khoschsorur, G., Tiran, A., Horina, J.H., Holzer, H., & Winkelhofer-Roob, B.M. (2000). Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. Journal of the American Society Nephrology, 11, 539-49.

Tarng, B.C., & Huang, T.P. (1998). A parelllel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anemia in hemodialysis patients with iron overload. Nephrology Dialysis Transplantation, 13, 2867-2872.

Wicke, C., Halliday, B., Allen, D., & Roche, N.S. (2000). Effects of steroids on wound healing. Archives of Surgery, 135, 12651270.

Witte, M.B., & Barbul, A. (2003). Arginine physiology and its implication for wound healing. Wound Repair and Regeneration, 11, 419-423.

Zaloga, G.P., Siddiqui, R., Terry, C., & Marik, P.E. (2004). Arginine: Mediator or modulator of sepsis. Nutrition in Clinical Practice, 75,201-219.

Ann Beemer Cotton, MS, RD, is Clinical Dietitian in Transplant, Methodist Hospital, Indianapolis, IN.

Copyright Anthony J. Jannetti, Inc. Sep/Oct 2005

By Eberhardie, Christine

Summary

Over-the-counter food supplements and herbal medicines are a growth industry in the UK and are now regulated under European Union (EU) directives 2002/46/EC, 2004/24/EC and 2004/27/EC (European Parliament and Council of the European Union 2002, 2004a, 2004b). In practice, the use of food supplements and herbal medicines should be considered in association with the individual’s diet, medical history and prescribed treatments, especially drug therapy, since interactions with drugs can be dangerous and even fatal in some cases. As members of the interprofessional team, nurses can play a key role in identifying problems through careful assessment and prevention by health education.

Keywords

Alternative therapies; European Union; Law; Nutrition and diet

These keywords are based on the subject headings from the British Nursing Index. This article has been subject to double-blind review. For related articles and author guidelines visit our online archive at www.nursing-standard.co.uk and search using the keywords.

THERE ARE a variety of definitions for food supplements and herbal medicines in the international literature (World Health Organization (WHO) 2000). Food supplements are sometimes also referred to as dietary supplements (US Food and Drug Administration 1994, Office of Dietary Supplements 2004). Until 2002 the term ‘food supplement’ had no clear definition in the European Union (EU) and the industry was poorly regulated. There was confusion in this growth industry which, in the UK alone, was valued at 335 million in 2000 (Mintel 2001). Extravagant claims were made for the healing properties of a variety of vitamins and minerals and regulation came under the Trades Description Act 1968, the Food Safety Act 1990 and the Food Labelling Regulations (amended) Act 1996. Food supplements and herbal medicines were therefore not subject to the same stringent regulations as prescribed medicines.

There was considerable concern in medical and scientific nutritional circles worldwide about insufficient rigour in establishing the safe dosage of food supplements and herbal medicines, safe manufacture and side effects and interactions with pharmaceutical medicines (Barnes 2003, Ferner and Beard 2005). At the same time, the differences in availability of these products throughout the EU were leading to confusion for the consumer and inequality in the market. It was decided that EU directives controlling the market would result in safer food supplements and herbal medicines throughout the EU (European Commission 2001, Medicines Control Agency (MCA) 2002).

The Food Supplements directive (2002/46/EC) came into force on August 1 2005 and the acts implementing the Traditional and Herbal Medicines directives (2004/24/EC and 2004/27/EC) will come into force on October 30 2005 (European Parliament and Council of the EU 2002,2004a, 2004b). Along with the EU Clinical Trials directive (2001/20/EC) (European Parliament and Council of the EU 2001), they will affect nurses who are carrying out research into herbal medicines and food supplements, and those who practise relevant complementary therapies such as optimum nutrition therapy or herbal medicine.

In EU directive 2004/24/EC there was also recognition that many modern pharmaceutical drugs had been developed originally from plant sources and that some have a well-established safety record as well as proven efficacy. To ensure that a traditional herbal medicine product is recorded on the approved list the applicant has to give written evidence of its ‘medicinal use throughout a period of at least 30 years preceding the date of the application, including at least 15 years within the European Union’ (EU Directive 2004/24/EC Article 16c/1c) (European Parliament and Council of the EU 2004a).

To the lay person the situation remains confused at present and it is in this context that patients are at risk. Is it better to take a supplement? Are supplements safe? If not, what are the risks?

Box 1 outlines some of the reasons that patients may take food supplements and herbal medicines.

Food supplements directive

The EU directive for the regulation of food supplements is 2002/ 46/EC. It defines food supplements as ‘foodstuffs the purpose of which is to supplement the normal diet and which are concentrated source of nutrients or other substances with a nutritional or physiological effect, alone or in combination marketed in dose form, namely forms such as capsules, pastilles, tablets, pills and other similar forms, sachets of powder, ampoules of liquids, drop dispensing bottles and other similar forms of liquids and powders designed to be taken in measured small unit quantities’ (EU Directive 2002/46/EC Article 2).

In accordance with the directive, the four countries of the UK have drawn up national regulations based on the EU directives. They are similar and the English regulations, for example, are the Food Supplements (England) Regulations 2003 (The Stationery Office 2003).

The directive came into force on August 1 2005. In the past three years the food supplements industry has had the opportunity to adopt the required changes and submit safety dossiers to the European Food Safety Authority (EFSA) for supplements which they consider are safe to produce and sell but which are not on the ‘positive list’ – the list of approved food supplements and their active ingredients. The directive prohibits the sale of all vitamins and minerals not on the positive list and ensures that supplements are sold to the consumer in a prepackaged form with appropriate labelling. The Food Standards Agency Expert Group on Vitamins and Minerals (EVM) (2003) has produced a comprehensive survey of the safe upper limits of vitamins and minerals, which will inform national upper limits of vitamins and minerals in the future. Some examples of the information currently available are shown in Table 1.

However, there is still further work to be done on drug-nutrient and nutrient-nutrient interactions with daily users of supplements who have a high vitamin and mineral content in their diet.

Herbal Medicines directive

Herbal medicines are now subject to EU directives on traditional herbal medicinal products (2004/24/EC) and medicinal products for human use (2004/27/EC) and many will be unavailable for purchase after October 30 2005, for example, 1,000mg and above doses of vitamins such as vitamin C, and minerals such as boron, tin, nickel, silicon and cobalt. A medicinal product is defined in the directive as: ‘a) any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or b) any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis’ (2004/2 7/EC Article 1).

Chemical and microbiological contamination during the production of herbal medicines on a large scale have been major issues (EFSA Scientific Committee 2004). Some Chinese herbal medicines have been mixed with synthetic chemicals including heavy metals (Ernst 2002, EFSA Scientific Committee 2004).

Another concern is the extent to which the concentrations of an active ingredient are consistent, in other words, whether each drop or pill contains the same concentration of the active ingredient (MCA 2002). The directive seeks to ‘harmonise’ legislation and regulation throughout the EU.

Both directives have been controversial, especially among those who favour high-dose vitamin therapy. The Alliance for Natural Health (2005) believes that modern farming methods and Western lifestyles have so depleted the soil that we must take supplements to have a healthy body. However, organisations which produce or promote herbal medicines, such as the Herb Society (2005), have acknowledged that EU directive 2004/27/EC provides a legal basis for these substances for the first time and so has prevented herbal medicines being taken off the market. Herbal medicines have been safeguarded in the EU legislation but manufacturers have to be more rigorous with regard to ingredients, packaging, labelling and advertising.

BOX 1

Patients’ reasons for taking food supplements and herbal medicines

The role of the nurse

The public should have clear definitions and factual information on food supplements and herbal medication. The producers of food supplements and traditional herbal medicines should acknowledge the actual and potential dangers of over-promotion of products in isolation from other dietary and therapeutic factors and the effects of misleading advertising. It is here that the nurse can play a key role in the assessment of the patient because legislation alone will not prevent the potential dangers of vitamins, minerals and herbal medicines when taken inappropriately. Danger occurs when there is interaction between any one or more of these substances (Sorensen 2002, De Smet 2004).

TABLE 1

Examples of vitamin and mineral dosages and the effects of deficiency and overdosage

Holistic and detailed assessment of patients can aid the prevention of ill health and promote wellbeing. Assessment should take account of the patient’s daily diet related to lifestyle, age and activity, prescribed and over-the-counter medicines, food supplements and complementa\ry therapy nutrients, botanicals and other products, such as ointments and oils which can be absorbed into the bloodstream.

Some of the concerns that patients may have can be met by ensuring a good, healthy balanced diet and an examination of lifestyle. Nurses can help by giving advice on healthy eating, and non-pharmacological therapies such as relaxation, counselling, massage and exercise, which will not only prevent illness and disability but reduce the risk of depression and poor quality of life. Supplements, medicinal remedies and drugs are not the only option for many patients and other options should be discussed and information provided. Some patients may benefit from being referred to a dietician.

Nurses should inform patients of the potential dangers of self- medication and of mixing different medicinal approaches to address a health problem. There is a need to be cautious about food supplements and herbal medicines without condemning them. Patients should be asked to inform medical staff of any over-the-counter pharmaceutical or herbal medicines and food supplements they are already taking. They should be encouraged to discuss any proposed new remedies or supplements with the GP before taking them.

The risks

Even when supplements or herbal medicines are well manufactured and given at a safe dose, it is important to find out if the patient is taking a prescribed medication to assess the risk of interaction. This is particularly important in multicultural settings and as a result of international travel. In some parts of Europe and the wider world herbal medicines are used more frequently than in the UK.

In a UK study of 2,723 pre-operative patients, anaesthetists Skinner and Rangasami (2002) found that 4.8 percent were taking one or more herbal medicines such as garlic, ginseng, ginkgo biloba, St John’s wort and echinacea. All of these substances can ha ve a peri or post-operative effect. Garlic, ginseng and ginkgo biloba can all increase the risk of bleeding. Some examples of common food supplements and herbal remedies, and their interactions with drugs are outlined in Table 2.

St John’s wort reduces the plasma levels of prescribed drugs such as indinavir, cyclosporin and digoxin. Patients who are HIV- positive should not take St John’s wort but if they have, they should stop and have their HIV viral load checked. St John’s wort also interacts with, among others, warfarin, digoxin, carbamazepine, phenobarbital, phenytoin and oral contraceptives. In all of these cases, St John’s wort reduces the blood levels of the prescribed drug. It should be stopped immediately if the patient is taking oral contraceptives or antidepressive triptans such as sumatriptan or selective serotonin reuptake inhibitors (SSRIs) (Committee on the Safety of Medicines 2000). St John’s wort should not be taken with, or within two weeks of having taken, SSRIs such as citalopram or fluoxetine because it can cause an increase in serotonin. Excess serotonin can cause tremor, altered mental state and other unpleasant side effects (Haller 2004). Taken on its own St John’s wort is a mild antidepressant.

Conclusion

Many food supplements and herbal remedies are taken quite safely by the public even when there is no scientific proof of their efficacy. Herbal remedies and over-the-counter food supplements may not in themselves be dangerous but mixed with other nutrients or medicines they can create metabolic imbalance, toxic effects and/or impairment of treatment efficacy (MCA 2002). More research is needed in the light of the new regulations and nurses should take a lead in the assessment and evaluation of such therapies. To this end, the WHO research guidelines may be helpful (WHO 2000)

TABLE 2

Examples of common food supplements and herbal remedies and drug interactions

Eberhardie C (2005) Food supplements and herbal medicines. Nursing Standard. 20, 3, 52-56. Date of acceptance: August 16 2005.

References

Alliance for Natural Health (2005) www.alliance-natural- health.org/ (Last accessed: September 2 2005.)

Barnes J (2003) Quality, efficacy and safety of complementary medicines: fashions, facts and the future. Part 1. Regulation and quality. British Journal of Clinical Pharmacology. 55, 3, 226-233.

Committee on the Safety of Medicines (2000) Important Safety Information for People Taking St John’s Wort Preparations. http:// medicines.mhra.gov.uk/ ourwork/monitorsafequalmed/ safetymessages/ sjwfsp.pdf (Last accessed: September 15 2005.)

De Smet PAGM (2004) Health risks of herbal remedies: an update. Clinical Pharmacology and Therapeutics. 76, 1, 1-17

Department of Health (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom, Report of the Panel on Dietary Reference Values of the Committee on Medical Aspects of Food Policy. Report on Health and Social Subjects 41. HMSO, London.

Ernst E (2002) Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. Journal of Internal Medicine. 252, 2, 107-113.

European Commission (2001) Discussion Paper on Nutrition Claims and Functional Claims. http://europa.eu.int/comm/food/foo d/ labellingnutrition/claims/claims_ discussion_paper.pdf (Last accessed: August 25 2005.)

European Food Safety Authority Scientific Committee (2004) Botanicals and Botanical Preparations widely used as Food Supplements and Related Products: Coherent and Comprehensive Risk Assessment and Consumer Information Approaches. EFSA/SC/26 Discussion Paper. EFSA, Brussels.

European Parliament and Council of the European Union (2001) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal of the European Communities. 1 May 2001, L121/34-L121/44.

European Parliament and Council of the European Union (2002) Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements. Official Journal of the European Communities. 12 July 2002, L183/51-L183/57.

European Parliament and Council of the European Union (2004a) Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal of the European Union. 30 April 2004, L136/85-L136/90.

European Parliament and Council of the European Union (2004b) Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal of the European Union. 30 April 2004, L136/34-L136/57.

Ferner RE, Beard K (2005) Regulating herbal medicines in the UK. British Medical Journal. 331, 7508, 62-63.

Food Standards Agency Expert Group on Vitamins and Minerals (EVM) (2003) Safe Upper Limits for Vitamins and Minerals. Food Standards Agency, London.

Haller CA (2004) St John’s wort, depression, and catecholamines. Clinical Pharmacology and Therapeutics. 76, 5, 393-395.

Herb Society (2005) A Guide to the EU Traditional Herbal Medicines Directive and its Possible Implications, www.herbsociety.co.uk/legislation.htm (Last accessed: August 26 2005.)

Mason P (Ed) (2001) Dietary Supplements. Second edition. Pharmaceutical Press, London.

Medicines Control Agency (2002) Safety of Herbal Medicinal Products. www.mca.gov.uk/ ourwork/licensingmeds/herbalmeds/ herbsafejuly2002.pdf (Last accessed: August 25 2005.)

Mintel (2001) Complementary Medicines: Market Intelligence. Mintel International, London.

Office of Dietary Supplements (2004) Dietary Supplements: Background Information. http://ods.od.nili.gov/factsheets/ DietarySupplements_pf.asp (Last accessed: September 2 2005.)

Skinner CM, Rangasami J (2002) Preoperative use of herbal medicines: a patient survey. British Journal of Anaesthesia. 89, 5, 792-795.

Sorensen JM (2002) Herb-drug, food-drug, nutrient-drug and drug- drug interactions: mechanisms involved and their medical implications. Journal of Alternative and Complementary Medicine. 8, 3, 293-308.

The Stationery Office (2003) Food Supplements (England) Regulations 2003. Statutory Instrument 2003 No. 1387. The Stationery Office Books, London.

US Food and Drug Administration (1994) Dietary Supplement Health and Education Act of 1994 Public Law 103-417103rd Congress. www.fda.gov/opacom/laws/ dshea.html (Last accessed: August 25 2005.)

Vogler BK, Pittler MH, Ernst E (1999) The efficacy of ginseng. A systematic review of randomised clinical trials. European Journal of Clinical Pharmacology. 55, 8, 567-575.

World Health Organization (2000) General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine. WHO, Geneva.

Author

Christine Eberhardie is senior lecturer in nursing, Faculty of Health and Social Care Sciences, Kingston University and St George’s, University of London, London. Email: [email protected]

Copyright RCN Publishing Company Ltd. Sep 28-Oct 4, 2005

By Mary Powers powers@commercialappealcom

School’s back in session. The holidays are just ahead.

Gas prices are surging. The Mid-South’s largest utility is warning of heating bills up as much as 70 percent this winter.

And, don’t forget public health experts advice that American adults get 60 to 90 minutes of exercise. Every day.

It’s enough to send anyone searching for an energy boost .

Enter vitamin B12.

Despite continuing skepticism in some medical circles, B12 shots remain a favorite among the frazzled and weary.

We need B12 for normal nerve function and red blood cell production. It also plays a role in making the genetic material DNA found in nearly every cell.

Too little B12 is linked to a form of anemia, the nerve damage known as neuropathy and a long list of symptoms that include balance and memory problems, fatigue, depression and the confusion known as dementia.

But federal nutritional surveys found most American children and adults get the recommended amounts of B12 in their diet. B12 is found naturally in meat, fish, eggs and dairy products. It’s also available in fortified cereal and other food.

Yet plenty of us are apparently wondering if we might benefit from a dash more.

Kaye Ivanoff, of The Shot Nurse, said B12 shots are extremely popular with men and women. The Memphis company offers B12 injections, vaccinations and other services on a walk-in basis at its office at 4646 Poplar, Suite 100, or on location at area companies. “There is a percentage of people who will benefit from B12, even if their lab work doesn’t indicate a deficiency,” she said.

“I get a lot of questions about it,” said Dr. Allison Stiles, a Memphis doctor specializing in internal medicine and pediatric care.

Stiles had a long list of folks who might benefit from some extra B12.

Most are candidates because the vitamin is missing from their diets or they are less able to absorb it because of medications or health problems.

Her list includes vegetarians, pregnant women, those battling alcoholism, the AIDS virus or certain immune disorders.

Other candidates are individuals taking medicine to block stomach acid, those who underwent gastric bypass surgery for weight loss or older patients, especially those who have endured decades of indigestion.

All are at risk for B12 shortfalls because the vitamin requires stomach acid and proteins from the pancreas to help the body digest and absorb the vitamin.

The diabetes drug Metformin can also interfere with B12 metabolism.

Missing from Stiles’s list are healthy adults. “Normal young folks would not benefit from the shots,” she said.

It would likely be tough convincing Jennifer Moreau, 33, of Germantown.

She’s a single mother with two pre-school children and a full- time job as a sales assistant in the investment department of AM South Bank.

She credits the monthly B12 shots she’s gotten for the past year through The Shot Nurse with helping her manage stress, sleep better and increase her energy.

“The first month I didn’t really notice anything. By the second month I was sleeping better. The shot kind of keeps you on an even keel,” she said.

She said she started the injections “thinking what could it hurt? Now I’ve worked it into my budget.” The shots cost $20 each.

Diane Lawton, 46, works in customer service at the same East Memphis bank branch.

She was looking not for more energy, but relief from migraine headaches , when she started getting B12 shots several years ago.

Since then she’s gone from two or three migraines per month to just occasional headaches. “If I have a headache every once in a while, that’s OK,” she said. Lawton said the B12 injections didn’t increase her energy.

Both women said they haven’t made other changes in their work or home lives that would explain their increased energy or decreased headaches.

Although Moreau and Lawton aren’t his patients, Dr. Ray Walker said he’s heard similar testimonials from those who are.

“Many people say they feel better,” said Walker, a family practice physician and a University of Tennessee Health Science Center associate professor.

But so far the evidence to support such reports is sparse, he said. Walker said the placebo effect, in which a patient’s confidence in a treatment affects the outcome, is one possible explanation.

When patients ask about B12, Judi Harrick’s likely to recommend a B complex supplement that includes the other B vitamins, such as B2 and B6.

Harrick is a founder of the Healing Arts Medical Group, which combines traditional and alternative medicine. Her credentials include national certification as an acupuncturist.

“We push concentrating on foods that are rich in B vitamins,” she added.

She and others said there’s no evidence B vitamins supplements pose a health risk. “The body will take what it needs and pee off the rest,” she explained.

Stiles said she screens some patients, particularly older patients, for B12 deficiencies. She’ll recommend a nasal spray or injection for patients who have B12 levels at the low edge of normal and balance or nerve problems that might have a B12 link.

Reversing symptoms linked to B12 shortfalls often takes months, she added.

Both Stiles and Walker said if patients want a B12 shot, they’ll provide it.

A fact sheet from the National Institutes of Health’s Office of Dietary Supplements noted that older individuals are more likely than their children or grandchildren to develop B12 deficiencies.

“As a general rule, most individuals who develop a vitamin B12 deficiency have an underlying stomach or intestinal disorder that limits the absorption” of the vitamin, the NIH background sheet noted.

It cited insufficient information and side-stepped making a recommendation about B12 supplments for younger adults. It said better tools and standards are needed for diagnosing B12 deficiencies.

——————–

How much B12 do folks need and where can they find it?

Fish, meat, poultry, eggs and dairy products are all good sources of vitamin B12. Here is a sample of how those sources compare.

Type of Food / Amount per serving* / Percent of recommended daily amount** /

100 percent fortified cereal, cup / 6 / 100 /

Salmon, 3 oz. cooked / 4.9 / 80 /

Sirloin, broiled, 3 oz. / 2.4 / 40 /

Fast food cheeseburger, double patty / 1.9 / 30 /

Canned tuna, 3 oz. / 1 / 15 /

Milk, 1 c. / 0.9 / 15 /

Egg / 0.6 / 10 /

Source: National Institutes of Health Office of Dietary Supplements

*micrograms per serving

**Developed by the federal Food and Drug Administration

——————–

Recommended shots for adults

Even adults who aren’t interested in B12 shots, will sometimes need shots. Here are the three most commonly recommended adult vaccines.

Influenza: Federal health officials recommend a flu shot annually beginning at age 50 or for anyone who is pregnant, battling chronic illness, provides patient care or cares for or lives with an infant younger than 6 months old. The shots are offered at public and private clinics, physician offices, churches and businesses. They are free to qualified Medicare patients. Others should expect to pay at least $17.

Pneumococcal pneumonia: Designed to prevent a bacterial infection that’s responsible for the most common type of pneumonia, the shot is recommended for adults battling chronic diseases like diabetes or lung problems. Check with a doctor about a booster shot after age 65. It’s recommended at age 65 for healthy adults. The vaccine’s available at area clinics and physician offices. Expect to pay at least $30.

Tetanus-diphtheria: A shot is recommended at least every 10 years. A booster might be recommended after five years following an injury or for someone traveling internationally. It is widely available. Expect to pay at least $40.

– Mary Powers

By Nita Bhalla

FERNEY VALLEY, Mauritius (Reuters) – Nestling at the foot
of Mauritius’s east coast Bambous mountains, Ferney Valley is a
thick canopy of lush vegetation, hiding some of the world’s
rarest plants and animals within its depths.

Soaring ebony trees draped with lianas, orchids and vines
dominate fragrant forests where endangered tropical birds fill
the air with shrieks and squawks and spring waters feed unique
flora and fauna.

Unchanged since the first European settlers arrived more
than 400 years ago, Ferney Valley is one the last remaining
indigenous forests on the Indian Ocean island.

However, environmentalists say the forest is under threat
as construction gets under way to build a highway through it,
primarily to service the island’s lucrative tourism industry.

“Given the tiny amount of good quality tropical forest
remaining on Mauritius, this development can only be viewed as
catastrophic to the native biodiversity,” says Achim Steiner,
director-general of the World Conservation Union.

The aim of the 25-km (16-mile) South Eastern Highway is
primarily to promote tourism, by providing a shorter route from
the airport to east coast resorts for the thousands of visitors
who flock to palm-fringed Mauritian beaches every year.

Tourism is a key economic pillar for the tiny island of 1.2
million people, host to more than 700,000 tourists a year.

LONG AND WINDING ROAD

With sugar and textile exports threatened by liberalised
trade laws, the island wants to fully exploit its tourism
sector which generated 23,448 million rupees last year — a
20.8 percent rise compared with the previous year.

“At the moment there is only one main road from the airport
along the east coast, which is a long, winding and often
congested and unsafe route,” says Sadruddin Diljore, divisional
manager of the Road Development Authority.

“The new highway will provide a better alternative route
and will support productive sectors of the economy and promote
tourism.”

Opponents of the $19 million project, funded by the African
Development Bank, argue that the government could upgrade the
existing coastal route or investigate alternative routes which
will save Ferney Valley and benefit poor local communities.

About 60,000 people live in fishing villages on the east
coast, yet the area remains one of the island’s most
under-developed, with low incomes and high unemployment.

“If the existing road was upgraded or another route going
through the villages was considered it could benefit local
people who could set up cafes, shops and restaurants,” said
George Ah Yan, president of the Mahebourg Citizens Welfare
Organization, a local community group.

“No one stays in Ferney Valley, so it would not benefit
anyone to put a road there,” he adds.

However, the government says upgrading the existing road
would mean a costly relocation of communities, adding that
abandoning the Ferney Valley route would incur contractual
penalties of $1 million — a hefty sum for a country with a
budget deficit of five percent of gross domestic product.

NOISE, LITTER, FUMES

Since the first Europeans arrived on the island in 1598,
the natural habitat has gradually been devastated by human
habitation, the introduction of alien plants and animals, sugar
cane cultivation and tourism.

Only 1.6 percent of the original forests remain and the
World Conservation Union has ranked Mauritius, off East
Africa’s coast, as having the third most endangered flora in
the world.

Scientists estimate more than 100 endemic plant and animal
species are now extinct, including the island’s most famous
symbol, the dodo, a large, flightless bird which became extinct
in the late 17th century because of over-hunting and habitat
destruction.

Other extinct species include bats, reptiles, and birds
such as the solitaire and the Mauritius blue-pigeon. The island
has more threatened species per unit of area than any other
country.

Environmentalists say Ferney Valley is vital for the
survival of threatened flora and fauna and is home to six
species of critically endangered trees, including the Eugenia
Bojeri, Pandanus Macrostigma, Pandanus Iceryi — trees assumed
extinct until their discovery a few months ago.

The forest is also home to half the world’s population of
Mauritius kestrels, once the world’s rarest bird. From near
extinction in the 1970s, its population has grown to almost
1,000 as a result of a captive breeding programme in Ferney
Valley.

Authorities say less than one percent of the 700 hectares
(1,730 acres) of forest will be removed by the road, adding
they will mitigate any damage by replanting four times as many
trees.

Opponents of the project say losing even a tiny fraction of
the original forest will be detrimental in the long term.

“We have to think about what will happen in the years to
come with the toxic fumes of cars, noise and litter that the
road will bring,” says Yan Hookoomsing, vice-president of
Nature Watch, a local environmental group campaigning against
the project.

By Vashisht, Arvind; Wadsworth, Fred; Carey, Adam; Carey, Beverley; Studd, John

Abstract

Natural progesterone creams are gaining popularity as a possible treatment for menopausal symptoms, and many women may be using them with estrogen. We planned to evaluate, using an open plan study, the systemic absorption of a combination of transdermal estrogen and progesterone. Women applied transdermal progesterone 40 mg and transdermal estrogen 1 mg daily over 48 weeks. Women were assessed at intervals of 12 weeks. Significant increases in plasma levels of progesterone and estradiol were seen after 12 weeks, although only low plasma progesterone levels were found (median 2.5 nmol/l) and no further increase was noted over the remainder of the study period. A significant correlation was found between plasma levels of the two hormone (r = 0.315, p = 0.045). Women reported significant reductions in menopausal symptoms, as measured by the Green Climacteric Scale, after 24 and 48 weeks of combined treatment. There may be similar mechanisms of absorption of the two hormones, although the doses used in our study produced sub-luteal levels of progesterone. There was no evidence of accumulation of progesterone with time, and further study is needed to assess the efficacy and safety of this combination of hormones.

Keywords: Transdermal natural progesterone, plasma hormone levels, climacteric symptoms

Introduction

The mainstay of hormone replacement for the postmenopausal woman is estrogen therapy. For those women with an intact uterus, there is the necessity of adding in a progcstogen to prevent the effects of endometrial hyperplasia. Because of the poor absorption of oral natural progesterone, a variety of synthetic progestogens have been routinely added to estrogen therapy. Unfortunately, these products may be associated with adverse metabolic, psychological and physical effects [I]. To avoid these problems associated with systemic synthetic progestogens, more local forms of progestogen delivery have been suggested, such as the levonorgestrel intrauterine device, or reverting to using different forms of progestogen. Natural progesterone is a possible substitute.

The pharmacokinetics of progesterone are diverse and have not been elucidated. The use of progesterone has been limited because of poor absorption when given orally and because greater than 90% is metabolized during the first hepatic pass [2], leading to low serum concentrations of the active steroid [3,4]. Furthermore, the hepatic metabolism results in unphysiologically high levels of progesterone metabolites, particularly those at the reduced 5α position such as 5α-pregnanolone, which can cause drowsiness [3,5,6]. Attempts have been made to administer progesterone in other ways. Vaginal pessaries and gels have been used [7], the transbuccal route has been proposed [8], and it may be micronized, a process to decrease particle size, to speed up its absorption when given orally [9].

It has been suggested that because estradiol, which is chemically similar to progesterone, is well absorbed by the skin [10], absorption of progesterone by the skin may be clinically feasible. Animal studies have shown that topically applied progesterone is rapidly absorbed transdermally and that its patterns of distribution and metabolism are comparable to those noted for intravascular administration [U]. The transdermal route is suggested to be of benefit as there is absorption into the skin, which can act as a reservoir ensuring a sustained release of hormone. Recently there has been an increased interest amongst women and in the lay press about the merits of transdermal natural progesterone. Despite this, and the frequent use of progesterone creams by postmenopausal women both alone and in conjunction with estrogens, the proven merits of the creams are few. It has been suggested to have a favorable effect on vasomotor symptoms in the postmenopausal woman [12], and some have even suggested its role in the prevention and reversal of osteoporosis [13]. Others are more concerned by earlier studies that have revealed low systemic hormone levels after short-term administration, questioning the feasibility of any biological efficacy.

The present study aimed to look at the systemic absorption of a daily dose of natural progesterone cream, used in conjunction with transdermal estrogen as part of a continuous combined hormone replacement therapy. In particular we were interested to evaluate progesterone levels over the period of a year to determine if there was a net accumulation of hormone over that time. Also, we wished to observe if there was a relationship between plasma estradiol and progesterone levels in women using transdermal preparations of both hormones. In addition, symptom changes were noted although it was an uncontrolled study.

Methods

Women were recruited locally from a specialist menopause clinic and nationally by means of a newspaper advertisement. Women were adjudged suitable if they had a raised level of follicle- stimulating hormone ( > 30 nmol/1) and were at least 2 years’ postmenopausal. Women with previous breast or gynecological malignancy, undiagnosed vaginal bleeding or previous use of estradiol implants were excluded. Any woman who was currently taking any form of hormone replacement therapy was subject to a 3-month washout period.

Each patient recruited was supplied with clearly labeled separate containers filled with Progestelle 6% progesterone cream (Higher Nature, Burwash Common, UK) and estradiol gel (Sandrena; Organon, Cambridge, UK) sachets. A leaflet with written instructions about how to apply the cream appropriately was provided to each patient and they were also given a verbal explanation. Each treatment unit consisted of 12 pots of cream containing 30 g of 6% progesterone. Each pot contained sufficient cream for 4 weeks’ treatment. The cream was applied using a validated measuring device to a templated area (measuring 100 cm^sup 2^) of the forearm. A total of 40 mg progesterone was given each day. The estrogen gel in the form of a daily sachet was applied to the inner aspect of the upper leg, delivering 1 mg estradiol/day. Both sites were alternated between left and right each day.

The study was conducted as an open plan study over 48 weeks. Subjects were assessed at 12-week intervals during the study period. A medical and physical examination was performed. At this time, assessment was made of improvements in menopausal symptoms (vasomotor, anxiety and depression scores as measured by the Greene Climacteric Scale) and the occurrence of any adverse event. Blood tests to measure plasma estradiol and progesterone levels were also carried out.

Differences between normally distributed data were assessed by the Student t test and between non-parametric data by the Wilcoxon matched pair test. Correlation coefficients between variables were calculated using the Pearson correlation. The Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) was used for data analysis.

Results

A total of 54 women were recruited, of whom 41 (75.9%) finished the study (Table I). The mean age of the women was 57.4 years (standard deviation 4.9 years).

For statistical purposes, hormonal levels are included only for those women who completed the study. The median estradiol and progesterone concentrations are displayed in Table II. The increases from baseline levels at each time interval were all significant (p

Means were calculated at the end of 48 weeks to work out each woman’s average plasma levels of estradiol and progesterone during the study period. Using Pearson correlation, a significant positive relationship (r= 0.315, p = 0.045) was found between the log- transformed levels of the two hormones (Figure 1).

After both 24 and 48 weeks, there were highly significant reductions in anxiety, depression, vasomotor symptoms and libido problems compared with baseline (p

Discussion

The main concern that many physicians have with the use of natural progesterone cream is that it is not adequately absorbed to have a significant biological effect. Although subject to extensive hepatic metabolism, oral progesterone has been shown to be physiologically active, producing increases in levels of the breast, endometrium and myometrium [14]. Vaginal delivery of progesterone is associated with lower plasma levels of hormone than by oral or intramuscular administration [15]. Despite this many authors suggest a local direct vagina-to-uterus transport, resulting in preferential uterine uptake of progesterone [16] perhaps making serum values less comparable. This way, luteal endometrial responses are found with subphysiological levels of progesterone.

Table I. Primary reasons for study withdrawals.

Table II. Hormone levels over the study period: median (interquartile range).

Figure 1. Relationship between log mean estradiol level and log mean progesterone level.

Figure 2. Symptom reduction with duration of treatment. Significant reduction vs. baseline: *p

In our s\tudy, significant increases from baseline were seen in both estradiol and progesterone levels after 12 weeks of treatment. Burty and colleagues suggested that by use of 30-60 mg of progesterone cream, luteal levels could be achieved [17]. The maximum median plasma progesterone level in our study of 2.5 nmol/1 is far lower than that typically seen in the luteal phase of a premenopausal woman, and lower than levels achieved with standard doses of oral or vaginal progesterone. Similar low levels have been seen in other studies using transdermal cream [18]. Twice daily administration of Progest cream resulted in median plasma progesterone after 10 days of 2.9 nmol/1, and the authors concluded these inadequate plasma levels were unlikely to have an effect when used with estrogen therapy [19]. In the study by Wren and associates in estrogenized women, even the highest dose of progesterone (64 mg) produced low serum levels in a range of 0.6-3.2 nmol/1 [20].

All of the previous studies were conducted over a relatively short period of time. In an earlier study by Carey and co-workers also using 40 mg of transdermal progesterone cream, the maximum rise in serum progesterone of 5.3 nmol/1 was found after 42 days. It was hypothesized that there may be an accumulation of hormone and that progressively levels will rise over a longer period of time. In the present study, the maximum plasma progesterone levels were seen after 12 weeks and there was no significant increase beyond this time. Indeed, using oral and vaginal progesterone, no particular change in bioavailability of progesterone has been seen over time [21,22].

Some proponents of transdermal progesterone assert that actually plasma levels of progesterone do not accurately represent the bioavailability of progesterone. It is argued that as progesterone is very hydrophobic, it easily permeates through the skin [23] and seeks out other hydrophobic entities such as the red cell membrane, leaving only very little apparent in the plasma [24]. However, this has not been borne out in a study that looked in particular at red cell progesterone levels [25], with the authors concluding that red cells are not important in the delivery of progesterone to target tissues. Others suggest that despite low plasma levels of hormone, resolution of vasomotor symptoms may indicate a systemic effect possibly by an unexplained, bioactive progesterone availability undetected by conventional assays [12].

There was found to be a significant positive relationship between the mean log-transformed plasma estradiol and progesterone levels. In a smaller study using 50 g transdermal estrogen and 30-60 mg transdermal Progest cream, a similar association between estradiol and progesterone levels was seen suggesting the possibility of similar mechanisms of absorption for both hormones [17].

Our study has shown that a combination of daily 1 mg estradiol and 40 mg transdermal natural progesterone cream leads to a significant reduction in menopausal symptoms of anxiety, depression, vasomotor and libido problems. These improvements were evident after 24 weeks of therapy, and a further reduction in symptoms of anxiety was evident after 48 weeks. We also found the incidence of side- effects to be low. Other authors have also found a combination of estrogen and either oral [26,27] or vaginal [28,29] natural progesterone to have a beneficial effect on symptoms of estrogen deficiency with few side-effects. From our study it is impossible to determine quantitatively whether these improvements in symptoms are due to the effects of estrogen, progesterone or the combination of the two hormones.

The recent adverse results from studies such as the Women’s Health Initiative suggest that conventionally available combined preparations of estrogen and progestogen may pose a particular concern in terms of adverse events, especially regarding breast cancer incidence [3O]. It is imperative that clinicians continue to seek novel and perhaps safer forms of hormone replacement, in particular with different methods of delivering progesterone, in order to produce a safe and effective therapy for women who continue to suffer debilitating menopausal symptoms. What is clear from our study is that there is some percutaneous absorption of transdermal progesterone cream, although further study is necessary to determine the safety and the clinical worth of the hormone levels found using this particular combination of hormones.

References

1. Magos AL, Brewster E, Singh R, O’Dowd T, Brincat M, Studd JW. The effects of norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. Br J Obstet Gynaecol 1986;93:1290-1296.

2. Nahoul K, Dehennin L, Jondet M, Roger M. Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas 1993; 16:185- 202.

3. Maxson WS, Hargrove JT. Bioavailabiliry of oral micronized progesterone. Fertil Steril 1985;44:622-626.

4. Padwick ML, Endacott J, Maison C, Whitehead MI. Absorption and metabolism of oral progesterone when administered twice daily. Fertil Steril 1986;46:402-407.

5. Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988;159:12031209.

6. Norman TR, Morse CA, Dennerstein L. Comparative bioavailability of orally and vaginally administered progesterone. Fertil Steril 1991;56:1034-1039.

7. Fanchin R, De Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396-401.

8. Wren BG, Day RO, McLachlan AJ, Williams KM. Pharmacotdnetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric 2003;6:104-111.

9. Simon JA. Micronized progesterone: vaginal and oral uses. Clin Obstet Gynecol 1995;38:902-914.

10. Sitruk-Ware R, de Lignicrcs B, Basdevant A, Mauvais-Jarvis P. Absorption of percutaneous oestradiol in postmenopausal women. Maturitas 1980;2:207-211.

11. Waddell BJ, O’Leaiy PC. Distribution and metabolism of topically applied progesterone in a rat model. J Steroid Biochem MoI Biol 2002;80:449-455.

12. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmcnopausal bone loss. Obstct Gynecol 1999;94:225-228.

13. Lee JR. Osteoporosis reversal with transdermal progesterone. Lancet 1990;336:1327.

14. Ferre F, Uzan M, Jansscns Y, Tanguy G, Jolivct A, Breuiller M, Sureau C, Cedard L. Oral administration of micronized natural progesterone in late human pregnancy. Effects on progesterone and cstrogen concentrations in the plasma, placenta, and myometrium. Am J Obstet Gynecol 1984;148:26-34.

15. Bourgain C, Devroey P, Van Waesberghe L, Smitz J, Van Steirteghcm AC. Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure. Hum Reprod 1990;5:537-543.

16. Bulletti C, De Zieglcr D, Flamigni C, Giacomucci E, Polli V, Bolelli G, Franccschetti F. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997;12:1073-1079.

17. Burry KA, Fatten PE, Hcrmsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal cstrogen. Am J Obstet Gynecol 1999;180:1504-1511.

18. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause 2003;10:13-18.

19. Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJ, Collins WP. Systemic absorption of progesterone from Progest” cream in postmenopausal women. Lancet 1998; 351:1255-1256.

20. Wren BG, McFarland K, Edwards L. Micronised transdermal progesterone and endomctrial response. Lancet 1999;354: 1447-1448.

21. Bolaji II, Talion DF, O’Dwyer E, Fottrell PF. Assessment of bioavailability of oral micronized progesterone using a salivary progesterone enzymeimmunoassay. Gynecol Endocrinol 1993;7:101-110.

22. Miicioiu C, Ferju A, Ncagu A, Gnu E, Calin G1 Miron DS. Phaimacokinetics of progesterone in postmenopausal women: 1. Phaimacokinetics following intravaginal administration. Eur J Drug Metab Pharmacokinet 1998;23:391-396.

23. Johnson ME, Blankschtein D, Langer R. Permeation of steroids through human skin. J Pharm Sci 1995;84:1144-1146.

24. Lcc JR. Use of Pro-Gest cream in postmenopausal women. Lancet 1998;352:905.

25. Lewis JG, McGiIl H, Patton VM, Elder PA. Caution on the use of saliva measurements to monitor absorption of progesterone from transdcrmal creams in postmenopausal women. Maturitas 2002;41:1-6.

26. Darj E1 Nilsson S, Axclsson O1 Hellberg D. Clinical and endomctrial effects of oestradiol and progesterone in postmenopausal women. Maturitas 1991;13:109-115.

27. Bolaji II, Mortimer G, Grimes H, Talion DF, O’Dwyer E, Fottrell PF. Clinical evaluation of near-continuous oral micronized progesterone therapy in estrogcnizcd postmenopausal women. Gynccol Endocrinol 1996; 10:41-47.

28. Warren MP, Billcr BM, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained- release vaginal gel Crinonc (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999; 180:42- 18.

29. Maruo T, Mishell DR, Ben Chetrit A, Hochner-Cclnikier D, Hamada AL, Nash HA. Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy. Feral Steril 2002;78:1010-1016.

30. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progcstin in healthy postmenopausal women: principal results from the Women’s He\alth Initiative randomized controlled trial. J Am Med Assoc 2002;288:321-333.

ARVIND VASHISHT1, FRED WADSWORTH1, ADAM CAREY1, BEVERLEY CAREY1, & JOHN STUDD2

1 Chelsea and Westminster Hospital, London, UK, and 2 Lister Hospital, London, UK

Correspondence: A. Vashisht, 98 Brackenbuiy Road, London W6 OBD, UK. Tel: 44 7957 570 739. Fax: 44 20 7823 6108. E-mail: [email protected]

Copyright CRC Press Aug 2005

By Unfer, Vittorio; Casini, Maria Luisa; Marelli, Guido; Costabile, Loredana; Et al

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in woman of reproductive age. Although extensive studies have been performed in past decades to investigate the pathobiological mechanisms underlying the unset of this disease, its etiology remains unknown. Progesterone is a hormone of paramount importance in ovulation, implantation and luteal phase support. Low levels of progesterone have been found in the early luteal phase in PCOS patients. Granulosa cells from polycystic ovaries show an altered progesterone production. Moreover, the lack of cyclical exposure to progesterone may have a role in the development of the gonadotropin and androgen abnormalities found in PCOS patients. Ovulation failure and progesterone deficiency may facilitate the hypothalamic- pituitary abnormalities causing the associated disordered luteinizing hormone secretion in PCOS. Progesterone may be administered to PCOS patients in the following cases: to induce withdrawal bleeding, to suppress secretion of luteinizing hormone, in ovulation induction in clomiphene citrate-resistant patients and in luteal phase support in assisted reproduction. We discuss the pharmacologie characteristics of the different routes of progesterone administration with reference to these diverse indications, the therapeutic objectives and patient compliance.

Keywords: Polycystic ovary syndrome, progesterone pharmacology, luteal phase support

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age [1-3]. Although extensive studies have been performed in past decades to investigate the pathobiological mechanisms underlying the unset of this disease, its etiology remains unknown [4].

Progesterone plays an important role in ovulation [5,6], in embryo implantation and in luteal phase support [7-1O]. Increasing evidence also indicates that human parturition is initiated by decreased myometrial responsiveness to progesterone, i.e., functional progesterone withdrawal [11-13]. Moreover, we know that the incidence of anovulation and miscarriage in PCOS patients is high [14]. Low levels of progesterone have been found in the early luteal phase in PCOS patients [15,16]. Granulosa cells from polycystic ovaries demonstrate an altered ability to synthesize progesterone both in vivo and in vitro [6].

The lack of cyclical exposure to progesterone has been suggested to have a role in the development of the gonadotropin/androgen synthesis alterations found in PCOS patients [5]. Ovulation failure and progesterone deficiency may facilitate the development of the hypothalamic-pituitary abnormalities that determine the altered lutcinizing hormone (LH) secretion which is characteristic of PCOS [5]. Moreover, adults with PCOS require higher progesterone concentrations to inhibit the gonadotropinreleasing hormone (GnRH) (LH) pulse frequency compared with normal women. This contributes to establishment of the persistently rapid GnRH pulses and elevated LH levels found in PCOS [17].

All these findings may explain the presence of anovulation, the delay in conception and the high prevalence of miscarriage that occur in PCOS patients [18]. Moreover, they also reveal the reason why PCOS patients undergoing assisted reproductive techniques represent a great challenge for the fertility specialist [14]. Considering everything mentioned above, in these patients progesterone supplementation in in vitro fertilization (IVF) cycles is highly recommended for achieving a successful pregnancy [19].

An impaired adrenal function is a common characteristic of patients with PCOS [2O]. Consequently, basal androgen and 17ot- hydroxy-progesterone (17-OHP) levels are routinely measured for the hormonal evaluation of suspected PCOS women [21,22]. Androgen levels are generally determined to establish the presence of hyperandrogenemia whereas basal 17-OHP levels are determined to screen for 21-hydroxylase-deficient non-classic adrenal hyperplasia [23]. Generally, to maintain sampling uniformity and avoid increases in 17-OHP levels due to corpus luteum function, these levels are obtained during the follicular phase. However, since most hyperandrogenic patients are oligomenorrheic, it is frequently necessary to administer a progestogen to induce the withdrawal bleeding and properly time the blood sampling [22]. Progestogens such as medroxyprogesterone acetate (MPA) are commonly used to induce withdrawal bleeding in PCOS patients [5]. Recent studies have shown that the administration of progesterone to women with PCOS results in a temporary, although clinically relevant, suppression of circulating androgen levels, which is significantly higher than the one achieved by MPA [22,24]. These observations may favor the use of progesterone to induce withdrawal bleeding in these patients.

Undoubtedly, the treatment of anovulatory PCOS patients who are resistant to clomiphene citrate (CC) is challenging for the fertility specialist. The administration of progesterone before CC therapy has been effective in inducing the responsiveness to CC [25,26] due to the progesterone-related suppression of follicle- stimulating hormone (FSH) and LH secretion.

In summary, in clinical practice we may administer progesterone to PCOS patients in the following cases:

(1) To induce withdrawal bleeding;

(2) To suppress LH secretion in the normalization of the menstrual cycle;

(3) In ovulation induction in CC-resistant patients;

(4) To support the luteal phase after assisted reproductive techniques.

In the present review we discuss the pharmacologie characteristics of the different routes of administration with reference to these diverse indications, the therapeutic objectives and patient compliance.

Different routes of administration of progesterone and its pharmaceutical form

Once the therapeutic need for progesterone has been established, the question is which route of administration should be preferred [27,28]. In general, the route of administration of a drug is chosen on the basis of appropriate anatomic, physiopathologic and pharmacotherapeutic considerations [28,29] rather than practical aspects or even patient compliance. However, it is important to mention that from a pharmacological point of view the main factors that determine the success of absorption of a drug from the administration site are three:

(1) The pharmaceutical form (tablets, suppositories, gel, solution for injection, etc.);

(2) The solubility of the drug at the tissue level;

(3) The hematic now at the tissue level.

As regards therapy with progesterone, all possible administration routes have been used with distinct results.

Transdermal route of administration

The transdermal route of administration would be easy to use because it offers good compliance from the patient. However, it does not permit the achievement of adequate plasma levels of progesterone. In fact, progesterone is a lipophilic compound and is not easily absorbed by the skin [3O]. Considering that the daily production of progesterone is on average 25 mg, using the transdermal route of administration about half of the body should be utilized as absorbing surface [31]. The unsuitability of the transdermal administration of progesterone makes difficult to conceive any viable therapeutic application for progesterone administered by this route.

Rectal route of administration

The rectum presents a complex hematic and lymphatic vascularization. The rectal mucosa is not considered an important site for drug administration due to the great variability of absorption [32], However, emphasis should be placed on the fact that as many active components are absorbed by the rectal mucosa as by other lipoproteic membranes [33] and, indeed, non-ionic and lipophylic compounds are absorbed easily by the rectal mucosa [34]. Some authors emphasize that drugs which are easily metabolized by the liver may be more effective when administered by the endorectal route [29,35]. When an active component is absorbed in the lower portion of the rectum, via the inferior hemorrhoidal veins it reaches the general circulation directly, bypassing the hepatic first-pass elimination. On the contrary, if the compounds are absorbed by the superior rectal ampulla, they will reach the portal circulation via the superior hemorrhoidal vein [28,35].

This route of progesterone administration, which still does not have sufficient bibliographic support, is used in some Anglo-Saxon countries for hormone replacement therapy (HRT) in combination with estrogen administration. The plasma peak of progesterone is reached 8 h after administration and is followed by a gradual decline of the plasma levels. As mentioned above, there is a wide variability of absorption among patients that makes the hematic peaks range between 15 and 52 ng/ml after the administration of 100 mg of progesterone [36]. This variability in absorption makes difficult to conceive the practical utility of progesterone administration by this route to PCOS patients in any of the previously mentioned therapeutic targets.

Sublingual route of administration

Few studies have been performed on administration of progesterone by the sublingual route [37-39]. In 1996 Stovall and collaborators [37] used this route of progesterone administration for luteal phas\e support in patients undergoing embryo transfer. The authors demonstrated that, after the administration of 50 or 100 mg of progesterone dissolved in 1 ml of sublingual suspension, the plasma peaks were reached in 30-60 min and levels were on average 17.61 3.78 ng/ml when 100 mg progesterone was administered. However, the maintenance of adequate plasma concentrations through the day required the administration to be repeated two or three times. Preliminary data of the Iowa Assisted Reproduction Program showed that 400 mg of progesterone has to be administered sublingually every 8 h to obtain plasma levels similar to those achieved with intramuscular administration of 100 mg progesterone/day [4O]. Further studies are necessary in order to evaluate the effectiveness of progesterone administration by this route, and hence its potential role in the therapy of PCOS patients.

Transnasal route of administration

Nasal mucosa represents a potential site for progesterone administration due to its high vascularization and the presence of microvilli that expand the absorbing area considerably [41,42]. Such a route of administration was proposed by Steege and co-workers in 1986, and in 1993 Cicinelli and associates evaluated the possibility of progesterone administration through nasal spray [43-46]. The results of this study were very interesting, although the plasma levels achieved did not permit therapeutic effectiveness to be reached in clinical obstetrics and hence in PCOS. This route of administration could be proposed for HRT in menopause [47].

Intrauterine route of administration

The intrauterine route of administration consists of the application of an intrauterine device and is of particular interest in contraception and pre-menopause [48]. Clearly, it cannot be proposed in obstetrics because it would act as a contraceptive [49]. Like for the transnasal route of administration, in this case we also do not reach adequate plasma levels of hormone to propose this route of progesterone administration in any of the therapeutic targets in PCOS mentioned above.

Oral route of administration

The oral route of progesterone administration offers high compliance for the patient even though it presents evident disadvantages. First of all, there is a great variability of absorption depending on individual factors and gastric filling [50,51]. Moreover, oral progesterone shows poor bioavailability [52] and a rapid clearance rate [53].

Progesterone administered by the oral route is first absorbed at the intestinal level and then reaches the liver, passing through the portal vein where it is rapidly converted into metabolites. This enterohepatic passage determines important side-effects such as dizziness, sleepiness, nausea, etc. [7] caused by the formation of these metabolites. In addition, due to the rapid metabolism, plasma levels of oral progesterone tend to be relatively low. Consequently, to reach plasmatic levels that are adequate for an effective therapeutic action, it is necessary to administer high and repeated dosages of progesterone during the day [54,55]. Unfortunately, this makes plasma levels of progesterone metabolites rise further. Therefore, considering the previously mentioned issues, the development of a progesteronecontaining drug that could pass throughout the gastric barrier and release the active component at the intestinal level may be advantageous. Consecutive dosages could be reduced in number and also side-effects will occur less frequently.

In recent years an oral micronized preparation of progesterone has become available on the market. This formulation leads to a higher absorption of the active component [52,56] in comparison with the classical oral formulation. The production of micronized progesterone requires transformation of the chemical compound into very fine powder that in turn has to be suspended in an oil vector, a process that may considerably increase its bioavailability [57]. Notwithstanding the process of micronization, the intestinal absorption of progesterone is still limited. Moreover, considerable inter-subject variability in the extent of progesterone absorbed after administration of oral micronized progesterone is still present [50,51]. The absorption of oral micronized progesterone is doubled in the presence of food. However, the bioavailability of oral micronized progesterone is approximately 10% compared with intramuscular progesterone [52].

Oral micronized progesterone has been administered in IVF for luteal phase support. Studies demonstrated that oral progesterone is associated with a significantly lower implantation rate per embryo compared with intramuscular progesterone in luteal phase support in IVF cycles [58,59]. This difference was observed despite the fact that circulating levels of progesterone were similar in both groups. Buvat and colleagues [60] demonstrated that use of oral micronized progesterone in oil (100 mg at 08.00, 100 mg at 12.00 and 200 mg at 20.00 hours) resulted in a clinical pregnancy rate of 23% and an implantation rate per embryo of 7.5%, compared with 45% and 19%, respectively, for intramuscular progesterone. All these differences were statistically significant. However, Pouly and collaborators [59] reported that oral progesterone (100 mg in the morning and 200 mg in the evening) resulted in a clinical pregnancy rate of 25% and an implantation rate of 29.9%, compared with 28.8% and 35.3%, respectively, for progesterone vaginal gel. This difference was not statistically significant.

We know that the rapid metabolism of oral progesterone leads to a high concentration of circulating metabolites, including deoxycorticosterone, estrone and estradiol. The most common metabolites, the 5α- and 5β-reduced pregnanolone, are present in concentrations higher than that of progesterone itself [61,62]. The metabolites of progesterone, being highly concentrated, may bind progesterone receptors and interfere with the normal action of the hormone. Moreover, the 5α- and 5β-reduced pregnanolone are known to have a high affinity for γ- aminobutyric acid receptors [63]. These receptors are present in the reproductive organs [64] and their activation may adversely effect the outcome of pregnancy.

The clearance of orally administered progesterone has been studied by Whitehead and co-workers [65] in five postmenopausal women. Progesterone 100 mg/day was administered orally for five consecutive days. Progesterone represents an important metabolic step in the biosynthesis of many steroids, including some glucocorticoids and mineralocorticoids. The transformation of exogenous progesterone into other hormones with diverse biological activity represents a limit in clinical practice. Circulating progesterone may be converted into deoxycorticosterone at peripheral tissue level; the extra-adrenal synthesis of this potent mineralocorticoid from endogenous and exogenous progesterone has been well documented [66-68].

Progesterone is widely metabolized at the intestinal and hepatic level by the reduction of the C-3 and C-20 carbonyl groups; by reduction of the C-4 to C-5 double bond; by hydroxylation at C-16 to C-21; and by conjugation with glucuronic and sulfuric acids [69]. Progesterone may compete with mineralocorticoids at the receptor level, thus acting as a mineralocorticoid antagonist [70-72]. Unfortunately, a conspicuous amount of progesterone is converted to deoxycorticosterone [68].

During the menstrual cycle in women of reproductive age, progesterone and deoxycorticosterone levels rise concomitantly, reaching a maximum concentration during the luteal phase [66]. In women during the follicular phase and in men, circulating deoxycorticosterone is produced by the adrenal cortex. On the other hand, during the luteal phase more than 75% of the circulating deoxycorticosterone comes from the peripheral conversion of progesterone [66,67]. The exogenous administration of progesterone is followed by a rapid increase of plasma deoxycorticosterone levels, and the route of progesterone administration may influence the progesterone/deoxycorticosterone ratio. The effects of mineralocorticoids and of deoxycorticosterone are partly antagonized by the antimineralocorticoid effects of progesterone itself. One may hypothesize that some clinical manifestations, i.e., premenstrual syndrome, pregnancy-related edema as well as hypertensive disorders in pregnancy, could be linked to the alterations of the progesterone/ deoxycorticosterone ratio.

In conclusion, the oral administration of progesterone offers high compliance even though the associated inconveniences should be taken into consideration, especially in those indications where the administration of this hormone has to be protracted [73]. Conversely, where we need a short therapy, oral progesterone could be preferred to intramuscular administration. For example, this route of progesterone administration could be indicated to induce bleeding in PCOS oligomenorrheic patients, where progesterone is more effective than MPA in suppressing circulating androgen levels [22,24].

Vaginal route of administration

The vaginal route of progesterone administration provides many advantages such as lack of local pain, avoidance of first-pass hepatic metabolism and rapid absorption. However, this route of administration results in localization of the bioavailability of the active component at endometrial level [74-77]; consequently, this route of progesterone administration does not permit high plasma levels of the hormone to be reached.

Recently progesterone has been formulated in bioadhesive gel preparations. These preparations elicit better compliance compared with cream formulations and suppositories, which are known to cause uncomfortable vaginal discharges and consequently an irregular absorption of the active component [78]. Studies comparing intramuscular and vaginal progesterone in \inducing a secretory transformation of the endometrium have led to controversial results regarding the superiority of one or the other [79].

As stated above, vaginal administration of progesterone results in high concentration of the hormone at the uterine level (first uterine passage). This may represent an advantage for certain indications such as HRT [80,81]. After the estrogenic stimulation, in HRT the aim is to provoke the secretive transformation of the endometrium to avoid the adverse effects of estrogen at endometrial level. This effect may not be adequate/advisable in other therapeutic indications. For example, in luteal phase support after assisted reproduction, the vaginal administration of progesterone results in a lower pregnancy rate in comparison to intramuscular progesterone [82,83]. In fact, in assisted reproduction the secretive transformation of the endometrium has to be synchronous in all its tissue components. This does not occur if progesterone is administered vaginally [84].

The rational behind these clinical findings may be easily understood if one considers that implantation of the conceptus may only occur with a balancing of permitting and blocking factors [85]. These factors are hormone-dependent in the sense that circulating levels of the single hormone may both induce and inhibit the synthesis of these factors, depending on the concentration of the hormone itself. That is to say, progesterone may act either towards implantation as a permissive factor in a certain range of concentration or as a blocking factor when its concentrations are lower or higher than a cut-off value [86,87]. This is evident if we remember that the first contraceptive used in therapy was a high- dosage progesterone preparation. However, some studies have not found statistically significant differences in terms of pregnancy rates in patients undergoing IVF where luteal phase support was given by either intramuscular or vaginal progesterone [88-9O].

Intramuscular route of administration

The intramuscular route of progesterone administration is the one most commonly used for this hormone in clinical practice. With reference to the pharmacokinetics of intramuscular progesterone, the definition ‘intramuscular route of administration’ should be substituted with ‘intergluteal route of administration’. It has been shown that when progesterone is administered by an injection into the gluteus, its half-life is significantly longer than when the hormone is injected into the superior part of the arm [52]. This difference may be determined by the different concentrations of adipose cells between the arm and gluteus: in fact, progesterone shows a high affinity for adipose cells. Consequently, after administration of the hormone into the gluteus, progesterone is stored in adipose cells and released only when the plasma levels decrease. This effect may be denned as a depot effect of progesterone, which permits a singular daily administration of the hormone even though progesterone’s half-life in the blood is extremely short (5-20 min) [91].

Unfortunately, the intramuscular administration of progesterone causes pain at the site of injection, sometimes the formation of a bruise and, in rare cases, sterile abscess [92]. On the other hand, intramuscular administration is the only route that guarantees adequate and verifiable plasma levels of the active component. It is clear that in assisted reproduction, and in therapy to reduce the threat of abortion and the risk of preterm labor, patients tolerate the discomfort related with the therapy because of their high level of motivation [93]. Conversely, this route of administration does not seem to be recommended in menopause, where the vaginal route seems to be equally effective and more tolerated by the patient.

In conclusion, for all the reason mentioned above concerning the intramuscular route of progesterone administration, this should be preferred in the treatment of PCOS patients in the case of CC resistance in ovulation induction and, obviously, for luteal phase support after assisted reproduction.

Studies of progesterone use in polycystic ovary syndrome

As mentioned in the Introduction, it has been suggested that the lack of cyclical exposure to progesterone may play an important role in the development of gonadotropin and androgen abnormalities in PCOS [5]. Furthermore, progesterone may also be involved in PCOS- associated anovulation and miscarriage [6].

It is known that an increment in LH level is a typical finding in PCOS patients. This unsuitable elevation of LH is suspected to adversely influence follicular development and ovulation. In the study of Buckler and associates [94], progesterone was administered because of its suppressive action on LH secretion (if progesterone is administered continuously in physiological dosages). Ten PCOS patients were treated with vaginal progesterone 100 mg twice a day for 10 days. Mean serum progesterone levels reached 16 ng/ml 4 days after the treatment and remained in the mid-luteal phase range thereafter. The mean serum LH concentrations decreased significantly (p ^ 0.01) after 8 days of treatment and continued to fall progressively until the end of progesterone administration. In another study of Pastor and collaborators [95], LH levels were normalized when progesterone vaginal suppository and transdermal estradiol were administered, reaching plasma progesterone concentrations of 13-15 ng/ml. These results are in contrast to those of other studies in which the administration of vaginal progesterone did not permit the achievement of high and stable plasma levels of progesterone [79,81,96]. In conclusion, although further studies should be undertaken before assessing a definitive therapeutic role of exogenous administration of progesterone in PCOS, the possibility to normalize LH levels in PCOS patients with progesterone administration has been found effective.

Table I. Summary of the possible therapeutic approaches in the treatment of patients with polycystic ovary syndrome (PCOS) in relation to the diverse indications in which progesterone could be used.

Progesterone plays an important role in oocyte fertilization and embryo implantation. Therefore, when performing assisted reproduction in PCOS patients, progesterone supplementation in these patients is highly recommended in order to achieve a successful pregnancy [18,19,97], Since the most reliable and stable plasma levels are achieved only with the intramuscular route of administration, treatment with intramuscular progesterone at a dosage of 50 mg/day from the beginning to the 12th week of gestation is suggested.

Progesterone can also be used in ovulation induction in PCOS patients who have been found to be CC-resistant. The pretreatment with progesterone results in suppression of the secretion of FSH and LH, which in turn restores the responsiveness to the estrogenic treatment [25,26]. Ten PCOS women previously found to be CC- resistant were administered 50 mg progesterone intramuscularly for 5 days. After the treatment, in seven of these women LH and FSH levels fell. Consequently, the responsiveness to CC was restored and three of the seven women conceived in the first treatment cycle. The women in whom LH levels were not suppressed remained unresponsive to CC.

Regarding the induction of bleeding in PCOS oligomenorrheic patients, we have reported the results of some studies showing that the use of progesterone to induce withdrawal bleeding results in a temporary although clinically relevant suppression in circulating androgen levels [22,24] which is significantly higher than the one provoked by MPA. These observations may favor the use of progesterone to induce withdrawal bleeding. For this indication the best route of administration may be the oral one (100 mg in the morning and 200 mg before bedtime for 7 days).

Table I summarizes the therapeutic approaches in PCOS patients.

Conclusions

The production of progesterone in PCOS patients is often inadequate. This impairment has been correlated not only with occurrence of anovulatory cycles, but also to the reduced ability of granulosa cells to synthesize progesterone [6].

The lack of cyclical exposure to progesterone has been suggested to have a role in the development of alterations in the synthesis of gonadotropins and androgens found in PCOS [5]. The deficiency in progesterone production and ovulation failure may facilitate the development of the hypothalamic-pituitary alterations that in turn provokes the alteration in LH secretion which is typical of PCOS [5]. PCOS patients require higher progesterone concentrations to inhibit the GnRH (LH) pulse frequency in comparison to normal women.

In conclusion, the use of progesterone in PCOS patients may have different therapeutic objectives. As shown in the present review, the different routes of administration as well as its pharmaceutical form strongly modify the bioavailability and metabolism of progesterone. Hence its therapeutic effects may show a significant difference and this in consequence may affect the possibility of the occurrence of side-effects.

We may conclude by saying that the choice of the modality of progesterone administration has to work with the therapeutic objectives. Consequently, this choice should be guided by the patient’s compliance only if the therapeutic options in terms of administration route and pharmaceutical form lead to the same desired efficacy of treatment.

Acknowledgments

We would like to thank Dr Suzette Paolella for her valuable support.

References

1. Goudas VT, Dumesic DA. Polycystic ovary syndrome. Endocrinol Metab Clin North Am 1997;26:893-912.

2. Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mcllitus. Fcrtil Steril 2002;77:1095- 1105.

3. Azziz R. PCOS: a diagnostic challenge. Reprod Biomed Online 2004;8:644-648.

4. Strauss JF 3rd. Some new thoughts on the path\ophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci 2003;997:42- 48.

5. Fiad TM, Cunningham SK, McKcnna TJ. Role of P deficiency in the development of luteinizing hormone and androgen abnormalities in polycystic ovary syndrome. Eur J Endocrinol 1996; 135:335-339.

6. Doldi N, Gessi A, Dcstcfani A, Calzi F, Ferrari A. Polycystic ovary syndrome: anomalies in progesterone production. Hum Reprod 1998; 13:290-293.

7. Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet Gynccol Scand 2001;80:452-466.

8. Bagchi IC, Li Q, Cheon YP. Role of steroid hormone-regulated genes in implantation. Ann N Y Acad Sci 2001;943:68-76.

9. Cavagna M, Mantcsc JC. Biomarkers of cndometrial receptivity – a review. Placenta 2003;24(Suppl B):S39-S47.

10. Posaci C, Smitz J, Camus M, Osmanagaoglu K, Devroey P. Progesterone for the luteal support of assisted reproductive technologies: clinical options. Hum Reprod 2000;15(Suppl 1): 129- 148.

11. Mcsiano S. Myometrial progesterone rcsponsiveness and the control of human parturition. J Soc Gynecol Investig 2004;11:193- 202.

12. Madsen G, Zakar T, Ku CY, Sanborn BM, Smith R, Mesiano S. Prostaglandins differentially modulate progesterone receptor-A and – B expression in human myometrial cells: evidence for prostaglandin- induccd functional progesterone withdrawal. J Clin Endocrinol Mctab 2004;89:1010-1013.

13. Nculcn J, Brcckwoldt M. Placental progesterone, prostaglandins and mechanisms leading to initiation of parturition in the human. Exp Clin Endocrinol 1994:102:195-202.

14. Franks S, Roberts R, Hardy K. Gonadotrophin regimens and oocytc quality in women with polycystic ovaries. Reprod Biomed Online 2003:6:181-184.

15. Joseph-Home R, Mason H, Batty S, White D, Hillier S, Urquhart M, Franks S. Luteal phase progesterone excretion in ovulatory women with polycystic ovaries. Hum Reprod 2002;17:1459-1463.

16. Fleming R, McQueen D, Yatcs RW, Courts JR. Spontaneous follicular and luteal function in infertile women with oligomenorrhoea: role of luteinizing hormone. Clin Endocrinol (Oxf) 1995:43:735-739.

17. Chhabra S, McCartney CR, Yoo RY, Eaglcson CA, Chang RJ, Marshall JC. Progesterone inhibition of the hypothalamic gonadotropin-relcasing hormone pulse generator: evidence for varied effects in hypcrandrogcncmic adolescent girls. J Clin Endocrinol Metab 2005;90:2810-2815.

18. Doldi N, Marsiglio E, Destefani A, Gessi A, Mcrati G, Ferrari A. Elevated serum progesterone on the day of HCG administration in IVF is associated with a higher pregnancy rate in polycystic ovary syndrome. Hum Reprod 1999; 14:601-605.

19. Dale PO, Tanbo T, Abyholm T. In-wtro fertilization in infertile women with the polycystic ovarian syndrome. Hum Reprod 1991;6:238-241.

20. Luboshitzky R, Ishai A, Shen-Or Z, Herer P. Evaluation of the pituitary-adrenal axis in hypcrandrogenic women with polycystic ovary syndrome. Neurocndocrinol Lett 2003;24:249-254.

21. Chang RJ. Polycystic ovaries in 2001:physiology and treatment. J Gynecol Obstet Biol Reprod (Paris) 2002;31:IS 15-1S19.

22. Woods KS, Reyna R, Azziz R. Effect of oral micronizcd progesterone on androgen levels in women with polycystic ovary syndrome. Fertil Steril 2002:77:1125-1127.

23. Azziz R. The time has come to simplify the evaluation of the hirsute patient. Fcrtil Steril 2000;74:870-872.

24. Anttila L, Koskinen P, Erkkola R, Irjala K, Ruutiainen K. Serum testosterone, androstcncdione and lutcinizing hormone levels after short-term mcdroxyprogcstcrone acetate treatment in women with polycystic ovarian disease. Acta Obstet Gynccol Scand 1994;73:634- 636.

25. Homburg R, Weissglas L, Goldman J. Improved treatment for anovulation in polycystic ovarian disease utilizing the effect of progesterone on the inappropriate gonadotrophin release and clomiphcnc response. Hum Reprod 1988;3:285-288.

26. Dale PO, Tanbo T, Kjckshus E, Abyholm T. Pregnancy after transfer of cryoprcserved embryos in clomiphcne citrate resistant polycystic ovarian syndrome. Fertil Steril 1990;53:362-364.

27. Fotherby K. Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy. Contraception 1996;54:59-69.

28. Ritschcl WA. Targeting in the gastrointestinal tract: new approaches. Methods Find Exp CUn Pharmacol 1991;13:313-336.

29. Gibaldi M, Boycs RN, Feldman S. Influence of first-pass effect on availability of drugs on oral administration. J Pharm Sci 1971;60:1338-1340.

30. Bercovici JP, Darragon T. Administration route of natural sex steroids (estradiol, progesterone, testosterone). Nouv Presse Med 1980;9:179-183.

31. Mauvais-Jarvis P, Kuttcnn F, Wright F. La progesterone administre par voie percutane. Ann Endocrinol (Paris) 1975;36:56- 62.

32. Gladtke E, von Hattingberg HM. Problems of rectal application of drugs. Dtsch Mcd Wochenschr 1970;95:1494-1496.

33. Muranishi S. Characteristics of drug absorption via the rectal route. Methods Find Exp Clin Pharmacol 1984;6:763-772.

34. Corbo DC, Liu JC, Chien YW. Drug absorption through mucosal membranes: effect of mucosal route and penetrant hydrophilicity. Pharm Res 1989;6:848-852.

35. de Boer AG, Moolcnaar F, de Lecdc LG, Breimcr DD. Rectal drug administration: clinical pharmacokinetic considerations. Clin Pharmacokinct 1982;7:285-311.

36. Chakmakjian ZH, Zachariah NY. Bioavailability of progesterone with different modes of administration. J Reprod Med 1987;32:443- 448.

37. Stovall DW, Van Voorhis BJ, Mattingly KL, Sparks AET, Chaplcr FK, Syrop CH. The effectiveness of sublingual progesterone administration during cryopreserved embryo transfer cycles: results of a matched follow-up study. Fcrtil Steril 1996;65:986-991.

38. Miller BE, De Souza MJ, Slade K, Luciano AA. Sublingual administration of micronizcd estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. Menopause 2000;7:318-326.

39. Vaugelade C, Rohmcr AC, Burel F, Belleney J, Duclos R, Buncl C. Progesterone freeze-dried systems in sublingual dosage form. Int J Pharm 2001;229:67-73.

40. Unfer V, Oostabile L, Gerli S, Marelli G. Farmacocinctica e farmacodinamica del progesterone: diverse vie di somministrazionc. In: Il progesterone. Rome: Verduci Editore; 1999. p 21.

41. Cicinelli E, Ragno G, Cagnazzo I, Fanelli F Vetuschi C, Schonauer S. Progesterone administration by nasal spray. Fertil Steril 1991;56:139-141.

42. Wuthrich P, Buri P. The transnasal route of drug administration. Aspects of nasal anatomy and physiology. Pharm Acta HeIv 1989;64:322-331.

43. Steege JF, Rupp SL, Stout AL, Bernhisel M. Bioavailability of nasally administered progesterone. Fertil Steril 1986;46:727729.

44. Cicinelli E, Ragno G, Fanelli F, Vetuschi C, Cantatore FP. Nasally-administered progesterone: comparison of ointment and spray formulation. Maturitas 1991;13:313-317.

45. Cicinelli E, Cignarelli M, Resta L, Scorcia P, Petruzzi D, Santoro G. Effects of the repetitive administration of progesterone by nasal spray in postmenopausal women. Fertil Steril 1993;60:1020- 1024.

46. Cicinelli E, Petruzzi D, Scorcia P, Resta L. Effects of progesterone administered by nasal spray on the human postmenopausal cndomctrium. Maturitas 1993;18:65-72.

47. Wattanakumtornkul S, Pinto AB, Williams DB. Intranasal hormone replacement therapy. Menopause 2003;10:88-98.

48. Williams JK. Contraceptive needs of the perimenopausal woman. Obstct Gynccol Clin North Am 2002;29:575-588.

49. Croxatto HB, Diaz S. The place of progesterone in human contraception. J Steroid Biochem 1987;27:991-994.

50. McAuley JW, Kroboth FJ, Froboth PD. Oral administration of micronized progesterone: a review and more experience. Pharmacotherapy 1996; 16:453-457.

51. Levine H, Watson N. Comparison of the pharmacokmetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women. Fertil Steril 2000;73:516-521.

52. Simon JA, Robinson DE, Andrews MC, Hildebrand JR 3rd, Rocci MLJr, Blake RE, Hodgen GD. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril 1993;60:26- 33.

53. Maxson WS, Hargrove JT. Bioavailability of oral micronized progesterone. Fertil Steril 1985:44:622-626.

54. Ottosson UB. Oral progesterone and estrogen/progestogen therapy. Acta Obstet Gynecol Scand 1984;27:94-106.

55. Ottoson UB, Carlstrom K, Damber JE, von Schoultz B. Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parentcral administration. Br J Obstet Gynaecol 1984;91:1111-1119.

56. Hargrove JT, Maxson WS, Wentz AC. Absorption of oral progesterone is influenced by vehicle and particle size. Am J Obstet Gynecol 1989;161:948-951.

57. Chakmakjian ZH, Zachariah NY. Bioavailability of progesterone with different modes of administration. J Reprod Med 1987:32:443- 448.

58. Licciardi FL, Kwiatkowski A, Noyes NL, Berkeley AS, Krey T-I- i Grifo JA. Oral versus intramuscular progesterone for in vitro fertilization: a prospective randomized study. Fertil Steril 1999:71:614-618.

59. Pouly JL, Bassil S, Frydman R, Hedon B, Nicollet B, Prada Y, Antoine JM, Zambrano R, Donnez J. Luteal support after intrim) fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Hum Reprod 1996; 11:2085-2089.

60. Buvat J, Marcolin G, Guittard C, Herbaut JC, Louvet AL, Dehaene JL. Luteal support after luteinizing hormone releasing hormone agonist for in vitro fertilization; superiority of human chorionic gonadotropin over oral progesterone. Fertil Steril 1990;53:490-494.

61. Nahoul K, Dehennin L, Jondet M, Roger M. Profiles of plasma cstrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas 1993;16:185- 202.

62. Vanselow W, Dennerstein L, Greenwood KM, de Lignieres B. Effect of progesterone \and its 5a and 5/

63. Wilson MA. GABA physiology: modulation by benzodiazepines and hormones. Grit Rev Neurobiol 1996; 10:1-17.

64. Perusquia M, Villalon CM. The relaxant effect of sex steroids in rat myometrium is independent of the gamma-amino butyric acid system. Life Sci 1996;58:913-926.

65. Whitehead MI, Townsend PT, Gill DK, Collins WP, Campbell S. Absorption and metabolism of oral progesterone. Br Med J 1980;280:825-827.

66. Antonipillai J, Moghissi E, Hawks D, Schneider T, Horton R. The origin of plasma deoxycorticostcronc in men and in women during the menstrual cycle. J Clin Endocrinol Mctab 1983;56:93-98.

67. casey ML, MacDonald PC. Formation of deoxycorricosterone from progesterone in extraadrenal tissues: demonstration of steroid 21- hydroxylasc activity in human aorta. J Clin Endocrinol Metab 1982;55:804-806.

68. Winkel CA, Parker CR Jr, Simpson ER, MacDonald PC. Production rate of deoxycorticosterone in women during follicular and luteal phases of ovarian cycle: the role of extraadrenal 21-hydroxylation of circulation progesterone in deoxycorticosterone production. J Clin Endocrinol Metab 1980;51:1354-1358.

69. Adlercreutz H, Martin F. Biliary excretion and intestinal metabolism of progesterone and estrogens in man. J Steroid Biochem 1980;13:231-244.

70. Landau RL, Lugibihl K. Inhibition of the sodium retaining influence of aldosterone by progesterone. J Clin Endocrinol Metab 1958;18:1237-1245.

71. Sharp GWG, Komack CL, Leaf A. Studies on the binding of aldosterone in the toad bladder. J Clin Invest 1966;45:450-459.

72. Wambach G, Higgins I. Antimineralocorticoid action of progesterone in the rat: correlation of the effect on electrolyte excretion and interaction with renal mineralocorticoid receptors. Endocrinology 1978;102:1686-1693.

73. Fanchin R, de Ziegler D, Bergeron C, Righini C, Torrisi C, Frydman R. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396-401.

74. Von Eye Corleta H, Capp E, Cardoso Ferreira MB. Pharmacokinetics of natural progesterone vaginal suppository. Gynecol Obstet Invest 2004;58:105-108.

75. Alam V, Vega M, Risquez F. Luteal phase support. Reprod Biomed Online 2001;3:250-262.

76. Weckstein LN, Jacobson A, Galen D, Hampton K, Ivani K, Andres J. Improvement of pregnancy rates with oocytes donation in older recipients with the addition of progesterone vaginal suppositories. Fertl Steril 1993;60:573-575.

77. Maddocks S, Hahn P, Moller F, Reid RL. A double-blind placebo- controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome. Am J Obstet Gynecol 1986;154:573- 581.

78. Kalund-Jensen H, Myren CJ. Vaginal absorption of oestradiol and progesterone. Maruritas 1984;6:359-367.

79. Tavaniotou A, Smitz J, Bourgain C, Devroey P. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update 2000;6:139-148.

80. Cicinelli E, Borraccino V, Petruzzi D, Mazzotta N, Cerundolo ML, Schonauer LM. Pharmacokinetics and endometrial effects of the vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women. Fertil Steril 1996;65:860-862.

81. Norman TR, Morse C, Dennerstein L. Comparative bioavailability of orally and vaginally administered progesterone. Fertil Steril 1991;56:1034-1039.

82. Perino M, Brigandi FG, Abate FG, Costabile L, Balzano E, Abate A. Intramuscular versus vaginal progesterone in assisted reproduction: a comparative study. Clin Exp Obstet Gynecol 1997;24:228-231.

83. Abate A, Perino M, Abate FG, Brigandi A, Costabile L, Mann F. Intramuscular versus vaginal administration of progesterone for luteal phase support after in vitro fertilization and embryo transfer. A comparative randomized study. CHn Exp Obstet Gynecol 1999;26:203-206.

84. Sauer MV, Stein AL, Paulson RJ, Moycr DL. Endometrial responses to various hormone replacement regimens in ovarian failure patients preparing for embryo donation. Int J Gynecol Obstct 1991;35:61-68.

85. Archer DF, Fahy GE, Viniegra-Sibal A, Anderson FD, Snipes W, Foldesy RG. Initial and steady-state pharmacokinetics of a vaginally administered formulation of progesterone. Am J Obstet Gynecol 1995;173:471-477.

86. Villanueva B, Casper RF, Yen SCS. Intravaginal administration of progesterone enhanced absorption after estrogen treatment. Fertil Steril 1981;35:433-437.

87. Erny R, Simoncini C, Chastclliere N, de Lignres B. Variation de la progesterone plasmatiquc induites par l’administration vaginale d’Utrogcstan. J Gynecol Biol Reprod 1989; 18:229-234.

88. Penzias AS, Alpcr MM. Luteal suppon with vaginal micronized progesterone gel in assisted reproduction. Reprod Biomed Online 2003;6:287-295.

89. Anserini P, Costa M, Remorgida V, Sarli R, Guglielminetti E, Ragni N. Luteal phase suppon in assisted reproductive cycles using cither vaginal (Crinonc 8) or intramuscular (Prontogcst) progesterone: results of a prospective randomized study. Minerva Ginecol 2001;53:297-301.

90. Lightman A, KoI S, Itskovitz-Eldor J. A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles. Hum Reprod 1999; 14:2596- 2599.

91. Can KJ. ABC of endocrinology. I. Hormones in general. Lancet 1970; 1:763-765.

92. Smitz J, Devroey P, Fagucr B, Bourgain C, Camus M, Van Stcrteghem AC. A prospective randomized comparison of intramuscular or intravaginal natural progesterone as a lutcal phase and early pregnancy supplement. Hum Reprod 1992;7:168-175.

93. Nillius SJ, Johansson EDB. Plasma progesterone levels after intramuscular or rectal administration of progesterone. Acta Obstet Gynecol Scand 1971;50:46.

94. Buckler HM, Bangah M, Healy DL, Burger HG. Vaginal progesterone administration in physiological doses normalizes raised luteinizing hormone levels in patients with polycystic ovarian syndrome. Gynecol Endocrinol 1992;6:275-282.

95. Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J CHn Endocrinol Metab 1998;83:582-590.

96. Balasch J, Fabregues F, Casamitjana R, Penarrubia J, Vanrell JA. A pharmacokinctic and endocrine comparison of recombinant follicle-stimulating hormone and human mcnopausal gonadotrophin in polycystic ovary syndrome. Reprod Biomed Online 2003;6:296-301.

97. Urman B, Tiras B, Yakin K. Assisted reproduction in the treatment of polycystic ovarian syndrome. Reprod Biomed nline 2004;8:419-430.

VITTORIO UNFER1, MARIA LUISA CASINI2, GUIDO MARELLJ3, LOREDANA COSTABILE1, SANDRO GERLI4, & GIAN CARLO DI RENZO4

1AGUNCO Obstetrics and Gynecology Centre, Rome, Italy, 2Department of Human Physiology and Pharmacology ‘Vittorio Erspamer’, University ‘La Sapienza’, Rome, Italy, 3 Department of Obstetrics and Gynecology, San Raffaele Scientific Institute, University of Milan, Italy, and 4Centre of Perinatal and Reproductive Medicine, Department of Gynecological, Obstetrical and Paediatrk Sciences, University of Perugia, Perugia, Italy

(Received 25 March 2005; revised 17 May 2005; accepted 11 July 2005)

Correspondence: V. Unfcr, AGUNCO Obstetrics and Gynecology Centre, via G. Cassiani, Rome 15-00155, Italy. Tel: + 39 06 4050 0835. Fax: +19 06 324 1284. E-mail: vittorio.unierfajycos.com\

Copyright CRC Press Aug 2005

NEW YORK (Reuters Health) – As many as one quarter of young
women with uterine cancer also have ovarian cancer, new
research suggests.

Several groups advocate ovary-sparing treatment to
safeguard fertility in young women with uterine cancer, the
authors explain, but reports have suggested that these women
have ovarian cancer rates ranging from 5 to 29 percent,
according to a report in the journal Obstetrics & Gynecology.

Dr. Ilana Cass from UCLA and Cedars-Sinai Medical Center,
Los Angeles, and colleagues investigated the frequency of
coexisting ovarian cancer in 102 women, age 45 years or
younger, who underwent hysterectomy for uterine cancer.

Twenty-six of the women, or 25 percent, had coexisting
ovarian cancer, the authors report. Aside from three cases in
which the ovarian cancer had spread from uterine cancer, all of
the ovarian cancers were new, separate cancers.

Most of the cases occurred in women with early uterine
cancer. Moreover, in a few cases, standard X-ray methods failed
to detect the ovarian cancer.

“Based on our data, we would recommend a cautious approach
to (ovary-sparing treatment) in young patients with uterine
cancer,” the authors conclude. “The high incidence of
coexisting (cancer) in the ovaries and the young age of
diagnosis suggest an increased susceptibility of the
reproductive organs to” becoming cancerous.

“If the ovaries are preserved at the time of hysterectomy,”
the researchers advise, “patients may need continued
postoperative surveillance” of the fallopian tubes and ovaries.
At the minimum, careful assessment of the fallopian tubes and
ovaries is warranted in all young patients with uterine cancer.

SOURCE: Obstetrics and Gynecology, October 2005.

NEW ORLEANS — The tomb of 18th Century voodoo queen Marie Leveau and graves of other famed artists and musicians have been unscathed in New Orleans’ most famous “city of the dead,” despite fears the flood waters from two hurricanes would destroy above-ground graves and scatter the remains of the long deceased.

Like many other graveyards in the city, St. Louis Cemetery No. 1 was submerged when the levees and flood walls that protect New Orleans gave way under the pressure from the storm surge caused by Hurricane Katrina in August.

But New Orleans’ above-ground tombs held fast, while traditional graves in outlying areas in flood regions were destroyed, scattering coffins and human remains.

“These cemeteries are truly unique in the world,” said Rob Florence, the author of two books about New Orleans, as he made his first return this week to St. Louis Cemetery No. 1, the oldest surviving city graveyard which was opened in 1789 when the city was under Spanish rule.

Leveau, the 18th century hairdresser hailed as the matriarch of voodoo, lies in a family tomb in the cemetery that is just outside the famous French Quarter and attracts thousands of tourists each year.

The final resting place for musicians, artists and luminaries from the city’s colorful past, the cemetery was also the site of a famous scene in the film “Easy Rider” when Peter Fonda clambered up a statue of the Italian Mutual Benevolent Society Tomb.

Other famous people laid to rest in the cemetery include jazz legend Isdore Barbarin, whom Louis Armstrong called “Pops,” Benjamin Latrobe, the father of the U.S. architectural profession, and, more recently, Ecuadoran-born painter George Febres.

The cemetery’s architectural style and design borrow heavily from the French and Spanish traditions, Florence said, except that New Orleans, long prone to flooding because of its low lying areas, chose to house the bodies higher in the brick and marble tombs that stand like tiny houses.

A handful of the marble inscription tables were destroyed in the flooding, but damage to the fragile monuments and statues appeared to be very minor, Florence said.

“I’m just delighted to see this. It’s uplifting. I would have thought this cemetery would have taken a beating,” he said.

Church officials were relieved their historic city cemeteries had withstood the hurricane, but in nearby St. Bernard Parish, coffins did float out of graves and some human remains were exposed.

“We’ve gotten some reports and it’s not good,” said Jody Rome, assistant director for the New Orleans’ Archdiocesan Cemeteries.

Hurricane Rita also lifted grave covers in Cameron and scattered coffins in southwestern Louisiana, much of which remains under water.

HIGH AND DRY

Historical accounts are sparse, Florence said, but records show the early settlers along the bends of the Mississippi River near the Gulf Coast buried their dead in low-lying areas, often to disastrous ends.

That prompted the wealthier residents of New Orleans to place their caskets above ground inside the tombs, unlike their European counterparts who built similar monuments, but placed the bodies in the ground.

“They did it so that during events like Hurricane Katrina, the would not have bodies floating,” Florence said.

The lock to the gates of the cemetery had been cut, apparently by the national guard troops who patrol the city, and there were signs that some of the city’s homeless had returned to claim their spots in the empty wall vaults among the dead.

The tomb of the voodoo queen attracts the most attention in the cemetery and visitors had already returned, leaving offerings of champagne, chocolates an even a wicker chair on a faded rug.

Covering the tomb are Xs, written in pen or scratched into the marble using the bricks from deteriorating graves nearby. Those marks are a voodoo sign, but Florence said the Xs were often made by the tour guides to add to the allure of voodoo at that spot.

“The family that owns the (Leveau) tomb doesn’t call it voodoo, they call it vandalism. And the real voodoo practitioners call it desecration,” he said.

By Lange, U; Teichmann, J; Strunk, J; Mueller-Landner, U; Uhlemann, C

For the treatment of osteoporosis, appropiate physiotherapy needs to use the given or remaining abilities of a patient to modulate and optimize the biological functions and structures (bone, muscle) in an adaptive, stimulating and regenerating sense. In addition physiotherapy can set serial physical stimuli to minimize pain perception by bio-psychosocial effects. Physiotherapy for osteoporosis has to be seen equivalent to pharmacotherapy with respect to prevention, cure and rehabilitation. In general, 2 different aims for effective treatment can be defined: 1. Aims that can be achieved solely with physical therapy, such as structural improvement of the existing and pharmacologically increased bone mass, slowdown of round-back formation and fall prophylaxis. 2. Aims that can be mainly achieved with physiotherapy and pharmacotherapy, such as increase of bone density and differentiated amelioration of pain. This article summarises the current knowledge on exercise and physiotherapy in preventing and treating osteoporosis, and focuses specifically on the diagnostic-orientated stimulating preventative, curative and/or rehabilitative effects, in which the choice of the individual regimen and the dosage need to be optimized for every patient individually.

Key words: Osteoporosis, diagnosis – Osteoporosis, therapy – Exercise – Physiotherapy.

Physical activity/exercise and bone

Exercise plays an important role in the prevention and treatment of osteoporosis. The overall aims of physiotherapy and sports therapy are the stabilization of the skeleton, a substantial remineralization, amelioration of pain and prophylaxis of fall.

Unfortunately, a randomized double-blind placebo-controlled study demonstrating that physical activity and exercise in youth, adulthood or in the elderly reduces fragility or osteoporosis- related fractures is difficult (or even impossible) to perform. On the other hand, a well-known relation between reduced physical activity and loss of bone mass exists, especially after post surgical immobilisation following spinal cord injury. Immobilised patients may lose 40% of their original bone mass in 1 year, whereas physical activity, e.g. standing in upright position for as little as 30 min each day prevents substantial bone loss.1

Role of exercise in prevention of fractures

It is widely accepted that physical activity is beneficial for the skeleton. Therefore, physical exercise is recommended to preserve skeletal health and to prevent age-related fractures.2 In addition, there is compelling evidence that exercise diminishes the risk factors for fall, and that exercise results in improved muscle strength as well as co-ordination and balance capabilities.

It needs to be noted that the extraskeletal effects of physical exercise, particularly with respect to the improvements in circulation, coordination, general well-beeing, sleep, social contacts, and even preventing of infectious disease,3 all contribute to an improved quality of life, and may also indirectly reduce the risk of falls and fractures.4 Assuming that a large proportion of osteoporosis fractures are a consequence of traumatic falls and are not spontaneous due to osseous instability, preventive physical therapy should target the muscular weakness, overall mobility and the visual capabilities.

There is several mechanisms by which exercise can reduce the incidence of age-related fractures. Of there, fitness programms that have been started in childhood have demonstrated a substantial positive effect on bone geometry, mass and mineral density. In this context, the benefical effect of exercise on bone mineral density (BMD) can especially be observed during growth: the higher BMD is the result of surface-specific periostal modelling, which increases bone mass and endostal (endocortical, trabecular, intracortical) thickness.5 However, no data are available whether the cortices themselves become less porous (due to few or smaller haversian canals). Mechanical stimuli and their effect on cellular activity trigger bone remodelling and osteoclastogenesis that, however, at present the type, duration and intensity of mechanical load will produce the most intensive osteogenic stimulus is not known. Therefore, to examine the influence of physical activity on bone mass, it is important to understand how physical activity contributes to the mechanical loaddependent mineralization of a given skeletal tissue.

In young adults, for example, exercise increases the peak bone mass, which lowers the risk for fractures at a higher age. In early menopausal women, exercise attenuates the rapid bone loss associated with estrogen deficiency, and in elderly individuals, exercise retards age-related decreases in general bone mass, reduces the incidence of falling and decreases the severity of falls.

On the other hand, the basis for the idea that exercise reduces fractures is derived from studies with rather low levels of evidence, namely retrospective and prospective observation cohort studies and case-control studies, but the contradictory null hypothesis that exercise has no effect on frature risk, can also not be rejected.

Fractures and exercises in women

There are several studies, which show that individuals with a lower prevalence of past or current physical activity are at an higher risk for hip-fractures 6,7 and that daily activity climbing stairs and walking are associated with a lower risk for hip- fractures.8,9 A longitudinal study of osteoporotic fractures6 and some prospective studies 10-14 demonstarted also that physical activity was protective. In addition, the European Vertebral Osteoporosis Study (EVOS), a longitudinal study, reported a protective effect of continuous exercise to reduce the number of vertebral fractures.15

Fractures and exercise in men

A protective effect of vigorous physical activiy and exercise to prevent hip fractures has been demonstrated in the Leisure World Study,11 a longitudinal study. Similar results could be observed in 4 prospective studies.11-14

Physiotherapeutic strategies in osteoporosis

Defined and validated physiotherapeutic regimen for the various forms of osteoporosis do not exist at present. However, physiotherapeutic strategies for the prevention and therapy of manifest osteoporosis have to be regarded a mandatory supplement to osteoprotective medication.

Physiotherapy offers the possibility of ameliorating local symptoms (i.e. pain and malfunction), improves the functional capabilities and affects the whole organism by positive physiological stimuli. In general, all pysiotherapeutic strategies improve mobility and flexibility by repeated stimulation and induce adaptation to an altered mechanical load.

Of the physiotherapeutic strategies used in daily practice, repeated application of hydrotherapy and exposure to ultraviolet light exerts a strengthening effect, and massage, group physiotherapy and body-awareness training are helpful procedures to achieve well-being, increased self-competence, and empowerment. Special goals of physiotherapy in patients with osteoporosis include strategies to optimize body static and movement schemes and stimulating techniques for muscle strength.

In addition, aberrant pathways of bone metabolism needs also to be eliminated, especially the reduction of pain.

When targeting the latter, it is necessary to differentiate between the different forms of pain in osteoporotic patients. Nociceptive pain needs physical stimulation, which influences predominately chemical composition of body fluids; neuralgic pain requires a stimulation, which results in a positive neuralgic reaction; whilst in the case of psychosomatic pain, it is necessary to use to treat the person as a whole. Active mobilising therapy and physiotherapy have common and diverging elements within the treatment strategies for osteoporosis and must be used in accordance with the actual physical ability of each patient.

In summary, physiotherapy for osteoporosis is mainly a diagnostic- orientated stimulating, preventive, curative and/or rehabilitative therapy.

Physiotherapy of the osteoporosis-syndrome special aspects

The specific pathogenetic process of osteoporosis itself proceeds painlessly.16-18 Therefore, based on the different levels of severity, manifestation forms and complications of osteopenia and osteoporosis, a functional diagnostic under pathomorphological and pathofunctional aspects is indespensable.

Identification of the pain in osteoporosis

Identification of the origin of pain as well as the nociception regarding its etiology (dysfunction, destruction, degeneration) and pathomechanism (mechanical, chemical, psychosomatic maltension) are of essential importance for the adequate choice of physiologically optimal physiotherapeutic treatment.

Nociceptive pain in osteoporosis presents as a receptor pain in the following structures: cords, tendons, muscles, periost, intervertebral disk and capsule, whereas neurogenic pain presents as irritations of the spinal cord and the roots of the peripheral nerves. Psychosomatic pain, however, presents as a comprehensive psychophysic maltension with changing localisation.19

Differential physiotherapy

Physical pain therapy includes electric (direct current, low- frequency stimulation current), thermic (hydrothermic, high frequency thermic – short-wave, ultrasound, li\ght-thermic – red- light) and mechanical (massage, physiotherapy) stimuli which can be applied regionally, locally or comprehensively20,21 (Figure 1). An efficient pain therapy requires that a differentiation can be made between acute and chronic pain episodes.22,23 Whereas physiotherapy in acute pain demands immediate therapy (normally rest and mild cold applications), it has to fulfile an adaptive performance therapy of neuronal structures in chronic pain (formative-adaptive physiotherapy, improving trophic thermotherapy, direct current, transcutaneous electric nerve stimulation, TENS).

Nociceptive pain

Nociceptive pain can be aggravated by longitudinal and exercise loads. This intensification usually occurs later like an episode (after pain). According to Senn,24 it is also defined as an irritational syndrome (mechanically and metabolically caused tissue inflammation) of the mesenchymal tissue; it has a dystrophic effect on all mesenchymal structures and can also be the late reaction to a phase of increased strain (decompensated strain syndrome). The physiotherapy in this case consists of a contineous easing of stress on the spine, which entails decreased axis loading and alleviation of physical strain, and of “mild” cryotherapy (e.g. cold packs) several times a day.

Acute osteogenic pain, causes by micro- and macrofractures or by stress-related, extremely high bone resorption, occurs frequently during the night.25 In this cases, pharmacotherapy has the top priority, and the physiotherapeutic applications include relief positioning and mild cryotherapy several times a day (e.g. cold air at – 30C, 300 L/min, 10 min or cold packs).

Chronic bone pain, on the other hand, responds well to mild thermal therapy (e.g. peloids at 38C) and active exercise therapy (muscle detonising, stabilising techniques).21,26

Diathermal ultrasound, which exerts its main effect in the subcutaneous tissue compartments results in an upregulated tissue metabolism, hyperemia, increased elasticity of connective-tissue fibres, and tissue-trophic improvement.27 It needs to be noted at frequently an increase in pain occurs, which secondarily leads to a relief of pain. Furthermore, appropiate doses of ultrasound (0.7- 1.2 Watt/cm^sup 2^, 10 min per region, 10-15 treatments) results in a stimulation of osteogenesis, most likely by a mechanical action on the piezoelectric potential of the bone. The application of low- frequency ultrasound dominates the mechanical components, which is by far more relevant than high-frequency ultrasound in the context of osteoporosis for influencing the altered process of remodelling.28,29

Figure 1.-Differential physiotherapy procedures for pain in osteoporosis based on curative aspects.

Tendomyoses (pain along the muscle chain) usually present with pain at early morning hours.30 In these patients, specific physiotherapy includes special massage techniques (frictions), exercise therapy (postisometric relaxation), short-wave ultrasound and TENS. Here, the treatment of trigger points by dry needling (intramuscular stimulation) 31 prove to be efficient as “well.

Neurogenic pain

Physiotherapeutic applications that activate neural mechanisms especially the inherited pain-blocking mechanisms of the organism resulting in analgesia can be used for the treatment of neurogenic pain, which is projected into the receptor- or autonomy region (dermatome, myotome, sklerotome).21,26 The most important physiotherapeutic procedures to treat this type of pain are cryotherapy short-time stimuli with an application time of less than 3 min, low-frequency electric stimuli (TENS), as well as special connective-tissue-massage techniques. A certain analgetic potency can also be achieved by direct-current applications, which is based on the depletion of neuropeptides (substance P, CGRP) comparable to the operating mechanism of capsaicine.32

Psychosomatic pain

The key accers to psychosomatic pain is the determination of the type of pain, e.g. nonlocalisability, resistance to therapy, accompanying psychovegetative instability, signs of autonomous dysregulation,19 as patients with osteoporosis have a sense of suffering that facilitate secondary, reactive, psychosomatic reactions. In contrast to treatment of localised symptoms for psychosomatic complaints holistic physiotherapeutic techniques such as thermoneutral immersion, training in body perception, therapy according to Schaarschuch-Haase, progressive muscle relaxation according to Jacobson, concentrative relaxation or psychophysical detonisation including whole-body massages can be used. At play here are a primary sense perception that triggers physical stimuli and a hedonic, emotional experience as a holostic therapeutic agent.33

Role of exercise in preventing and treating osteoporosis

Data from retrospective and prospective observational and case- control studies support the idea that physical activity is associated with a reduced fracture risk and that physical activity is beneficial to the skeleton.2,5,34,35 Exercise is associated with improved muscle strength, coordination and balance which is illustrated by the observation that bone mass of trained athletes exceeds that of nonathletic controls. There are several mechanisms by which exercise may reduce the incidence of age-related fractures, but the exact stimuli and the respective effect on cellular activity that trigger bone remodelling are not known, the type, duration, and intensity of mechanical load that will produce the most intensive osteogenic stimulus.

Various investigations have revealed a positive relationship between lifelong physical activity patterns and bone remodelling.36,37 For example, tennis players38 and squash players39 can develop an osseous hypertrophy in the region of the lower arm, joggers in the lumbar spine. According to published studies, an increase in bone density of approximately 26% is possible in certain localisations of the osseous parts of the skeleton as a result of physical exercise.40 Longitudinal studies have also provided evidence of a positive effect on bone mass.41,44 The increase in bone density that can be achieved, however, is dependent on the kind of exercise, the duration and the intensity as well as on the age, sex, and genetic disposition of the individual. Nevertheless, it must be noted that a reduced rate of fractures in general has not been reported for athletes.45,46 An interesting detail revealed a comparative study of rural and urban populations in the context of the effect of physical activity on bone mass: the prevalence of osteoporotic fractures was considerably lower among the hardworking country population.47

The influence of sport/physical activity on the risk of falling

Physical training has several benefits for elderly individuals: it stabilises circulation and improves their ability to avoid stumbling or falling, and reduces subsequently also the rate of fractures.48 However, all additional intrinsic risk factors for falling (e.g. blood pressure, pulse, cerebral ischaemia) as well as the environment-related ones should be reduced. For example, it has been possible to achieve a considerable improvement in balance and a reduction in the risk of falling by using special cardio-exercise therapy or Chinese training programmes.49

Physical activity as a therapeutic principle

Physical activity is a strong stimulus for the formation of biological tissues and the modulation of their individual functions, and appropriate stimuli are also necessary for the homeostasis of the interacting and adaptative systems nerve – muscle – bone. For effective treatment of osteoporosis physical therapy should be motor- function-regulative, structure-formative and movement0 – educative.21,50 Muscle traction and pulsating pressure are the therapeutic elements that need to be combined with gymnastics techniques and/or concepts and with sports medicine.”51-54 On the other hand, the type of exercise, the intensity of the physical therapy and the application schedule with respect to duration and intervals must be adapted to the function and individual condition of the motor system and the structural quality of the bone. In this context, previous fractures and corticoid therapy need to be taken into account.55-59 The evaluation of randomised clinical studies on the effect of physical therapy on osteoporosis in women provided evidence that regular endurance training (even normal walking), weightlifting, and heavy exercise leads to an increase in bone densitiy and a reduction of the risk of fractures in women of all age groups when compared to women without physical exercise.60 The best everyday activities or types of sport for the bones are those that force the patient to act against gravity. Usual everyday activities include climbing stairs and normal walking, even better types of sports with regard to bone protection are cycling, jogging/ running, cross-country skiing, dancing, mountain climbing and moderate weightlifting.61 Of these, especially weightlifting exercises are best suited to increasing bone density.62

Heavy exercise, however, in contrast to endurance training and aerobics,63 walking, or tap-dancing, has no influence on the bone density in the femoral neck region.64 Of interest, weight-relieving sports such as swimming did not show any effect on increasing bone density.65

With regard to gymnastics, dynamic stabilisation involving antigravitation with additional pressure on the body structure (weight bearing) 51,66,67 facilitates effects towards formative mobility. Regional remineralization and counteracting osteoclastogenesis can be achieved by moderate muscle-strengthening and holistic-orientated exercises such as aerobic endurance (fitness) and axis loading.51,54,68 This positive correlation between muscle strength, physical activity in the context of a normal life style and bone quality has been thoroughly investigated and confirmed.51,66,69,70 Nega\tive correlations have also been found in cases of inappropriate exercise, especially inadequate stress and tension.59,68,69,71

Osteoporosis patient associations have also a particular psychologic effect, specifically on experience orientation, cognitive therapy participation, empowerment, and a long-term motivation to deal with the course of the disease.33,72

One of the key parts of patient education are the instructions in proper movement behavior at home, at work, in their leisure time, and in their athletic activities.

For example, bending of the torso and kyphotic movements under stress must be strictly avoided, similar to jumping exercises, sit- ups, trunk rotation, and/or lateral flexion of the spine as well as excessive muscle stretching- and strengthening movements.17,59,71,73

Hower, the role of gymnastics to counterbalance and/or even correct subject to the deformations of the spine and to prevent fractures is still discussion. On one hand, the erection of the pelvis and thorax by muscle-stabilisation techniques and the prophylaxis of falls by coordination training can significantly ameliorate the situation of the patients, on the other hand, these attempts have limitations due to pain, progression of the pathogenetic process, lack of adaptationcapable structures as well as regulative functions and the age-related reduction of sensorimotor abilities.55, 56,74 of note, both corticosteroid- dependent osteoporosis and advanced stages of the osteoporotic deformation process necessitate a differentiated application of physiotherapy techniques, which includes also the reduction of unnatural stress on the skeleton. In this case, holistic tension exercises below the individual pain threshold, are recommendable.57,58,75

Isometric muscle-tension movements (isolated or in function chains) as well as proprioceptive neuromuscular facilitation (PNF) techniques facilitate an additional stability of the motor system for the patient with osteoporosis.75 Here, to modulate adequately the disturbed remodelling process, a structure-formative pressure stimulus in the direction of the axis (axis loading) along with isometric traction is essential.54,60,68

Elastic corsages should be recommend if the targeted parameters of gymnastics are limited by the pathogenetic process, and in case of vertebral fractures, an adequate corsage protecting the fractored area is mandatory. 53

In the context of osteoporosis, gymnastics and sport therapy have similarities as well as differences.76 Whereas gymnastics are predominantly symptomsyndrome orientated, sport therapy is directed towards influencing systemic (holistic) physical performance.

The relevance of physiotherapy within the concert of osteoprotective strategies consists on one hand in ameliorating pain; on the other hand, it improves disturbed muscular tension, supporting muscle-strengthening stabilisation (correction of posture problems), and consecutively fall prophylaxis and ADL training (everyday activites). In fall prophylaxis, the result of physiological ageing (bending-forward posture, taking little steps, reduced balancing reaction) and osteoporosis dependent incorrect posture and altered mechanisms of movement must be taken into account.24 The techniques for fall prophylaxis include balancing exercises in water (easy exercises to practice standing up straight, walking and fall behavior) as well as training static balance (therapy spin, balancing seesaw) and dynamic balance (exercises with partners, balancing over gymnastic bench).

Specific training programmes aimed at muscle remodelling under axial weigth bearing are the domain of sport therapy from the aspect of physiological training. Especially movement in water has a distinct significance for the osteoporosis syndrome due to the physical properties of water and the resulting influence on the physiological regulatory system.76 The advantageous buoyancy due to the minimisation of gravity, although the loss positive-trophic bone stimulation of gravitation, results in an adjustment of the nominal value of proprioception that corresponds to a relief of stress on the structures of the motor system. Thus, it is possible to exercise the joints without stress and stress dependent pain, which is amplified by the thermic components of water, and the diminished fear to fall during exercise. Furthermore, by varying the viscosity of the immersion medium, a tactile stimulus of the skin can be used for modulating and improving body perception. In addition moderate training by a dynamic stabilisation (movement against the resistance of the medium) is possible.

Osteoporosis – Recommendations for physical activity

In the holistic therapy concept for prevention and therapy of osteoporosis, at present no validated qualitative and quantitative minimum standards for physiotherapy exists. In general, in osteoporosis of the spine it is recommended that stress on the ventral side of the vertebral column is avoided, which should be combined with a strengthening of the back extensors. Hiking, cycling, dancing and swimming are preferentail sports activities. A current survey provides general suggestions for the type and intensity of physical activity depending on the individual severity of a given osteoporosis patient.62 These recommendations correspond to those of the German Society for Sports Medicine and the American College of Sports Medicine expecially with regard to training endurance, stength and flexibility and selecting coordination exercises.

Recommendation for therapy of osteoporosis in daily practice

The recommendations for therapy of osteoporosis in daily practice according to Lange et al.77,78 are the following:

1. Acute pain, in the bones as well as in soft parts, (fractures, irritation syndrome) requires analgetic cryotherapy in the form of mild cold (.e.g. cold compresses 150 -20, 10-15 min and/or cold air – 30C 300 L per minute for 10 min) along with stress-free positioning over a period of 5-7 days. It needs to be noted that active gymnastics are counterproductive.

2. For chronic pain caused by incorrect posture, dystrophic structures of the motor system and limitation of mobility, tratments with heat, massages and galvanisation from daily to 3 times a week in a series of 10-15 treatments are effective. Appropriate physiotherapeutic techniques with thermic effects are ultrasound (1.0 Watt/cm^sup 2^, 10 min per region), peloids (mudpacks 40C 30 min, fango packs 38C 30 min), haysack therapy (alternative-medicine morphine!) 48C, 30 min and short wave (codenser field method, 80 watts, 10 per region). With regard to massage therapy, the general massage that uses specific hand techniques to treat altered soft- tissue structures must be distinguished from the connective-tissue massage as a reflex-zone massage for the treatment of neurogenic pain (e.g. for algodystrophy). In addition, the analgetic potency of galvanization (direct current) is used with the hydroelectric-full- bath therapy (38C, 200 mA, 20 min) for pain in the entire body has proven to be effective.

3. Gymnastic exercise programmes can be used both as individual therapy and as group therapy (including a psychotonus-stimulating option), but muscle strengthening, joint mobilising, and coordinative techniques to influence posture and maintain agility as well as fall prophylaxis are also an essential component of the treatment.

In the latter, the ideal is series of treatments for 2-3 times a week for a period of 6-9 weeks.

4. Mobility therapy in water is of significant importance because of the lacking weight of the body during the exerise. However, the motor system is not only relieved of stress and of stress-related pain but also from the fear of falling.

5. Physiotherapy as pain therapy and exercising therapy regarded as an influence on positive-trophic factors must be interreted in the context of formative-training sport therapy.

References

1. Marcus R. Role of exercise in preventing and treating osteoporosis. Rheum Dis Clin North Am 2001;27:131-41.

2. Bouxsein ML, Marcus R. Overview of exerice and bone mass. Rheum Dis Clin North Am 1994;20:787-802.

3. Kriska AM, Bayles C, Cauley JA, LaPorte RE, Sandier RB, Pambianco G. A randomized exercise trial in older women: increased activity over two years and the factors associated with compliance. Mecl Sci Sports Exerc 1986;18:557-62.

4. Gerber NJ. Prophylaxis of falls and treatment of fractures. Baillire’s Clin Rheumatol 1993;7:56l-71.

5. Karlsson M, Bass S, Seeman E. The evidence that exercise during growth or adulthood reduces the risk of fragility fractures is weak. Best Pract Res Clin Rheumatol 2001;15:429-50.

6. Gregg EW, Cauley JA, Seeley DG, Ensrucl KE, Bauer DC. Physical activity and osteoporotic fracture risk in older women. Study of Osteoporosis Fractures Research Group. Ann Int Med 1998;129: 81-8.

7. Wickham CA, Walsh K, Cooper C, Barker DJ, Margetts BM, Morris J et al. Dietary calcium, physical activity, and risk of hip fracture: a prospective study. BMJ 1989;299:889-92.

8. Cooper C, Barker DJ, Wickham C. Physical activity, muscle strength, and calcium intake in fracture of the proximal femur in Britain. BMJ 1988;297:1443-6.

9. Coupland C, Wood D, Cooper C. Physical inactivity is an independent risk factor for hip fracture in the elderly. Epidemiol Commun Health 1993;47:441-3.

10.Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. New Engl Med 1995; 332:767- 73.

11. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Exercise and other factors in the prevention of hip fracture: the Leisure World study. Epidemiology 1991;2:l6-25.

12. Farmer ME, Harris T, Madans JH, Wallace RB, Cornoni-Huntley J, White LR. Anthropometric indicators and hip fracture. The NHANES I epidemiologic follow-up study. Am Geriatr Soc 1989:37:9-16.

13. Joakimsen RM, Fonnebo V, Magnus JH, StormerJ, Tollan A, Sogaard AJ. The Tromso Study: physical activity and the incidence of fractures in a middle-aged population. J Bone Miner Res 1998; 13:1149-57.

14. Meyer HE, Tverdal A, Falch JA. Risk factors for hip fracture in middle-aged Norwegian women and men. Am Epidemiol 1993; 137:1203- 11.

15. Silman AJ, O’Neill TW, Cooper C, Kanis J, Felsenberg D. Influence of physical activity on vertebral deformity in men and women: results from the European Vertebral Osteoporosis Study. J Bone Miner Res 1997;12:813-9.

16. Glaser DL, Kaplan FS. Osteoporosis, Definition and clinical presentation. Spine 1997;22:12S-6S.

17. Keck E, Kruse HP. Osteoporose: Klinik – Diagnostik – Therapic. Jena: Gustav Fischer Verlag; 1994.

18. Schacht E. Die Differentialtherapie von Osteoporosen – ein berblick auf der Basis neuerer Erkenntnisse zur Pathogenese. Z Rheumatol 1994;53:274-98.

19. Mathies H. Psychorheumatologische Diagnostik in der Praxis. Tremsbtittel: S. Sosnowski; 1997.

20. Uhlemann C, Callis R, Abendroth K. Physiotherapie beim Osteoporosesyndrom. Z Physiother 1989;41:319-39.

21. Uhlemann C. Strategien der Physiotherapie beim Osteoporosesyndrom. Osteologie 1998;4:190-202.

22. Zenz M, Jurna I. Lehrbuch der Schmerztherapie: Grundlagen, Theorie und Praxis fr Aus- und Weiterbildung. Stuttgart: Wiss. Verlagsgesellschaft; 1993.

23. Malmros B, Mortensen L, Jensen MB, Charles P. Positive effects of physiotherapy on chronic pain and performance in Osteoporosis. Osteoporosis Int 1998;8:215-21.

24. Senn E. Physikalische Therapie der Osteoporose. In: Werle J editor. Osteoporose und Bewegung. Berlin, Heidelberg, New York: Springer-Verlag; 1995.

25. Myers ER, Wilson SE. Biomechanics of Osteoporosis and vertebral fracture. Spine 1997;22 (24 Suppl):25S-31S.

26. Uhlemann C. Physiotherapie als Schmerztherapie. Krankengymnastik (KG) 1997;49:1867-76.

27. Schreiber UL, Ott L, Steiner R, Smolensk) U, Callis R, Kleditzsch J. Ultraschallintensitt und Durchblutungsandeaing – Untersuchungen mittels Laser-Doppler-Spektroskopie. Phys Rehab Kur Med 1994; 4:202-5.

28. Knoch HG. Der niederfrequente Ultraschall. rztezeitschrift fr Naturheilverfahren 1997;38:20-4.

29. Uhlemann C, Radandt RR. Wirkungsphysiologische Aspekte des niederfrequenten Ultraschalls (nf-US) – eine therapeutische Option in der Osteologie? Phys Med Rehab Kuror 2003;13:240.

30. Simons DG. Symptomatologie und klinische Pathophysiologie des myofaszialen Schmerzes. Manuelle Medizin 1994;32:47-56.

31. Gunn Chan C. The gunn approach to the treatment of chronic pain. New York, Edingburgh, London, Madrid, Melbourne, San Francisco and Tokyo: Churchill Livingstone; 1996.

32. Schnizer W, Korr H, Lindner J, Magyarosy J, Wenemoser A. Die Untersuchung physikalisch-medizinischer und balneotherapeutischer Erytheme (Warme, Gleichstrom, CO2) am Capsaicinmodell. Phys Rehab Kur Med 1993;3:125-9.

33. Bhring M. Naturheilkunde, Grundlagen, Anwendungen, Ziele. Mnchen: C.H. Beck; 1997.

34. Venth RT. Bewegungstherapie as Prophylaxe und Therapie bei Osteoporose. Z Gastroenterol 2002;40 Suppl l:S62-7.

35. Hertel KL, Trahiotis MG. Exercise in the prevention and treatment of osteoporosis: the role of physical therapy and nursing. Nurs Clin North Am 2001;36:441-53.

36. Tylavsky FA, Anclerson JJB, Talmage RV, Taft TN. Are calcium intakes and physical activity patterns during adolescence related to radial bone mass of white college-age females? Osteoporosis Int 1992;2:232-40.

37. McCulloch R, Bailey D, Houston C, Dodd BL. Effects of physical activity, dietaiy calcium intake and selected lifestyle factors on bone density in young women. Can Med Assoc J 1990;142:221- 7.

38. Huddleston A, Rockwell D, Kulund D, Harrison RB. Bone mass in lifetime tennis athletes. JAMA 1980;244:1107-9.

39. Kontulainen S, Kannus P, Haapasalo H, Sievanen H, Pasanen M, Heinonen A et al. Good maintenance of exercise-induced bone gain with decreased training of female tennis and squash players: a prospective 5-year follow-up study of young and old starters and controls. J Bone Min Res 2001;l6:195-201.

40. Sharkey NA, Williams NI, Guerin JB. The role of exercise in the prevention and treatment of osteoporosis and osteoarthritis. Rheumatology 2000;35:209-22.

41. Chilibeck PD, Sale DG, Webber CD. Exercise and bone mineral density. Sports Med 1995;19:103-22.

42. Mosekilde L. Osteoporosis and exercise. Bone 1995;17:193-5.

43. Sinaki M. Exercise and osteoporosis. Arch Phys Med Rehabil 1989; 70:220-9.

44. Smith EL, Gilligan C. Physical activity effects on bone metabolism. Calcif Tissue Int 1991;49 Suppl:S50-4.

45. Joakimsen RM, Magnus JH, Fonnebo V. Physical activity and predisposition for hip fractures: a review. Osteoporosis Int 1997;7:503-15.

46. Lin IT, Lane JM. Nonmedical management of osteoporosis. Curr Opin Rheumatol 2002;l4:441-6.

47. Jonsson B, Gardsell P, Johnell O, Redlund-Johnell I, Sernbo I. Differences in fracture pattern between an urban and a rural population. A comparative population-based study in southern Sweden. Osteoporosis Int 1992;2:269-73.

48. Pfeifer M, Dreher R, Minne HW. Osteoporose: Nicht- medikamentse MalSnahmen. Akt Rheumatol 2001;26:219-26.

49. Hong Y, Li JX, Robinson PD. Balance control, flexibility, and cardiorespiratory fitness among older Tai Chi practitioners. BrJ Sports Med 2000;34:29-34.

50. Uhlemann C, Bocker B, Abendroth K. Vergleich einer 1- bzw. 2 mal tglichen Bewegungstherapie bei stationren Patienten mit einem Osteoporosesyndrom bezttglich Akzeptanz und Schmerzverhalten. Osteologie 1998;1:760-1.

51. Gutin B, Kasper MJ. Can vigorous exercise play a role in osteoporosis prevention? A Review. Osteoporosis Int 1992;2:55-69.

52. Price RL. Practise guidelines for the treatment of osteoporosis. Calcif Tissue Int 1996;59:520-3.

53. Riggs BL, Melton LJ. Osteoporosis: Etiology, Diagnosis and Management. New York: Raven Press; 1988.

54. Werle J. Osteoporose und Bewegung. Berlin, Heidelberg, New York: Springer-Verlag; 1995.

55. Ringe JD. Altersosteoporose- Prophylaxe und Thrapie. Z Gerontol 1993;26:34-8.

56. Ringe JP, Meunier PJ. Senile Osteoporose. Stuttgart, New York: Thieme-Verlag; 1996.

57. Sambrock PN. Corticosteroid osteoporosis. Br J Rheumatol 1995; 34:8-12.

58. Reid IR. Glucocorticoid-induced osteoporosis and other forms of secondary osteoporosis. In: Meunier PJ editor. Osteoporosis. Diagnosis and management. London: Martin Dunitz; 1998.

59. Sinaki M. Postmenopausal spinal osteoporosis. Mayo Clin Proc 1982;57:699-703.

60. Ernst E. Exercise for Female Osteoporosis. Sports Med 1998;25: 359-68.

61. Bartl R. Osteoporose. Pravention – Diagnostik – Therapie. Stuttgart, New York: Thieme-Verlag; 2001.

62. Scheel AK, Backhaus M, Koziolek M, Strutz F. Osteoporose und Sport. Akt Rheumatol 2003;28:203-9.

63. Chien MY, Wu YT, Hsu AT, Yang RS, Lai JS. Efficacy of a 24- week aerobic exercise programm for osteopenic postmenopausal women. Calcif Tissue Int 2000;67:443-8.

64. Minne HW, Pollahne W, Pfeifer M. Nichtmedikamentse Mafinahmen. In: Pollahne W, Broil H, Burckhardt P, Delling G, Minne HW editors. Therapie primrer und sekundrer Osteoporosen. Stuttgart, New York: Thieme-Verlag; 1999. p.25-33.

65. Risser WL, Lee EJ, LeBlanc A, Poindexter HB, Risser JM, Schneider V. Bone density in eumenorrheic female college athletes. Med Sci Sports Exerc 1990;22:570-4.

66. Lane JM. Osteoporosis, medical prevention and treatment. Spine 1997;22:32S-7S.

67. Murray TM. Prevention and management of osteoporosis: consensus statements from the scientific advisory board of the osteoporosis society of Canada. Calcium nutrition and osteoporosis. Can Med Assoc J 1996;155:935-9.

68. Sabo D, Reiter A, Pfeil J, GulSbacher A, Niethard FU. Beeinflussung der Knochenqualitt durch extreme korperliche Belastung. Z Orthop 1996;134:l-6.

69. Dppe H, Grdsell P, Johnell O, Nilsson BE, Ringsberg K. Bone mineral density, musclestrength and physical activity. Acta Orthop Scand 1997;68:97-103.

70. Kelly GA. Exercise and regional bone mineral density in postmenopausal women. AmJ Phys Med Rehabil 1998;77:76-87.

71. Sinaki M, Warmer HW, Offord KP, Hodgson SF Efficacy of nonloading exercises in prevention of vertebral bone loss in post- menopausal women: A controlled trial. Mayo CHn Proc 1989;64: 762-9.

72. Tosteson ANA. Quality of life in the economic evaluation of osteoporosis prevention and treatment. Spine 1997;22 (24 Suppl):58S- 62S.

73. Wiemann K. Beeinflussung muskularer Parameter durch ein zehnwochiges Dehnungstraining. Sportwissenschaft 1991;3:295-306.

74. Gallagher JC. Vitamin D metabolism and therapy in elderly subjects. South Med J 1992;85:2S43-7.

75. Brunkow R, von Rose Marie Bold, Grossmann A, Block R. Stemmfuhrung nach Brunkow. 5. Uberarb. Auflage, Stuttgart: Enke- Verlag; 1989.

76. Uhlemann C, Abendroth K. Mglichkeiten, Notwendigkeiten und Tatschlichkeiten der Physikalischen und Rehabilitativen Medizin in der Therapie des Osteoporosesyndroms. Osteologie 1998;1:54.

77. Lange U, Teichmann J, Uhlemann C. Role of physiotherapeutic strategies in osteoporosis. Osteologie 2004;13:109-13.

78. Lange U, Teichmann J, Uhlemann C. Current knowledge about physiotherapeutic strategies in osteoporosis prevention and treatment. Rheumatol Int 2004 Nov 27; [Epub ahead of print].

U. LANGE1,2 J. TEICHMANN3, J. STRUNK1,2, U. MUELLER-LANDNER1,2, C. UHLEMANN4

1 Kerckhoff Clinic, Department of Rheumatology Clinical Immunology, Physical Medicine and Osteology, Bad Nauheim, Germany

2 Department of Internal Medicine and Rheumatology University of Gien, Gieen, Germany

3 Medical Clinic C, City-Hospital Ludwigshafen Ludwigshafen, Germany

4 Institute of Physiotherapy, University Jena, Jena, Germany

Address reprint requests to: Priv.-Doz. Dr. med. U. Lange, Kerckhoff Clinic, Department of Rheumatology, Clinical Immunology, Physical Medicine and Osteology, Sprudelhof 11, 61231 Bad Nauheim, Germany. E-mail: [email protected]

Copyright Edizioni Minerva Medica Jun 2005

NEW YORK — Heartburn occurs when stomach acid backs up into the esophagus, causing chest pain. Gastroesophageal reflux disease or GERD, as it’s called technically, has nothing to do with the heart … or does it?

Polish researchers report that people with existing coronary artery disease may also have GERD, and this can trigger constriction of the heart’s blood vessels and cause ischemia — restricted bloody supply that can damage the heart further.

However, this chain of events can be prevented with drugs that reduce the production of gastric acid, the team reports in the International Journal of Cardiology.

Dr. Slawomir Dobrzycki from the Medical University in Bialystok and colleagues had 50 patients with proven coronary artery disease undergo 24-hour continuous recording of the acidity in the esophagus and the heart’s electrical rhythm.

Then the 23 patients found to have GERD were given the acid-reducing drug omeprazole to take twice daily for seven days. On the seventh day, the simultaneous ECG and acidity Holter monitoring was repeated.

Overall, 45 (21 percent) of a total of 218 episodes of heart ischemia seen on the ECG recording coincided with episodes of acid reflux. GERD patients had significantly more ischemic events.

However, by comparing the recordings obtained before and after treatment with omeprazole, the researchers concluded that the anti-reflux therapy reduced the amount of ischemia suffered by the heart.

They say a “multidisciplinary approach” to evaluating patients with chest pain should be able to uncover the underlying problem and lead to the best treatment.

SOURCE: International Journal of Cardiology, September 15, 2005.