Patients who use certified specialists are being advised to check their doctors’ credentials, as many are nearing a compulsory retesting or expiration date for the first time.

The recertification issue, the topic of an April 5 article by AP Medical Writer Marilynn Marchione, dates back to the 1990s. Before then, a specialist needed to complete a test once, and was then certified for life. Now, however, he or she “must retest every six to 10 years to prove their skills haven’t gone stale,” according to Marchione.

Some doctors are complaining about the new policy, while others, such as 52-year-old Dr. Stephen Mester of the Brandon Region Hospital in Florida, are voluntarily seeking recertification, even though they don’t have to.

As Dr. Mester told the Associated Press (AP), “It’s just an opportunity to maintain my skills and confirm to myself that I can do what I’ve been trained to do. Most of what I do today didn’t exist, and some of it not even thought of, when I was in medical school.”

One organization that certifies doctors is the American Board of Internal Medicine (ABIM), and they require testing every 10 years for anyone certified on or after 1990.

According to the group’s official website, “Certification demonstrates that physicians have met rigorous standards through intensive study, self-assessment and evaluation,” and all ABIM certified doctors are “strongly urged” to retest, even if not so required, because “the program helps improve the quality of care delivered to patients.”

For those patients who are curious, the American Board of Medical Specialties (ABMS) offers an Internet database of medical specialists on their website’s “Is Your Doctor Certified?” page. Registered users can log in and check on the certification status of most doctors (save for American Board of Pediatrics certified doctors, which does not include termination dates on newly issued certificates) online.

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On the Net:

• American Board of Internal Medicine (ABIM)
• ABMS: Is Your Doctor Certified?

Whether it is about who gets to ride shotgun or who wore a shirt without asking, siblings fight. While seemingly innocent, a recent study at the University of Missouri reveals that certain types of fights can affect the quality of sibling relationships. MU researchers identified two major types of conflict among adolescent siblings and found that conflicts about personal space have a negative impact on trust and communication between siblings.

“The first conflict area we found includes issues about physical and emotional personal space, such as borrowing items without asking and hanging around when older siblings have friends over,” said Nicole Campione-Barr, assistant professor in the MU Department of Psychological Sciences. “When these issues were present, both younger and older siblings reported less trust and communication. The second conflict area includes equality and fairness issues, such as taking turns and sharing responsibilities. These conflicts had no impact on relationship quality.”

While both younger and older siblings reported personal space conflicts, older siblings reported these conflicts more frequently, according to the researchers. This suggests that older siblings are more sensitive to personal space issues and may indicate the beginning of their separation from the family.

The findings of this study can help parents, psychologists and other individuals who work with teens understand the impact that conflicts can have on sibling relationships. For parents, Campione-Barr suggests setting up family boundaries to reduce sibling conflicts about personal space.

“Parents need to establish and enforce family rules about respecting privacy, personal space and property,” Campione-Barr said. “However, when sibling conflicts occur, there needs to be negotiations between siblings. Previous research tells us that parents should step aside because they have a tendency to make matters worse.”

In the study, the researchers interviewed and surveyed pairs of siblings, ages 8-20. This study is the first to examine types of sibling conflict between adolescent age children. Research has traditionally focused on sibling relationships among younger children. Campione-Barr is conducting a follow-up study to examine the impact that conflicts have on the adjustment of adolescents as individuals.

The study, “Who Said You Could Wear My Sweater? What Adolescent Siblings Fight About and How it Affects Their Relationship,” recently was published in Child Development. It was co-authored by Judith Smetana in the Department of Clinical and Social Sciences in Psychology at the University of Rochester.

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On the Net:

• University of Missouri
• Child Development

Rapamycin proves mettle in second model of memory-robbing disease

If research results continue to be repeated and are turned into clinical trials, a drug already approved for some uses could be marshaled “” sooner than we expect “” to prevent Alzheimer’s disease in humans and improve health to the end of life.

A few weeks after a report that rapamycin, a drug that extends lifespan in mice and that is currently used in transplant patients, curbed the effects of Alzheimer’s disease in mice, a second group is announcing similar results in an entirely different mouse model of early Alzheimer’s.

Both reports are from The University of Texas Health Science Center at San Antonio, where the rapamycin studies are conducted in the Sam and Ann Barshop Institute for Longevity and Aging Studies and in basic science departments.

The second report, released April 1 by the journal PLoS ONE, published by the Public Library of Science, showed that administration of rapamycin improved learning and memory in a strain of mice engineered to develop Alzheimer’s. The improvements in learning and memory were detected in a water maze activity test that is designed to measure learning and spatial memory. The improvements in learning and memory correlated with lower damage in brain tissue.

Less sticky

“Rapamycin treatment lowered levels of amyloid-beta-42, a major toxic species of molecules in Alzheimer’s disease,” said Veronica Galvan, Ph.D., assistant professor from the Barshop Institute and the Department of Physiology. “These molecules, which stick to each other, are suspected to play a key role in the early memory failure of Alzheimer’s.”

This strain of mice has been engineered to have defects in the genes that make amyloid precursor protein, ultimately resulting in the abnormal accumulation of amyloid-beta-42 that dampens synaptic connections. Synapses are junctions where neurons communicate with each other, providing the essential “wiring” for normal function of the brain. Without this communication, neurons die, leading to the memory losses seen in Alzheimer’s.

Longer life for mice

In July 2009, Barshop Institute researchers and colleagues at two other institutions reported that microencapsulated rapamycin extended the life span of mice, possibly by delaying aging. A bacterial product first isolated from soil of Easter Island, rapamycin is approved by the U.S. Food & Drug Administration to prevent organ rejection in transplant patients. Rapamycin is the first pharmacologic intervention shown to extend life in an animal model of aging.

If rapamycin treatment indeed delays aging in mice, are age-associated diseases, such as Alzheimer’s, delayed or blocked? The new study, authored by Spilman et al, sought to answer this question. In the study, the same rapamycin-supplemented diet as in the life span study was fed to groups of the Alzheimer’s-susceptible mice and their normal littermates. A non-rapamycin diet was fed to control groups. Rapamycin feeding began at 4 months of age, when the susceptible mice show high amyloid-beta-42 levels and synaptic dysfunction, but do not yet have amyloid beta plaques or spatial memory impairments.

Get out of the water

After 13 weeks of treatment, all groups were trained in the water maze exercise to see how quickly they could learn to exit the water via a hidden platform. Doing so requires the use of spatial cues, such as patterned posters or photos, positioned all around the water tank. The Alzheimer’s model mice that were fed the control diet predictably showed significant losses in learning and memory and reduced performance.

“Strikingly, the Alzheimer’s mice treated with rapamycin displayed improved performance on the maze, even reaching levels that were indistinguishable from their normal littermates,” Dr. Galvan said. “Levels of amyloid-beta-42 were also reduced in these mice after treatment, and we are seeing preserved numbers of synaptic elements in the brain areas of Alzheimer’s disease mice that are ravaged by the disease process.”

Intriguingly, differences in resistance to swimming in the middle of the pool (a measure of anxiety) and in floating (a measure of hopelessness) were not observed among groups. “This suggests that improved performance in rapamycin-treated, Alzheimer’s-susceptible mice is a result of effects on purely cognitive processes but is not due to effects related to non-cognitive components of behavior, such as helplessness and anxiety,” Dr. Galvan said.

Changing a toxic process

“The fact that we are seeing identical results in two vastly different mouse models of Alzheimer’s disease,” Dr. Galvan added, in reference to the recent study by Caccamo et al, “provides robust evidence that rapamycin treatment is effective and is acting by changing a basic pathogenic process of Alzheimer’s that is common to both mouse models. This suggests that it may be an effective treatment for Alzheimer’s in humans, who also have very diverse genetic makeup and life histories.”

Grants from the Alzheimer’s Association and the National Institute on Aging supported the study. Co-authors are Drs. Patricia Spilman, Natalia Podlutskaya, Matthew J. Hart, Jayanta Debnath, Olivia Gorostiza, Dale Bredesen, Arlan G. Richardson, Randy Strong and Veronica Galvan. Collaborating institutions are the UT Health Science Center San Antonio (Barshop Institute, departments of Physiology, Pharmacology, Cellular and Structural Biology, and Molecular Medicine); the South Texas Veterans Health Care System (Geriatric Research, Education and Clinical Center and Research Service); the University of California, San Francisco (Department of Pathology); and the Buck Institute for Age Research, Novato, Calif.

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On the Net:

• University of Texas Health Science Center at San Antonio
• PLoS ONE

Traditional Chinese acupuncture (TCA), where very thin needles are used to stimulate specific points in the body to elicit beneficial therapeutic responses, may be an effective treatment option for patients who suffer from persistent post- viral olfactory dysfunction (PVOD), according to new research in the April 2010 issue of Otolaryngology ““ Head and Neck Surgery.

Olfactory dysfunction can arise from a variety of causes and can profoundly influence a patient’s quality of life. The sense of smell determines the flavor of foods and beverages and also serves as an early warning system for the detection of environmental hazards, such as spoiled food, leaking natural gas, smoke, or airborne pollutants. The loss or distortions of smell sensation can adversely influence food preference, food intake, and appetite.

Approximately 2 million Americans experience some type of olfactory dysfunction. One of the most frequent causes of loss of smell in adults is an upper respiratory tract infection (URI). Patients usually complain of smell loss following a viral URI. The smell loss is most commonly partial, and reversible. However, occasionally patients may also present with parosmia (a distortion of the sense of smell), phantosmia (smelling things that aren’t there), or permanent damage of the olfactory system.

To date, there is no validated pharmacotherapy for PVOD, but attempts have been made to establish a standardized treatment. In the literature, systemic and topical steroids as well as vitamin B supplements, caroverine, alpha lipoic acid, and other drugs were used to treat patients. The researchers point out that in addition to these treatments, complementary and alternative medicines are currently being employed by many patients on their own, and that exploration into their usefulness by traditional Western medicine should be validated.

In the current study, 15 patients presenting to an outpatient clinic with PVOD were treated by TCA in 10 weekly 30-minute sessions. Subjective olfactometry was performed using the Sniffin’ Sticks test set. Treatment success was defined as an increase of at least six points in the sticks test scores. The effects of TCA were compared to matched pairs of people suffering from PVOD who had been treated with vitamin B complex. Eight patients treated with TCA improved olfactory function, compared with two treated with vitamin B complex.

The authors acknowledge that their study is limited by its size, and that further studies should be conducted in a larger population. However, the authors write “”¦the observed high response rate of about 50 percent under TCA was superior to that of vitamin B complex or that of spontaneous remission, and offers a possible new therapeutic regimen in postviral dysosmia.”

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On the Net:

• American Academy of Otolaryngology — Head and Neck Surgery

German researchers determined that concentrations of the sex hormones, testosterone in men and estrogen in women, may have a positive effect on the regenerative potential of cartilage tissue. The study suggests hormone replacement in the joint fluid of men and women might be beneficial in treating late stages of human osteoarthritis (OA) by regenerating damaged tissue. Details of this evidence-based study appear in the April issue of Arthritis & Rheumatism, a journal published by Wiley-Blackwell on behalf of the American College of Rheumatology.

Free moving (diarthrodial) joints, such as the knee and hip, produce smooth and painless limb movement when there is adequate transmission of forces between the bones and joint (articular) cartilage. Disturbances in joint architecture due to trauma, abnormal load, endocrine diseases (diabetes, hypothyroidism) or inflammatory conditions may result in OA. Worldwide estimates say 9.6% of men and 18% of women 60 years or older have OA symptoms and the World Health Organization (WHO) projects that by 2020, OA will be the fourth leading cause of disability.

Nicolai Miosge, M.D., Ph.D., and colleagues from the August University in Goettingen, Germany examined the regenerative potential of chondrogenic progenitor cells (CPCs) that are present in arthritic tissue during the late stages of OA. The research team speculated that these CPCs might be influenced by sex steroids, and therefore hormone replacement therapy directed to the joint fluid could be beneficial in restoring damaged tissue. Tissue samples from 372 patients who underwent total knee replacement were analyzed. The mean age was 71 years of age for men and 72 years for women, with women representing 64.25% of participants.

Estrogens are known to influence bone metabolism and researchers found that 17ÃŽ²-estradiol (E2), which increases calcium deposition in both sexes, was present in the joint fluid of study participants. CPCs positive for estrogen receptors (ERÃŽ± and ERÃŽ²) as well as androgen receptors were present in the OA tissue as well. Both estrogen and testosterone influenced the expression of all 3 receptor genes and the CPCs by regulating gene expression.

Researchers found late-stage OA cartilage populated with elongated cells that were not present in healthy connective tissue. Upon investigation of the elongated cells, the team identified a unique progenitor cell population (CPCs). “We were able to isolate CPCs in 95.48% of female patients and 96.97% of male patients, making these cells a good target for future therapeutic intervention for a very large number of OA patients,” Dr. Miosge said. “Hormone replacement therapy in joint fluid may help mitigate the effects of OA and further investigation is needed,” concluded Dr. Miosge.

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Wiley-Blackwell

“The value of animal experiments for predicting the effectiveness of treatment strategies in clinical trials has remained controversial, mainly because of a recurrent failure of interventions apparently promising in animal models to translate to the clinic,” say authors in a Research in Translation piece published in PLoS Medicine this week. The PLoS Medicine magazine article by H. van der Worp (University Medicine Centre Utrecht) and colleagues discusses the controversies and possibilities of translating the results of animal experiments into human clinical trials.

Related research, published in PLoS Biology, shows how selective reporting of medical research carried out on animals may be creating a false impression of how effective drugs might be. A team of researchers, led by the University of Edinburgh, say this is because medical journals are more likely to publish positive results that highlight medical advances than negative or neutral findings, which are deemed less interesting.

Citation: Can animal models of disease reliably inform human studies? by van der Worp et al (published in PLoS Medicine). van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, et al. (2010) Can Animal Models of Disease Reliably Inform Human Studies? PLoS Med 7(3): e1000245. doi:10.1371/journal.pmed.1000245

Funding: This work was supported in part by the MRC Trials Methodology Hub and the National Health and Medical Research Council. The funders played no role in the decision to submit the article or in its preparation.

Competing Interests: Malcolm R. MacLeod is on the Editorial Board of PLoS Medicine.

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On the Net:

• PLoS Medicine

Deep vein thrombosis (DVT) in pregnant patients is more likely to occur on the left side, and in particular in the left leg, write the authors of a Review article in CMAJ (Canadian Medical Association Journal).

“In nonpregnant patients, DVT, the formation of a blood clot, is most common in the calf veins,” write Dr. Wee-Shian Chan, Women’s College Hospital and coauthors. “This review was conducted to see whether this is also the case for pregnant women in order to limit diagnostic procedures, such as x-rays, because of the effects on the fetus.”

The authors reviewed 1098 papers, and found only six that met the inclusion criteria. Despite, the limited number of studies on this area it has been found that left-sided DVT and proximal DVT are common in pregnancy.

The authors conclude that until prospective diagnostic studies are available for pregnant patients, it may be prudent to conduct a routine examination of the iliofemoral system when a pregnant patient presents with suspected deep vein thrombosis.

In a related commentary, Dr. Ristaa Kajaa, Professor of Medicine, Turku University, Satakunta Central Hospital, writes that despite the limited number of pertinent studies presenting data in this area, the results of this study suggest that the anatomic distribution of deep vein thrombosis in pregnant women may differ from nonpregnant patients. The increased prevalence of isolated proximal vein DVT seen in this study is clinically important because of the high risk of pulmonary embolism.

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On the Net:

• Canadian Medical Association Journal

How do we handle the ethical dilemmas of research on adults who can’t give their informed consent? In a recent article in the journal Bioethics, ethicist Stefan Eriksson proposes a new approach to the dilemma of including dementia patients and others with limited decision making capabilities in research.

There is a need for research on persons with impaired decision making, for example dementia patients. Without their participation we stand to lose knowledge necessary for future treatments that can benefit these groups. There are ethical guidelines to guard their interests, but they are somewhat ill-guided, says Stefan Eriksson, associate professor of research ethics at the Centre for Research Ethics & Bioethics (CRB).

“We are sometimes led to believe that these guidelines conclusively state that research on these groups is permitted only in exceptional cases, but they don’t,” he says.

According to Stefan Eriksson, today’s guidelines are often arbitrary. On one hand, research that benefits some groups, for example one’s own age group, is allowed. On the other hand, research that benefits other groups, for example one’s own children or community is not allowed. The previous will or interests expressed by person has little or no weight in these situations.

Another problem that Stefan Eriksson highlights is that some ethical standards simply make no sense for these groups. For example, the idea of a “Ëœminimal risk standard’ builds on the idea that there is something ordinary or routine about the risks we take in our daily lives. Such risks should then be acceptable in research as well. This kind of reasoning doesn’t work for someone with for example Alzheimer’s. The same is true for “Ëœvery slight impact’ and “Ëœroutine examination’, notions that doesn’t translate well to a person with dementia who might very well react in a very different way than a person without dementia.

“The guidelines that researchers act according to allows for vulnerable persons to be exploited,” says Stefan Eriksson.

Instead of trying to translate the norm to those who fall outside it, we need to address the real issues at stake and re-write the guidelines that apply today Stefan Eriksson says. We need to rid them of notions of exceptionality, minimal risk and group beneficence. We also need to monitor this kind of research more closely and provide legal obligations to compensate for any injuries suffered. He concludes:

“But we also need to consider other issues, such as how surrogate decision-makers can be of use to these persons and how to find ways to estimate a dementia patient’s capacity for autonomy. We need to continue the debate and do more research on the ethics of research on persons with limited decision-making capacity.”

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On the Net:

• Centre for Research Ethics & Bioethics
• Bioethics Abstract

Patients who have a history of bladder control problems may benefit from an implantable device that uses electrical pulses to alter abnormal communication between bladder nerves and the brain, said a urologist at Baylor College of Medicine.

“Patients with these bladder issues often suffer from significant embarrassment and a low quality of life,” said Dr. Christopher Smith, associate professor in the Scott Department of Urology at BCM. “This has been a life-changing treatment for some patients who have not responded to other therapies.”

Urinary conditions

The treatment, called InterStim Therapy, has been approved by the U.S. Food and Drug Administration for patients with urinary frequency and urgency; urge incontinence, characterized by involuntary leakage, usually associated with an urge to urinate; and urinary retention, an inability to urinate.

The bladder is controlled by the brain and sacral nerves, said Smith, a specialist in male and female incontinence and voiding dysfunction, or difficulty urinating. When there is miscommunication between the brain and the bladder nerves, the nerves cannot tell the bladder how to function properly, causing problems with controlling and emptying the bladder.

Helps control bladder function

The new treatment is like a pacemaker for the bladder, said Smith. It helps control bladder function by filtering signals that may be causing the problem.

“With overactivity, the treatment blocks the signals telling the brain to go often,” said Smith. “With urinary retention, it filters signals to the lower pelvis to allow the pelvic muscles to relax and the bladder muscles to contract.”

InterStim is recommended for patients who have not had success with diet and behavioral changes, or oral medications.

Trial phase

To determine if the treatment works, patients undergo a three to 14-day trial phase that tests the device’s ability to improve symptoms.

“Through a needle, a temporary wire is passed through to the sacral nerves,” said Smith. “The wire is attached to the skin and connected to an external stimulator worn by the patient that sends electrical pulses to the sacral nerves.”

The test phase is required for getting insurance coverage, said Smith.

Minimally invasive procedure

If the patient’s symptoms significantly improve, the temporary wire will be replaced with a permanent wire. Using a small incision, a stimulator will be implanted in the buttocks area and connected to the permanent wire in such a way that the whole device will be located beneath the skin, invisible to the naked eye.

Patients can control the intensity of the electrical pulses with a remote control.

“A major benefit of the treatment is that it is minimally invasive,” said Smith. “It can be done in an outpatient setting using a local anesthetic.”

Follow-up exams

Patients should have follow-up exams every 6 to 12 months, Smith said. The device is controlled by batteries that last for three to five years.

Smith said it’s important to understand that patients who have obstructive issues such as benign prostatic hyperplasia (i.e. enlarged prostate), cancer, or urethral strictures will not benefit from this procedure.

Patients with multiple sclerosis, often characterized with bladder control problems, should consult their neurologists first if they are interested in InterStim.

“A majority of MS patients are followed up with magnetic resonance imaging, or MRI,” said Smith. “As of now, MRI studies are contraindicated in patients with the device.” However, there may be other scanning methods available for MS patients.

Patients who think they may be eligible to test this procedure should get a referral to see a urologist who specializes in this treatment.

InterStim is manufactured by MedTronic.

An estimated that 33 million Americans suffer from bladder control problems.

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On the Net:

• Baylor College of Medicine
• Scott Department of Urology
• MedTronic

Knocking out apoptosis genes is critical, but so is revving up insulin pathway

University of California, Berkeley, biologists have found a signal that keeps stem cells alive in the adult brain, providing a focus for scientists looking for ways to re-grow or re-seed stem cells in the brain to allow injured areas to repair themselves.

The researchers discovered in fruit flies that keeping the insulin receptor revved up in the brain prevents the die-off of neural stem cells that occurs when most regions of the brain mature into their adult forms. Whether the same technique will work in humans is unknown, but the UC Berkeley team hopes to find out.

“This work doesn’t point the way to taking an adult who has already lost stem cells and bringing them back mysteriously, but it suggests what mechanisms might be operating to get rid of them in the first place,” said Iswar K. Hariharan, UC Berkeley professor of molecular and cell biology. “Plus, if you were able to introduce neural stem cells into an adult brain, this suggests what kinds of mechanisms you might need to have in place to keep them alive.”

Hariharan noted that other researchers have gotten neural stem cells to persist by blocking genes that cause them to die. Yet this alone does not produce healthy, normal-looking neural stem cells that can make mature neurons. The UC Berkeley team’s new finding shows that it also is necessary to provide an insulin-like signal. If stopping neural stem cell death is analogous to taking your foot off the brake, then providing an insulin-like signal is like stepping on the gas, he said. Both are essential.

Hariharan, post-doctoral researcher Sarah E. Siegrist and their colleagues published their findings Thursday, March 25 in the online version of the journal Current Biology. Their report will appear in the journal’s April 13 print edition.

Most areas of the adult mammalian brain and fruit fly brain are devoid of neural stem cells, the only cells able to generate full-fledged neurons. Presumably, Hariharan said, the lack of neural stem cells is why the injured brain is unable to replace dead neurons.

In the new study, Siegrist showed that the stem cells present in the pupal stage of fruit flies are gone in the adult brain because they die off, rather than merely mature into neurons. The stem cells that persisted the longest were in the mushroom body, a region of the fly brain responsible for memory and learning that, in some ways, is like the hippocampus in humans.

In subsequent experiments, she attempted to prevent the death of neural stem cells in fruit flies by genetically blocking a process called programmed cell death (apoptosis). While this allowed the stem cells to survive longer, the cells were small and did not make many neurons. In fact, Siegrist said, they showed signs of impaired growth, suggestive of insulin withdrawal.

She then tried various genetic manipulations to mimic an insulin-type signal, this time using mutant fruit flies with their apoptosis genes also blocked. Amazingly, the neural stem cells persisted for at least a month and even generated many mature, apparently normal, nerve cells.

“These neural stem cells seem to behave properly, they express the proteins that you expect neural stem cells to express, they look like their normal counterparts, and most importantly, they spin off cells which become normal mature nerve cells that put out processes (axons) that, in some cases, seem to go where normal processes go,” Siegrist said. “We don’t know whether these cells function normally or whether they are electrically active. At least it is encouraging that we can get nerve cells made in a part of the (fruit fly) brain that normally cannot make nerve cells in the adult brain.”

“Sarah had to do two manipulations together to keep these neural stem cells alive, and neither worked alone,” Hariharan said. “One was to keep the insulin signal on, and one was to block programmed cell death. Each improved things a little bit, but when you did the two together, the neural stem cells survived for a month, at which time they were throwing off mature neurons or normal looking neurons that sent out processes.”

Siegrist plans to continue her search through mutant fruit flies to find other genes that improve survival in the mushroom body and allow stem cells in other areas of the fly brain to persist. She also plans collaborations to explore similar mechanisms in mammals, to see if analogous manipulations could keep neural stem cells alive in the mammalian brain.

“In fruit flies, pathways downstream of the insulin receptor are important in keeping these neural stem cells alive,” Siegrist said. “Mammals have the same genes downstream of their insulin receptors, so we may find the same response to insulin or insulin-like growth factors in mammals.”

Other coauthors are former UC Berkeley undergraduate Najm Haque, now a technician in Hariharan’s lab; Chun-Hong Chen of the National Health Research Institutes in Zhunan Town, Taiwan; and Bruce A. Hay of the California Institute of Technology (Caltech) in Pasadena, Calif.

The research is funded by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.

By Robert Sanders, UB Berkeley

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Image Caption: These are mushroom bodies (red), which are the center of learning and memory in the brain, from two adult fruit flies. Normally, new neurons do not appear in the adult mushroom body. UC Berkeley biologists altered neural stem cells to allow them to persist for at least a month in the adult brain, and to give rise to newborn nerve cells (green) that send out axons to other areas of the mushroom body, just like normal neurons. Credit: Sarah Siegrist/UC Berkeley

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On the Net:

• University of California – Berkeley
• Current Biology

Two genes have been associated with autistic spectrum disorders (ASD) in a new study of 661 families. Researchers writing in BioMed Central’s newly launched journal Molecular Autism found that variations in the genes for two brain proteins, LRRN3 and LRRTM3, were significantly associated with susceptibility to ASD.

Anthony Monaco from the Wellcome Trust Centre for Human Genetics, University of Oxford, UK, worked with an international team of researchers to study four candidate genes in families from the UK, the Netherlands, Italy and Germany. He said, “To our knowledge, this is one of the most comprehensive genetic analyses of association between these important genes in brain connections and ASD risk”. The proteins encoded by these two genes have been implicated in brain development, which is often impaired in autistic individuals. In particular, LRRN3 is thought to play a role in the development and maintenance of the nervous system, while LRRTM3 is part of a family of proteins thought to organize synaptic connections.

According to Monaco, ” A focused candidate gene study was carried out using association approaches to identify common variants in the UK cohort and in additional European populations. This study covered four brain-enriched leucine-rich repeat candidates and taken together, there is converging evidence that common genetic variants in LRRTM3 and LRRN3 confer susceptibility to ASD. Future studies of these genes and their function will provide valuable insights into their role in ASD pathogenesis”.

* Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry. Inês Sousa, Taane G Clark, Richard Holt, Alistair T Pagnamenta, Erik J Mulder, Ruud B Minderaa, Anthony J Bailey, Agatino Battaglia, Sabine M Klauck, Fritz Poustka, Anthony P Monaco and International Molecular Genetic Study of Autism Consortium. Molecular Autism 2010, 1:7 doi:10.1186/2040-2392-1-7

Article available at journal website http://www.molecularautism.com/content/1/1/7

New study shows that preparedness does not improve memory performance in older adults

One of the most common complaints among healthy older adults relates to a decline in memory performance. This decline has been linked to an inability to ignore irrelevant information when forming memories. In order to ignore distracting information, the brain should act to suppress its responses to distractions, but it has been shown that in older adults there is in fact an increase in brain activity at those times. In a new study published in the April 2010 issue of Elsevier’s Cortex researchers at the University of California San Francisco have shown that even prior knowledge of an impending distraction does not help to improve the working memory performance of older adults.

Drs. Theodore Zanto and Adam Gazzaley studied 21 adults aged between 60 and 80 years while they performed a working memory task in which they were shown random sequences of pictures containing faces and scenes. From a given sequence, participants were asked to remember either only the faces (ignoring scenes) or only the scenes (ignoring faces). In a second round of testing, the participants were given prior information about which specific pictures in the sequence would be relevant and which to ignore. The participants’ brain activity during the tasks was recorded using electroencephalograms (EEGs).

Previous research from this laboratory has indicated that the increase in brain activity in response to distractions occurs very soon (within 200 milliseconds) after the distraction appears. Since there is only a very short amount of time allotted for the brain to identify an item as irrelevant and suppress any further neural processing, it was suggested that older adults might benefit from prior knowledge of the impending distraction. However, results from the new study have proved that this is not the case.

Interestingly, the researchers found that later stages of neural processing (500-650 milliseconds after item presentation) do show signs of suppression, confirming that the “suppression deficit” is related to early stages of neural processing. The findings suggest that a working memory decline in older adults is indeed due to an inability to ignore distracting information, which furthermore cannot be improved with preparedness.

The article is “Predictive knowledge of stimulus relevance does not influence top-down suppression of irrelevant information in older adults” by Theodore P. Zanto, Kelly Hennigan, Mattias ×stberg, Wesley C. Clapp and Adam Gazzaley and appears in Cortex, Volume 46, Issue 4 (April 2010), published by Elsevier in Italy.

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• Cortex

CHICAGO — Flip-flops and sneakers with flexible soles are easier on the knees than clogs or even special walking shoes, a study by Rush University Medical Center has found. And that’s important, because loading on the knee joints is a key factor in the development of osteoarthritis.

The study has been published online in the journal Arthritis Care & Research.

“Traditionally, footwear has been engineered to provide maximum support and comfort for the foot, with little attention paid to the biomechanical effects on the rest of the leg,” said Dr. Najia Shakoor, a rheumatologist at Rush and the primary author of the study. “But the shoes we wear have a substantial impact on the load on the knee joints, particularly when we walk.”

“Our study demonstrated that flat, flexible footwear significantly reduces the load on the knee joints compared with supportive, stable shoes with less flexible soles.”

Osteoarthritis is the most common form of arthritis and a significant source of disability and impaired quality of life. A higher-than-normal load on the knees during walking is a hallmark of the disease, associated with both the severity of osteoarthritis and its progression.

Shakoor and her colleagues analyzed the gait of 31 patients with symptoms of osteoarthritis in the Rush Motion Analysis Lab while they walked barefoot and with four popular shoe types: Dansko clogs, which are often worn by healthcare professionals who have to be on their feet much of the day; Brooks Addiction stability shoes, which are prescribed for foot comfort and stability; Puma H-Street shoes, a flat athletic shoe with flexible soles; and flip-flops.

The loads on the knee joints differed significantly depending on the footwear. For the clogs and stability shoes, the loads on the knee joints were up to 15 percent greater than with the flat walking shoes, flip-flops or barefoot walking. Knee loading was roughly the same whether the subject wore flips-flops or walked barefoot.

“Currently, knee braces and wedged orthotic shoe inserts are used to relieve the load on the knee joints of patients with osteoarthritis, but everyday footwear is also a factor to consider. The results in our study demonstrate that the reduction in load achieved with different footwear, from 11 to 15 percent, is certainly comparable to reduction in load with braces and shoe inserts ,” Shakoor said.

According to Shakoor, several aspects of footwear affect the joint loading.

“Heel height is one factor, and may explain why the stability shoes and clogs in our study, both of which had higher heels, produced greater knee loads,” Shakoor said.

“Stiffness is also a factor. We’ve shown in earlier studies that barefoot walking is associated with lower knee loads than walking with conventional footwear. It may be that the flexible movement of the bare foot is mechanically advantageous. The natural flex of the foot when it contacts the ground probably attenuates the impact on the joint, compared to the artificial ‘stomping’ movement created by a stiff-soled shoe.”

In the present study, Shakoor said, flip-flops and the walking shoe were flat, flexible and lightweight and seemed to mimic the mechanics when walking with bare feet.

“Clogs and stability shoes, conventionally believed to provide appropriate cushioning and support, actually increased the loading on the knee joints, as opposed to shoes with less ‘support,’ flatter heels and more flexibility,” Shakoor said.

Shakoor cautioned, however, that knee loading is not the only consideration in any clinical recommendations based on her study.

“For the elderly and infirm individuals, flip-flops could contribute to falls because of their loose-fitting design. Factors like these need to be taken into account,” Shakoor said.

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Rush University Medical Center

Montreal — The ability to taste and smell can be lost or impaired after a head injury, according to a new study by scientists from the Universit© de Montr©al, the Lucie Bruneau Rehabilitation Centre, as well as the Center for Interdisciplinary Research in Rehabilitation of Greater Montreal. Published in the journal Brain Injury, the investigation established that mild to severe traumatic brain injury could cause olfactory loss.

“The study clearly demonstrates that olfactory deficits can occur in mild traumatic brain injury patients as well as in moderate and severe TBI patients,” says study co-author and neuropsychologist Maurice Ptito, a professor at the Universit© de Montr©al School of Optometry. “We also found that patients with a frontal lesion were more likely to show olfactory dysfunctions.”

The research team recruited 49 people with TBI (73 percent male with a median age of 43) who completed a questionnaire and underwent two smell tests to measure their olfactory loss. The result: 55 percent of subjects had an impaired sense of smell, while 41 percent of participants were unaware of their olfactory deficit.

“Both tests indicated the same results: patients with frontal injury are more likely to suffer olfactory loss,” says lead author Audrey Fortin, a professor at the Universit© de Montr©al School of Optometry and researcher at the Lucie Bruneau Rehabilitation Centre.

Smell plays a vital role in our lives, says Dr. Fortin, since olfaction influences what we eat, can help us detect gas leaks or fires. Smell also has a huge impact on interpersonal relationships, since olfactory disorders have been associated with poor quality of life, depression, mood swings, worries about personal hygiene, loss of appetite and cooking difficulties.

“Olfactory dysfunctions have a negative impact on daily life, health and safety,” says Dr. Fortin. “It is important to pay attention to this symptom once a patient’s condition has been stabilized following a traumatic brain injury.”

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University of Montreal

Barcelona, Spain — Recurrence of breast cancer in the same area as the original tumour remains the strongest, independent prognostic factor for subsequent metastasis and death, even for patients who have been free of disease for a very long time, according to research presented today (Wednesday) at the seventh European Breast Cancer Conference (EBCC7).

Dr Sven Mieog, MD, a research fellow at Leiden University Medical Centre (Leiden, The Netherlands) will tell the conference that in women treated with breast conserving treatment for early stage breast cancer, a locoregional recurrence remained the most important prognostic factor after a disease-free interval of five years. Moreover, after a disease-free interval of ten years, locoregional recurrence remained the sole independent prognostic factor.

“In patients who were free of disease for more than ten years after primary treatment, locoregional recurrence had a significant impact on both disease-free survival and overall survival,” he said. “The increased risk of metastases after a recurrence was approximately four times higher than if there had been no recurrence, and the risk of dying after a recurrence was around eight times higher. However, these levels of increased risk need to be treated with caution because, with the longer time interval between the primary cancer and the recurrence, the number of events goes down, making these calculations less certain, although they remain important for clinicians when deciding on the best treatments.”

Dr Mieog and his colleagues pooled data from 7,749 early stage breast cancer patients taking part in four trials run by the European Organisation for Research and Treatment of Cancer (EORTC). The average length of follow-up was 10.9 years and three different analyses looked at: 1) all the patients, 2) only patients without further cancer after at least five years, and, 3) patients without further cancer after at least 10 years.

In the analysis of all patients, locoregional recurrence, tumour size, whether the cancer had spread to the lymph nodes, young age, oestrogen receptor status and treatment with chemotherapy were all independent prognostic factors with a significant impact on long-term outcome, with locoregional recurrence being the strongest factor.

In the second analysis looking at patients who were disease-free after at least five years, locoregional recurrence was the strongest independent prognostic factor for overall survival and metastases-free survival. In the third analysis looking at patients who were disease-free after at least ten year, locoregional recurrence was the only independent prognostic factor.

Dr Mieog said: “These findings suggest that even after a long, event-free interval, locoregional recurrence seems to be associated with distant disease rather than a cause of subsequent distant disease.”

Dr Jos A. van der Hage, MD PhD, a surgical oncologist at The Netherlands Cancer Institute (Amsterdam, The Netherlands) who collaborated with Dr Mieog but was unable to attend EBCC7, explained: “Locoregional recurrence is a well-known risk factor for subsequent distant disease and death. The nature of this relationship is not clear. However, most recurrences are not causes of subsequent disease spread but rather a symptom of disease progression, associated with a high likelihood of simultaneous metastases.

“On the other hand, approximately 25% of all local recurrences are believed to be able to induce further disease progression themselves. This rationale is based upon the fact that radiotherapy trials demonstrate a decrease in local recurrence rates as well as improved long-term outcome in patients receiving adjuvant radiotherapy after breast surgery.

“The fact that locoregional recurrence is still a very strong prognostic factor, even after a long disease-free interval suggests that it probably is a symptom of (and therefore associated with) distant disease occurring at the same time, and not the instigator of disease progression in the majority of cases.”

However, he said that further research on locoregional recurrences was needed. “To date, it remains difficult to assess whether a locoregional recurrence is a true recurrence or a second primary. This is of significant importance for clinicians when they assess the indications for giving adjuvant systemic therapy. There are not many large-scale studies, which address this clinical feature of breast cancer disease. Since breast cancer may recur even after 15 years of follow-up, studies demonstrating the prognostic impact of events that happen after primary treatment are very important.”

The research provides further information for the ongoing debates about how long women who have been treated successfully for breast cancer should be followed up by doctors. While not giving any definitive answers on this, the study does show that breast cancer can recur and progress even after a long time disease free. “Therefore, clinicians and patients should consider adjuvant systemic, both for the treatment of the primary cancer and in the event of any recurrence,” said Dr van der Hage.

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ECCO-the European CanCer Organisation

Motherhood appears to protect against suicide, with increasing numbers of children associated with decreasing rates of death from suicide, found an article in CMAJ (Canadian Medical Association Journal).

The study, following 1 292 462 women in Taiwan over 20 years, was undertaken to confirm a hypothesis postulated by the renowned sociologist Emile Durkheim in 1897 that parenthood is protective against suicide. It found a 39% decrease in suicide-related mortality among women with two live births and a 60% decrease among women with three or more births compared to women with one child. The participants, who were followed until Dec. 31, 2007, gave birth between Jan. 1, 1978 and Dec. 31, 1987.

As the limited number of previous studies were conducted in developed countries with smaller sample sizes, this study is significant because of its large size and the number of deaths from suicides ““ 2252 ““ in the cohort.

In Taiwan, suicide is the eighth leading cause of death among men and the ninth among women and has been consistently increasing since 1999. Most Western countries have had a stable or decreasing suicide rate in the 1990s. The male to female ratio of suicide is often greater than 3:1 in Western countries, whereas it is 2:1 in Taiwan because of high suicide rates in women. In Western countries, rates of suicide among women have been decreasing while rates among men have been increasing.

“A clear tendency was found toward decreasing suicide rates with increasing number of children after controlling for age at first birth, marital status, years of schooling, and place of delivery,” writes author Dr. Chun-Yuh Yang, Kaoshiung Medical University, Kaoshiung, Taiwan. “The protective effect of parity on risk of death from suicide was much stronger than previously reported estimates. Given that the women included in this study were young (the large majority of suicide-related deaths occurred before premenopausal age) and were among the youngest reported for any country, this finding is particularly noteworthy.”

Having children may protect against suicide because children may increase a mother’s feelings of self-worth. Children may also provide emotional and material support to a mother and provide her with a positive social role. As well, motherhood may enhance social networks and social support. The finding is in agreement with Durkheim’s hypothesis.

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Canadian Medical Association Journal

The utilization rates of noninvasive diagnostic imaging procedures such as computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET) for the Medicare population vary substantially from region to region, with Atlanta, GA, having the highest utilization rate and Seattle, WA, having the lowest, according to a study in the April issue of the American Journal of Roentgenology (www.ajronline.org).

“Underlying regional variation in imaging utilization raises concerns about cost and quality,” said Laurence Parker, PhD, lead author of the study. “Wide geographic variation in utilization raises questions about underutilization and quality on the low side and overutilization and costs on the high side,” said Parker.

Researchers at the Thomas Jefferson University Hospital in Philadelphia, PA, calculated the overall noninvasive diagnostic imaging procedure utilization rate based upon data from the Centers for Medicare and Medicaid Services Physician Supplier Procedure Summary Files for 1998-2007. Results showed that in 2007, the Atlanta region had the highest utilization rate, with 4.60 procedures per capita “” compared to 3.47 in 1998 and 3.95 in 2002; and Seattle had the lowest utilization rate in 2007, with 2.99 procedures per capita “” compared to 2.33 in 1998 and 2.69 in 2002.

‘Per capita utilization in the highest region has been about 50 percent greater than in the lowest region over the course of the study, with this percentage increasing from 1998 to 2007,” said Parker. “This is a substantial difference, greater than the increases within regions from 1998 to 2007. However, it’s a much smaller difference than the eightfold variation in Medicare payments reported in previous studies, and we think a more accurate number,’ he said.

‘When we focus on high-technology, high-cost imaging categories, like CT, MRI and PET, many categories of imaging show more than 100 percent greater utilization. Many of the high variation categories are types of cardiovascular imaging,’ said Parker.

“There are many factors involved in regional variation in utilization, including morbidity and risk factors in the population, access-to-care factors, and general population factors. However, it seems very clear that there is substantial regional variation in imaging utilization, and it should be further explored,” he said.

While regional variations exist, Medicare Payment Advisory Commission (MedPAC) statistics show that overall Medicare per-beneficiary imaging growth for 2006, 2007 was only 2 percent nationally “” at or below the growth rate of other physician services.

This study appears in the April issue of the American Journal of Roentgenology. For a copy of the full study or to request an interview with Dr. Parker, please contact Heather Curry via email at [email protected] or at 703-390-9822.

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About ARRS

The American Roentgen Ray Society (ARRS) was founded in 1900 and is the oldest radiology society in the United States. Its monthly journal, the American Journal of Roentgenology, began publication in 1906. Radiologists from all over the world attend the ARRS annual meeting to participate in instructional courses, scientific paper presentations and scientific and commercial exhibits related to the field of radiology. The Society is named after the first Nobel Laureate in Physics, Wilhelm Röentgen, who discovered the x-ray in 1895.

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ARRS

INDIANAPOLIS ““ Living wills and surrogate decision makers account for only a portion of the many factors weighed by physicians when making medical decisions for hospitalized patients lacking the capability to make their own decisions, according to a recently published study.

Researchers who queried 281 physicians report their conclusions in a study that appears in the March 2010 issue of the Journal of the American Geriatrics Society.

“A growing number of hospitalized adults are incapable of making their own health decisions,” said Alexia Torke, M.D., senior author of the study. “Doctors balance a lot of important considerations when caring for a patient who cannot voice his or her own preferences. These considerations include what the patient would have wanted and what the physician and family think is best for the patient overall. While prior discussions or living wills may be helpful especially in circumstances when the patient expressed strong beliefs and is facing a difficult illness, these preferences are only part of the equation.” Dr. Torke is an assistant professor of medicine at the Indiana University School of Medicine, a Regenstrief Institute investigator, and an IU Center for Aging Research scientist.

The study surveyed 281 internists, family practice doctors, intensive care unit physicians and hospitalists, about half of whom were in private practice. Slightly over half were male. Each was asked questions about caring for their most recent patient who was unable to make his or her own decisions and rated the importance of each of the factors that influenced decisions on how to care for the patient.

The researchers found that when asked to identify the single most important factor in making decisions for their patient, physicians most commonly reported “what was best for the patient overall” (33 percent), “what the patient would have wanted you to do” (29 percent), “the patient’s pain and suffering” (13 percent), and “the patient’s prognosis” (12 percent).

“Even though standard ethical models say that patient preferences should be the most important factor in surrogate decision making, in reality doctors consider many factors and weight them differently in each case,” said Dr. Torke.

“We have come to consensus in our society that people should have a lot of input into their own medical decisions. But when the patient can’t made decisions we have much less consensus on how to proceed. While physicians weigh various factors, we learned from our study that what’s going on at the time the treatment decision is being made is as important as previous medical directives. We did not find evidence that living wills or prior discussions with patients about their preferences for care made a difference in the decision making for most patients,” she said.

“We also found a decreased reliance on patient preferences with increasing age. This may reflect ageist assumptions that the preferences and values of older adults are less important than those of younger adults. Another possible explanation is that when caring for older adults, physicians may accept that death is an unavoidable event and that for many patients, health care in advanced age should focus more on quality of life than extension of life,” said Dr. Torke, who is also affiliated with the Fairbanks Center for Medical Ethics at Clarian Health.

In a study published last year in the Journal of General Internal Medicine, Dr. Torke and colleagues found that one in five of the same doctors surveyed for the new study are not comfortable working with a surrogate decision maker. The doctors reported ineffective communication, lack of satisfaction with the outcome of the decision, and an increase in stress level as a result of the surrogate decision making process.

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Indiana University School of Medicine

Radiographs (standard X-rays) are often inconclusive in the detection of hip and pelvic fractures in the emergency department, according to a study in the April issue of the American Journal of Roentgenology (www.ajronline.org).

“The diagnosis of traumatic fracture most often begins and ends with X-rays of the hip, pelvis, or both,” said Charles Spritzer, MD, lead author of the study. “In some cases though, the exclusion of a traumatic fracture is difficult,” said Spritzer.

The study, performed at Duke University Medical Center in Durham, NC, included 92 patients who underwent X-rays followed by magnetic resonance imaging (MRI) for the evaluation of hip and pelvic pain. “Thirteen patients with normal X-ray findings were found to collectively have 23 fractures at MRI,” said Spritzer. “In 11 patients MRI showed no fracture after X-rays had suggested the presence of a fracture. In another 15 patients who had abnormal X-ray findings, MRI depicted 12 additional pelvic fractures not identified on X-rays,” he said.

“Accurate diagnosis of hip and pelvic fractures in the emergency department can speed patients to surgical management, if needed, and reduce the rate of hospital admissions among patients who do not have fractures. This distinction is important in terms of health care utilization, overall patient cost, and patient inconvenience,” said Spritzer.

“Use of MRI in patients with a strong clinical suspicion of traumatic injury but unimpressive X-rays has a substantial advantage in the detection of pelvic and hip fractures, helping to steer patients to appropriate medical and surgical therapy,” he said.

This study appears in the April issue of the American Journal of Roentgenology. For a copy of the full study or to request an interview with Dr. Spritzer, please contact Heather Curry via email at [email protected] or at 703-390-9822.

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About ARRS

The American Roentgen Ray Society (ARRS) was founded in 1900 and is the oldest radiology society in the United States. Its monthly journal, the American Journal of Roentgenology, began publication in 1906. Radiologists from all over the world attend the ARRS annual meeting to participate in instructional courses, scientific paper presentations and scientific and commercial exhibits related to the field of radiology. The Society is named after the first Nobel Laureate in Physics, Wilhelm Röentgen, who discovered the x-ray in 1895.

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ARRS

British Italian doctors said they have carried out groundbreaking surgery to help rebuild the windpipe of a 10-year-old boy by using stem cells developed from his own body.

Doctors at London’s Great Ormond Street Children’s Hospital implanted the boy with a donor trachea that had been stripped of its cells and injected with his own.  The operation took place last week and lasted nearly nine hours.

Doctors expect the boy’s bone marrow stem cells to begin transforming themselves over the next month into tracheal cells.  This process could lead to a revolution in regenerative medicine.

The boy’s immune system is not expected to reject the new organ because the cells are derived from his own tissue.

“This procedure is different in a number of ways, and we believe it’s a real milestone,” Professor Martin Birchall, head of translational regenerative medicine at University College London, told the AFP new agency.

“It is the first time a child has received stem cell organ treatment, and it’s the longest airway that has ever been replaced.”

He said that more clinical trials were needed to demonstrate that the process worked.  However, if it did then it could lead to other organs, such as the larynx or esophagus, being transplanted in hospitals around the world.

The boy was born with a life-threatening condition known as long segment tracheal stenosis, which causes a tiny windpipe not to grow.  The team of doctors said the effect of this condition is like breathing through a straw.

The boy’s doctors called in Professor Paolo Macchiarini, a stem cell pioneer at the Careggi University Hospital in Florence. 

Two years ago in Spain, Macchiarini led 30-year-old Claudia Castillo to surgery to be the first person to receive a transplant organ created from stem cells.

However, in her case the tissue was developed outside her body.  It is far less complicated to grow stem cells within the body.  The boy is only the second patient and the first child to have a procedure like this.

Professor Martin Elliot, a cardiothoracic surgeon and the director of tracheal services at Great Ormond Street, said the boy was recovering well.

“The child is extremely well. He’s breathing completely for himself and speaking, and he says it’s easier for him to breathe than it has been for many years,” Elliott said.

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• Great Ormond Street Children’s Hospital
• University College London
• Careggi University Hospital

Certain rare mutations in the ataxia telangiectasia mutated (ATM) gene, combined with radiation exposure, may increase a woman’s risk of developing a second cancer in the opposite breast, according to a study published online March 19 in the Journal of the National Cancer Institute.

Breast cancer survivors are at increased risk of developing a second cancer in the other, or contralateral breast, compared to women who have not had breast cancer. The ATM gene is known to play a role in cells’ response to DNA damage caused by ionizing radiation, another breast cancer risk factor. But it has been unclear whether women who carry ATM mutations are especially susceptible to radiation-induced breast cancer.

To address this issue, Jonine Bernstein, M.D., of the Memorial Sloan-Kettering Cancer Center in New York, and colleagues, compared ATM mutations among women who had developed a second cancer in the contralateral breast to mutations in those who had a cancer in only one breast. The women were participants in the Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study, an international case”“control study. There were 708 case subjects””women with contralateral cancer””and 1,397 control subjects who did not have a second cancer but were similar to the case subjects in other respects, such as age and race.

All the women underwent full mutation screening of the entire ATM gene. For those who had received radiation therapy, the researchers estimated the amount of radiation to the contralateral breast using treatment records and radiation measurements.

Women who carried certain rare ATM mutations–missense variants predicted to be deleterious–and who also received radiation had a higher risk of contralateral breast cancer compared with women who did not have these mutations and had not had radiation. The difference was statistically significant. Women with both a mutation and radiation exposure also had a higher risk than women who had a mutation but no radiation exposure.

The authors note that the missense variants were found in fewer than 1% of study participants. They conclude that breast cancer survivors who do have such variants and who also received radiation may be at an elevated risk for a contralateral breast cancer. “However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers,” they write.

In an accompanying editorial, David Brenner, Ph.D., of Columbia University Medical Center in New York, notes that strategies to prevent second cancers, such as use of tamoxifen in women with estrogen receptor positive tumors, are desirable. One potential option, he suggests, is prophylactic irradiation of the contralateral breast, using doses too low to cause tumors but sufficient to kill premalignant cells.

The WECARE results, he writes, “reemphasize that we do not yet understand most of the etiology of the disturbingly high long-term risks of second breast cancers. It is important, therefore, to continue to seek prophylactic preventative options that are useful for all breast cancer survivors.”

Study limitations: There were few carriers of missense variants that were predicted to be deleterious in the study population, which limited the precision of the estimates.

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• Journal of the National Cancer Institute

Self-reliant diabetes patients had a 33 percent higher mortality rate during a 5-year study, compared to diabetes patients who interacted easily with others and sought support

Mistrust can exact a high toll. Being overly cautious or dismissive in relating to people, researchers are learning, may shorten the lives of people with diabetes.

Diabetes patients who have a lower propensity to reach out to others have a higher mortality rate than those who feel comfortable seeking support. These are the findings of a five-year study reported by Dr. Paul Ciechanowski, associate professor of psychiatry and behavioral sciences at the University of Washington (UW) and an affiliate investigator at Group Health Research Institute in Seattle.

Ciechanowski also directs the training insitute at the Center for Healthcare Improvement for Addictions, Mental Illness and Medically Vulnerable Populations (CHAMMP) at Harborview Medical Center, which is part of UW Medicine.

The report was published in this month’s Diabetes Care, a professional journal of the American Diabetes Association.

This is the first known study, the research team believes, to examine the association between relationship styles and mortality.

The researchers examined 3,535 adult patients with type 1 and type 2 diabetes enrolled as Group Health Cooperative patients in the Puget Sound area of Washington state. Because depression has been linked to premature death from diabetes, patients with depression were not included to avoid confounding the study results.

The patients completed a relationship questionnaire, developed in 1994 by Griffin and Bartholomew. Based on the results of this survey, patients were divided into two groups: those with an interactive style and those with an independent style in relating to people.

Individuals with an interactive style find it easy to get close to others and rely on them, and in turn are dependable for others. Those with an independent style tend to be either dismissive or fearful of close relationships. Some people with this style would like emotional closeness, but find it hard to trust or depend on others. Others can be indifferent to close relationships, preferring instead to be free and self-reliant.

“These ways of relating often extend to their relationships with health-care providers,” the researchers said.

Regardless of their style, most patients Ciechanowski and his colleagues have studied over several projects perceive health care as rushed, impersonal and fragmented. Those with an independent style also reported feeling threatened by the power health-care providers had. Some were highly attuned to signs of rejection; others were sensitive to being controlled, and at the same time worried that help would not be available for them. Those with an independent style in relationships often felt a wall existed between patients and providers.

Interactive patients tended to understand the pressures health professionals were under, and overlooked minor shortcomings, previous research by Ciechanowski and his team has found. Such patients were more likely to value ongoing relationships with their providers, even when circumstances weren’t ideal, and respected their training and knowledge.

During the course of the most recent study, diabetes patients who were mistrustful of people, including health-care providers, had a 33 percent higher mortality rate than those who interacted easily with others and sought comfort and support. The researchers found the significantly higher risk of death among diabetes patients who were less likely to seek support still held after controlling for other potential risk factors for mortality such as age, marital status, other medical conditions, complications of diabetes and body mass index.

The exact mechanisms behind the link between an independent relationship style and a higher mortality rate are not yet known, the researchers said, and further research is needed to delineate the reasons and to develop effective interventions.

“Prior studies have shown that lower support seeking is associated with poorer adherence to treatment,” Ciechanowski noted. An independent relationship style, he explained, is often played out in missed appointments, higher glucose readings, lower satisfaction with health-care, and poorer home treatment of diabetes in such areas as foot care, exercise, diet, oral and injectible medication use, blood sugar monitoring, and smoking cessation.

“Many self-management behaviors related to diabetes are optimally carried out in collaboration with others — family, peers and health-care providers,” Ciechanowski noted. Planning and cooking diabetic-friendly meals, exercising, and quitting smoking are best undertaken, he added, with motivational support. Also, as diabetes gets more severe or complications arise, a self-reliant attitude that worked in the past may become a liability.

There are approaches, according to Ciechanowski, that health-care providers can try to improve collaboration with diabetes patients who have an independent relationship style, such as directly and non-judgmentally talking about this style. Also, providers might coach patients and help them set simple goals in seeking support in managing their diabetes. However, the effectiveness of such approaches in reducing the higher death rates among such patients has not yet been tested.

“Our research is based on a developmental theory known as attachment theory where earlier experiences often shape an individual’s ability to trust later in life,” Ciechanowski explains. “As clinicians, we have to keep in mind that what we say and how we say it can make a big difference in trust between clinician and patient — which has implications for treatment adherence and health outcomes. Bedside manner matters. Also, as stewards of health care, we have to be mindful about what our fast-paced health-care system says to patients to engender trust or not. Long waits, less face-to-face time with providers, rashly delivered health information, and lack of continuous care can reduce trust — particularly in those with an independent relationship style.”

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University of Washington

It has long been known that alcohol exposure is toxic to the developing fetus and can result in lifelong brain, cognitive and behavioral problems. Now, a new report out of UCLA shows that the effects of prenatal methamphetamine exposure “” or worse, a combination of methamphetamine and alcohol “” may be even more damaging.
 
Reporting in the March 17 issue of the Journal of Neuroscience, UCLA professor of neurology Elizabeth Sowell and her colleagues used structural magnetic resonance imaging (sMRI) to show for the first time that individuals whose mothers abused methamphetamine during pregnancy, with or without alcohol abuse, had structural abnormalities in the brain that were more severe than those seen in children whose mothers abused alcohol alone.
 
The researchers identified the brain structures that are vulnerable in such exposure, which may help predict particular learning and behavioral problems in methamphetamine-exposed children.
 
“We know that alcohol exposure is toxic to the developing fetus and can result in lifelong problems,” said Sowell, the study’s senior author. “In this study, we show that the effects of prenatal meth exposure, or the combination of meth and alcohol exposure, may actually be worse, and our findings stress the importance of seeking drug-abuse treatment for pregnant women.”
 
In particular, said Sowell, a structure in the brain called the caudate nucleus, which is important for learning and memory, motor control, and punishment and reward, was one of the regions that was more reduced by methamphetamine than alcohol exposure.
 
Of the more than 16 million Americans over the age of 12 who have used methamphetamine, about 19,000 have been pregnant women, according to 2002″“04 data from the National Survey on Drug Use and Health.
 
“About half of women who say they used meth during pregnancy also used alcohol,” Sowell said, “so isolating the effects of meth on the developing brain was difficult.”
 
The researchers overcame this challenge, she said, by recruiting women who abused alcohol but not methamphetamine during pregnancy and compared them to the children with exposure to both drugs, and to a group that was not exposed.
 
The neuroscientists evaluated the specific effects of prenatal methamphetamine exposure by comparing brain scans of 61 children, whose average age was 11. Of these, 21 had prenatal methamphetamine and alcohol exposure, 13 had heavy alcohol exposure only and 27 were unexposed. Structural magnetic resonance imaging showed that the sizes and shapes of certain brain structures varied depending on prenatal drug exposure.
 
Previous studies have shown that certain brain structures are smaller in alcohol-exposed children. In this study, the authors found that these brain regions in methamphetamine-exposed children were similar to those in alcohol-exposed children and that in some areas they were even smaller. Some brain regions were larger than normal. For example, an abnormal volume increase was noted in methamphetamine-exposed children in a region called the cingulate cortex, which is associated with control and conflict resolution.
 
“Either scenario “” smaller or larger growth “” could be a bad thing in kids with prenatal drug exposure,” Sowell noted. “There are enormous developmental changes that take place during adolescence. These drugs are likely altering the trajectory of development, and clearly not in a good way.”
 
This brain imaging may also aid in treatment. Because the researchers were also able to predict a child’s past exposure to drugs based on imaging and IQ information, detailed data about vulnerable brain structures may eventually be used to diagnose children with cognitive or behavioral problems, even when well-documented histories of drug exposure are not available.
 
“The tragedy here is that all these developmental problems are 100 percent avoidable,” Sowell said. “The important message is to urge drug abusing women to seek treatment during pregnancy.”
 
Other authors on the paper included Alex D. Leow, Susan Y. Bookheimer, Lynne M. Smith, Mary J. O’Connor, Eric Kan, Carly Rosso, Suzanne Houston, Ivo D. Dinov and Paul M. Thompson, all of UCLA.
 
The research was supported by the National Institute of Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the March of Dimes. Additional support was provided by the National Center for Research Resources, the General Clinical Research Center, and the National Institutes of Health.

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UCLA