Over 500 million medical imaging tests are performed each year, making MRIs, CT Scans and X-rays a critical part of every U.S. patient’s medical life. Today’s healthcare consumers, however, have few resources to learn about and choose from among the nearly 7,000 medical imaging centers that perform Radiology tests. At www.remakehealth.com, consumers now have an online resource to find a local imaging center, request appointments for Radiology tests and look up medical imaging prices.

200 different Radiology tests are available on the site. Medical imaging tests include MRIs, Ultrasounds, CT Scans, X-rays, and more. RemakeHealth’s technology matches healthcare consumers to local Radiology centers, showing facilities who take their insurance and can perform the test. Many centers also list cash prices for patients paying out of pocket.

Featuring a look and feel similar to travel websites, RemakeHealth lets healthcare consumers quickly search for a Radiology facility and learn more about their local providers. Each facility’s profile includes information such as office hours, location, imaging tests, and certification. Using the site, consumers can substantially reduce the time usually spent making an appointment.

“Medical imaging is one of the fastest growing healthcare segments. Our site is one of the few online resources that connects consumers directly with Radiology providers,” said Ravinder Sohal M.D., RemakeHealth’s founder and CEO. “Healthcare consumers can now learn more about their local Radiology facilities, compare services and request an appointment.”

The Company has partnered with imaging centers in the San Francisco Bay Area, Orlando/Central Florida, Las Vegas and Phoenix. Featured Radiology groups include BMC Diagnostics, California Advanced Imaging, Drew Medical, and Red Rock Radiology. Their facilities offer a wide array of medical imaging tests such as MRI, CT scan, Ultrasound, X-ray, DEXA Bone Densitometry, Mammography, Nuclear Medicine and PET.

“Working with these Radiology groups has allowed RemakeHealth to create compelling content,” said Rob Parsons, VP of Operations. “With more people using the internet to find healthcare information, our partners are committed to making their Radiology services easier to find and accessible.”

For the latest list of Radiology facilities and coverage areas, please visit www.remakehealth.com.

About RemakeHealth

RemakeHealth, Inc. was founded in 2007 to create a better internet healthcare experience. The Company’s technology platform connects healthcare consumers to medical service providers. RemakeHealth’s Radiology Search makes finding local imaging centers and scheduling appointments easier. RemakeHealth is a privately held company, based in Silicon Valley, CA.

Radiology providers interested in partnering with RemakeHealth can visit www.remakehealth.com/radiology or call 408-524-1644.

 Contact: Ravinder Sohal RemakeHealth, Inc. Phone: 408-524-1643 Email Contact

SOURCE: RemakeHealth

By Chelsea Keeney, Omaha World-Herald, Neb.

Jun. 25–A new program developed by the Nebraska Medical Center gives rural health care facilities around-the-clock, online access to pharmacists.

The Remote Pharmaceutical Care program arranges for an on-call pharmacist to provide advice to rural doctors and nurses about the medications they’re prescribing, said Paul Baltes, a medical center spokesman. The on-call pharmacist works under a contract with the Omaha hospital and is equipped with a computer at home.

Large hospitals have enough pharmacists on staff that one is available at any time to review the medications that physicians order for patients, said Dr. Lori Murante, pharmacy relations and clinical support administrator at the medical center.

She said rural hospitals need the same coverage to protect patients. Currently, at some rural hospitals, physicians will prescribe medication, but a pharmacist isn’t available to offer advice until later.

“There’s a standard of care that’s been in place for a long time for large hospitals,” Murante said. “And it seems like the same safety should be at every hospital.”

She said there is a national shortage of pharmacists, and smaller communities are having trouble attracting and retaining pharmacists.

The only hospital to use the program so far, Litzenberg Memorial County Hospital in Central City, Neb., began using it June 11. Murante said the Howard County Community Hospital in St. Paul, Neb., should have the system running by early August.

Reg Hain, pharmacy director at Litzenberg, said that after working out a few mechanical bugs, the program is providing additional safety and alleviating some of the workload.

“This helps reduce medication errors because the pharmacist is reviewing it before it goes to the patient,” he said.

Hain, one of two full-time pharmacists at Litzenberg, said the program is reducing his overtime hours. “It gives us a break from being on call so much.”

Baltes said 63 of Nebraska’s 93 counties face a shortage of hospital pharmacists.

Murante said 10 pharmacists are trained for the program, and she can hire up to 15. She said nearly 25 hospitals have expressed interest in the program, including a couple in Iowa and one in Missouri.

The computers that the pharmacists use are equipped with video conferencing systems and have access to all the resources available to in-house pharmacists at the medical center.

Each hospital using the program can choose its coverage, ranging from 24 hours a day, seven days a week, to just weekends or holidays.

Murante said the program is “not a moneymaker per se” and declined to provide any figures related to its cost.

The medical center, she said, is “just trying to help out our neighbors.”

–Contact the writer: 444-3110, [email protected]

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To see more of the Omaha World-Herald, or to subscribe to the newspaper, go to http://www.omaha.com.

Copyright (c) 2008, Omaha World-Herald, Neb.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

By Maddalena Jackson, The Sacramento Bee, Calif.

Jun. 25–As the Sacramento area settled into what promises to be a week of hazy air, more attention was being paid to what that could mean in terms of health.

“There are almost 1,000 fires in Northern California,” said Daniel Berlant of the state Department of Forestry and Fire Protection. The smoke “is a combination of all these fires.” He checked his numbers. “Nine hundred eighty three fires.”

Air quality is determined by forcing air through a fine mesh and trapping tiny particles that contribute to the murk.

If the filters straining Sacramento Valley air looked like dirty shirts, everyone could breathe a sigh of relief. But when they look like they fell into the mud, it’s time to worry about breathing at all.

“During the San Diego fire, they would come back just black — to the point where they just couldn’t hold any more particulate matter,” said Gennet Paauwe, spokeswoman for the California Air Resources Board. “That’s a reflection of what you’re breathing into your lungs.”

Jeff Cook, Air Resources Board emergency response coordinator, expressed “no doubt” that if you looked at the filters under current conditions, “you would see very dark brown, which is typical of high concentration.”

It is too early to know the full extent of health effects from smoke in the Valley.

Bart Ostro, chief of air pollution epidemiology within the state’s Office of Environmental Health Hazard Assessment, expects a repeat of the 2006 fire season, when data showed increases in asthma attacks and what looked like increases in hospitalization for heart disease.

“It’s likely that we’d see something pretty similar,” he said.

Northern California fires continued to threaten communities and force evacuations Tuesday night.

In Butte County, 27 lightning-caused fires had scorched about 5,000 acres by Tuesday night, prompting 1,000 evacuations and threatening about 1,000 structures, fire officials said. The fires — the Butte lightning complex — were 5 percent contained.

One of those fires, burning west of Highway 32 in Tehama County, forced immediate evacuation of about 250 campers from Camp Lassen, a Boy Scout camp.

Cindy Wilson, a Cal Fire spokeswoman, said that if the fire jumped the highway, the campers would have had no way out. About 100 of the evacuees, some of whom belong to Boy Scout groups, have been picked up by their parents at a Chico church, Wilson said.

A precautionary evacuation was in place for the communities of Butte Meadows and Jonesville.

Two fires, one in the area of Rim Road and Highway 70 and at the northern end of Concow Reservoir, was threatening the community of Concow, prompting evacuations and road closures, Wilson said.

Fire officials were concerned about a fire east of the west branch of the Feather River drainage. If it jumped the river, it could prompt evacuations in Magalia.

In Tahoe National Forest, lightning strikes caused 25 fires, grouped into the American River complex and the Yuba River complex fires.

The Yuba River complex had charred about 2,060 acres, and one of its fires was threatening the town of Washington. Residents were advised to prepare for evacuations, said Kathy Van Zuuk, Tahoe National Forest fire information officer.

The American River complex had burned about 1,210 acres.

Smoke has caused poor visibility, making it difficult to bring in aircraft, Van Zuuk said.

Most of the hospitals in the Sacramento region reported no increase in the number of patients complaining of air-related problems on Tuesday. Mercy San Juan Medical Center reported that about two dozen people had complained of health problems from the hazy air, about twice the typical number for this time of year, according to spokesman Bryan Gardner.

Smoke is what happens when a fire doesn’t burn perfectly. It spits out minuscule particles of soot, toxins and metals that could hide easily in the end of a human hair. Smoldering fires are the worst.

In a breath of smoky air, large particles attempt to turn the corners of airways and thud into the walls. Smaller particles swirl in as a mist, settling onto any surface they touch. Midsize particles, able to navigate the twisted paths of the lungs, go deep into airways and settle there.

Bodies try to evict the dirt, triggering coughs and sneezes, the need to blow a nose and reflexive swallowing to clear lungs of invaders.

Particles too deep in the lungs to catch a ride up to the throat meet the body’s predators.

These cells, called macrophages, police the lungs for bacteria and harmful objects. Drawn to the area by chemical distress calls or already on the scene, macrophages defeat harmful particles by swallowing them whole.

Things can easily go wrong, but it isn’t always known how or why.

Particles and heart and lung conditions go hand in hand, explained Kent Pinkerton, director of the UC Davis Center for Health and the Environment.

There are many possible causes of damage — toxic particles that kill macrophages and damage cells and DNA, particles so fine they sink into the walls of the lung, others that set off chain reactions that scar and inflame the respiratory system and yet others that trigger responses in the brain that can affect the heart or trigger asthma attacks.

Ostro of Environmental Health Hazards Assessment said short-term exposure to smoke inhalation can result in heart attack, increased bronchitis, reduced lung function and other physical problems, in addition to work and school time lost.

“The more serious effects are on people who already have pre-existing conditions,” Ostro said.

Experts advocate caution, but not panic.

“It’s really important to keep in mind that the majority of us who are exposed to smoke particles will do just fine,” Pinkerton said. “We might experience mild wheezing, mild chest tightness — certainly if we are exercising. It’s those people who are very exquisitely sensitive where it might be enough to put them into the hospital.”

—–

To see more of The Sacramento Bee, or to subscribe to the newspaper, go to http://www.sacbee.com/.

Copyright (c) 2008, The Sacramento Bee, Calif.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

By Mankoff, David A Link, Jeanne M; Linden, Hannah M; Sundararajan, Lavanya; Krohn, Kenneth A

Tumor receptors play an important role in carcinogenesis and tumor growth and have been some of the earliest targets for tumor- specific therapy, for example, the estrogen receptor in breast cancer. Knowledge of receptor expression is key for therapy directed at tumor receptors and traditionally has been obtained by assay of biopsy material. Tumor receptor imaging offers complementary information that includes evaluation of the entire tumor burden and characterization of the heterogeneity of tumor receptor expression. The nature of the ligand-receptor interaction poses a challenge for imaging-notably, the requirement for a low molecular concentration of the imaging probe to avoid saturating the receptor and increasing the background because of nonspecific uptake. For this reason, much of the work to date in tumor receptor imaging has been done with radionuclide probes. In this overview of tumor receptor imaging, aspects of receptor biochemistry and biology that underlie tumor receptor imaging are reviewed, with the estrogen-estrogen receptor system in breast cancer as an illustrative example. Examples of progress in radionuclide receptor imaging for 3 receptor systems- steroid receptors, somatostatin receptors, and growth factor receptors-are highlighted, and recent investigations of receptor imaging with other molecular imaging modalities are reviewed. Key Words: tumors; receptors; imaging

J Nucl Med 2008; 49:149S-163S

DOI: 10.2967/jnumed.107.045963

Cancer therapy is becoming increasingly directed and specific, taking advantage of biologic targets that are uniquely expressed or markedly overexpressed in tumors. Tumor receptors have been some of the earliest targets for cancer therapy, with notable successes in the treatment of endocrine-related cancers such as breast, prostate, and thyroid cancers (1-3). Advances in molecular cancer biology have revealed an ever-increasing number of tumor targets, many of which are receptors, such as the epidermal growth factor (EGF) receptor (EGFR) (4). The ability to measure the expression of tumor receptors is essential for selecting patients for receptor-targeted therapy (2). Although this information traditionally has been obtained by in vitro assay of biopsy material, recent studies have highlighted the complementary value of tumor receptor imaging for measuring regional tumor receptor expression, which can be quite heterogeneous.

Tumor receptor imaging emphasizes important emerging themes in molecular imaging: characterizing tumor biology, identifying therapeutic targets, and delineating the pharmacodynamics of targeted cancer therapy (5,6). The advantages of imaging include noninvasiveness, the ability to measure receptor expression for the entire disease burden and thereby to avoid the sampling error that can occur with heterogeneous receptor expression, and the potential for serial studies of the in vivo effects of a drug on the target. A very practical consideration is that imaging can assess receptor expression at sites that are challenging to sample and assay, such as bone metastases. This review discusses receptor pharmacology, the biology of tumor receptors, and special considerations for tumor receptor imaging, with the estrogen receptor (ER) as an illustrative example. This discussion is followed by highlights of recent work in the imaging of steroid receptors, somatostatin receptors (SSTRs), and growth factor receptors, as examples of 3 different types of tumor receptors. These topics were selected from a broad range of investigations in tumor receptor imaging (Table 1).

RECEPTOR PHARMACOLOGY

Common to all receptors is the interaction of a ligand and the receptor, in which specific binding of the ligand to the receptor results in downstream biochemical or physiologic changes {7,8). Ligand-receptor binding can activate or inhibit downstream processes through a variety of mechanisms, such as G-protein activation (e.g., PARI), tyrosine kinase activation (e.g.. EGFR), or activation of transcription (e.g., ER) (9-11). Ligands that cause physiologic changes with receptor binding, typically the naturally occurring ligands. are called agonists. Ligands that bind to the receptor and block the binding of agonists but that do not activate changes are known as antagonists. Drugs directed toward tumor receptor systems most frequently use a receptor antagonist, for example, tamoxifen, which blocks estrogen binding to the ER. Alternatively, some drugs lower the level of an agonist to decrease ligand-receptor interactions, for example, levothyroxine, which suppresses thyroid- stimulating hormone levels in the treatment of thyroid cancer (12).

TABLE 1

Selected Examples of Tumor Receptor Imaging Agents

The ligand-receplor interaction is a bimolecular chemical reaction. The concentration of the receptor is typically quite low; for example, the level of ER expression in breast cancer is in the range of 3-100 fmol per milligram of protein (13). Furthermore, receptor-specific ligands bind to receptors with a high affinity and often with a very low ligand-receptor dissociation rate (7). The combination of a low receptor concentration and a high ligand- receptor affinity leads to a low overall capacity for ligand- receptor binding. This property is helpful for drug therapy, in which the goal is to saturate the receptor with an antagonist to prevent receptor activation by an agonist. However, the high- affinity, low-capacity ligand-receptor binding reaction presents a challenge for imaging in that the number of molecules that can contribute to the specific receptor image is small. Furthermore, nonspecific binding of ligands to plasma proteins and nontarget tissues can limit imaging agent delivery and contribute to nontarget image background. For these reasons, imaging of receptor binding, as opposed to imaging of an enzymatic reaction, such as glucose phosphorylation. in which it is difficult to saturate the uptake mechanism, is challenging. It is important for receptor imaging probes to have very low molecular concentrations. Even small molar quantities of imaging agents may saturate receptors, limiting the ability to visualize receptor expression and increasing the background of nonspecific binding (14). Therefore, molecular imaging of tumor receptors has been mainly confined to radionuclide imaging (PET and SPECT). with which it is possible to generate images with micromolar to picomolar concentrations of imaging probes.

It is important to note that the criteria for a suitable receptor imaging agent are different from those for a receptor-targeted drug. Although selectivity for the drug requires an effect on the tumor in the absence of appreciable toxicity from nontarget tissue drug action, the requirement for high target uptake and low image background in imaging places constraints on radiopharmaceutical selectivity and background clearance that can be even more stringent than those for therapeutic drugs.

The estrogen-ER system is an illustrative example of a receptor system with relevance to cancer (15). The ER is importunt in female reproductive physiology and is selectively expressed in a variety of normal tissues-most notably, breast, uterus, ovary, bone, and pituitary tissues (9). Estradiol is a naturally occurring agonist ligand for the ER. The molecular mechanism of estradiol action through the ER has been well studied (3,9). Estradiol is lipophilic, allowing access across cell membranes to the ER, a nuclear receptor. The ER has 2 receptor subtypes: ER-alpha and ER-beta. ER-alpha serves mainly as an activator of downstream events related to breast and female sex organ function. The function of ER-beta is less well understood; in some situations, ER-beta may inhibit ER-alpha by forming a heterodimer wilh ER-alpha (16). Estradiol binding to ER- alpha in the nucleus results in dimerization of the receptor and allows interactions with specific DNA sequences known as the estrogen response elements (15), leading to the selective regulation of target gene transcription.

ER activation leads to different physiologic actions in different tissues. Much of the tissue specificity appears to be attributable to coregulators that interact with the ER homodimer and the estrogen response elements and that can affect the pattern of gene transcription (15). In the uterus, estrogens hound to the ER stimulate endometrial growth and are critical in maintaining a functioning uterine-placental unit during pregnancy. Estradiol promotes new bone formation and is important in maintaining bone mineral density, especially in women (9,17). Also, estrogens affect the cardiovascular system, mainly through their beneficial effect on serum lipids. In breast tissue, estradiol promotes ductal epithelial cell proliferation and is a key component stimulating lactation. Estrogens are established growth factors for endometrial and many breast cancers. Over 70% of breast cancers express the ER, and estradiol and other estrogens provide a key stimulus for tumor growth and a target for endocrine system-based therapy (endocrine therapy) (2.3,18-21). Tissue-specific coregulators interact with ligand-ER dimers and may affect the physiologic actions of different ligands when they bind to the ER. For example, drugs known as selective ER modulators (SERMs) exhibit various degrees of either ER agonist or antagonist behavior in different tissues, an effect thought to be based on the differential expression of ER coregulators in different tissues (9). The circulating levels of agonists for the ER are variable but are tightly regulated in normal human physiology (IT). The agonist estradiol has 2 sources: synthesis in the ovary in premenopausal women and conversion from adrenal steroids, mainly through aromatization (and aromatase enzymes) present in a variety of tissues-most notably, fat, breast tissue, and breast cancers (22,23). Premenopausal levels of estradiol vary, depending on the phase of the menstrual cycle, reaching levels as high as 500 pg/mL (1.7 nM) at midcycle (17). In postmenopausal women and men, the levels are generally less than 30 pg/mL (0.1 nM). Estradiol is very lipophilic and is generally present at slightly higher concentrations in tissues with higher fat contents, providing an opportunity for nonspecific uptake. Circulating estradiol is mainly protein bound. This binding occurs with a high affinity but a low capacity to sex hormone-binding globulin (SHBG or SBP) and wilh a low affinity but a high capacity to albumin (24,25). Much of circulating estradiol is bound to SHBG, and the remainder is bound to albumin (24). Binding to both SHBG and the ER appears to be important for normal estrogen physiology and also appears to be important for ER imaging agents (25-27). One of the physiologic roles of SHBG appears to be the regulation of estrogen metabolism (25). Estradiol is highly metabolized in the liver to estrone and conjugates of both estradiol and estrone (29) and enters a cycle of enterohepatic circulation (30-32). Binding to SHBG. extraction by the liver, and reabsorption of conjugated estrogens in the small intestine all play important roles in regulating estradiol levels in normal physiology (24,28).

Considerations for imaging of the ER include the need for low injected molar doses to remain below physiologic levels (typically 30 pg/mL or higher), the need for imaging agents to bind to both the ER and the transport protein (SHBG). normal routes of estrogen metabolism and excretion, and nonspecific binding in the blood and lipophilic tissues (33). These considerations are discussed in more detail in the following sections as we examine other aspects of tumor receptor imaging. Overall, the complex nature of ER physiology emphasizes the need for a detailed understanding of receptor pharmacology and physiology in developing tumor receptor imaging approaches.

BIOLOGY AND PHYSIOLOGY OF TUMOR RECEPTORS

The biologic role of most receptor systems important in cancer is derived from their role in the tissue of cancer origin. In general, tumor receptors are expressed in the parent cell lineage and have an established physiologic function. For example, ER expression is essential to the function of normal mammary gland epithelial cells (9,15). When estradiol binds to ductal epithelial ER, it stimulates mammary gland growth, maintenance, and physiologic function (9,15). Many tumor receptors also play an important role in promoting carcinogenesis or tumor growth, as is the case for steroid receptors in breast and prostate cancer (34). The dependence on the receptor pathway for tumor growth makes the receptor an ideal target for therapy, because interruption of the receptor-initiated signal will result in a cessation of tumor growth and often tumor cell death (3, 10).

For many tumor receptors expressed in the normal parent cell lineage, the receptors are expressed at levels comparable to those in normal cells, and tumor growth stimulation occurs in concert with other factors contributing to the dysregulation of tumor cell growth. This mechanism appears to be the case for steroid receptors, although gene amplification may occur in some cases (35). For other receptors, overexpression of the receptors leads to aberrant stimulation of the signaling pathway. Examples of this mechanism include EGFR in lung cancer and HER in breast cancer (3,10,36). In this situation, aberrant expression (overexpression) becomes an important marker for the activation of the pathway and predicts the likely efficacy of therapy directed against the target. For example, the overexpression of HER2 is highly predictive for a response to trastu7,umab, a monoclonal antibody directed against HER2 (37). In all cases, knowledge of the levels of receptor expression, which may vary considerably in different tumors and even in different sites in the same tumor, is required to infer the likelihood that receptor- directed therapy will be effective.

For tumor receptor systems, considerable variability exists in both ligands and receptors. Ligands may be naturally occurring small molecules, such as estradiol and testosterone, synthesized and secreted in endocrine organs, such as the adrenal gland, ovary, and testis, or peptides assembled and secreted by different types of endocrine cells (38). Receptors can be located on the cell membrane, for example, EGFR and SSTRs (36). or localized within the cell, for example, steroid receptors in the nucleus (9). In some cases, such as steroid receptors, the binding of the agonist ligand to the receptor is well understood, and there is a clear causal relationship between binding and pathway activation (15). In other cases, such as HER2, the pharmacologie significance of ligand- receptor binding in activating the pathway is less well understood; however, receptor-targeted therapy can still be effective at interrupting the signaling pathway through antagonism (10,39).

The approaches to tumor receptor-targeted therapy vary. In many situations, receptor-targeted antagonists bind to the receptor and block the normal agonist ligand from binding and activating the pathway; for example, the drugs tamoxifen and flutamide block the ER and the androgen receptor (AR), respectively (9,40,41). Many receptor-blocking agents have structures relatively similar to that of the natural ligand and are designed to bind to the same site as the agonist; examples are antiestrogens and antiandrogens. Blocking agents can also bind through immune recognition; for example, the agents trastuzumab and cetuximab bind to HER2 and EGFR, respectively (36).

An alternative therapeutic strategy is to deplete the ligand. This approach has been extraordinarily effective for estrogens and the ER in breast cancer, for which the use of aromatase inhibitors has met with considerable success (22, 23). With aromatase inhibitors, the drug is not a receptor antagonist ligand but rather is an enzyme inhibitor that blocks the synthesis of the naturally occurring agonist ligands estradiol and estrone (22). Aromatase inhibitors block the conversion of adrenal steroids to estrogens, the major source of estrogen in postmenopausal women, lowering estrogen concentrations both in the serum and in the local tumor environment (42). Aromatase inhibitors are now first-line adjuvant and primary metastatic breast cancer treatments in postmenopausal patients with ER-expressing tumors (43).

Despite the importance of tumor receptors in carcinogenesis and tumor growth, tumor receptors are not always effective targets for cancer treatment, because some cancers can sustain growth independently of receptor activation. In some situations, growth independence is accompanied by a loss of or a reduction in receptor expression, such as in ER-negative breast cancers (3). In such situations, the absence of receptor expression indicates a negligible chance of success of receptor-targeted therapy. In other situations, even though a receptor is still present, receptor pathway activation is not required for growth. For example, although 70% of breast cancers express the ER, only 50%-75% of ER-expressing primary breast cancers respond to endocrine therapy, and even fewer recurrent tumors respond (3). Redundant growth pathways may make the receptor system no longer necessary to sustain tumor growth. The latter situation appears to occur with breast cancers that both express ER and overexpress HER2 and that are often resistant to endocrine therapy, even when ER expression is preserved (44). These examples illustrate that although tumor receptor expression is necessary for a functional pathway, receptor expression does not necessarily guarantee the success of receptor-targeted therapy. The approach to patient selection is therefore sequential. The first step is the assay of receptor expression, because the absence of receptor expression invariably indicates that the receptor pathway is not a suitable target for therapy. After the selection of patients with receptor expression, the next step is to show that the pathway is functional and required, typically by assessing the response to receptor-targeted therapy. This clinical paradigm sets the stage for the goals of tumor receptor imaging.

SPECIAL CONSIDERATIONS FOR TUMOR RECEPTOR IMAGING

Tumor receptor imaging poses unique challenges for the design of radiopharmaceuticals and imaging approaches. Most receptors have high affinities for their ligands and are active at nanomolar concentrations of the ligands. For this reason, radiopharmaceuticals with high specific activity are essential. Even small molar quantities of an imaging agent may saturate a receptor and limit the ability to visualize receptor expression (14,33). For this reason, molecular imaging of tumor receptors has been most successful with radionuclide imaging (PET and SPECT), with which it is possible to generate images with nanomolar amounts of imaging probes. For larger molecules, such as peptides and monoclonal antibodies, other labels suitable for optical imaging, MRI, and ultrasound imaging are possible (Table 1); however, for small-molecule receptor imaging agents, such as labeled steroids for steroid receptors, radionuclide imaging appears to be the only feasible approach. The need for high specific activity (ratio of radioactive to nonradioactive molecules) also poses a challenge for radiopharmaceutical quality control (14,33). Specific activity often needs to be measured before each radiopharmaceutical administration to ensure that a failure to visualize the receptor is not the result of poor t racer-specific activity. The choice of a label depends on the nature of the receptor imaging probe. For example, somatostatin imaging of neuroendocrine tumors entails the use of a labeled peptide closely related to the naturally occurring peptide hormone somatostatin (45). In this situation, the imaging molecule is large enough to enable the use of chelating groups and radiometal labels without a loss of receptor binding. A variety of somatostatin imaging agents have been successfully developed with both single-photon emitters (^sup 111^In and ^sup 99m^Tc) and positron emitters (^sup 68^Ga and ^sup 64^Cu) (46-48),

For smaller molecules, the isotope label may significantly affect binding to the receptor, binding to transport proteins, and in vivo metabolism. In this situation, the choices of radionuclide and labeling position for imaging may be relatively limited, such as for ER imaging agents (14). Considerable work has been done with both single-photon-emitting and positron-emitting halides for ER imaging (49-51), but studies have suggested that ^sup 18^F is the most attractive label for PET ER imaging (14). Fluorine is a small halogen in which substitutions can be made at several positions of the estrogen while preserving binding affinities for both ER and SHBG (52.53). Furthermore. ^sup 18^F has a sufficiently long half- life to permit multistep synthesis of ligands (52,54) as well as uptake by target tissue and elimination by nontarget tissue during imaging (14,55); in addition, the use of PET permits quantitative imaging of regional receptor binding.

For small molecules, the location of the label can also be important. For ER imaging. ^sup 18^F substitution in the 16-alpha position for the steroidal analog estradiol to yield ^sup 18^F- 16- alpha-17-beta-fluoroestradiol (^sup 18^F-FES) resulted in highly selective uptake by target tissue, with a uterus-to-blood ratio of 39 (52). Changing the molecule or labeling can have unexpected results. For example, ^sup 18^F-labeled moxestrol (^sup 18^F-FMOX). another ER imaging agent, was developed with the goal of decreased metabolism and increased ER binding. Preclinical studies in vitro and in rats demonstrated better ER binding in vitro and increased uterine uptake in immature rats for ^sup 18^F-FMOX than for ^sup 18^F-FES (26.56). However, ^sup 18^F-FMOX performed poorly in human studies. The explanation for these findings was that poor binding of ^sup 18^F-FMOX to the steroid transport protein, SHBG, likely limited its utility in humans. Rats lack SHBG (25); therefore. ^sup 18^F-FMOX was an effective imaging agent in rats. In this example, a change in the imaging molecule that promoted increased ER binding unfavorably altered the binding to SHBG, resulting in a compound with poorer performance. This example illustrates the demanding nature of radiopharmaceutical design for tumor receptor imaging and the need for validation at each step of development, from the laboratory bench to the bedside.

For these reasons, considerable preclinical work and early testing in patients are necessary to develop and validate receptor imaging agents (33). In vitro studies must confirm the high- affinity receptor binding of a radiopharmaceutical as a starting point for development. Subsequently, in vitro and in vivo animal models must demonstrate that binding is specific to the receptor and that an excess of the nonlabeled natural Iigand, or a suitable substitute specific for the receptor, can displace or block the binding of the radiopharmaceutical. In vivo clearance, metabolism, and biodistribution in preclinical models and early patient studies must confirm sufficient tracer clearance to visualize uptake in tumors but sufficiently slow blood clearance and metabolism to permit uptake in receptor-rich tissues. Defining the nature of labeled metabolites is also important, because some metabolites may bind to the receptor, whereas others may not. For example, in humans, ^sup 18^F-FES-labeled metabolites are present mostly in the form of conjugates that do not bind to the receptor or have access to the nuclear receptor. These metabolites therefore contribute to nonspecific image background (27,55,57). In addition, assessment of nonspecific binding is important; nonspecific binding must be sufficiently low to avoid interference with the visualization and quantification of tumor uptake at target sites.

Receptor imaging poses some additional challenges for image acquisition and analysis. Because the absence of receptor expression may be even more important than the presence of a receptor, the imaging approach must be able to quantify low levels of radiopharmaceutical uptake and reliably identify situations in which a tumor is present but the uptake of a receptor imaging agent is low or absent. This approach requires multimodality imaging. Combined functional imaging and anatomic imaging, such as PET/CT or SPECT/ CT, may be essential for localizing tumor sites at which the uptake of a receptor imaging probe can be quantitatively interrogated. Because it may be difficult to identify active tumor sites by anatomic imaging alone, it may be necessary to align tumor receptor images with images obtained with another tumor imaging probe, such as ^sup 18^F-FDG, to identify viable tumor. We used this approach for the ER imaging of breast cancer; ^sup 18^F-FDG PET identified sites of active breast cancer at which to evaluate ER expression by ^sup 18^F-FES PET (Fig. 1). It may be beneficial to coregister different functional images; for example, for PET/CT and SPECT, the anatomic images may be used as the basis for coregi strati on. Finally, because radiopharmaceutical uptake may be at or close to background uptake in nontumor tissues, accurate correction for the imaging of physics-related background counts, such as scattered photons, is critical.

Another potential issue is separating the effects of imaging probe transport and binding in determining the overall image. It is possible that transport barriers will limit the in vivo access of the imaging probe to the site of tumor receptor expression. Therefore, it may be difficult to determine from a single static image whether the absence of radiopharmuceutical uptake at a tumor site is attributable to a lack of receptor expression or to a lack of delivery of the imaging probe. This is less likely to be an issue for small, lipophilic molecules, such as steroid imaging agents, but may pose an important consideration for peptides and especially monoclonal antibodies. In such situations, more sophisticated, dynamic imaging acquisitions may be required, along with more detailed and kinetic analyses.

FIGURE 1. Examples of different patterns of ER expression measured by ^sup 18^F-FES PET. Both patients had bone metastases arising from ER-expressing primary tumors, and both were treated with endocrine therapy. (A) For this patient, pretherapy ^sup 18^F- FDG and ^sup 18^F-FES PET scans showed ^sup 18^F-FES uptake at all sites of active disease seen by ^sup 18^F-FDG PET. Follow-up ^sup 18^F-FDG PET scan showed response to treatment after initiation of aromatase inhibitor therapy. (B) For this patient, there was no uptake at site of disease seen on ^sup 18^F-FDG PET scan (small arrow). Follow-up ^sup 18^F-FDG PET scan showed subsequent disease progression (small arrow) with endocrine therapy. (Reprinted with permission of (84).)

EXAMPLES OF TUMOR RECEPTOR IMAGING

Steroid Receptors

Steroid receptor targets in cancer include the ER and the progesterone receptor (PR) in breast cancer and the AR in prostate cancer. We first briefly review experience in AR and PR imaging and then discuss ER imaging, for which the most experience with steroid receptor imaging has been obtained.

Parallel to efforts for ER imaging, a variety of compounds have been developed for PET of the AR; these have been directed mainly toward prostate cancer imaging (58-64). AR imaging has proved to be somewhat more challenging than ER imaging, perhaps because of the relatively tighter binding of androgens than of estrogens to SHBG; the latter property may limit the delivery of the imaging agent over the time scale of PET, even though tight binding of the AR imaging agent to SHBG appears to be important in generating AR images (25,58). Preclinical studies in baboons, which have SHBG similar to that in humans, indicated that 16-beta-^sup 18^F-fluoro-5-alpha- dihydrotestosterone (^sup 18^F-FDHT) was a promising compound for PET (58). Early studies with ^sup 18^F-FDHT showed promise for the imaging of regional AR expression in prostate cancer (59,61). Larson et al. (61) reported significant ^sup 18^F-FDHT uptake in 7 patients with prostate cancer. Like that of ^sup 18^F-FES, ^sup 18^F-FDHT metabolism was rapid, with 80% of radioactivity in the blood in the form of metabolites at 10 min after injection. Cancer treatment diminished ^sup 18^F-FDHT uptake in the subset of patients re- imaged after therapy in that study. Dehdashti et al. (59) studied 20 patients with prostate cancer by ^sup 18^F-FDHT PET and found evidence of uptake in 63% of the patients; ^sup 18^F-FDHT PET revealed a substantial number of tumor sites that had not been identified by conventional imaging. Furthermore, in a subset of 12 patients who were re-imaged 1 d after the initiation of fiutamide therapy, the imaging demonstrated a significant (>50%) average decline in ^sup 18^F-FDHT uptake, indicating the ability to measure the pharmacodynamics of treatment with receptor antagonists. These encouraging results support the feasibility of PETAR imaging, and ongoing studies support the promise of imaging of AR expression in localizing prostate cancer and possibly predicting the response to antiandrogen therapy. Efforts to image the PR have been less successful (56,65). In a study of 8 patients with primary breast cancer, Dehdashti et al. found that 21-^sup 18^F-fluoro-16alpha- ethyl-19-norprogesterone was taken up in some tumors, but the level of uptake did not correlate with the level of PR expression (65). This result may have been attributable in large part to the relatively low affinity of progeslins for the PR. with binding affinities that are orders of magnitude lower than those of androgens for the AR and of estrogens for the ER (56). Therefore, relatively high nonspecific binding compared with specific binding of imaging probes may limit their utility for PR imaging. Later studies also showed that the radiopharmaceutieal tested had rapid metabolism in humans to a metabolite with poor receptor binding (66), a finding that was not predicted by preclinical models. Efforts to develop effective PR imaging agents continue (67).

The most experience to date with steroid receptor imaging for tumors has been obtained with ER imaging for breast cancer. Considerable efforts have been directed toward the development of radiopharmaceuticals for ER imaging (51). Early efforts to develop a labeling approach for PET focused on steroids labeled with bromine; promising early results were obtained with ^sup 77^Br-16alpha, 17beta-estradiol in animals and humans (68, 69). Parallel efforts to develop ^sup 123^I-labeled compounds for SPECT also yielded promising early results (70,71). Although a variety of ER imaging agents have been tested and continue to be developed and tested (14,53,72,71). the most successful ER imaging radiopharmaceutieal to date has been ^sup 18^F-FES (14,74). ^sup 18^F-FES has binding characteristics similar to those of estradiol for both the ER and the transport protein SHBG (27,52). Typically, in humans, about 45% of ^sup 18^F-FES in circulating plasma is bound to SHBG. and much of the remainder is weakly bound to albumin (27). The clearance and metabolism of ^sup 18^F-FES have been studied in both animals and humans (55,57,75.76). Like other steroids, ^sup 18^F-FES is rapidly taken up by the liver and metabolized shortly after injection. As a result, early blood clearance is rapid, reaching a plateau 20-30 min after injection (55). To date, no toxicity or significant adverse reactions have been reported for ^sup 18^F-FES. Radiation dosimelry studies have shown that organ doses associated with ^sup 18^F-FES PET are comparable to those associated with other commonly performed nuclear studies and that potential radiation risks are well within acceptable limits. The effective dose equivalent is 0.022 mSv/Bq (80 mrem/mCi), and the organ that receives the highest dose is the liver, at 0.13 mSv/Bq (470 mrad/mCi) (77). The recommended injection is 222 MBq (6 mCi) or less. ^sup 123^I-labeled compounds have also produced images of regional ER expression with acceptable radiation dosimetry (70.78), albeit with somewhat lower image quality. The quantification of radiopharmaceutical uptake appears to be important for ER imaging, and this quantification is more challenging for SPECT than for PET.

^sup 18^F-FES uptake has been validated as a measure of ER expression in breast tumors. In 1988, Minlun et al. (79) reported an excellent correlation between ^sup 18^F-FES uptake measured in primary tumors on PET images and tumor ER concentrations measured in vitro by radioligand binding after excision for 13 patients with primary breast masses. A preliminary comparison of ^sup 18^F-FES uptake with immunohistochemistry assays of biopsy material from patients with both primary and metastatic cancers also showed a good correlation (80,80a). Imaging results will not necessarily correlate perfectly with biopsy results. Differences between in vivo measures of ER expression by PET and in vitro assays of ER expression are to be expected, especially in comparisons of radioligand binding (e.g., ^sup 18^F-FES PET) and immune recognition (e.g.. immunohistochernistry assays of biopsy material).

In the earliest reported study of ^sup 18^F-FES PET in patients, ^sup 18^F-FES uptake was seen at sites of primary carcinomas, axillary nodes, and one distant metastatic site (79). The investigators then extended the use of this radiopharmaceutical for the imaging of metastatic breast cancer. Sixteen patients with melastatic disease underwent ^sup 18^F-FES PET; increased uptake was seen in 53 of the 57 metastatic lesions, for a sensitivity of 93%, and there were only 2 apparent false-positive results (81). Imaging results were reported quantitatively as percentage injected dose per milliliter (uptake), ratio of lesion to soft tissue, and ratio of lesion to uninvolved bone. The same group of investigators obtained similar results in a later study of ^sup 18^F-FES imaging in 21 patients with metastatic breast cancer; they reported 88% overall agreement between in vitro ER assays and ^sup 18^F-FES PET (82). In addition to subjective analysis, ^sup 18^F-FES uptake has been reported as a standardized uptake value (SUV). Using an SUV of greater than I to identify ER-expressing disease, Mortimer et al. (83) reported that the sensitivity of ^sup 18^F-FES imaging was 76%. with no false-positive results, in 21 patients with metastatic breast cancer.

One of the chief advantages of ER imaging over tissue sampling for determining ER expression is the ability to evaluate the heterogeneity of ER expression. Mortimer et al, (83) found that for 4 of 17 patients (24%) with metastatic breast cancer, there was a discordance in ^sup 18^F-FES uptake between sites in individuals. Mankoff et al. (80) reported the absence of ^sup 18^F-FES uptake at one or more metastatic sites in 10% of patients who had ER- expressing primary tumors. In this same preliminary study, the quantitative site-to-site variability in ^sup 18^F-FES uptake in individuals was high (coefficient of variation of approximately 30%). A total of 13% of patients (6/47) with ER-expressing primary tumors had one or more sites of ^sup 18^F-FES-negalive disease in a subsequent study by the same group of investigators (84). The rate of loss of ER expression at metastatic sites from ER-expressing tumors was comparable to (only slightly lower than) values obtained from tissue samples and reported in the literature (85.86), suggesting that sampling error may contribute to the apparent heterogeneity in tissue-based assay studies.

In clinical practice, in vitro ER assays are used primarily as predictive assays for endocrine therapy. Although ^sup 18^F-FES PET has not been prospectively tested as a predictive assay in clinical trials, a eomparison of ^sup 18^F-FES uptake and the response to endocrine therapy in some groups of patients has indicated the likely performance of ^sup 18^F-FES PET as a predictive assay. Mortimer et al. (87) showed that the level of ^sup 18^F-FES uptake predicted the response to tamoxifen, demonstrating the potential utility of ^sup 18^F-FES PET for predicting a response in the locally advanced and metastatic settings. Forty women with biopsy- proven ER-expressing breast cancer had ^sup 18^F-FES PET before and 7-10 d after the initiation of tamoxifen therapy, and tumor ^sup 18^F-FES PET was assessed with the SUV method. Both the percentage decrease in 1KF-FES uptake (responders, 55% +- 14% [mean +- SD]; nonresponders, 19% +- 17%) and the absolute change in tumor SUV (responders, decrease of 2.5 +- 1.8 SUV units; nonresponders. decrease of 0.5 +- 0.6 SUV units) predicted the response to tamoxifen. The level of ^sup 18^F-FES uptake before therapy also predicted the response to tamoxifen. The positive and negative predictive values for baseline ^sup 18^F-FES uptake with an arbitrary SUV cutoff of 2.0 were 79% and 88%. respectively (87). No patient with an SUV of less than approximately 1.5 responded.

Linden et al. (84) showed that the initial ^sup 18^F-FES uptake measurements in patients with ER-expressing tumors were correlated with subsequent tumor responses to 6 mo of hormonal therapy. Forty- seven patients with metastatic breast cancer from ER-expressing primary tumors, most of whom had been previously treated for breast cancer, many for some time and with several regimens, were given predominantly salvage aromatase inhibitor therapy. Objective responses were seen in 11 of 47 patients (23%). ^sup 18^F-FES PET was assessed qualitatively and quantitatively with SUV and flux calculations. Although no patient without ^sup 18^F-FES uptake at known tumor sites responded, qualitative ^sup 18^F-FES PET results did not significantly predict responses to hormonal therapy. However, quantitative results were predictive of responses in that O of 15 patients with initial SUVs of less than 1.5 responded to hormonal therapy, compared with 11 of 32 patients (34%) with initial SUVs of greater than 1.5 (P

Some preliminary studies have evaluated ^sup 18^F-FES PET in settings other than breast cancer. Moresco et al. (75, 76) studied ^sup 18^F-FES uptake in normal brain tissue and meningiomas, using measures similar to the flux measure defined earlier. Although ^sup 18^F-FES uptake in normal brain tissue was too low to quantify estradiol binding reliably by PET, significant ^sup 18^F-FES uptake was seen in some meningiomas. Selective ^sup 18^F-FES uptake by uterine endometrium has been shown in human imaging, with cyclic changes mirroring the menstrual cycle (89). ISF-FES uptake in endometrial cancer has been reported for a single patient studied by this method (90).

Overall, early studies of PET ER imaging have shown its promise as a tool for directing breast cancer treatment. The promising early results of the studies of Mortimer et al. (87) and Linden et al. (84) indicating the potential utility of ^sup 18^F-FES PET as a predictive assay need to be confirmed in larger trials involving more institutions and objective determinations of the appropriate ^sup 18^F-FES SUV cutoff for predicting a response to endocrine therapy. Ongoing studies, including prospective clinical trials, should define its potential use in clinical trials and clinical practice for breast cancer and possibly other ER-expressing tumors.

SSTRs

Somatostatin is a 28-amino-acid peptide agonist ligand secreted by endocrine D cells and neurons in the gastrointestinal (GI) tract and pancreas (91). SSTRs are membrane receptors for which 6 subtypes have been identified by molecular analysis (45, 91). Somatic tissues most commonly express receptor subtypes 2 and 5 (91). Somatostatin binding to the receptor activates G proteins, leading to downstream physiologic actions that are tissue specific. Primary among these actions is the inhibition of the release of endocrine and exocrine factors in the GI system (91). Therefore, somatostatin plays an important role in the regulation of the GT tract. In addition to normal tissues, SSTRs are expressed in a variety of tumors, especially endocrine tumors, such as carcinoids, gastrointestinal and pancreatic neuroendocrine tumors, pheochromocytomas, paragangliomas, medullary thyroid cancer, and pituitary adenomas (45). Somalostatin analogs, such as the 8-amino-acid peptides octreotide and Ianreotide, are used therapeutically to inhibit GI tract endocrine factor release in both nonmalignant disease (e.g., intractable diarrhea) and endocrine neoplasia, particularly pituitary and neuroendocrine tumors (91). Unlike somatostatin itself, which has a plasma half-life of approximately 2 min, octreotide has a half-life of 1.5-2 h, making it suitable for drug therapy (91, 92). In the treatment of neuroendocrine tumors, somatostatin analogs reduce the symptoms associated with excess hormone secretion and may also have direct antilumor effects (91).

The main focus of SSTR imaging has been neuroendocrine tumors and related tumors, including carcinoids, gastrointestinal and pancreatic neuroendocrine tumors, pheochromocytomas, paragangliomas, medullary thyroid cancer, and pituitary adenomas (45). Other tumors expressing SSTRs have also been studied and include Iymphomas, meningiomas, elhesioneuroblastomas, and lung cancers (93-95).

Most of the work carried out to date on SSTR imaging has used labeled somatostatin analogs, most commonly, octreotide or a closely related peptide (45). Octreotide is an 8-amino-acid peptide with stability in plasma, unlike somatostatin. which has a plasma half- life of less than 3 min (91). The labeling strategy is quite different from that used for a smaller molecule, such as estradiol. The first compound used in SSTR imaging, ^sup 123^I-^sup 3^Tyr- octreotide. was introduced in 1988 (96) and used direct halogenation of a tyrosine (45,96). However, the most widely used radiopharmaceutical s in current practice use a linked chelating group, such as diethylenetriaminepentaacetic acid (DTPA) or 1,4,7,10- tetraazacyclododecane-N,N’,N”,N”’-tetraacetic acid (DOTA). that binds to the peptide and chelates a radiometal, such as ^sup 99m^Tc. ^sup 111^In. ^sup 68^Ga, or ^sup 64^Cu (45,97-100). Currently, most clinical SSTR imaging is carried out with the agent ^sup 111^In- DTPA-pentetreotide (Octreoscan; Mallinckrodt), which is approved by the U.S. Food and Drug Administration for clinical SSTR imaging (101). Recent studies (48,98,100,102.103) examined octreotide-like compounds labeled with positron emitters (such as ^sup 64^Cu- and ^sup 68^Ga-labeled peptides), taking advantage of the higher spatial resolution and easier image quantification offered by PET than by SPECT (104-106). Of the 2 positron-emitting labels, ^sup 68^Ga is conveniently available from a generator but has the disadvantage of a higher positron range than ^sup 64^Cu.

Imaging of SSTR-expressing tumors has been applied to tumor detection and staging, prediction of the response to therapeutic somatostatin, and treatment planning for SSTR-directed radionuclide therapy (45,92). The most widely tested and clinically accepted indication is tumor staging, for which SSTR imaging has become part of the clinical routine for carcinoids and other neuroendocrine tumors (45,99,101). These tumors, frequently arising from the gut or other abdominal structures, can he challenging to identify by conventional anatomic imaging. Furthermore, welldifferentiated neuroendocrine tumors have fairly limited 1SF-FDG uptake, limiting the effectiveness of 18F-FDG PET in neuroendocrine tumor staging (104). Most comparisons have shown that SSTR imaging, mostly with ^sup 111^In-labeled compounds, has higher sensitivity and accuracy for neuroendocrine tumor localization than other modalities, supporting its ongoing use in clinical practice (45,107), SSTR imaging has a significant impact on neuroendocrine tumor treatment, making it effective in clinical management (108). Combined-modality (SPECT/CTand PET/CT) imaging increases the impact of SSTR imaging, especially with regard to direct tissue sampling or surgical resection (109, UO). Recent studies have suggested that the use of PET labels, such as ^sup 68^Ga, along with PET/CT may be especially effective in this regard (47). Studies have suggested that binding of the labeled peptide to the SSTR and clearance from the plasma are sufficiently rapid to permit visualization and quantification of the regional SSTR concentration by 45 min after injection, necessary for the short half-life of ^sup 68^Ga (111).

Some studies have also examined the presence or absence of uptake of SSTR imaging probes as a predictor of the response to somatostatin therapy, akin to studies of ^sup 18^F-FES PET as a predictor of the breast cancer response to endocrine therapy. Although there have been some promising studies (112), the results have been variable, and this indication is less common in clinical practice than simple tumor localization and staging. Several factors contribute to the lower success of SSTR imaging than of ER imaging in response prediction: SSTR imaging studies have been mainly nonquantitative, somatostatin therapy has limited efficacy in cytoreduction, and responses are difficult to measure in slowly growing tumors, such as neuroendocrine tumors (91). The effect of SSTR-directed therapy on SSTR expression may also be a confounding factor; some studies have suggested that somatostalin itself may affect receptor expression and the uptake of labeled analogs in a complex, rather than strictly competitive, fashion (113).

A rapidly emerging focus in radionuclide-labeled SSTR ligands is SSTR-directed radionuclide therapy (92). Neuroendocrine tumors can present with advanced, widespread disease that is often refractory to conventional chemotherapy (38). However, they are often slowly growing tumors, so that minor responses or disease stabilization can result in considerably prolonged survival (114). In this regard, radionuclide therapy with labeled SSTR ligands has been effective in treating advanced neuroendocrine tumors (92,115). The earliest studies used ^sup 111^In-DTPA-pentelriotide und showed up to an 80% disease stabilization rate (92,116). More recent studies have used ^sup 90^Y- and ^sup 177^Lu-labeled compounds, which have some advantages over ^sup 111^In-labeled compounds for radionuclide therapy. ^sup 90^Y is a pure beta-emitter with high-energy beta- emissions; ^sup 177^Lu has intermediateenergy beta-emissions and has a longer half-life than ^sup 111^In. Several studies have shown objective response rates higher than those obtained with ^sup 111^In, and some recent studies have shown significant improvements in time to progression and survival (92, 117, 118). For guiding SSTR- directed radionuclide therapy, SSTR imaging has been key (92) in showing uptake of the labeled peptide at all known tumor sites and in estimating radiation dosimetry. For dosimetry, the use of PET radiopharmaceuticals has been especially helpful (97), given the ability of PET to quantify radiopharmaceutical biodistribution. Recent studies have suggested that radionuclide SSTR imaging fused with anatomic imaging can be very effective in targeting meningiomas (119). This approach provides another novel application of SSTR imaging in directing therapy, namely, guiding conformai radiotherapy.

In summary, radionuclide SSTR imaging and SSTR-directed radionuclide therapy have been important in the diagnosis and therapy of SSTR-expressing tumors, especially neuroendocrine tumors. Although non-receptor-based imaging with compounds such as labeled metaiodobenzylguanidine and 3,4-dihydroxyphenylalanine has also played a role in the diagnosis of these tumor types (47,99), the specific imaging of SSTRs remains an important and evolving clinical tool with both diagnostic and therapeutic applications.

Growth Factor Receptors

A third and somewhat distinct receptor imaging example relates to the EGFR pathway, which has received considerable recent attention as a therapeutic and imaging target (10,36). EGFR is a membrane surface receptor that interacts with agonists such as EGF and transforming growth factor; however, receptor activation is complex, and the exact nature of the ligand-receptor interaction is not completely understood (4,39). It appears that activation of the EGFR pathway involves up to 4 related receptors, erbB1-erbB4 (also called HERI-HER4), which form homo- and heterodimers both in the presence and in the absence of a ligand (10,39). The result of these receptor interactions is the activation of a specific tyrosine kinase and a sequence of downstream reactions leading to diverse biologic consequences, which include cellular proliferation, angiogenesis, and resistance to apoptosis (10,39). The EGFR pathway has been implicated in the pathogenesis of many cancer types and has received considerable recent attention as a therapeutic target (4.10,39). The most notable and widely studied approaches are therapy directed to the EGFR (erbBI, HERl) for lung cancer and head and neck cancer and therapy directed to erbB2 (HER2 or HER2/neu) for breast cancer (4). Therapeutic strategies target either membrane receptors, typically with monoclonal antibodies (e.g., cetuximab for EGFR and trastuzumab for HER2), or tyrosine kinase, with small-molecule inhibitors (e.g., erlotinib for EGFR) (4).

FIGURE 2. Images of mouse model of HER2-expressing breast cancer before treatment (A) and 1 d (B), 5 d (C), 8 d (D), and 12 d (E) after treatment with 17-allylamino-17-demethoxy-geldanamycin (17AAG) taken with ^sup 68^Ga-DOTA-F(ab’)2-trastuzumab. Images show early decrease in HER2 expression shortly after 17AAG treatment, with reexpression of HER2 by day 12. Arrows indicate location of cancer. (Reprinted with permission of (145).)

Imaging approaches mainly parallel therapeutic approaches. Although there have been some studies of labeled receptor ligands (120-122), such as ^sup 111^In-DTPA-EGF, most efforts to date have focused on receptor. Some progress has been made for specific tyrosine kinase probes (123-729); however, the multiplicity and ubiquity of tyrosine kinase expression sites as well as lipophilicity and associated nonspecific binding have made probe development challenging (123,727).

The most success to date has been achieved (and the largest number of studies have been carried out) for the targeting of EGFR or HER2 by immune recognition, in parallel with therapeutic agents. Specific imaging probes have been based on radiolabeled antibodies or fragments (130-134) or on novel constructs, such as Affibodies (135,136). Most studies have been preclinical (137-141); however, some studies have reported HER2 imaging in patients (133,142-144). Studies carried out by Smith-Jones et al. (145,146) with a ^sup 68^Ga-labeled F(ab’)2 fragment of trastuzumab showed the feasibility of measuring regional HER2 expression in murine animal models. The imaging results clearly demonstrated alterations in HER2 expression accompanying experimental therapy with HSP90-directed agents (geldamycin analogs) to disrupt protein ehaperone functions and reduce HER2 expression (Fig. 2) (745.146). Studies with ^sup 131^I- or ^sup 111^In-labeled trastuzumab demonstrated the ability of trastuzumab to image tumor expression of HER2 and tumor and normal tissue accumulation (133,142,147). although there has been some controversy about the significance of uptake in normal tissues prone to trastuzumab toxicity, such as the heart (133,142). A promising early study in patients was also reported for ^sup 89^Zr-labeled trastuzumab (148). These early studies demonstrated the feasibility of HER2 and EGFR imaging, with the potential for directed therapy specific for HER2 and EGFR. In addition, recent studies suggested that altered glycolysis is an early event accompanying the interruption of the EGFR pathway (149,150), suggesting a role for combined HER2 or EGFR imaging and ^sup 18^F-FDG PET in predicting responses to targeted agents.

OTHER RECEPTOR IMAGING MODALITIES AND APPLICATIONS

As emphasized so far, the requirement for low concentrations of receptor imaging probes limits the choice of imaging modalities for most applications. For small-molecule ligands with a high affinity and a low capacity for receptor binding, such as the ligands used for steroid receptor imaging, radionuclide detection methods are required; the most success has been associated with high-specific- activity PET compounds (Table 1) (33,56). Peptide ligand imaging, such as SSTR imaging, is somewhat more flexible, and some success has been achieved with optical imaging probes for SSTR expression (151-154) or MRI probes for targets close to the vasculature (155). Studies of optical imaging of SSTR-expressing tumors in animal models have supported the feasibility of optical imaging of peptide ligands. Adams et al. (156) demonstrated the optical imaging of another peptide, EGF, with a fluorochrome label (157).

For imaging with monoclonal antibodies and fragments, as in HER and EGFR imaging, an even wider range of probes, such as optical, ultrasound, and MRI probes, may be possible (158-163). Koyama et al. (164) demonstrated specific fluorescence imaging of HER2-expressing lung metastases in an animal model, near-infrared imaging of HER2 expression in vitro with gold nanoshell bioconjugates was demonstrated by Loo et al. (765), and fluorochrome labeling was demonstrated by Hilger et al. (/66). Similar optical approaches have been tested for EGFR imaging (167-169). Multiparameter optical imaging combining HER2 and apoptosis probes revealed target expression and an early tumor response in a mouse model, and optical approaches were used to study the response to EGFR-directed therapy in glioma models (770). Preclinical studies with specific antibodies conjugated to gadolinium or magnetic nanoparticles demonstrated the feasibility of MRI antibody imaging in cells (171) and animal models (159). The feasibility of nanoparticle-based ultrasound probes conjugated to HER2-specific antibodies was demonstrated in early in vitro studies and simulated in vivo studies (160,172).

Besides detection and treatment guidance, a novel application of receptor imaging is gene therapy, in which receptors have been used as parts of PET reporter systems and receptor imaging has been used in some of the earliest studies designed to track gene transfection (173) and vector delivery (174-176). For this approach to be useful in tumor imaging, an appropriate choice of a receptor is required; typically, the receptor must be one that is not expressed by the nontransfected tumor or host tissue and for which uptake is not expected at sites at which the tumor will be imaged. Furthermore, it is important that the expression of the reporter does not elicit an immune response. Examples include the use of SSTR systems for vector delivery in non-SSTR-expressing tissues (174-176) and ER imaging for assessing gene transfection (177,178).

CONCLUSION

Tumor receptors are important in the biology of many malignancies. Receptor physiology is an important component of tumor pathogenesis, growth, and metastasis. The high-affinity, low- capacity nature of most ligand-receptor systems is ideal for therapeutic interventions. Receptor imaging can survey tumor receptor expression across the entire body and is therefore ideal for guiding receptortargeted interventions. However, receptor imaging presents some challenges, most importantly, the requirement for a low molecular concentration of the imaging probe. This requirement has limited tumor receptor imaging mainly to radionuclide methods. A variety of SPECT and PET tumor receptor probes have been developed, with notable progress in peptide receptors and, more recently, in steroid receptors. Recent progress in receptor imaging for other modalities suggests that non radionuclide receptor imaging is feasible for receptors that can be imaged with peptide ligands or antibodies. The importance of receptors in tumor biology and the abilities to predict responses to targeted therapy and to monitor drug interventions suggest that tumor receptor imaging will continue to be an important component of oncologic molecular imaging and will play a key role in cancer management.

ACKNOWLEDGMENTS

This work was supported in part by NTH grants P01CA42045, R01CA72064, and RR17229.

REFERENCES

1. Kaklamani V, O’Regan RM. New targeted therapies in breast cancer. Semin Oncol. 2004;31(2, suppl 4):20-25.

2. Osborne CK, Yochmowitz MG. Knight WA III. McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer. 1980;4602. suppl):2884-2888. 3. Sledge GJ. McGuire W. Steroid hormone receptors in human breast cancer. Adv Cancer Res. 1983;38:61-75.

4. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23:2445-2459.

5. Mankoff DA, Eary JF, Link JM, et al. Tumor-specific positron emission tomography imaging in patients: [^sup 18^F] fluorodeoxyglucose and beyond. Clin Cancer Res. 2007;13:3460-3469.

6. Mankoff DA, O’Sullivan F, Barlow WE, Krohn KA. Molecular imaging research in the outcomes era: measuring outcomes for individualized cancer therapy. Acad Radiol. 2007;14:398-405.

7. Krohn KA. The physical chemistry of ligand-receptor binding identifies some limitations to the analysis of receptor images. Nucl Med Biol. 2001;128:477-483.

8. Krohn KA, Link JM. Interpreting enzyme and receptor kinetics: keeping it simple, but not too simple. Nucl Med Biol 2003;30:819- 826.

9. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators: mechanisms of action and application to clinical practice. N Engl J Med. 2003;348:618-629.

10. Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(suppl 4): S3-S8.

11. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79-94.

12. Sherman SI, Angelos P, Ball DW, et al. Thyroid carcinoma. J Natl Compr Canc Netw. 2007;5:568-621.

13. Campbell FC, Elston CW, Blamey RW, et al. Quantitative oestradiol receptor values in primary breast cancer and response of metastases to endocrine therapy. Lancet. 1981;1:1317-1319.

14. Katzenellenbogen JA, Welch MJ, Dehdashti F. The development of estrogen and progestin radiopharmaceuticals for imaging breast cancer. Anticancer Res. 1997;17:1573-1576.

15. Katzenellenhogen BS, Fang H, Ince BA. et al. Estrogen receptors: ligand discrimination and antiestrogen action. Breast Cancer Res Treat. 1993;27:17-26.

16. Stein RA, McDonnell DP. Estrogen-related receptor alpha as a therapeutic target in cancer. Endocr Relat Cancer. 2006;13(suppl 1):S25-S32.

17. Hammond G. Steroid hormone action. In: Parker M, ed. Extracellular Steroid-Binding Proteins. New York. NY: Oxford University Press; 1993:210.

18. Pujol P, Hilsenbeck SG, Chamness GC, Elledge RM. Rising levels of estrogen receptor in breast cancer over 2 decades. Cancer. 1994;74:1601-1606.

19. Cigler T, Goss PE. Breast cancer adjuvant endocrine therapy. Cancer J. 2007;13;148-155.

20. Dunnwald LK, Rossing MA. Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9:R6.

21. Li CI, Dating JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol. 2003;21:28-34.

22. Kuerer HM, Buzdar AU, Singletary SE. Biologic basis and evolving role of aromatase inhibitors in the management of invasive carcinoma of the breast. J Surg Oncol. 2001;77:139-147.

23. Reed MJ, Purohit A. Aromatase regulation and breast cancer. Clin Endocrinol (Oxf). 2001;54:563-571.

24. Pan CC, Woolever CA, Bhavnani BR. Transport of equine estrogens: binding of conjugated and unconjugated equine estrogens with human serum proteins. J Clin Endocrinol Metab. 1985;61:499- 507.

25. Petra P. The plasma sex steroid binding protein (SBP or SBHG): a critical review of recent developments on the structure, molecular biology and function. J Steroid Biochem Mol Biol 1991;40:735-753.

26. Jonson SD. Bonasera TA, Dehdashti F, Cristel ME, Katzenellenbogen JA, Welch MJ. Comparative breast tumor imaging and comparative in vitro metabolism of q6alpha-[^sup 18^F]fluoroestradiol-17beta and 16beta-[^sup 18^F]fluoromoxestrol in isolated hepatocytes. Nucl Med Biol. 1999;26:123-130.

27. Tewson TJ, Mankoff DA, Peterson LM, Woo I, Petra P. Interactions of 16alpha-[^sup 18^F]-fluoroestradiol (FES) with sex steroid binding protein (SBP). Nucl Med Biol. 1999;26:905-913.

28. Plymate SR, Namkung PC, Metej LA, Petra PH. Direct effect of plasma sex hormone binding globulin (SHBG) on the metabolic clearance rate of 17 beta-estradiol m the primate. J Steroid Biochem. 1990;36:311-317.

29. Bolt HM. Metabolism of estrogens: natural and synthetic. Pharmacol Ther. 1979;4:155-181.

30. Fink BJ, Christensen MS. Bioavailability of oestradiol and oestriol administered orally to oophorectomized women. Maturitas. 1981;3:289-294.

31. Scharl A, Beckman MW, Artwohl JE, Kullander S, Holt JA. Rapid liver metabolism, urinary and biliary excretion, and emerohepatic circulation of 16alpha-radioiodio-17beta-estradiol. Int J Radiat Oncol Biol Phys. 1991;21:1235-1240.

32. White CM, Ferraro-Borgida MJ, Fossati AT, et al. The pharmacokinetics of intravenous estradiol: a preliminary study. Pharmacotherapy. 1998;18:1343-1346.

33. Katzenellenbogen J, The pharmacology of steroid radiopharmaceuticals: specific and non-specific binding and uptake selectivity. In: Nunn A, ed. Radiopharmaceuticals: Chemistry and Pharmacology. New York. NY: Marcel Dekker; 1992;297-331.

34. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.

35. Dickson RB, Stancel GM. Estrogen receptor-mediated processes in normal and cancer cells. J Natl Cancer Inst Munogr. 2000;27:135- 145.

36. Baselga J, Cortes J. Epidermal growth factor receptor pathway inhibitors. Cancer Chemother Biol Response Modif. 2005;22:205-223.

37. Slamon DJ. Leyland-Jones B, Shak S. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783- 792.

38. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma); current concepts. Hematol Oncol Clin North Am. 2007;21:395-407.

39. Scagliotti GV, Selvaggi G, Novello S. Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Rs*. 2004;10:4227s-4232s.

40. Buzdar AU. Endocrine therapy m me treatment of met

By CHRISTINE BARBER

Game

Cough. Oh, excuse me. Sneeze. I think I am still getting over my obesity virus. Sniffle.

Yes, it’s entirely possible I have the obesity virus. About 30 percent of obese people are infected with adenovirus 8036, according to Richard Atkinson, M.D., who has been studying the virus for years and started a company — Obetech — to attempt to develop both antiviral drugs and a vaccine to prevent the disease.

Atkinson knows he is something of a maverick when it comes to obesity research. Most obesity researchers do not share his core belief that the majority of obesity is caused by a viral disease.

And his preferred way to treat obesity — relying heavily on anti- obesity drugs and less on diet and exercise — is also controversial.

“Obesity is not a result of simple overeating. Behavior modification is not the answer. Obesity drugs are the future,” Atkinson said in a recent telephone interview. “The vast majority of obesity experts have their head in the sand.”

So he is used to naysayers like me, who believe that overeating is the main cause of obesity and that disease and genetic predisposition are the source of the problem for only a small number of people.

And he is used to people saying, “If there really is a virus, you are just giving people an excuse to be fat.”

But he sees his discovery not as a justification for obesity, but an explanation.

He compares the obesity virus to AIDS. He points out that people who have AIDS don’t feel like they have an excuse to be sick and instead take medicine to mitigate the effects of the illness.

“If you find you have a reason for obesity (such as a virus) you will take care of yourself,” he said.

The obesity virus is one of the more than 50 types of adenovirus, which cause a variety of illnesses like the common cold, pink eye, croup, bronchitis and pneumonia.

Atkinson believes that a person acutely infected with adenovirus 8036 might show symptoms ranging from a slight cold to diarrhea, but not increased weight gain. That comes later, after the virus has been defeated by the body’s immune system and the person feels better. But while the actual virus is gone, its remnants set up housekeeping in the fat cells, turning on enzymes that cause a cell to retain fat.

Then slowly, over years, the effect of these always-on enzymes can cause obesity, Atkinson says.

I write “can cause” because it is by no means certain that a person infected with the virus will become fat.

About 11 percent of lean people also have the virus. Atkinson says this might be because somewhere in their own personal history of disease, these people contracted a different pathogen that doesn’t allow the virus to fully express itself.

But he cautions those who are in the lean-but-infected category that they must be vigilant or they could become obese. They should eat right, exercise and start taking obesity drugs now as a precaution, he said.

Atkinson discovered the obesity virus, he said, through a series of studies that started with infecting chicken, rats, mice and monkeys with the virus. The result?

“Everything we infected got fat,” he said, “even when fed the exact same diet as those animals that were not infected. In fact, 100 percent of the monkeys got fat, an intriguing result for a mammal that shares 93 percent of our genes.”

Next, Atkinson’s team moved on to human studies.

They took blood from 500 people in the Eastern United States and found that 30 percent of the obese people and 11 percent of the non- obese people were infected. From this, they extrapolated that 15 percent of the total population may be infected with adenovirus 8036.

Atkinson believes his results also might explain why obesity rates jumped sharply almost 30 years ago yet are leveling off today. The virus could have mutated back in the 1970s — when only 13 percent of people were obese — to a new form that caused obesity. If the mutated virus kept infecting people, he said, obesity rates would have increased steadily, then eventually leveled off — as they have at 30 percent — as the population either became infected or fought off the disease.

Atkinson’s main goals at the moment are to develop an antiviral drug for people acutely infected with the virus and a vaccine he would like to see given along with the standard childhood series.

But all this research doesn’t mean much if someone who has the disease already is obese.

“Once you’re fat, you’re fat,” Atkinson said.

Meaning, even if I do have the virus, the only way to lose the excess weight is still through healthy eating and exercise.

Damn.

Want to know if you have the obesity virus? Go to Christine’s blog at etastesantafe.com to find out how you can get tested.

Christine Barber has been a journalist in New Mexico for 14 years. She is a pre-medical student at The University

of New Mexico. E-mail her at [email protected].

(c) 2008 The Santa Fe New Mexican. Provided by ProQuest Information and Learning. All rights Reserved.

CHICAGO, June 25 /PRNewswire/ — In response to news reports that Shawn Southwick King, wife of CNN host, Larry King, is allegedly being treated for medication use related to migraine, the National Headache Foundation today issued the following statement.

Migraine is not a daily headache and the use of any acute medications on a daily or near daily basis is not recommended.

Pain killers are not the optimal treatment for migraine. There are migraine-specific medications known as the triptans (there are currently seven on the market), which target the migraine mechanism. This type of medication is taken at the first sign of the migraine. If migraines are frequent or severe, prophylactic medication can be prescribed and is taken daily whether or not a headache is present.

If headache impacts one’s ability to perform at work, household chores or leisure activities and/or impairs one’s quality of life, it is recommended that an appointment should be made with a healthcare professional for headache diagnosis and treatment.

Migraine affects nearly 30 million Americans and seventy percent of migraine sufferers are women. We encourage those who would like more information on the symptoms and treatments for migraine and other headache pain to visit http://www.headaches.org/.

About The National Headache Foundation

The National Headache Foundation, founded in 1970, is a non-profit organization which exists to enhance the healthcare of headache sufferers. It is a source of help to sufferers’ families, physicians who treat headache sufferers, allied healthcare professionals and to the public. The NHF accomplishes its mission by providing educational and informational resources, supporting headache research and advocating for the understanding of headache as a legitimate neurobiological disease. For more information on headache causes and treatments, visit http://www.headaches.org/ or call 1-888-NHF-5552 (M-F. 9 a.m. to 5 p.m. CT).

Dr. Seymour Diamond, Executive Chairman, National Headache Foundation, is the director and founder of the Diamond Headache Clinic and the director of the Inpatient Headache Unit at Saint Joseph Hospital, Chicago. He is also Adjunct Professor of Cellular and Molecular Pharmacology at Chicago Medical School at Rosalind Franklin University of Medicine and Science and Clinical Professor in the Department of Family Medicine. Dr. Diamond has served as editor for 16 publications. He serves as editor-in-chief of the journal, Headache and Pain. Additionally, he has published more than 300 articles in professional literature and has authored or co-authored more than 30 books. Dr. Diamond received his medical degree from the Chicago Medical School.

Dr. Merle Diamond, Board of Directors, National Headache Foundation, is Associate Director at the Diamond Headache Clinic and Clinical Assistant Professor, Department of Medicine, at the Chicago Medical School at Rosalind Franklin University of Medicine and Science. Dr. Diamond attended Northwestern University, where she completed a residency program in both Emergency Medicine and Internal Medicine. She is board certified in internal medicine, and has been trained and practiced in emergency medicine. Dr. Diamond is a recipient of the Subspecialty Certification for Headache Medicine from the United Council for Neurologic Subspecialties.

   CONTACT:  Suzanne E. Simons                Ketura Lispi             Executive Director               Vox Medica             National Headache Foundation     (215) 925-9901, ext. 1426             (312) 343-6479                   [email protected]             [email protected]  

National Headache Foundation

CONTACT: Suzanne E. Simons, Executive Director National HeadacheFoundation, +1-312-343-6479, [email protected]; Ketura Lispi of Vox Medicafor National Headache Foundation, +1-215-925-9901, ext. 1426,[email protected]

HONG KONG, June 25 /Xinhua-PRNewswire-FirstCall/ — The Board of Directors of Golden Meditech Company Limited (the “Company”; stock code: 8180.HK) is pleased to announce today that the Company has made significant progress in entering China’s hospital management market through the acquisition of Topshine Hospital Management (China) Company Limited and Daopei Hospitals Group, the largest private haematologist hospitals with presence in Beijing and Shanghai in China. Upon completion, the company will become the first foreign institution in China granted with a license to manage and provide nationwide management consultancy to hospitals in China.

Pursuant to the terms of the agreement, Golden Meditech will acquire 70% of contributor’s interests in the Daopei Hospitals Group and 60% equity interests in Topshine Hospital Management Company (China) Limited for an aggregate cash consideration of HK$830 million.

Once the proposed transaction is completed, Golden Meditech will obtain the rights to manage hospitals nationwide. This marks the first time for a foreign institution to offer nationwide hospital management consultancy in China.

Mr. KAM Yuen, Chairman of Golden Meditech, explains that acquiring the Daopei Hospitals, the largest and most renowned hematologist hospital in China, represents a significant move by the company to optimize its business structures and strengthen its presence in China’s healthcare industry. Tremendous synergies will be created with the Company’s existing businesses especially in the areas of healthcare services, cord blood stem cells clinical applications and manufacture and sales of medical devices.

Mr. KAM Yuen points out through this acquisition, Golden Meditech will not only gain the opportunity to enter into the high-threshold hospital management industry, but also inherit experienced and seasoned medical staff and management teams, in addition to generating stable earnings. In future, the Company plans to expand the professional hospital management operations in areas of haematologies, tumor and pediatrics through its existing hospital network in a bid to become the largest professional hospital management group in China.

   Background Information:   China's Hospital Services Market:  

According to statistics, in 2007, China’s healthcare services expenditures accounted for less than 5% of the country’s GDP (gross domestic product), which is far behind 15% of USA during the same period. In addition, benefiting from the country’s booming economy, increase in government healthcare spending to extend the coverage of basic social medical insurance, the improvement in general living standards, and people becoming more health- conscious and expecting higher healthcare services standards, all these factors are believed to lead China’s healthcare services industry into golden era period.

However, at present, more than 90% of hospitals in China are state-owned nationwide, and less than 10% are owned by non-state-owned entities. This ratio of 10% is far lower compared with that of most Asian countries, whereas private hospitals account for almost 50% of the market shares. This means that China hospital market has a great market potential for future expansion.

Topshine China: Topshine Hospital Management (China) Company Limited is established by the management team of Daopei and it is the first foreign company allowed to provide nationwide hospital management services in China.

Daopei Hospitals: Headquartered in Beijing with a Shanghai branch, the Daopei hospitals have over 200 hospital beds in Beijing and Shanghai, and the largest number of laminar air-flow wards in Asia.

As a leading specialist hospital for diagnosis and treatment of blood- related diseases and malignant tumors, Daopei Hospitals are renowned to conduct sibling allogeneic cord blood stem cell transplantation, unrelated cord blood stem cell transplantation, umbilical cord blood stem cell transplantation, mismatched haploidentical transplantation, syngenic (twins) transplantation and autologous transplantation. During the past six years, Daopei Hospitals conducted about 690 cases of allergenic cord blood stem cell transplantation with successful implantation rate of 99.67% and overall survival rate of 70%, reaching an international level. The hospitals’ reputation attracts numerous domestic and overseas leukaemia patients every year, and currently, their utilization rates of hospital beds exceed 100%.

Mr. LU Dao Pei, founder of the Daopei Hospitals, is a renowned haematologist and the so-called “Father of Bone Marrow Transplant “in China, an elected member of the Chinese Academy of Engineering (Division of Medicine and Health), a committee member of the Academic Committee of Peking University Health Science Center, and the Chief Expert for Haematology, National Key Disciplines in Peking University.

The Beijing and Shanghai Daopei Hospital are few privately-run hospitals, covered by the country’s basic medical insurance scheme. In addition, Daopei Hospitals are also the only private specialist hospital endorsed to perform blood stem cell transplants.

Golden Meditech: Founded in 2000 and listed on the Growth Enterprise Market of the Stock Exchange of Hong Kong Limited in December 2001, Golden Meditech is the first hi-tech medical device enterprise that went public outside of the PRC. During the past few years, thanks to its great efforts in innovation and market expansion, as well as its first-mover abilities in capturing the emerging market opportunities, Golden Meditech’s medical device, cord blood banking services and natural herbal medicine have all established dominant positions in each of the segments that the company engages in. Going forward, Golden Meditech will continue its pursuit of becoming China’s leading integrated medical group through organic growth, acquisition and strategic investment.

For inquiry, please kindly contact the Investor Relations Division, Golden Meditech Company Limited.

   Contact:     Dennis Haikuan Lu    Investor Relations Manager    Golden Meditech Company Limited (8180.HK)    Tel:   +852-3605-8138    Fax:   +852-3605-8181    Email: [email protected]  

Golden Meditech Company Limited

CONTACT: Dennis Haikuan Lu, Investor Relations Manager of Golden Meditech,+852-3605-8138, or fax, +852-3605-8181, [email protected]

By Setacci, F Sirignano, P; de Donato, G; Chisci, E; Palasciano, G; Setacci, C

Adventitlal cystic disease (ACD) is an uncommon condition with only around 300 cases reported in the literature. ACD consists of a collection of gelatinous material within a cyst, that is adjacent or surrounding a vessel. In the last five years three cases of ACD have been observed: the first case was a 48-year-old man, ex nicotine abuser, with a four-month history of progressive claudication; the second case was a 55-year-old man, ex nicotine abuser, with ischemic heart failure and a one-year history of progressive claudication; the third case was a 70-year-old man, with diabetes, dislipidemia and current nicotine abuser with a few-day history of acute pain in the right leg. In two cases the cysts were incised and the contents evacuated. The adventitia was repaired and the wound closed. The first patient is currently asymptomatic after four years from surgery. The second one, at 21 months, follow-up, presented newly severe claudication. Duplex ultrasound scan and computed tomography angiography demonstrated a cranial progression of the lesions. This lesion was treated with bare stent, with complete regression of the symptoms. The third patient was treated with interposition of an autogenous saphenous vein. The patient is asymptomatic at the three- month follow-up. Even if ACD is quite rare, it should be taken in consideration in young patients with severe claudication and no- or poor comorbidities. The best treatment is the incision of the cysts and the advential reconstruction. Short lesions can be treated with endovascular therapy. KEY WORDS: Cysts – Popliteal artery – Intermittent claudication – Reconstructive surgical procedures.

Adventitial cystic disease (ACD) is an uncommon condition with only around 300 cases reported in the literature 1,2 since 1974, when the first case in the external iliac artery was described by Atkins and Key.3 ACD consists of a collection of gelatinous material within a cyst, that is adjacent to or surrounding a vessel. cases of ACD have been reported involving the external iliac, popliteal, femoral, radial, and ulnar arteries 4-8 and the external iliac, femoral and superficial veins.4, 9 The incidence of ACD is 1 out of 1 000 femoral angiograms and 1 out of 1 200 cases of claudication.9. 10 The ratio of males to females is 15:1.11 The onset age varies between the fifth (men) and sixth (women) decade of the life,9 although cases have been reported at other ages.10,12

In the last five years (2002-2007), in the Center of Vascular and Endovascular Surgery at the University of Siena (Siena, Italy) three cases of ACD have been observed.

Clinical series

Case 1.-The first case was that of a 48-year-old man, a former nicotine abuser, without comorhidities, with a four-month history of progressive claudication of the left leg. The Winsor Index was 0.7 in the left leg and >1 in the right. A duplex ultrasound scan (DUS) was performed and revealed a cystic formation compressing the right popliteal artery (Figure 1). Conventional angiography showed the typical curvilinear scimitar sign due to extrinsic compression of the lumen, without further signs of atherosclerosis. The magnetic resonance imaging (MRI) exposed a cystic structure closely related to and surrounding the popliteal artery, indicative of adventitial cystic disease (Figure 2). Surgical treatment involved a posterior approach to the popliteal fossa (Figure 3). The intraoperative findings confirmed the clinical and radiologic diagnosis of cystic adventitial disease of the popliteal artery. Three cysts were incised and the clear, mucinous contents evacuated (Figures 4, 5). The adventitia was repaired and the wound closed. The postoperative Winsor Index was >1 in the treated leg. The patient is currently asymptomatic, with a Winsor Index >1 at four-year follow-up.

Figure 1.-DUS of the involved popliteal artery.

Figure 3.-Surgical incision.

Figure 2.-MRA of the same lesion showed in figure 1.

Figure 4.-Cysts incision and evacuation of the clear, mucinous contents.

Case 2.-The second case was that of a 55-year-old man, a former nicotine abuser, with ischemic heart failure and one-year history of progressive claudication of the right leg. The Winsor Index was 0.9 in the left leg and 0.6 in the right one. The DUS showed a cystic formation compressing the popliteal artery. The MRI exposed a cystic structure surrounding the artery. A preoperative angiography was not performed. In this case, too, the surgical technique involved a posterior approach to the popliteal fossa. The cysts were incised and the contents evacuated, then the adventitia was repaired and the wound closed. The postoperative Winsor Index was =1 in the treated leg. At the 21-month follow-up, the patient presented new severe claudication. DUS and MRI demonstrated a cranial progression of the lesions (length=1 cm), the Winsor Index was 0.3- A periprocedural angiography was then performed. The exam confirmed progression of the disease with a tight stenosis of the AK popliteal artery. The lesion was treated with a bare stent. At three-year follow-up, the patient was completely asymptomatic, with a Winsor Index =1.

Figure 5.-Reconstruction of the adventitia.

Figure 6.-Autogenous saphenous vein graft, after the excision of the lesion.

Case 3.-The third case was a 70-year-old man, with diabetes and dislipidemia, a current nicotine abuser, without cardiac comorbidity and with a few-day history of acute pain on the right leg. The Winsor Index was 0.3 in the right leg and 0.8 on the left. DUS and MRI were performed, which revealed the presence of multi-loculated cysts compressing the popliteal artery and the total occlusion of the arterial segment. It was decided to substitute the diseased arterial segment with a reversed autogenous saphenous vein (Figure 6). The patient was asymptomatic at three-month follow-up.

Discussion

The etiology of ACD is currently unclear. Four theories have been proposed: 1) repetitive local trauma; 2) abnormalities in embryological development; 3) ACD as part of a systemic disease; 4) the synovial hypothesis.6, 11, 13, 14 The synovial (or ganglion) and the abnormal embryological development are currently the most accepted theories.15 Leu etal.4 believe that ACD is caused by a ganglion or bursalike ectopic tissue originating from scleroblastoma. Scleroblastoma is responsible for the formation of joint capsules and bursae. Both ganglia and Baker’s cysts might communicate with joints or with tendon sheaths. Cases of ACD in which the cyst was communicating with the adjacent knee joint and a Baker’s cyst have been described.14-16

The traumatic theory is unlikely because ACD can occur in children and is not frequent in athletes; also a past history of repetitive trauma is uncommon.4, 14 ACD has not shown any consistent association with a systemic disease.14

ACD of the popliteal artery should be clinically suspected in an adult male patient, between the fourth and fifth decades of life, who presents with a sudden onset of claudication in the legs without significant evidence of atherosclerotic disease.6, 11, 13, 15 There is, therefore, no age group that is immune from ACD. Early recognition of the condition is important, because it is often rapidly progressive 11 and because treatment of the condition before it progresses to popliteal occlusion is associated with lower morbidity. However, reaching a diagnosis of ACD is fraught with problems. The symptoms of calf claudication in patients with ACD tend to wax and wane. Severe claudication may suddenly improve spontaneously and completely disappear, only to recur a few months later.17, 18 Direct communication between the cyst and the knee joint is often demonstrated 4 and this could explain the reported waxing and waning of symptoms as well as the reported cases of spontaneous resolution of ACD. 19, 20 Such a history coupled with perfectly normal peripheral pulses and ankle pressure is enough to make a vascular cause for the presenting symptoms unlikely to all except the most attentive of clinicians. Normal pulses, ankle pressure and even ankle pressure after exercise have been reported in association with ACD.11, 21, 22 In patients with a clear history of intermittent claudication and normal peripheral pulses it is worth checking for foot pulses during knee flexion. Ishikawa reported the disappearance of foot pulses on knee flexion or after exercise in patients with ACD, now known as Ishikawa’s sign.23 The symptoms typically worsen with flexion of the knee.15 If direct communication of the adventitial cyst with the joint space or a Baker’s cyst exists, exercise or repetitive trauma can cause rapid growth of the cyst with an accelerated progression of symptoms.4, 13, 16 Spontaneous rupture of the cyst is a rare event and might result in relief of symptoms by decompression of the cyst.19 The recurrence after spontaneous rupture might depend on the extension of the perforation in the wall of the cyst.19 ACD is classically a unilateral process. It is generally not possible to feel the cyst on physical examination, but sometimes ACD can present as soft-tissue- like masses involving the extremities and causing it to be confused with a slowly growing soft tissue tumor.14, 23

When ACD involves the popliteal artery, stenosis is more common than occlusion. Arterial occlusion has been observed in 30% of patients.24 Clinical history and physical examination, plus a DUS examination is usually enough to establish a diagnosis of ACD. US is readily available and inexpensive. A gray-scale sonogram demonstrates hypoechoic cystic lesions with or without multiple septated hypoechoic spaces. DUS clearly shows stenosis with turbulent flow or arterial occlusion with absent color flow. An intra-arterial sonogram shows a large cystic mass arising from the adventitia of the vessel.25, 26 Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are excellent diagnostic tools that can accurately depict the anatomy of the popliteal fossa, showing the cystic lesions and their relationships to the vessels.9, 10, 13, 27 Additionally, MRA and CTA can noninvasively demonstrate arterial stenosis or occlusion and also determine the inflow and the distal runoff of the arterial segments.11, 27, 28

Digital angiography (DA) frequently shows a characteristic smooth tapering stenosis, referred to as the scimitar sign, without post- stenotic dilation and with no evidence of atherosclerotic disease.6 However, in 30% of cases ACD produces a non-specific complete occlusion that can easily be mistaken for an endoluminal lesion while in other cases angiography may be completely normal. Other disadvantages of arteriography include the high cost, invasiveness, and radiation exposure. While DUS can be helpful in identifying the cystic lesion of ACD around the vessel, lowechoic lesions can sometimes be missed and in other cases ultrasound may suggest a popliteal aneurysm.11 CTA, MRA and intravascular ultrasound have all been recommended in the diagnosis of ACD, and of these MRA imaging is probably being the best modality.29 In view of the difficulties raised by the presentation and investigation of the condition, it is not surprising that many cases are misdiagnosed. Several treatment options have been proposed for ACD. Aspiration of the cystic collection has been performed successfully, although recurrence is frequent. This is not surprising considering the fact that many of these cysts communicate with the adjacent joint and aspiration will clearly not obliterate the communication. Surgical incision and partial or complete excision without opening the artery has been performed with good results when the vessel is patent, excision of the lesion is mandatory when the popliteal segment involved is too long, in order to avoid restenosis. Identifying and ligating any channels with the adjacent joint is claimed to reduce the risk of recurrence following cyst excision. Most cases of popliteal occlusion secondary to ACD have been treated with resection of the affected segment and autogenous vein graft reconstruction.1 The complications associated with this procedure are more common and serious than with simple cyst excision. To avoid resection, thrombolytic therapy followed by non-resectional cystostomy has been used to treat ACD that has progressed to vessel occlusion.30

Conclusions

In summary, the clinician should be alert to the possibility of ACD in patients whose symptoms of claudication wax and wane and in whom claudication seems to develop rapidly. The presence of normal peripheral pulses and normal ankle pressure does not exclude ACD. MRA and DUS may be helpful in the diagnosis of this condition. DA may only demonstrate occlusion of the popliteal artery on knee flexion against resistance. Although the disease is rare, it should be take into consideration in young patients with severe claudication and non or limited co-morbidities. In our experience the best treatment is the incision of the cysts and the advential reconstruction. Short lesions can also be treated with endovascular therapy.

Received on September 18, 2007.

Accepted for publication on 10 March, 2008.

References

1. Tsolakis IA, Walvatne CS, Caldwell MD. Cystic adventitial disease of the popliteal artery: diagnosis and treatment. Eur J Vasc Endovasc Surg 1998;15:188-94.

2. Ishikawa K. Cystic adventitial disease of the popliteal artery and of other stem vessels in the extremities. Jpn J Surg 1987;17:221- 9.

3. Atkins HJB, Key JA. A case of myxomatous tumour arising in the adventitia of the left external iliac artery. Br J Surg 1947;34:426- 7.

4. Leu HJ, Largiader J, Odermatt B. Pathogenesis of the so- called cystic adventitial degeneration of peripheral blood vessels. Virchows Arch 1984;404:289-300.

5. Ejrup B, Hiertonn T. Intermittent claudication: three cases treated by free vein graft. Acta Chir Scand 1954;108:217-30.

6. Velasquez G, Zollikofer C, Nath H, Barreto A, Castaneda- Zuniga W, Formanek A et al. Cystic arterial adventitial degeneration. Radiology 1980;134:19-21.

7. Backstrom CG, Linell F, Ostberg G. Cystic, myxomatous adventitial degeneration of the radial artery with development of ganglion in the connective tissue. Report of two cases. Acta Chir Scand 1965;129:447-51.

8. Flanigan D, Burnham S, Goodreau J. Summary of cases of adventitial cystic disease of the popliteal artery. Ann Surg 1979; 189:16575.

9. Bergan J. Adventitial cystic disease of the popliteal artery. In: Rutherford RB, editor. Vascular Surgery. 4th ed. Philadelphia: WB Saunders; 1995. p. 883-7.

10. Lewis GJT, Douglas DM, Reid W. Cystic adventitial disease of the popliteal artery. Br Med J 1967;3:411-5.

11. Miller A, Salenius JP, Sacks BA, Gupta SK, Shoukimas GM. Noninvasive vascular imaging in the diagnosis and treatment of adventitial cystic disease of the popliteal artery. J Vasc Surg 1997;26:71520.

12. DeLaurentis DA, Wolferth CC Jr, Wolf FM, Naide D, Nedwich A. Mucinous adventitial cysts of the popliteal artery in an 11-year- old girl. Surgery 1973;74:456-9.

13. Sys J, Michielsen J, Bleyn J. Adventitial cystic disease of the popliteal artery in a triathlete. a case report. Am J Sports Med 1997;25:854-7.

14. Levien LJ, Benn CA. Adventitial cystic disease: a unifying hypothesis. J Vasc Surg 1998;28:193-205.

15. Papavassiliou VG, Nasim A, Awad EM. Adventitial cystic disease of the popliteal artery: diagnosis and treatment. A case report. J Cardiovasc Surg 2002;43:399-401.

16. Schroe H, Van Opstal C, De Leersnijder J, De Cort J, Suy R. Baker’s cyst connected to popliteal artery cyst. Ann Vasc Surg 1988;2: 385-9.

17. Vos LD, Tielbeek AV, Vroegindeweij D, van den Bosch HC, Buth J. Cystic adventitial disease of the popliteal artery demonstrated with intravascular ultrasound. J Vasc Interv Radiol 1996;7:583-6.

18. Devereux D, Forrest H, McLeod T, Ahweng A. The nonarterial origin of cystic adventitial disease of the popliteal artery in two patients. Surgery 1980;88:723-7.

19. Lossef SV, Rajan S, Calcagno D, Velinger E, Patt R, Barth KM. Spontaneous rupture of an adventitial cyst of the popliteal artery: confirmation with MR imaging. J Vasc Intervent Radiol 1992;3: 95-7.

20. Owen ERTC, Speechly-Dick EM, Kour NW, Wilkens RA, Lewis JD. Cystic adventitial disease of the popliteal artery: a case of spontaneous resolution. Eur J Vasc Surg 1990;4:319-21.

21. Hunt BP, Harrington MG, Goode JJ, Galloway JM. Cystic adventitial disease of the popliteal artery. Br J Surg 1980;67:811- 2.

22. Parks RW, D’Sa AA. Critical ischaemia complicating cystic adventitial disease of the popliteal artery. Eur J Vasc Surg 1994;8:508-13.

23. Ishikawa L, Mishima Y, Kobayashi S. Cystic adventitial disease of the poplteal artery. Angiology 1961;12:357-66.

24. Bunker SR, Lauten GJ, Hutton JE. Cystic adventitial disease of the popliteal artery. Am J Roentgenol 136:1209-12.

25. Peterson JJ, Kransdorf MJ, Bancroft LW, Murphey MD. Imaging characteristics of cystic adventitial disease of the peripheral arteries: presentation as soft-tissue masses. Am J Roentgenol 2003;180:621-5.

26. Landry G, Abou-Zamzam A, Edwards J. Non-atherosclerotic vascular disease. In: Moore WS, editor. Vascular Surgery. A Comprehensive Review. 6th ed. Philadelphia: WB Saunders;2002. p. 143- 4.

27. Elias DA, White LM, Rubenstein JD, Christakis M, Merchant N. Clinical evaluation and MR imaging features of popliteal artery entrapment and cystic adventitial disease. Am J Roentgenol 2003; 180:627-32.

28. Ruckert RI, Taupitz M Cystic adventitial disease of the popliteal artery. Am J Surg 2000;180:53.

29. Saeed M, Wolff YG, Dilley RB. Adventitial cystic disease of the popliteal artery mistaken for an endoluminal lesion. J Vasc Interv Radiol 1993;4:815-8.

30. Samson RH, Willis PD. Popliteal artery occlusion caused by cystic adventitial disease: successful treatment by urokinase followed by nonresectional cystotomy. J Vasc Surg 1990;12:591-3.

F. SETACCI, P. SIRIGNANO, G. de DONATO., E. CHISCI, G. PALASCIANO, C. SETACCI

Vascular and Endovascular Unit

Department of Surgery

University of Siena, Italy

Address reprint requests to: C. Setacci, Department of Surgery, Vascular and Endovascular Surgery Unit, University of Siena, viale Bracci, 53100 Siena, Italy. E-mail: [email protected]

Copyright Edizioni Minerva Medica Apr 2008

(c) 2008 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

By Croft, Barbara Y

PRESENTATIONS The mission of the Cancer Imaging Program (CIP) of the National Cancer Institute (NCI), a part of the National Institutes of Health (NIH), is to promote and support: (1) cancer- related basic, translational, and clinical research in imaging sciences and technology; and (2) integration and application of these imaging discoveries and developments to the understanding of cancer biology and to the clinical management of cancer and cancer risk. In short, the goals are to use cancer imaging to visualize problems and direct solutions. The CIP works to accomplish these goals using several strategic approaches, including but not limited to: ( 1 ) infrastructure and programs to support the discovery and development of molecular imaging for cancer care and understanding of cancer biology; (2) a set of imaging methods validated as cancer biomarkers. some of which are surrogate endpoints; (3) infrastructure and programs to support the discovery, development, and delivery of image-dependent interventions for cancer and precancer; (4) an implemented infrastructure based on standardized models for the design and conduct of clinical trials of or using imaging and image-guided interventions; (5) accelerated development and delivery of integrated imaging systems and methods for cancer care and research; (6) critical roles in NIH and NCI activities in emerging technologies, such as nanotechnology, proteomics, and high- throughput screening technologies; (7) an implemented informatics infrastructure to optimize the value of cancer imaging data; and (8) a strategy of imaging science and methods to detect, treat, and monitor response to therapy in precancer.

Supporting these far-reaching goals and already vigorous research efforts is challenging. Approximately 61% of the $4.8 billion NCI budget goes to research. However, these funds are challenged by eroding purchasing power, rising salaries, and escalating costs. The bottom line is that fewer studies can be funded and that already funded studies sometimes rind themselves struggling to meet budgeted costs.

Despite the somewhat unfavorable financial climate, this is a time of forward-looking planning for both NCI and CIP. A recent synopsis of the areas in which NCI hopes to encourage advances in 2009 includes personalized cancer medicine, much of which pertains directly to molecular medicine and molecular imaging. Under this heading are prognosis, prevention, and treatment, including the need for research to:

* Monitor changes in an individual’s cellular function in order to detect precancerous changes and intervene to prevent those changes from progressing to disease;

* Use genetic profiles to identify subsets of cancer types that define prognosis;

* Choose targeted therapies that minimize side effects and are based on both the type of cancer and the individual’s biological profile; and

* Use biospecimen tests and imaging techniques to measure the impact of interventions and refine treatment to improve outcomes.

Under the headings of detection and diagnosis, NCI hopes to encourage research to:

* Identify patterns of genes associated with the development of specific cancers;

* Study the ways in which genetic variations that change the function of proteins cause cells to function abnormally;

* Investigate the ways in which those changes are further affected by lifestyle behaviors and environmental factors; and

* Develop biomarkers (blood tests and other tests using human specimens, imaging techniques, and other new methods) to detect and measure changes in protein and cellular function associated with specific cancers.

Research: Review, Renewals, and Reissues

Research is under continuous review at CIP, and several large imaging projects or funding mechanisms with significance for molecular medicine are currently under review or have recently been renewed or reissued for new proposals. The following are among these:

* The American College of Radiology Imaging Network (ACRIN), an international cooperative clinical trials group, has a new chair (Mitchell Schnall, MD, PhD), and funding has been approved for renewal for years 10-15. The network’s goal is to use clinical trials of diagnostic imaging and image-guided therapeutic technologies to generate information that will lengthen and improve the quality of the lives of cancer patients. ACRIN clinical trials address both existing and emerging technologies as they apply to cancer screening, diagnosis, staging, imaging as a biomarker, and image-guided treatment.

* In vivo Cancer Molecular Imaging Centers (ICMICs) facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on cellular and molecular imaging related to cancer. Pre-ICMIC planning grants have provided time and funds for investigators and institutions to prepare themselves, organizationally and scientifically, to establish ICMlCs. We are currently reviewing various products that have come from these programs to determine levels of continued support.

* The NCi Small Animal Imaging Resource Program (SAIRP) is approaching its 10-year mark and is currently under review. Thirteen universities are funded through the SAIRP, which supports both shared imaging research resources to be used by NIH-sponsored cancer investigators and their research related to small animal imaging technology. These awards are intended to increase the efficiency, synergy, and innovation of preclinical small animal-based research and to foster research interactions that cross disciplines, approaches, and levels of analysis. The SAIRP has already enhanced functional and molecular imaging resources and advanced collaborative translational research across the spectrum of imaging modalities at institutions in the United States.

* The request for applications (RFA) to participate in the Network for Translational Research: Optical Imaging has been reissued with a new purpose: to develop, optimize, and validate imaging technology platforms and methods so that they can enter single or multisite clinical trials and eventually be incorporated into clinical practice. The response to the original RFA was much greater than early expectations, indicating the importance of optical and optical molecular imaging as the fastest-growing modality in cancer research. The new RFA focuses on translating innovations to clinical use across platforms through multisite teams that include broad national and international representation from academic, NIH intramural, and device and drug industry investigators.

Imaging Drug Development

CIP staff is actively involved in working with researchers on various aspects of drug development. The CIP has been creating Investigational New Drug (IND) applications for imaging agents to engage in multicenter clinical trials of these materials. Among agents under current investigation or consideration are: ^sup 18^F- D-cytidine, ^sup 13^N-gemcitabine, ^sup 11^C-SN-38, ^sup 18^F- paclitaxel, ^sup 18^F-DCFBC, ^sup 18^F-Her2 affibody, ^sup 18^F- FES, ^sup 18^F-fluorothymidine (^sup 18^F-FLT), ^sup 18^F- fluoromisonidazole (^sup 18^F-MlSO), ^sup 18^F-galactoRGD, ^sup 111^In-Herscan, ^sup 124^I-deoxyuridine, ^sup 64^Cu-ATSM, and ^sup 18^F-sodium fluoride. A subset of the documents filed for INDs is being made available to the research community to implement routine synthesis of tracers at their own facilities and to assist investigators with the filing of INDs. Sets of documents for ^sup 18^F-FLT, ^sup 18^F-MISO, and ^sup 18^F-FES are currently available and include a full set of manufacturing and quality control documents and an Investigator Drug Brochure, all of which have been accepted by the U.S. Food and Drug Administration as part of the NCI IND. Templates, synthesis information, and other materials are available on the Web site at: http://imaging.cancer.gov/ programsandresources/Cancer-Tracer-Synthesis-Resources.

The Development of Clinical Imaging Drugs and Enhancers (DCIDE) program is a competitive project to expedite and facilitate the development of promising investigational imaging enhancers (contrast agents) or molecular probes from the laboratory to IND status. Through the DCIDE program, the developer of a promising diagnostic agent or probe is given access to the preclinical development resources of NCI in a manner that is intended to remove the most common barriers between laboratory discoveries and IND status. CIP not only funds the toxicologie studies for these agents but provides guidance in the approval process. Despite the resources that CIP is able to contribute in this process, relatively few compounds have entered the DClDE pipeline.

In addition, we have developed the Molecular Imaging and Contrast Agent Database (MICAD; http://micad.nih. gov/), an online source of information on in vivo molecular imaging agents based on recommendations from the extramural community. MICAD was established as a key component of the Molecular Libraries and Imaging program of the NIH Roadmap, a set of major interagency initiatives accelerating medical research. MlCAD is edited by a team of scientific editors and curators at the National Library of Medicine and operates under the guidance of a trans-NIH panel of experts in the field. The database includes but is not limited to agents developed for PET, SPECT, MR, ultrasound, CT, optical, and planar gamma imaging as well as planar radiography. It contains textual information, references, numerous links to MEDLINE, and additional related resources at the National Center for Biotechnology Information and elsewhere. As of April 25, 455 agents were listed. Imaging-Related Clinical Trials

As part of its mission the CIP takes the lead in planning and recruiting for a number of imaging-related clinical trials, as summarized on the Web site at: http://imaging. cancer.gov/ clinicaltiials/. These include screening and interventional trials, trials assessing imaging response criteria, single-institution feasibility trials (R21), phase 1 and 2 trials, and ACRIN trials. Current phase 3 ACRIN trials all involve PET, including PET to: monitor treatment for malignant gastrointestinal stromal tumors, predict treatment response in lung cancer, and evaluate treatment response in lung cancer.

Facilities

CIP is involved in 2 facility improvements that will enhance our collaborative abilities in both basic and clinical translational imaging. The NCI-Frederick Small Animal Imaging Program (SAIP) was established to provide NCI investigators with a state-of-the-art in vivo imaging facility. The SAlP became operational in October 2006 with the installation of a 3.0-T MR imaging unit and now includes microPET, microSPECT/CT, optical, bioluminescence, and fluorescence imaging capabilities as well as real-time sonography. The NCI laboratory includes a very large mouse repository, with mouse models of human cancer. Much of the small animal instrumentation that has been installed at Frederick and is planned for the future will be used in experiments aimed at drug development for NCT.

NCI is also participating in renovations to Building 10 in the Clinical Center on the main NIH campus in Bethesda, MD. The result will be that NCI will have a separate imaging facility in support of clinical trials in cancer.

Information Technology: Integrating Data

One of the results of the rapidly expanding numbers of imaging modalities and their potential applications in molecular medicine is an accompanying and exponential increase in the amount of data. CIP, together with NCI and the rest of NIH, is participating in efforts not only to collect these data but to harness their collective power in support of synergies of knowledge and efficiencies of research that can advance the translation of scientific discovery to patient benefit. Among these efforts are the following:

* caBIG (cancer Biomedical Informatics Grid) Cancer Central Clinical Database (C3D), a next-generation computer implementation and clinical trials data management system, is designed to aggregate imaging results from trials. C3D collects clinical trial data using standardized case report forms based on common data elements.

* The Virtual Imaging Endpoint Workspace (VIEW) will be made up of a consortium of participating groups that will provide imaging core laboratory services to NCI-sponsored cooperative groups and other NCI-sponsored clinical trial programs, including developing cross-network information technology infrastructures and standardized operating procedures.

* Visually Assembled Access to Rembrandt Images (Vasari): The Rembrandt (REpository of Molecular BRAin Neoplasia Data) database contains images and tumor specimen information, including SNP array, expression array, proteomics, and clinical data from approximately 300 gliomas (https://caintegrator.nci. nih.gov/rembrandt). Vasari incorporates access to the images of the Rembrandt collection.

* Database development for computer-assisted diagnosis (CAD) is targeted at efforts to create uniformity in imaging across platforms and institutions, particularly in those images in which CAD is most suitable as an investigational tool. Among the current efforts are the following: (1) The National Cancer Imaging Archive (NCIA) is a searchable repository of in vivo cancer images in Digital Imaging and Communication in Medicine format. Images are available al no cost over the Internet in an open source format. The NCIA currently houses almost 1,000 images, and curators are gathering the metadata that will support research using these images. (2) The Reference Image Database to Evaluate Response (RIDER) is a Web-accessible public resource of validated image data for different organs/ diseases and different modalities that facilitates the investigation of appreciable differences and sources of variance of imaging techniques as well as the assessment of changes over time in the course of treatment.

More Information from CIP

For more information on CIP and its activities, as well as on the ways in which it interacts with other groups and agencies within and outside of NIH, visit http://imaging. cancer.gov. CIP staff members are often available in information booths on the exhibit floors at the annual meetings of SNM, the Radiological Society of North America, and the Academy of Molecular Imaging and at other imagingrelated events. The CIP Newsletter, distributed by e-mail, provides regular notification of funding opportunities and other issues related to imaging research, including relevant information from NIH Web pages and the NIH Guide. To sign up to receive the newsletter, send an e-mail message to: [email protected].

Barbara Y. Croft, PhD

NCI Cancer Imaging Program

Bethesda, MD

Copyright Society of Nuclear Medicine Jun 2008

(c) 2008 Journal of Nuclear Medicine, The. Provided by ProQuest Information and Learning. All rights Reserved.

By Tumeh, Paul C Radu, Caius G; Ribas, Antoni

Immune system activation can be elicited in viral infections, active immunization, or cancer immunotherapy, leading to the final common phenotype of increased glycolytic use by immune cells and subsequent detection by ^sup 18^F-FDG PET. Because ^sup 18^F-FDG is also used in baseline staging PET/CT scans and in tumor response assessment, physicians are faced with a unique challenge when evaluating tumor response in patients receiving cancer immunotherapy. The burgeoning field of cancer immunotherapy and the paucity of PET probes that can reliably differentiate activated immune cells from metabolically active cancer cells underscore the pressing need to identify and develop additional molecular imaging strategies. In an effort to address this concern, investigators have taken several molecular imaging approaches for cancer immunotherapy. Direct ex vivo labeling of T lymphocytes with radioactive probes before reinfusion represents the earliest attempts but has proven to be clinically limited because of significant PET probe dilution from proliferation of activated immune cells. Another approach is the indirect in vivo labeling of immune cells via PET reporter gene expression and involves the ex vivo genetic engineering of T lymphocytes with a reporter gene, reinfusion into the host, and the subsequent use of a PET probe specific for the reporter gene. The most recent approach involves the direct in vivo labeling of immune cells by targeting endogenous immune cell biochemical pathways that are differentially expressed during activation. In conclusion, these novel PET-based imaging approaches have demonstrated promise toward the goal of in vivo, noninvasive immune monitoring strategies for evaluating cancer immunotherapy. Key Words: cancer immunotherapy; adoptive cell transfer; molecular imaging; positron emission tomography; T lymphocyte

J Nucl Med 2008; 49:865-868

DOI: 10.2967/jnumed. 108.051342

An initial baseline staging PET/CT scan of a 37-y-oId man with newly diagnosed right eye choroidal melanoma demonstrated mild ^sup 18^F-FDG uptake in the right globe corresponding to the mass centered on CT and consistent with the known diagnosis. In addition, moderate to inlense ^sup 18^F-FDG PET uptake in multiple lymph nodes bilaterally in the neck and in the left tracheobronchial region of the chest was noted and reported to be consistent with metastatic disease (Fig. 1). Questioning of the patient elicited a recent upper respiratory tract infection with a productive cough and fever 3 d before PET/CT staging. A follow-up PET/CT scan demonstrated complete interval resolution of ^sup 18^F-FDG-positive cervical and thoracic adenopathy, with no evidence of malignant disease in the head and neck by ^sup 18^F-FDG PET/CT criteria.

Whether a patient experiences an upper respiratory tract infection or has recently received cancer immunotherapy, the clinical challenge of differentiating metabolically active cancer cells from activated immune cells via conventional radiotracer probes remains the same. This clinical case has been used for illustrative purposes and will be considered analogous to cancer immunotherapy, since both demonstrate an activated host immune system.

Adoptive cell therapy has become one of the great success stories in the field of cancer immunolherapy and is considered to be the most effective therapeutic strategy for patients with metastatic melanoma (1). Briefly, adoptive cell therapy is the administration of a patient’s own lymphocytes specific to melanoma antigens after a lymphodepleting regimen. In patients with metastatic melanoma refractory to all other treatments, 50% have demonstrated an objective response according to the Response Evalualion Criteria in Solid Tumors (RECIST), which is based on CT and MRI linear measurements of lesion size (2). Recently, however, the National Cancer Institute has called for the improvement of the RECIST methodology because these anatomic imaging techniques have proved to be less than optimal predictors of therapeutic response (3). In addition, end-stage anatomic changes in tumor size have not elucidated the reasons why certain patients respond to adoptive cell therapy and others do not.

Molecular imaging strategies using PET hold great promise for detecting molecular changes that manifest shortly after therapy and provide functional information about immune cells that may greatly facilitate advancements in the field of cancer immunotherapy. Specifically, PET enables noninvasive, quantitative, and tomographic assays of biologic processes using positron-emitting radioisotope- labeled probes (4). With this in mind, the conventional PET radiotracer that is routinely used to detect malignancies characterized by an increased rate of glycolysis is ^sup 18^F-FDG. However, herein lies the limitation with ^sup 18^F-FDG in the monitoring of transferred immune cells in a cancer setting. The uptake mechanism by which metabolically active cancer cells use this glucose analog has also been demonstrated to be operant in activated immune cells (5-7). Translated to the clinic, in a metastatic melanoma patient receiving adoptively transferred lymphocytes, assessing tumor response via ^sup 18^F-FDG uptake presents a unique challenge for the clinician because melanoma cells and activated immune cells undergo significant increases in glucose use and a high- intensity PET signal.

FIGURE 1. Comparison of ^sup 18^F-FDG PET and ^sup 18^F-FDG PET/ CT scans during and after acute upper respiratory tract infection. (A) Patient with ocular melanoma (melanoma lesion not shown) demonstrating moderate to intense ^sup 18^F-FDG PET uptake in multiple lymph nodes bilaterally in neck and chest during infection. (B and C) Fused axial PET/CT slices of neck and chest during infection. (D) Follow-up ^sup 18^F-FDG PET scan 2 mo later demonstrating complete interval resolution of ^sup 18^F-FDG- positive cervical and thoracic adenopathy. (E and F) Fused axial PET/ CT slices of neck and chest after infection.

To address this limitation, investigatory efforts are currently focused on developing novel PET strategies that can reveal and quantify characteristics unique Io immune cells, including immune cell regulatory dynamics, homeostatic expansion, lymphocyte trafficking, and transferred cell persistence. In addition, because adoptive cell therapy is a highly personalized treatment requiring unique reagents for each patient, probes that can accurately provide information on transferred cells may greatly facilitate therapeutic decisions by elucidating how the immune system interacts with cancer. Therefore, measuring these parameters may provide for noninvasive surrogate biomarkers of clinical endpoints, further emphasizing the need to identify such probes.

FIGURE 2. Bone marrow chimeric mice were generated by engraftment of hematopoieiic stem and progenitor cells transduced with trifusion reporter gene encoding synthetic Renilla luciferase, enhanced green fluorescent protein, and HSV-tk. Mice bearing rhabdomyosarcomas were challenged with Moloney murine sarcoma and leukemia virus complex, and induced immune response was monitored via 18F-FDG and 18FFHBG PET. (A) 18F-FHBG retention was detected in tumor and draining lymph nodes between days 8 and 14 after tumor challenge. (B) Using 18F- FDG, activated immune cells were observed at tumor draining lymph nodes between days 13 and 15. BM = bone marrow; H = heart; LN = lymph node; T = tumor.

Several immune cell PET strategies have been developed and can be categorized into direct and indirect imaging protocols: direct ex vivo labeling of immune cells, indirect in vivo labeling of immune cells via PET reporter gene expression, and direct in vivo labeling of immune cells via targeting of endogenous intracellular proteins.

Direct ex vivo labeling represents the earliest imaging strategy and was initially used to visualize the biodistribution of reinfused T lymphocytes (8,9). These studies demonstrated that T lymphocytes incorporated signilicant amounts of ^sup 18^F-FDG but released it shortly thereafter because of phosphatase activity. PET could follow their trafficking for 24-36 h, providing for a small window of opportunity to study in vivo lymphocyte trafficking. Significantly, however, this strategy precludes long-term immune cell monitoring because apoplosis or proliferation of these cells in vivo would lead to detrimental levels of probe dilution.

Indirect in vivo labeling via PET reporter gene constructs addresses the probe dilution problem and allows for serial imaging of cell trafficking and homeostatic expansion (Fig. 2) (10-12). Genetic engineering enables cells and their progeny to express a PET reporter gene that codes for a differentially expressed protein leading to enhanced uptake of the radiotracer. Several reviews have been provided for a more in depth discussion of the concepts, challenges, and advantages of reporter gene strategies (12-14). Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and its mutated derivative HSV-sr39tk have experienced the greatest advances in PET reporter gene strategies. Briefly. HSV1-tk converts thymidine to its phosphorylated form in addition to pyrimidine analogs such as acyclovir. ganciclovir. and penciclovir, leading to intracellular trapping (15). Positronemitting pyrimidine analogs, such as 9-(4- ^sup 18^F-fluoro-3-[hydroxymethyl]butyl)guanine (^sup 18^F-FHBG) and 2′-flouro-2′ deoxy-1-B-D-arabinofuranoysluracil (FIAU), have subsequently demonstrated preferential intracellular trapping by cells transduced with the HSV1-tk PET reporter gene. The use of picomolar amounts of these labeling substrates ensures against cellular toxicity observed after administration of pharmacologie doses of ganciclovir. Therefore, HSV1-tk and HSV-sr39tk serve a dual function in that, at low doses, imaging can be performed and, at pharmacologic doses, they serve as a suicide gene, protecting the patient from the potential of malignantly transformed genetically engineered cells or life-threatening auloimmunity. Several groups have used PET reporter gene strategies in adoptively transferred lymphocytes. Dubey et al. (16) demonstrated that small-animal PET could quantify adoptively transferred T lymphocytes eliciting an antitumor response in whole animals. T lymphocytes from animals that had rejected a inurine sarcoma were then transduced with HSV- sr39lk. injected into tumor-bearing mice, and imaged by small- animal PET. Localization of the adoptively transferred T cells in the antigen-positive tumor was detected by sequential imaging of the animals. In another study. Su et al. (17) correlated PET signal intensity with the number of cells in a region of interest. Different numbers of primary T lymphocytes were retrovirally transduced with the HSV-sr39tk and intratumorally injected followed by 18F-FHBG administration, providing for a proof-of-concept study that reporter genes could quantify transferred cell numbers via PET signal. Koehne et al. (18) demonstrated that Epstein-Barr virus (EBV)-specific T cells transduced with HSVl-tk could preferentially accumulate radiolabeled FIAU. After adoptive transfer. T lymphocytes labeled with ^sup 124^I-FIAU could be tracked by PET in severe combined immunodeficiency mice bearing human tumor xenografts.

In another strategy, investigators are exploring the use of a reporter gene that codes for a cell surface receptor. Kenanova et al. provided data (unpublished) that a modified carcinoemhryonic antigen gene could potentially be used as a reporter gene for clinical application. Theoretically, this approach may provide for a more facile method in quantifying PET signal with immune cell number when compared with intracellular enzymatic reporters, because a stoichiometric binding of probe and receptor is required. However, because this method lacks signal amplification, it requires a high number of cell surface receptors to be expressed and may experience challenges in the clinic from low sensitivity.

As reporter gene imaging strategics continue to advance, several key issues must be addressed to ensure successful translation of this strategy into the clinic. The first is sensitivity: lymphocyte trafficking leads lo a diffuse distribution throughout the body. PET visualization of these cells must be able to detect relatively small numbers of cells and provide for high resolution at a given anatomic location. The second is specificity: reporter gene proteins should be differentially expressed in immune cells with minimal endogenous expression, providing for an adequate signal-to-noise ratio. The third is toxicity: reporter gene proteins must not induce cell death or altered function at doses required for imaging. The last is immunogenicity: the reporter gene protein must not be immunogenic because that could lead to a host response to the transferred cells.

Most recently, Doubrovin et al. ( 19) explored the use of a human norepinephrine transporter and used a previously approved clinical- grade radiolabeled probe, metaiodobenzylguanidine. When human norepinephrine transporterpositive EBV-specific T cells were infused, PET enabled imaging over 28 d of their migration and specific accumulation in EBV-positive tumor xenografts expressing their restricted human leukocyte antigen allele. Ponomarev et al. (20) made a significant step toward a clinical-grade PET reporter gene when they demonstrated that a variant of thymidine kinase, human thymidine kinase 2, which is normally restricted in expression to the mitochondria, could be expressed in the cytosol of transduced cells via N-terminus truncation and intracellularly trap PET probes.

Although significant progress has been made in the Held of PET reporter gene strategies, an insoluble challenge lies in the extensive in vitro genetic manipulation of lymphocytes before reinfusion, potentially altering cell viability and function. This challenge has led investigators to take on another strategy: direct in vivo labeling of endogenous proteins in immune cells. Specifically, PET of metabolic signatures unique to activated immune cells may provide for a clinically signilicant imaging strategy.

Radu et al. (21) demonstrated a proof-of-concept study that exploited biochemical pathways as an endogenous PET reporter. In experimental autoimmune encephalitis, a murine model of multiple sclerosis. INF-FDG enabled visualization of spinal cord inflammation through activated lymphocytes. However, whereas ^sup 18^F-FDG PET could monitor response to corticosteroid lherapy, the magnitude of uptake did not correlate with disease progression in animals with advanced disease. This initial work in imaging endogenous pathways led the group to subsequently focus on metabolic signatures that may be more unique to immune cell activation than glycolysis.

Although most tissues predominantly use the de novo pathway for DNA synthesis, lymphoid organs extensively use the salvage pathway. A systematic approach was created where in vitro screening of nucleoside analogs for differential retention in proliferating and resting T lymphocytes was performed. A novel PET probe, 1-(2-deoxy- 2-flouro-arabinofuranosyD-cytosine (FAC) was identified as having significant accumulation in proliferating T cells (22). Subsequent radiochemical synthesis of 18F-FAC demonstrated greater specificity for lymphoid organs than PET probes for nucleoside metabolism (^sup 18^F-FLT, ^sup 18^F-FMAU) and glycolysis (^sup 18^F-FDG). Significantly, ^sup 18^F-FAC was further shown to preferentially accumulate in tumor-draining lymph nodes of oncoretrovirus-induced tumors in mice when compared with ^sup 18^F-FDG and ^sup 18^F-FLT. This work demonstrated that by exploiting metabolic signatures in activated immune cells, direct in vivo labeling sewed as a promising platform for PET probe development.

PET of cancer immunotherapy has made great progress in visualizing and quantifying lymphocyte homing and trafficking, homeostatic expansion, and transferred cell persistence. PET probes that can image these parameters may greatly facilitate therapeutic decisions in an accurate and timely manner by elucidating how the immune system interacts with cancer. Two main strategies are currently being investigated: reporter gene imaging and endogenous gene imaging. Humanized reporters and exploitation of biochemical signatures in activated immune cells are promising additional approaches to address current challenges.

REFERENCES

1. Rosenberg SA, Restifo NP. Yang JC, Morgan RA. Dudley ME. Adoptive cell iransfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008:8:299-308.

2. Dudley ME., Wunderlich JR. Yang JC, et al. Adoptive cell transfer therapy following non -myeloabative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005: 23:2346-2357.

3. Czemin J, Weher WA. Herschinan HR. Molecular imaging in the development of cancer therapeutics. Anna Rev Med. 2006:57:99-118.

4. Czrnin J. Phelps ME. Positron emission tomography scanning: current and future applications. Annu Rev Med. 2002:33:89-112.

5. Frauwirth KA, Riley JL. Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002:16:769-777.

6. Frauwirth KA. Thompson CB. Regulation of T lymphocyte metabolism. J Immmuno. 2004:172:4661-4665.

7. Shu CJ. Guo S, Kim YJ. et al. Visualization of a primary anti- tumor immune response by positron emission tomography. Pme Natl Acad Sci USA. 2005; 102:17412-17417.

8. Adonai N, Nguyen KN, Walsh J. et al. Ex vivo cell labeling with ^sup 64^Cupyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci USA. 2002; 99:3030-3035.

9. Botti C. Negri DR. Seregni E. et al. Comparison of three different methods for radiolabelting human activated T lymphocytes. Eur J Nad Med. 1997:24:497504.

10. Herschrnan HR. Noninvasive imaging of reporter gene expression in living subjects. Adv Cancel- Rex. 2004:92:29-80.

11. Herschman HR. PET reporter genes for noninvasive imaging of gene therapy, cell tracking and transgenic analysis. Crit Rev Oncol Hematol. 2004;51: 191-204.

12. Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003:17:545-580.

13. Gambhir SS, Barrio JR. Herschman HR. Phelps ME. Assays tor noninvasive imaging of reporter gene expression. Nucl Med Biol 1999;26:481-490.

14. Nair-Gill ED. Shu CJ. Radu CG. Witte ON. Non-invasive imaging of adaptive immunity using positron emission tomography, tmmunoi Rev. 2008;221: 214-228.

15. Tjuvajev JG. Avril N, Oku T, et al. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res. 1998;58:4333-4341.

16. Duhey P. Su H. Adonai N, et al. Quantitative imaging of the T cell antitumor response by positron-emission tomography. Proc Natl Acad Sci USA. 2003; 100:1232-1237.

17. Su H. Forbes A, Gambhir SS. Braun J. Quantitation of cell number by a positron emission tomography reporter gene strategy. Mol Imaging Biol. 2004;6:139-148.

18. Koehne G, Doubrovin M. Doubrovina E. et al. Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen- specific lymphocytes. Nat Biotechnol. 2003;21:405-413. 19. Douhrovin MM. Doubrovina ES, Zanzonico P. Sadelain M. Larson SM, O’Reilly RJ. In vivo imaging and quantitation of adoptively transferred human antigen-specific T cells transduced to express a human norepinephrine transporter gene. Cancer Res. 2007;67:11959-11969.

20. Ponomarev V. Doubrovin M, Shavrin A, et al. A human-derived reporter gene for noninvasive imaging in humans: mitochondrial thymidine kinase type 2. J Nucl Metl. 2007;48:819-826.

21. Radu CG. Shu CJ, Shelly SM, Phelps ME, Witte ON. Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2007;104: 1937-1942.

22. Radu CG, Shu CJ, Nair-Gill ED. et al. Molecular imaging of lymphoid organs and immune activation using positron emission tomography with a new ^sup 18^F-labeled 2′-deoxycytidine analog. Nat Med. In press.

Received Apr. 23, 2008; revision accepted Apr. 24. 2008.

For correspondence or reprints contact either of the following:

Antoni Ribas, Division of Hemalology/Oncology; UCLA Medical Center; 11 -934 Factor Building; 10833 Le Conte Ave., Los Angeles. CA 90095-1782.

E-mail: [email protected]

Paul C. Turnen, Division of Hematology/Oncology; UCLA Medical Center; 11 -934 Factor Building; 10833 Le Conte Ave., Los Angeles, CA 90095-1782.

E-mail: [email protected]

COPYRIGHT (c) 2008 by the Society of Nuclear Medicine, Inc.

Paul C. Tumeh

Caius G. Radu

Antoni Ribas

UCLA

Los Angeles, California

ACKNOWLEDGMENTS

This research is supported in part by the Scholars in Molecular imaging Fellowship and by grant P50 CA086306 from lhe National Institutes of Health.

Copyright Society of Nuclear Medicine Jun 2008

(c) 2008 Journal of Nuclear Medicine, The. Provided by ProQuest Information and Learning. All rights Reserved.

By Carrier, M Emery, R; Kandzari, D E; Harrington, R; Guertin, M-C; Tardif, J-C

Aim. Aortic cross-clamp time remains a significant marker of mortality and morbidity after coronary artery bypass graft (CABG) surgery. Pyridoxal-5-phosphate (MC-1), blocking purinergic receptors and intracellular influx of calcium, was shown to decrease the incidence of perioperative myocardial infarction in the prospective, randomized, double-blinded MC-1 to Eliminate Necrosis and Damage in CABG (MEND-CABG) clinical trial. Methods. We studied the relationship between treatment with MC-1 and aortic cross-clamping relative to the incidence of cardiovascular (CV) death and myocardial infarction (MI) in the trial that enrolled 901 high-risk patients undergoing CABG with cardiopulmonary bypass. Patients were randomized to receive either placebo, MC-1 250 mg/day or MC-1 750 mg/ day starting 3-10 h before CABG and continued for 30 days after surgery. Serial creatine kinase-myocardial band (CK-MB) determinations, ECGs and clinical evaluations were performed.

Results. Cross-clamping time increased the event rate of death and MI with an odds ratio (95% confidence interval) of 1.67 (1.17- 2.37, P=0.0044). Treatment with MC-1 decreased the rate of events (P=0.0073) with odds ratios of 0.52 (0.31-0.88 for MC-1 250 mg/day versus placebo) and 0.48 (0.29-0.82 for MC-1 750 mg/day versus placebo). There was no interaction between cross-clamp time and treatment (P=0.61) on the occurrence of the combined endpoint.

Conclusion. MC-1 decreased the incidence of CV death and MI (CK- MB >/=100 ng/mL) during the first 90 days after CABG in the MEND- CABG trial. Although longer aortic clamping time increased the risk of cardiovascular events, the protective effect of MC-1 was independent of ischemic time during CABG.

KEY WORDS: Ischemia – Coronary artery disease – Coronary artery bypass.

Myocardial ischemia occurring during coronary artery bypass grafting surgery (CABG) remains related with aortic cross clamping and cardioplegic arrest of the heart. Clinical studies have shown that the duration of myocardial ischemia represented by the aortic cross-clamping time was strongly related with early mortality and morbidity after CABG.1,2

Several methods of myocardial protection have been well studied, described in great detail and widely applied in the current clinical practice of cardiac surgery3-5 Pyridoxal-5-phosphate monohydrate, referred to as MC-1, is a natural metabolite of pyridoxine that inhibits purinergic (P2) receptors and the intracellular influx of calcium thereby reducing cell damage in laboratory experiments. In a phase 2 clinical trial, 10 mg/kg/day of MC-1 given for up to 14 days in patients undergoing high-risk percutaneous coronary intervention resulted in a decrease in infarct size over the first 24 h following angioplasty suggesting the cardioprotective properties of MC-1 in the setting of myocardial ischemia and reperfusion.6 The MC-1 to Eliminate Necrosis and Damage in CABG (MENDCABG) trial enrolled 901 high-risk patients who underwent CABG with cardiopulmonary bypass. Patients were randomized to receive either placebo, MC-1 250 mg/day or MC-1 750 mg/day starting 3-10 h before CABG and continued for 30 days after surgery. The study showed that MC-1 may be cardioprotective, especially in preventing larger more significant myocardial infarctions (MI) defined as a postoperative peak CK-MB greater than 100 ng/mL.7

The objective of the present analysis was to retrospectively evaluate the effects of treatment with MC1 and ischemia associated with aortic cross-clamping on the incidence of cardiovascular (CV) death and MI in the MEND-CABG trial.

Materials and methods

Study protocol and patient population

The patient population, study design and main findings of the MEND-CABG trial have been published.7 In summary, eligible patients included those scheduled for isolated CABG under cardiopulmonary bypass with at least two of the following baseline risks factors: age >/=65 years; current smoker; history of diabetes mellitus requiring treatment other than diet; history of non-disabling stroke, transient ischemic attack or carotid endarterectomy; prior peripheral artery surgery or angioplasty; recent MI between 48 h and 6 weeks before CABG; evidence of left ventricular dysfunction or congestive heart failure; need for urgent CABG; renal dysfunction with creatinine between 133 and less than 250 [degrees]=mol/L (1.5- 2.8 mg/dL); or presence of stenosis (>50%) in at least one carotid artery. The trial was conducted in 40 clinical centers in Canada and the United States, and the institutional review boards or equivalent approved the protocol at each site. All patients provided written informed consent.

Patients were randomized in a double-blind fashion to receive MC- 1 250 mg, MC-1 750 mg, or matching placebo tablets administered orally once daily. The first dose of study medication was administered 3-10 h prior to CABG surgery and treatment continued for 30 days after surgery. Patients were followed for in-hospital adverse events and clinical endpoints. In addition, patients underwent clinical evaluation at 30 and 90 days after CABG surgery.

Endpoints

For the present study focusing on myocardial ischemia and aortic cross clamping time during CABG surgery, CV death and MI were analyzed 90 days after surgery. Death was considered of cardiovascular etiology unless there was a clear non-cardiovascular cause. Myocardial infarction was defined as follows in our post-hoc analysis, based on central laboratory or core electrocardiogram (ECG) laboratory data: a peak creatinine kinase-myocardial band (CK- MB) of 100 ng/mL or above on days up to and including postoperative (POD) 4; or a new Q-wave evidence of MI along with CK-MB of 35 ng/ mL or above on days up to and including POD 4; or a peak CK-MB of 25 ng/mL or above occurring after POD 4; or a new Q-wave evidence of MI that was not present at POD 4; or a Q-wave or non-Q-wave MI as identified by the investigator.

Patient blood samples were collected before CABG surgery (baseline) and 4, 8, 12, 16, 24, 36, 48, 72 and 96 h and 30 and 90 days after CABG surgery. All samples were submitted to a central laboratory (Cirion BioPharm Research, Inc., Laval, QC, Canada) for CKMB measurements. A 12-lead ECG was performed at baseline and on POD 2, 4, 30 and 90 and submitted to the core laboratory (Dynacare Laboratories, Edmonton, AB, Canada) for centralized reading. Electrocardiographic tracings were analyzed using the Minnesota code.

Statistical analysis

The present study focused solely on the 861 patients in whom the aortic cross clamping time was available (861/901, 95%). Multivariate logistic regressions were used to study the effects of MC-I treatment and aortic cross-clamping time on the combined endpoint of CV death and MI as previously defined. The interaction between aortic cross-clamping time and treatment was investigated. Logistic regression models were also used to adjust for potential covariates such as type of cardioplegic solutions used (blood or crystalloid) and the baseline risk factors identified above. Baseline risk factors retained to be part of the final model are those that showed an association (P

TABLE I.-Patient characteristics.

All statistical testing was performed at a two-sided 0.05 significance level. Analyses were done with SAS 8.2.

Results

Patient characteristics, operative data and clinical outcomes

The mean patient age was 65+-10 years (range, 34 to 95 years), and 79% of patients were men (Table I). An average of 3.5+-1.0 coronary bypass grafts was performed per patient (Table II). Most patients underwent cardioplegic arrest of the heart with a blood based solution administered at cold or warm temperature (784/842, 93%), compared with a crystalloid solution (58/842, 7%). The type of solution used was not known in 19 patients. Among the 861 patients who were available for the analysis, 97 had an event (CV death or MI up to day 90 after CABG, 97/861, 11%) (Table III).

Effects of aortic cross-clamping time, MC-1 and other factors on clinical outcomes after CABG

Aortic cross-clamping time averaged 66+-31 min in the 861 patients included in the present analysis. Crossclamping time increased the event rate of CV death and MI with an odds ratio (OR) (95% confidence interval) of 1.67 (1.17-2.37, P=0.0044). Treatment with MC-1 decreased the rate of events (P=0.0073) with ORs of 0.52 (0.31-0.88 for MC-1 250 mg/day versus placebo) and 0.48 (0.29-0.82 for MC-1 750 mg/day versus placebo). There was no interaction between cross-clamp time and treatment (P=0.61) on the occurrence of the combined endpoint.

TABLE II.-Operative data.

TABLE III.-Clinical outcomes at 90 dayspost-CABG.

After adjusting for the type of cardioplegic solution and the risk factors found to be associated with the combined endpoint in the univariate analyses, namely renal dysfunction and carotid stenosis, aortic cross clamping time was still associated with more MIs and CV deaths after CABG (OR: 1.65, 1.13-2.41, P=0.0098) and MC- 1 treatment significantly (P=0.0088) decreased the event rates (OR: 0.53, 0.31-0.89 and OR: 0.48, 0.28-0.82 respectively for MC-1 250 mg and 750 mg). Again, no interaction was found between cross-clamp time and treatment (P=0.77).Effect of prolonged aortic cross clamping time on clinical outcomes Among the 448 patients with aortic cross-clamping times longer than 60 min, 58 patients (58/ 448, 12.9%) had a MI or CV death after CABG, compared with 39 who had events of the 413 patients (39/413, 9.4%) who underwent shorter cross-clamping. Aortic cross-clamping time longer than 60 min increased event rates with an OR of 1.43 (0.93-2.20, P=0.1059). Treatment with MC-1 250 mg/day and 750 mg/day decreased event rates (P=0.0085) with ORs of 0.52 (0.31-0.87) and 0.50 (0.30-0.84) respectively. There was no interaction between treatment with MC-1 and aortic cross clamping time of 60 min (P=0.865) (Table IV).

TABLE IV.-Effect of aortic cross-clamping time on composite endpoint of death and MI.

Discussion

The MEND-CABG trial demonstrated that MC-1, a purinergic P2 receptor inhibitor, was effective in reducing the incidence of perioperative MI defined by peak CK-MB values greater that 100 ng/ mL after CABG surgery. Because several studies have clearly demonstrated that elevated CK-MB release after CABG was strongly associated with worse 6-month and one-year survival rates, MC-1 could become an interesting adjunct treatment for CABG patients.7,8

Consistent with previous studies, this trial demonstrated a direct relationship between cross-clamp time and the extent of myocardial injury. The risk of myocardial infarction after CABG was higher in patients with cross-clamping times of 60 min or more, and was almost doubled in patients with an aortic cross-clamping time equal to or longer than 90 min. In addition, MC-I was effective in decreasing by almost half the risk of myocardial infarction (CK-MB >100 ng/mL) after CABG, and there was no statistical interaction between MC-1 treatment and aortic cross-clamping time, suggesting that MC-1 is as effective in patients with long ischemic times as it is for those with shorter cross-clamping.

The duration of aortic cross-clamping has previously been shown to be a predictor of clinical outcomes after CABG. Our study confirms this relationship in a population at high risk for events, particularly if we consider the incidence of MI in the placebo group. This relationship persisted when the results were adjusted for different factors including the type of cardioplegic solution. The present trial was not designed to study the role of different solutions used for cardioplegic arrest. Although Mallidi et all suggested that warm or tepid blood cardioplegic arrest may be associated with better early and late event-free survival than is cold cardioplegia, the present analysis showed that myocardial ischemic injury remains of serious concern despite the use of blood cardioplegic arrest during CABG surgery. The adjunct treatment with MC-1 could increase myocardial resistance to injury during cardioplegic arrest with ischemia and at the time of myocardial reperfusion, which is an unmet clinical need. MC-1 is a purinergic P2-receptor antagonist that inhibits the binding of ATP and thereby decreases calcium flux into cardiomyocytes.9, 10 Extracellular ATP is released during various stress conditions, such as ischemia or reperfusion injury, and acts on purinergic P2-receptors to initiate an increase in intracellular calcium. Because calcium overload leads to cell damage and is responsible for cell death during ischemia followed or not by reperfusion, reduction in calcium influx may explain the beneficial effects observed with MC-1 in animal models and in clinical studies.

Several large clinical trials have examined therapies intended to decrease myocardial ischemic damage in the peri-operative setting. The GUARDIAN trial tested the effect of cariporide, a sodium/ hydrogen exchanger inhibitor, and yielded overall negative results.11, 12 The PRIMO-CABG I trial in testing the effect of pexelizumab, a C5 complement inhibitor, resulted in a reduction in death and MI events after CABG that did not reach statistical significance.13 Similarly, the PRIMOCABG II trial enrolled a larger group of patients and was also unable to show a statistically significant reduction in the primary end-points combining post- operative death and MI. An effective approach to reduce perioperative events in high-risk patients undergoing CABG is therefore required.

The reduction in CV death and MI with MC-1 in the MEND-CABG trial was observed when a cut-off value of CK-MB >/=100 ng/mL was used in a post-hoc analysis. The reduction in the prespecified composite endpoint did not reach statistical significance in the main study when the cut-off value of 50 ng/mL was used.7 Although the post-hoc nature of this finding represents a limitation, the cut-off value of CK-MB of 100 ng/mL was explored because of previous studies linking it with future cardiovascular events.14 The PRIMO-CABG trial using a similar cut-off value of CK-MB of at least 100 ng/mL after surgery showed that patients with adjudicated MI through day 4 experienced a higher rate of mortality up to 180 days after surgery.13 The GUARDIAN trial also showed that patients with CK-MB values greater than 10 times the upper limit of normal after CABG had a higher rate of mortality 6 months after surgery.14 The two latter clinical trials suggest that large amounts of CK-MB enzyme release after CABG are associated with significant elevations of medium-term mortality after surgery.

Conclusions

MC-1 decreased the incidence of myocardial infarction (>100 ng/ mL) and death during the first 90 days after CABG in the MEND-CABG trial. Although longer aortic cross-clamping time increased the risk of cardiovascular events, the protection with MC-I was independent of ischemic time during CABG. The adjunct treatment with MC-I would therefore be expected to benefit high-risk patients undergoing CABG, irrespective of the aortic cross-clamping time and even after adjustment for type of administration of cardioplegic solutions.

Fundings.-The MEND-CABG trial was funded by Medicare, Winnipeg, Canada.

Acknowledgements.-Statistical analysis was done by the Montreal Heart Institute Coordinating Center.

Received on January 14, 2008.

Accepted for publication on January 17, 2008.

References

1. Raman JS, Bellomo R, Hayhoe M, Tsamitros M, Buxton BF. Metabolic changes and myocardial injury during cardioplegia: a pilot study. Ann Thorac Surg 2001;72:1566-71.

2. Onorati F, De Feo M, Mastroroberto P, Cristodoro L, Pezzo F, Renzulli A et al. Determinants and prognosis of myocardial damage after coronary artery bypass grafting. Ann Thorac Surg 2005;79:837- 45.

3. Mallidi HR, Sever J, Tamariz M, Singh S, Hanayama N, Christakis GT et al. The short-term and long-term effects of warm or tepid cardioplegia. J Thorac Cardiovasc Surg 2003;125:711-20.

4. Rosenkranz ER, Buckberg GD, Laks H, Mulder DG. Warm induction of cardioplegia with gluthamate-enriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intra-aortic balloon support. J Thorac Cardiovasc Surg 1983;86:507- 18.

5. Buckberg GD. Myocardial protection: entering the new millennium. J Card Surg 2002;17:447-50.

6. Kandzari DE, Labinaz M, Cantor WJ, Madan M, Gallup DS, Hasselblad V et al. Reduction of myocardial ischemic injury following coronary intervention (the MC-I to Eliminate Necrosis and Damage trial). Am J Cardiol 2003;92:660-4.

7. Tardif JC, Carrier M, Kandzari DE, Emery R, Cote R, Heinonen T et al. for MEND-CABG Investigators. Effect of pyridoxal-5-phosphate in patients undergoing high-risk coronary artery bypass surgery: results of the MEND-CABG study. J Thorac Cardiovasc Surg 2007; 133:1604-11.

8. Klatte K, Chaitman BR, Theroux P, Gavard JA, Stocke K, Boyce S et al. for the GUARDIAN Investigators. Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release. J Am Coll Cardiol 2001;38:1070-7.

9. Wang X, Dakshinamurti K, Musat S, Dhalla NS. Pyridoxal 5- phosphate is an ATP-receptor antagonist in freshly isolated rat cardiomyocytes. J MoI Cell Cardiol 1999;31:1063-72.

10. Trezise DJ, Bell NJ, Khakh BS, Michel AD, Humphrey PA. P2 purinoceptor antagonist properties of pyridoxal-5-phosphate. Eur J Pharmacol 1994;259:295-300.

11. Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS et at. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemie situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) investigators. Circulation 2000; 102:3032-8.

12. Chaitman BR. A review of the GUARDIAN trial results: clinical implications and the significance of elevated perioperative CKMB on 6 months survival. J Card Surg 2003;1:13-20.

13. Verrier ED, Shernan SK, Taylor KM, Van de Werf F, Newman MF, Chen JC, PRIMO-CABG Investigators. Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA 2004;291:2319-27.

14. Gavard JA, Chaitman BR, Sakai S, Stocke K, Danchin N, Erhardt L etal. for the GUARDIAN Investigators. Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome. J Thorac Cardiovasc Surg 2003; 126: 807- 13.

M. CARRIER 1, R. EMERY 2, D. E. KANDZARI3, R. HARRINGTON 3, M.- C. GUERTIN 4, J.-C. TARDIF 5

1 Department of Surgery

Montreal Heart Institute and Universite de Montreal

Montreal, QC, Canada

2 Department of Cardiovascular Surgery

St. Joseph’s Hospital Health East Care System

St. Paul, MN, USA

3 Department of Interventional Cardiology Research

Duke Clinical Research Institute

Durham, NC, USA

4 Montreal Heart Institute Coordinating Center

Montreal, QC, Canada

5 Department of Medicine

Montreal Heart Institute and Universite de Montreal

Montreal, QC, Canada

Address reprint requests to: M. Carrier, Department of Surgery, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. E-mail: [email protected]

Copyright Edizioni Minerva Medica Apr 2008

(c) 2008 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

By Popov, A F Hinz, J; Liakopoulos, O J; Schmitto, J D; Seipelt, R; Quintel, M; Schoendube, F A

Aim. The angiotensin I-converting enzyme insertion/deletion polymorphism (ACE-I/D), including three genotypes (II, ID, DD), with a known impact on midterm mortality and morbidity in patiente after coronary artery bypass graft surgery (CABG), was studied. Since this polymorphism has been linked with increased vascular response to phenylephrine during cardiopulmonary bypass (CFB), we investigated its possible effect on perioperative hemodynamlcs in patiente undergoing CABG. Methods. Genotyping for the ACE-I/D was performed by polymerase chain reaction (PRC) amplification in 110 patiente who underwent elective CABG with CPB. Patiente were assigned to two groups according to their genotype (group II [II genotype] and group ID/DD [ID and DD genotypes]). Systemic hemodynamics were measured directly before and at 4 h, 9 h, and 19 h after CPB.

Results. Genotype distribution of ACE-I/D was 18%, 57%, and 25% in genotypes II, ID, and DD, respectively. The two groups were similar in age (group II: 66+-6 years, group ID/DD: 66+-8 years), body-mass-index (BMI) (group II: 28+-2, group ID/DD: 29+-5 kg/m^sup 2^), male: female ratio (group II: 16: 4, group ID/DD: 63: 27) and Euroscore (group II: 3.1+-1.9, group ID/DD: 3.5+-2.1). There were no differences in mortality rate or perioperative systemic hemodynamics. The pulmonary vascular resistance before cardiopulmonary bypass was higher in the ID/DD genotypes than in the II genotypes (227+-121 vs 297+-169 dyn-s-1-m2-cm-5). Four hours after CPB no difference remained; at 9 h after cardiopulmonary bypass there was a slight difference in pulmonary vascular resistance between the two groups (247+-134 vs 290+-117 dyn*s^sup – 1^*m^sup 2^*cm^sup -5^) and a significant difference in pulmonary arterial pressure (19+-6 vs 23+-8); at 19 h after CPB the differences were no longer detectable.

Conclusion. ACE-I/D had no influence on perioperative systemic hemodynamlcs. However, transitory differences in pulmonary hemodynamic were observed after CPB. These differences may have been due to changes in serum ACE activity during CPB.

KEY WORDS: Cardiopulmonary bypass – Polymorphism, genetic – Hemodynamics.

Angiotensin I-converting enzyme (ACE), an important enzyme in the renin-angiotensin system, helps to regulate blood pressure, cellular growth and cardiovascular remodeling. Insertion (I) or deletion (D) polymorphism in the ACE gene is due to the presence or absence, respectively, of a 287 Alu repeat sequence in intron 16 of the ACE gene and results in three genotypes (II, ID, DD) of this sequence – 1 Increased ACE levels in plasma and in cardiac tissue have been reported in individuals with the ID and the DD genotype.2 Numerous association studies have investigated possible links of this polymorphism with several cardiovascular disorders.3-7 It is associated with hypertension and cardiovascular diseases (CVD) such as left ventricular hyperthrophy, cardiomyopathy and myocardial infarction.8, 9

Patients with the DD genotype are at an increased risk of midterm mortality and cardiac morbidity after coronary artery bypass graft (CABG) surgery.10 Our study investigated only midterm results during a 2-year period, without taking into account the early influence of this polymorphism on perioperative mortality and morbidity in CABG surgery patients. Patients with the DD genotype are also noted to have an increased vascular response to phenylephrine during cardiopulmonary bypass.11 This polymorphism is associated with impaired endothelial-dependent vasodilation in vitro in human internal mammary arteries.12 Also, in vivo studies have shown that the endothelium-dependent dilation in response to pharmacologie stimulation is impaired in D-allele carriers.13, 14 Lasocki et al. confirmed the impact of this polymorphism on vascular reactivity in humans and found that among patients with cardiopulmonary bypass Dallele carriers have a minor decrease in vascular resistance.15 Against this pathophysiological background we hypothesized that the presence of the D allele may be associated with changes in perioperative hemodynamics during CABG surgery and investigated the influence of this polymorphism on perioperative hemodynamics and mortality in these patients.

Materials and methods

Study population

The study protocol was approved by the ethics committee of the University of Gottingen, and all patients gave written informed consent. A total of 110 patients who underwent elective CABG were included into this prospective study. Patients were excluded who had a previous or concomitant cardiac surgical procedure, age >80 years, acute myocardial infarction (2.0mg/dL) or known neoplasms.

Operative technique

Anesthesia was induced and maintained using sufentanil, midazolam and pancuronium. Coronary artery bypass graft surgery was performed via median sternotomy and moderate hypothermie (32 [degrees]C) non- pulsatile cardiopulmonary bypass was established via cannulation of the ascending aorta and right atrium. Cardioplegic cardiac arrest was achieved by intermittent antegrade/retrograde infusion of cold blood cardioplegia. After rewarming and weaning from cardiopulmonary bypass, systemic anticoagulation was reversed 1: 1 by protamine sulfate administration. Initiation of treatment with inotropic drugs or nitroglycerine was at the discretion of the attending surgeon and anesthesiologist and based on hemodynamics at cardiopulmonary bypass and in the intensive care unit (ICU).

Hemodynamic measurements

After induction of anesthesia, a pulmonary catheter was inserted for hemodynamic measurement by means of the thermodilution technique. Hernodyhamic parameters were heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP). Cardiac index (CI), systemic (SVRI) and pulmonary vascular resistance (PVRI) indices were calculated from standard formulas. Hemodynamics were measured during steady-state conditions at least 20 min before cardiopulmonary bypass and at 4 h, 9 h, and 19 h after cardiopulmonary bypass in the ICU. Postoperative data recording included mean inotropic support, nitroglycerine therapy, markers of myocardial damage (troponin T, creatinine phosphokinaseAMB fraction), creatinine concentration, urine output and drainage blood loss 19 h after cardiopulmonary bypass. Ventilation time, length of ICU stay, length of stay in hospital and in-hospital mortality were also recorded.

Genotyping

DNA was isolated from leucocytes collected from whole blood by standard method.11 Insertion/deletion polymorphism in the ACE gene was identified by the polymerase chain reaction (PCR) according to Rigat et al.1 The following primers were used: forward primer 5′- CTG GAG ACC ACT CCC ATC CTT TCT-3′ (Biomers.net GmbH, Ulm, Germany) and the reverse primer ‘5- GAT GTG GCC ATC ACA TTC GTC AGA T 3′ (Biomers.net GmbH, Ulm, Germany). Genotypes were interpreted according to the length of the PCR products: 190 and 490 base pairs for the deletion and insertion alleles, respectively. In DD homozygotes we confirmed the accuracy of the genotyping results by using an insertion-specific primer pair (5′ TGG GAC CAC AGC GCC CGC CAC TAC 3′; 5′ TCG CCA GCC CTC CCA TGC CCA TAA 3’) (Biomers.net GmbH, Ulm, Germany) (Figure 1).

Figure 1.-Gel electrophoresis of the angiotensin I!-converting enzyme insertion/deletion polymorphism from three different patients. Lane 1: DNA ladder with base pair (bp) marker. Lane 2-3: patient homozygous for insertion polymorphism (II genotype). Lane 4- 5: patient homozygous for deletion polymorphism (DD genotype). Lane 6-7: patients heterozygous for insertion/deletion polymorphism (ID genotype).

Patients were assigned to two groups depending on their genotype: (group II [II genotype], group ID/DD [ID and DD genotype]). Acquisition of hemodynamics and perioperative data was performed in a blinded manner.

Statistical analysis

Statistical analysis was computed using commercial available software (SPSS for Windows, SPSS Inc. Chicago, USA). Pre- and postoperative data were compared using Student’s t-test and the chi^sup 2^ test. The hemodynamic data were compared using ANOVA for repeated measurements followed by post hoc tests. Allele frequencies in the study population were counted and compared with an expected distribution in a normal population by Hardy-Weinberg equilibrium and checked with the chi^sup 2^ test. Only 27 patients were homozygous for the D allele. Genotypes were defined as carriers (ID/ DD) and noncarriers (II) of the D allele. Statistical difference was set at P>0.05.

Results

Out of a total of 110 patients, 20 were homozygous for the insertion in the ACE gene, 63 were heterozygous for the insertion/ deletion, and 27 were homozygous for the deletion. Accordingly, the allele frequency of the insertion allele was 46.8% and 53.2% for the deletion. Genotype distribution of the ACE-I/D polymorphism was confirmed to be in prediction with Hardy-Weinberg equilibrium. The genotype and allelic frequencies of the polymorphism in this study population closely matched those published elsewhere (Table I).3, 8, 10

TABLE I.-Distribution of angiotensin I-converting enzyme insertion/deletion polymorphism genotypes and allele frequencies. TABLE II.-Pre- and intraoperative characteristics of patients (N=110) with angiotensin I-convening enzyme insertion/deletion polymorphism. Patients were grouped according to genotype (II: II genotype, ID/DD: ID and DD genotype).

There were no differences in the preoperative characteristics of the two groups with respect to age, gender, BMI, use of ACE inhibitors, creatinine level, left ventricular ejection fraction, and additive Euroscore. No differences were noted in aortic clamp time, cardiopulmonary bypass time, reperfusion time or cardiopulmonary bypass temperature during cardiopulmonary bypass (Table II).

Hemodynamic measurements and postoperative characteristics

No differences between the groups were noted in perioperative systemic hemodynamics with respect to heart rate, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac index and systemic vascular resistance index.

TABLE III.-Perioperative hemodynamics of patients (N=110) with angiotensin I converting enzyme insertion/deletion polymorphism. Hemodynamic data of patients grouped by genotype (II: II genotype, ID/DD: ID and DD genotype).

TABLE IV.-Postoperative characteristics of patients N=110) with angiotensin I converting enzyme insertion/deletion polymorphism and grouped by genotype (II: II genotype, ID/DD: ID and DD genotype).

Differences in pulmonary hemodynamics were observed, however. The pulmonary vascular resistance index was higher before cardiopulmonary bypass in individuals carrying the D allele (227+- 27 vs 296+18 dyn*s^sup -1^*m^sup 2^*cm^sup -5^; P=0.05). Directly after cardiopulmonary bypass and 4 h later these differences were no longer detectable. At 9 h after cardiopulmonary bypass the Dallele carriers were noted to have a higher pulmonary vascular resistance index (247+-30 vs 290+-12 dyn*s ^sup -1^*m^sup 2^*cm^sup -5^; P=0.19). These differences disappeared at 19 h after cardiopulmonary bypass. The mean pulmonary pressure was comparable during the study period, except at 9 h after cardiopulmonary bypass in the patients carrying the D allele (19+-1 vs 23+-1; P

The postoperative characteristics of the two groups are illustrated in Table IV. No D-allele dependent differences were observed in markers for myocardial damage, renal function, ventilation time, length of ICU stay, length of hospital stay or in- hospital mortality.

Discussion

We investigated the influence of ACE-I/D polymorphism on perioperative hemodynamics and perioperative mortality in patients undergoing CABG surgery. In our study sample, the distribution of genotypes and alleles was comparable to that of a metaanalysis that investigated the ACE-I/D polymorphism in Caucasian populations.8 We observed no perioperative differences in systemic hemodynamics between the two groups.

This result disagrees with previous findings concerning vascular response in patients undergoing cardiopulmonary bypass. Lasocki et al. demonstrated in patients with the DD genotype a modified vascular response and suggested that this reactivity could be a result of increased vascular smooth tone or endothelial dysfunction.15

In our patients, however, those carrying the D allele were noted to have significant differences in pulmonary hemodynamics before and at 9 h after cardiopulmonary bypass. Analysis of the perioperative data revealed higher PVRI and PAP in patients with the D allele. These differences had no early perioperative clinical impact, however, as indicated by the comparable cardiac index and consumption of cardiac inotropia in both groups.

Carriers of the DD genotype are at increased risk of midterm mortality and cardiac morbidity after CABG.10 Plasma and tissue levels of ACE are higher in these patients than in those with the II genotype, while patients with the ID genotype have an intermediate ACE level.1,2 Given the influence of the ACE-I/D polymorphism on plasma and tissue levels of ACE and the important role ACE plays in cardiovascular disease, the DD genotype has been implicated as a genetic marker that predisposes patients to a variety of cardiovascular diseases.10, 16-8

Although our study did not identify any underlying mechanisms, it is known that the expression of ACE increases remodelling19 and atherosclerosis20 and that blood pressure is regulated by the renin- angiotensinaldosterone system. Increasingly, studies are uncovering the genetic influences on the components of this system and their impact on the development of coronary artery disease (CAD). The ACE- I/D polymorphism has engendered numerous reports of possible allelic influences on intermediate and complex phenotypes, such as serum levels of ACE,1, 18, 21 conversion of Angiotensin I to Angiotensin II, and blood pressure,22 on risk factors such as hypertension,6, 23 left ventricular function, 24 and on outcome such as myocardial infarction, 17, 25 ischemic stroke 26 and hypertrophie cardiomyopathy.27

In-hospital mortality was similar in both groups and comparable to 30-day mortality after cardiac surgery.28 Although our patients were distributed according to Hardy-Weinberg equilibrium, our study is limited by the small number of patients in group II, which may have affected hospital mortality rates. Because the study population was selected from patients undergoing elective isolated CABG surgery, the sample size was smaller than in gene polymorphism studies in patients with cardiovascular diseases.1

Another limitation to the study was that only some patients received preoperative ACE inhibitors. However, there were no differences in this distribution across the studied genotypes. Patients treated with ACE inhibitors received various other drugs as well. Licker et al. demonstrated in a cardiopulmonary bypass model that the chronic use of ACE inhibitors attenuates vascular response to norepinephrine.29 But drug-specific or class-specific interactions with the D allele have not been investigated so far, and our analysis showed no association between the use of ACE inhibitors and genotype. In brief, it cannot be ruled out that this may have influenced our study results.

Conclusions

The ACE-I/D polymorphism does not influence perioperative systemic hemodynamics or mortality in patients undergoing elective CABG surgery. Pulmonary hemodynamics was affected by this polymorphism, but this may not have a clinical impact in the perioperative phase. Further study is needed to verify these findings.

References

1. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I- converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.

2. Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA elal. Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995;92:1387-8.

3. Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-4.

4. Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L et al. large-scale test of hypothesized associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5 000 cases and 6 000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet 2000;355:434-42.

5. Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F et al. A prospective evaluation of an angiotensin- converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706-11.

6. O’Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer FJ et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 1998;97:1773-9.

7. Pinto YM, van Gilst WH, Kingma JH, Schunkert H. Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study Investigators. J Am Coll Cardiol 1995;25:1622-6.

8. Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A. ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol 2000;20:484-92.

9. Arnett DK, Borecki IB, Ludwig EH, Pankow JS, Myers R, Evans G et al. Angiotensinogen and angiotensin converting enzyme genotypes and carotid atherosclerosis: the atherosclerosis risk in communities and the NHLBI family heart studies. Atherosclerosis 1998;138:111-6.

10. Volzke H, Engel J, Kleine V, Schwahn C, Dahm JB, Eckel L et al. Angiotensin I-converting enzyme insertion/deletion polymorphism and cardiac mortality and morbidity after coronary artery bypass graft surgery. Chest 2002;122:31-6.

11. Henrion D, Benessiano J, Philip I, Vuillaumier-Barrot S, Iglarz M, Plantefeve G et al. The deletion genotype of the angiotensin I-converting enzyme is associated with an increased vascular reactivity in vivo and in vitro. J Am Coll Cardiol 1999;34:830-6.

12. Buikema H, Pinto YM, Rooks G, Grandjean JG, Schunkert H, van Gilst WH. The deletion polymorphism of the angiotensin-converting enzyme gene is related to phenotypic differences in human arteries. Fur Heart J 1996; 17:787-94.

13 Perticone F, Ceravolo R, Maio R, Ventura G, Zingone A, Perrotti N et al. Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated hypertensive patients. Hypertension 1998;31:900-5.

14. Butler R, Morris AD, Burchell B, Struthers AD. DD angiotensin- converting enzyme gene polymorphism is associated with endotheHal dysfunction in normal humans. Hypertension 1999;33:1164-8. 15. Lasocki S, Iglarz M, Seince PF, Vuillaumier-Barrot S, Vicaut E, Henrion D et al. Involvement of renin-angiotensin system in pressure- flow relationship. Anaestesiology 2002; 96:271-5.

16. Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991;19:5444.

17. Beohar N, Damaraju S, Prather A, Yu QT, Raizner A, Kleiman NS et al. Angiotensin converting enzyme genotype DD is a risk factor for coronary artery disease. J Invest Med 1995;43:275-80.

18. Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensinconverting enzyme polymorphism in hypertrophie cardiomyopathy and sudden cardiac death. Lancet 1993;342:1085-6.

19. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H etal. Evidence for direct local angiotensin in vascular hypertrophy: in vivo gene transfer of Angiotensin converting enzyme. J Clin Invest 1994;94:978-84.

20. Pitt B. Angiotensin-converting enzyme inhibitors in patients with coronary atherosclerosis. Am Heart J 1994;128:1328-32.

21. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F et al. Evidence from combined segregation and linkage analysis, that a variant of the angiotensin !-converting enzyme (ACE) gene controls plasma ACE levels. AmJ Hum Genet 1992;51:197-205.

22. Lachurie ML, Azizi M, Guyene TT, Alhenc-Gelas F, Menard J. Angiotensin converting enzyme gene polymorphism has no influence on the circulating rerun angiotensin-aldosterone system or blood pressure in normotensive subjects. Circulation 1995;91:2933-^i2.

23. Harrap SB, Davidson HR, Connor JM, Soubrier F, Corvol P, Fraser R et al. The angiotensin !-converting enzyme gene and predisposition to high blood pressure. Hypertension 1993;21:455-60.

24. Clarkson PB, Prasad N, MacLeod C, Burchell B, MacDonald TM. Influence of the angiotensin converting enzyme I/D gene polymorphisms on left ventricular diastolic filling in patients with essential hypertension. J Hypertens 1997;15:995-1000.

25. Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin converting enzyme gene with myocardial infarction. Circulation 1996;94:708-12.

26. Margaglione M, Celentano E, Grandone E, Vecchione G, Cappucci G, Giuliani N etal. Deletion polymorphism of the angiotensin- converting enzyme gene in patients with a history of ischaemic stroke. Arterioscler Thromb Vase Biol 1996; 16:304-9.

27. Lechin M, Quinones MA, Omran A, Hill R, Yu QT, Rakowski H et al. Angiotensin I-converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophie cardiomyopathy. Circulation 1995;92:1808-12.

28. Osswald BR, Blackstone EH, Tochtermann U, Thomas G, Vahl CF, Hagl S. The meaning of early mortality after CABG. Eur J Cardiothorac Surg 1999;15:401-7.

29. Licker M, Neidhart P, Lustenberger S, Valloton MB, Kalonji T, Fathi M et al. Long-term angiotensin-converting enzyme inhibitor treatment attenuates adrenergic responsiveness without altering hemodynamic control in patients undergoing cardiac surgery. Anaestesiology 1996; 84:789-800.

A. F. POPOV1, J. HINZ2, O. J. LIAKOPOULOS1, J. D. SCHMITTO1, R. SEIPELT1, M. QUINTEL2, R A. SCHOENDUBE1

1 Department of Thoracic Cardiovascular Surgery

University of Gottingen, Gottingen, Germany

2 Department of Anesthesiology

Emergency and Intensive Care Medicine

University of Gottingen, Gottingen, Germany

Acknowledgements.-The project was supported by in part by grants from the Department of Thoracic Cardiovascular Surgery and the Department of Anaesthesiology, Emergency and Intensive Care Medicine, University of Gottingen, Germany. We thank PhD Hilgers, (Department of Medical Statistics, Georg-August University Gottingen, Germany) for his help with the statistical analysis.

Received on February 12, 2008.

Accepted for publication on March 19, 2008.

Address reprint requests to: A. F. Popov, Department of Thoracic and Cardiovascular Surgery, University of Gottingen, Robert-Koch- Strasse 40, 37099 Gottingen, Germany. E-mail: [email protected] goettingen.de

Copyright Edizioni Minerva Medica Apr 2008

(c) 2008 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

By Vallina-Victorero, M Vaquero, F; Alvarez, A; Ramos, M J; Vicente, M; Alvarez, J

Aim. The aim of this study was to determine the prevalence of carotid stenosis (CS) in the over-65 population segment residing in a catchment area (Gijon) served by the Asturias Health Service (Spain) as a necessary step in planning medical care for treating cerebrovascular disease in the elderly. Methods. In this descriptive transversal study, 232 subjects (114 men and 118 women) randomly chosen from health card data underwent colour-flow duplex scanning of the supra-aortic trunks.

Results. The prevalence of CS in this sample was 21.5%. When stratified by sex and age (65-74 and >75 years of age), the CS rate was 5 points higher in the older than in the younger group, and 4 points higher among males (23.6%) than among females (19.2%).

Conclusion. Approximately one in every 5 subjects over 65 years of age presents with CS; CS prevalence was higher in the over-75s and among males, although the differences were not statistically significant.

KEY WORDS: Atherosclerosis – Carotid arteries – Prevalence – Risk factors – Ultrasonography.

On Stroke Day, held in Spain in November 2006, Dr. Sabin, the coordinator of the Cerebrovascular Disorders Study Group of the Spanish Neurology Society, disclosed recent stroke statistics for the Spanish population: one stroke-related death occurs every 14 minutes; 26% of stroke victims die within 6 months of the first episode; 120 000 cases are reported every year, 20% of which die after the first stroke and 34.7% after the second attack (around 80 000 deaths in all); 39% of those who suffer a second stroke risk loss of functional dependence; one in every 10 deaths in Spain is caused by a stroke, ranking it the second cause of death in the country and the first among women; as the population ages, the number of people who will suffer their first stroke is estimated to increase by 30% over the coming 15 years.

Equally alarming is the general epidemiological trend: 700 000 strokes per year,1 with 165 000 deaths in the United States alone2 where it is now the third cause of death1 and the second worldwide.2 It is estimated that approximately 20% of strokes are due to carotid disease.

According to the Transatlantic Inter-Society Consensus (TASC) study, around half of patients with peripheral arteriopathy have a heart complaint that can be detected by means of simple tests.3 While the proportion of demonstrable cerebrovascular disease is much lower,4-7 Dormandy et al.8 report that over 60% of persons with claudication present some evidence of cerebrovascular disease. Between 12.5 and 60.5% of patients with intermittent claudication were found to have carotid disease at duplex ultrasonography, 9-18 Studies on the general population have reported an even wider prevalence of carotid disease (7.9-82.5%), 1926 depending on the age groups evaluated.

The aim of this study was to determine the prevalence of carotid stenosis (CS) in persons over 65 years of age residing in Gijon (Spain), as an essential step to planning medical care for treating cerebrovascular diseases in the elderly.

Materials and methods

A descriptive transversal study was carried out in a health services catchment area with a population of around 300 000 inhabitants, of which 64 133 are aged over 65 years. The sample size was calculated (EPIDAT 3.1 software package) for finite populations to define an expected prevalence of 7.5% with a precision of +-3% at the 95% confidence level. The result obtained was 295 individuals.

Three hundred men and women over 65 years of age were then randomly chosen from individual health card data. Written informed consent was obtained from all subjects.

Data were collected from January through March 2006 by means of interviews investigating the subjects’ medical history in relation to age, cardiovascular risk factors (smoker, ex-smoker, high blood pressure, diabetes, cholesterol), episodes of prior illness and treatments received. Obesity was classified according to the Body Mass Index (BMI) or the Quetelet Index.

Blood chemistry laboratory determinations included renal and hepatic function, glucose, total cholesterol and fractions, triglycerides, sodium and potassium ions, c-reactive protein (CRP) and homocysteine tests.

Elevated arterial blood pressure was defined as >140 mm Hg systolic pressure and >90 mm Hg diastolic pressure.

Colour-flow duplex scanning of the supra-aortic trunks was carried out (Toshiba Aplio Model SSA70OA Colour Doppler ECHO System) to determine the possible presence of carotid stenosis (CS). Stenosis severity was classified as: grade I (0-20% reduction in diameter – normal calibre or slight stenosis); grade II (21-50% reduction – moderate stenosis); grade III (SI70% reduction – significant stenosis); grade FV (71-99% reduction – severe-critical stenosis; grade V (occlusion).

Spectral parameters for stenosis grade evaluation were standardized according to diagnostic criteria validated for the vascular laboratory of Cabuenes Hospital Vascular Surgery Service. Grade I was defined as a maximum systolic velocity (MSV) 120 cm/s with a final diastolic velocity (FDV) 200 cm/s, with the stenosis considered critical when FDV was >130 cm/s); grade V was the absence of the wave. Stenosis grades II, III, IV and V were analyzed for the purposes of this study.

Statistical analysis

The data were entered on an Excel spreadsheet and processed using the SPSS-10 statistical software package. Univariate and bivariate descriptive analysis of the variables was carried out to calculate frequencies and means. Confidence intervals were calculated for a confidence level of 95%. The chi^sup 2^ test with correction for continuity and Fisher’s exact test were applied. Student’s t-test and analysis of variance were used to compare the means. Stratified analysis and control for possible confounding factors between the different risk factors and CS were performed using logistic regression analysis for descriptive purposes, constructing a model that included the different risk factors and the disease under study. Given the purely descriptive nature of this study, no procedure was employed in the selection of variables.

Results

The study population was 232 subjects (114 males and 118 females; average age 74.1 years, range 65-96) and constituted 78.6% of the initially calculated sample. The prevalence of CS was 21.5% (confidence interval [CI] 16.04-27.05). The sample was subdivided into two age groups: 135 (58.2%) subjects aged 65-74 years and 97 (41.8%) aged over 75 years.

The prevalence of CS was higher in the older group, although this difference was not statistically significant (P=0.3). The CS rate in the 65-74 age group was 19.2% (CI 12.2-26.2) versus 24.7% (CI 15.6- 33.8) in the older group and was higher among the men than the women, but here, too, this difference was not statistically significant (23.6% [CI 15.4-31.91 versus 19.4% [CI 11.9-27]; P=0.4). Table I lists CS prevalence by grade of severity.

The prevalence of CS in symptomatic and asymptomatic patients was 6% (CI 1.2-16.5) and 94% (CI 83.4-98.7), respectively; carotid disease was unilateral in 38% (CI 23.5-52.4) and bilateral in 62% (CI 47.576.4).

Table II summarises the risk factors and concomitant conditions in the subject sample. The average number of vascular risk factors presented by a patient with CS was 1.2 per subject versus an average of 1 in those without the disease. The difference was not statistically significant (P=0.09).

TABLE I.-Prevalence of carotid stenosis by different grades of severity (95% CI).

TABLE II.-Prevalence of cardiovascular risk factors and other conditions (95%CI).

TABLE III.-Blood chemistry values vs case history data.

TABLE IV.-Percent of subjects who referred taking a prescription drug.

In our sample, 25% of the smokers were found to have CS, 27.6% also had hypertension, 40% had insulindependent diabetes mellitus (IDDM), 25.8% had noninsulin dependent diabetes (NIDDM) and 20.7% had elevated cholesterol levels. Logical regression analysis of the relationship between CS and the risk factors for atherosclerosis showed a statistically significant association only with arterial hypertension (P=0.03). The estimated risk of suffering from CS was 2.1 times higher in patients with hypertension, 1.9 times in those with IDDM, and 2.4 times in those with diagnosed chronic lower limb ischemia. In contrast, this risk was not found to increase in patients with high cholesterol levels (odds ratio [OR] = 0.9). Table III lists the blood pressure values and blood chemistry parameters.

The prevalence of other disorders was also noted: obesity (55.7%), chronic renal insufficiency (CRI) (3.4%), chronic obstructive pulmonary disease (COPD) (10.3%), ischemic cardiopathy (IC) (16.8%), auricular fibrillation (CaxAF) (6.9%), cerebrovascular insufficiency (CVI) (7.8%) and deep vein thrombosis (DVT) (2.2%).

Approximately 76% of subjects referred using prescription drugs: 22.4% regularly took an antiaggregant and 22.8% a lipid-lowering agent (statins 21.1%)(Table IV).

Discussion and conclusions

The over-65 age segment accounts for nearly 21.4% of the general population and makes up a large proportion of patients with vascular diseases. In this sample, the prevalence of carotid stenosis (CS) was high, affecting approximately one in every 5 subjects. However, as O’Leary et al.23 underline, the frequency of severe disease is low. Compared with other studies on the general population, our data (7.8% prevalence of CS ?50% in both men and women) are in line with those reported in other studies: O’Leary et al.,23 CS >50% in 7% of men and in 6% of women; Ramsey et al.19 7% of CS >50%; Toshifumi et al,26CS >50% in 7.9% of men aged 50-79 years. Our rates are slightly higher than those given by Josse et al.,21 (CS >50% in 6.1% of men aged 75-89 years) and higher still than those reported by Colgan et al.,20 5% prevalence of CS >50%, probably because of the extremely wide age range (24-91 years) since it included younger subjects who contributed to lowering the overall CS prevalence. This might be the same reason why Prati et al.22 found a CS prevalence of 2.7% in men and 1.5% in women (age range 18-79 years). Bonithon-Kopp et al.,25 however, pointed out that there are very few longitudinal studies on early atherosclerotic lesions in the general population.

The high percentage of subjects with asymptomatic CS is noteworthy. Early detection of CS through programmes targeting people presenting with certain risk factors or associated illnesses could be one way to develop prophylactic strategies, including medical treatments. Detection of severe CS would permit prompt conventional or endovascular surgical treatment as recommended by scientific societies guidelines.

Studies on patients with peripheral arterial disease or cardiac ischemia obtained higher prevalence figures due to the multifocality of this disease. Published data report a CS prevalence ?30% (range 210 -60.57%.12, 15, 27 In studies on CS ?50% the rates range between 14% and 33%,13, 14, 16, 17 and between 12.5% and 14.9% in CS ?700 – 75%.11, 18All these studies included patients with peripheral arterial disease, except for Rajamani et al.,27 who refered to Afro- American patients with cardiac ischemic disease. Klopp et al.,11 Marek et al.13 and Kurvers et al.18 reported that the high prevalence of CS in peripheral arterial disease suggests the need for ultrasound screening of these patients to detect high grade stenosis. However, Cina et al.17 state that, while justifiable, such imaging studies are not mandatory. It should be remembered that in our sample the risk of suffering from CS was 2.4 times higher for patients diagnosed with peripheral arterial disease, although this association was not statistically significant.

As regards risk factors, in our sample there was a low prevalence of smokers, a high prevalence of exsmokers, as well as patients with high blood pressure and elevated hypercholesterolemia. The prevalence of MDDM was also high, though less so. The figures for smokers and ex-smokers could be explained by the presence of a concomitant illness that had forced them to stop smoking. Related studies conducted in Spain report similarly low prevalence rates for smokers.28,29

Analysis of the number of subjects with altered blood chemistry values shows that diabetes, hypertriglyceridemia and, above all, chronic renal insufficiency may be underdiagnosed (a bias could have been introduced by subjects not having correctly followed instructions not to eat before blood sample drawing, etc.), while hypercholesterolemia was correctly identified. The prevalence of increased homocysteine is not considered representative because this test was performed in only 22 patients owing to laboratory problems (Table III).

Approximately three in every four patients (75.9%) receive some kind of medical treatment. Besides hypercholesterolemia, the prevalence of ischemic cardiopathy and cerebrovascular insufficiency is noteworthy-all pathologies for which statins are given prophylactically-suggesting that this group of drugs is used less than advisable. These figures cannot be correlated with those published in the REACH study (31), in which the sample was composed of patients already diagnosed with an arterial disease (coronary, cerebrovascular or peripheral), which increases the percent of subjects taking these drugs.

Recruiting patients was the most laborious phase of the study because of their elevated age, which imposes physical limitations, and because of a lack of health education. A percentage loss

References

1. Rajamani K, Chaturvedi S. Medical management of carotid artery disease. Semin Neurol 2005;25:376-83.

2. Ingall T. Stroke-incidence, mortality, morbidity and risk. J Insur Med 2004;36:143-52.

3. Dormandy JA, Rutherford JB. Management of peripheral arterial disease (PAD). TASC Working Group. Transatlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31:S14.

4. Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978; 1:1379-81.

5. Da Silva A, Widmer LK, Ziegler HW, Nissen C, Schweiger W. The Basle longitudinal study; report on the relation of initial glucose level to baseline ECG abnormalities, peripheral artery disease, and subsequent mortality. J Chronic Dis 1979;32:797-803.

6. Aronow WS, Ahn C. Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women

7. Ogren M, Hedblad B, Isacsson SO, Janzon L, Junqquist G, Lindell SE. Ten year cerebrovascular morbidity and mortality in 68- year-old men with asymptomatic carotid stenosis. Br Med J 1995;310:1294-8.

8. Dormandy J, Heeck L, Vig S. Lower-extremity arteriosclerosis as a reflection of a systemic process: implications for concomitant coronary and carotid disease. Semin Vasc Surg 1999;12:118-22.

9. Turnipseed WD, Berkoff HA, Belzer FO. Postoperative stroke in cardiac and peripheral vascular disease. Ann Surg 1980; 192:3658.

10. Hennerici M, Aulich A, Sandeman W, Freund HJ. Incidence of asymptomatic extracranial arterial disease. Stroke 1981;12:750-8.

11. Klop RBJ, Eikelboom BC, Taks ACJM. Screening of the internal carotid arteries in patients with peripheral vascular disease by colour-flow duplex scanning. Eur J Vasc Surg 1991;5:41-5.

12. Alexandrova NA, Gibson WC, Morris JW, Maggisano R. Carotid artery stenosis in peripheral vascular disease. J Vasc Surg 1996;23:645-9.

13. Marek J, Mills JL, Harvich J, Cui H, Fujitani RM. Utility of routine carotid duplex screening in patients who have claudication. J Vasc Surg 1996;24:572-7.

14. Miralles M, Corominas AQ, Cotillas J, Castro F, Clara A, VidalBarraquer F. Screening for carotid and renal artery stenosis in patients with aortoiliac disease. Ann Vasc Surg 1998;12:17-22.

15. Ballotta E, Da Giau G, Renon L, Abbruzzese E, Saladini M, Moscardo P et al. Symptomatic and asymptomatic carotid artery lesions in peripheral vascular disease: a prospective study. Int J Surg Investig 1999;1:357-63.

16. Simons PC, Algra A, Eikelboom BC, Grobbee DE, Van der Graaf Y. Carotid artery stenosis in patients with peripheral arterial disease: the SMART study. SMART study group. J Vasc Surg 1999;30:519- 25.

17. Cina CS, Safar HA, Maggisano R, Bailey R, Clase CM. Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease. J Vasc Surg 2002;36:75-82.

18. Kurvers HA, Van der Graaf Y, Blankensteijn JD, Visseren FL, Eikelboom BC. Screening for asymptomatic internal carotid artery stenosis and aneurysm of the abdominal aorta: comparing the yield between patients with manifest atherosclerosis and patients with risk factors for atherosclerosis only. J Vasc Surg 2003;37:126-33.

19. Ramsey DE, Miles RD, Lambeth A, Sumner DS. Prevalence of extracranial artery disease: a survey of an asymptomatic population with non-invasive techniques. J Vasc Surg 1987;5:584-8.

20. Colgan MP, Strode GR, Sommer JD, Gibbs JL, Sumner DS. Prevalence of asymptomatic carotid disease: results of duplex scanning in 348 unselected volunteers. J Vasc Surg 1998;8:674-8.

21. Josse MO, Touboul PJ, Laplane D, Bousser MG. Prevalence of asymptomatic internal carotid artery stenosis. Neuroepidemiology 1987;6:150-2.

22. Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA et al. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992;23:1705-11.

23. O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK Jr et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke 1992;23:1752-60.

24. Willeit J, Kiechi S. Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis. A population-based study. Arterioscler Thromb 1993;13:66l-8.

25. Bonithon-Kopp C, Jouven X, Taquet A, Touboul PJ, Guize L, Scarabin PY. Early carotid atherosclerosis in healthy middle-aged women. A follow-up study. Stroke 1993;24:1837-43.

26. Toshifumi M, Masamitsu K, Shunroku B, Nobuo N, Atsushi T. Prevalence of asymptomatic carotid atherosclerotic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese study. Stroke 1997;28:518-25.

27. Rajamani K, Sunbulli M, Jacobs BS, Berlow E, Marsh JD, Kronenberg MW et al. Detection of carotid stenosis in African Americans with ischemic heart disease. J Vasc Surg 2006;43:1162-5.

28. Puras Mallagray E, Cairols Castellote MA, Vaquera Morillo F. Estudio piloto de prevalencia de la enfermedad arterial periferica en atencion primaria. Angiologia 2006;58:119-25. 29. Vicente I, Lahoz C, Taboada M, Garcia A, San Martin MA, Perol I et al. Prevalencia de un indice tobillo/brazo patologico segun el riesgo cardiovascular calculado mediante la funcion de Framingham. Med Clin (Barc) 2005;124:641-4.

30. Bhatt DL, Steg PG, Magnus E, Hirsch AT, Ikeda Y, Mas JL et al. International prevalence, recognition and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180-9.

M. VALLINA-VICTORERO, F. VAQUERO, A. ALVAREZ, M. J. RAMOS, M. VICENTE, J. ALVAREZ

Section ofAngiology

Vascular and Endovascular Surgery

Hospital de Cabuenes, Gijon, Spain

Fundings -The authors are grateful to the Asturian Society of Angiology, Vascular and Endovascular Surgery for funding this study.

Received on October 9, 2007.

Accepted for publication on February 8, 2008.

Address reprint requests to: M. Javier Vallina-Victorero Vazquez, Servicio de A. y Cirugia Vascular, Hospital de Cabuenes, Cabuenes s/ n 33394, Gijon, Asturias, Spain. E-mail: [email protected]

Copyright Edizioni Minerva Medica Apr 2008

(c) 2008 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.

By Joe Depriest, The Charlotte Observer, N.C.

Jun. 24–Cleveland County authorities have located all three teenage girls missing since they walked away from a group home worker Sunday at the Broad River Greenway south of Boiling Springs.

Shikeyla Wilfong, 15, and Brittany Roper, 16, were picked up Tuesday at the Bargain Shoe Store outside Gaffney, S.C., according to Boiling Springs Police Chief Marty Thomas.

Taylor Sandefer, 13, called her mother and told her that she was at a gas station in Cannons Campground in Spartanburg, S.C., Thomas said.

Authorities said all the girls were safe and uninjured.

Officers from Cherokee and Spartanburg counties assisted with temporarily detaining the girls until Boiling Springs police assumed custody.

The three teens were living at a Cleveland County group home and had been on an outing with an employee at the greenway on Sunday. When the employee called to the teens and told them it was time to leave, the three girls walked away, police said.

Searchers looked throughout the night Sunday and for several hours Monday without finding them.

According to Thomas, one of the girls said they met several young men at the greenway. The men gave the girls a ride to an unknown address in Spartanburg County, S.C. and they stayed there until Tuesday, Thomas said.

The girls then made several calls to the group home and to one parent, hoping to get a ride back to Cleveland County, The group home workers immediately notified Boiling Springs police, Thomas said.

Taylor has been released to her mother. Shikeyla Wilfong has been released back into the care of the group home and Brittany Roper has been released to Henderson County Department of Social Services.

—–

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Copyright (c) 2008, The Charlotte Observer, N.C.

Distributed by McClatchy-Tribune Information Services.

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A Newly refurbished ward at Clevedon Cottage Hospital has been named in memory of a former nurse.

The ward has been named in memory of district nurse Sheila Ostrehan.

Sheila joined the primary care trust (PCT) in April 2002, but had been a registered nurse in the NHS since 1973.

The ward was officially opened by Sheila’s mother Pauline Ostrehan, PCT associate director of nursing and quality Eileen Raynes-White and hospital matron Gwen Hobbs.

Sheila, who worked in the local community and had patients who underwent treatment at the hospital, died in June last year, aged 56.

The ceremony was also attended by members of primary care trust staff.

As well as re-naming the ward, it has also been refitted and now provides palliative care and an isolation room.

Mrs Raynes-White said: “Sheila was an exceptional nurse who was much loved, admired and respected by her patients, colleagues and friends.

“Sheila loved Clevedon and it is very fitting that a ward at Clevedon Hospital should be re-named to commemorate her contribution to nursing and the PCT.”

(c) 2008 Evening Post (Bristol UK). Provided by ProQuest Information and Learning. All rights Reserved.

Study seeks to determine if presence of certain gene impacts patient outcome

GPC Biotech AG

Investor Relations & Corporate Communications

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MC Services AG

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GPC Biotech AG (Frankfurt Stock Exchange: GPC, NASDAQ: GPCB) today announced the initiation of a Phase 2 study evaluating satraplatin in combination with the steroid, prednisone, in patients with metastatic hormone-refractory prostate cancer (HRPC) who previously have been treated with docetaxel (Taxotere(R)). The study is being sponsored by the U.S. National Cancer Institute (NCI), and the principal investigator is William L. Dahut, MD, Chief, Genitourinary Research Section, Medical Oncology Branch, Center for Cancer Research, NCI.

The trial is a single-arm study with a planned enrollment of 66 patients with metastatic HRPC who have been previously treated with docetaxel therapy and with no more than one other previous cytotoxic chemotherapy regimen. The primary objective of the trial is to determine if the presence of certain variants of the gene, ERCC1, affects progression-free survival in this patient population. ERCC1 is involved in DNA damage repair. Satraplatin, like other platinum agents, has been shown to work via targeting the DNA in tumor cells.

“The results of this trial may provide important information in determining which hormone-refractory prostate cancer patients are more likely to benefit from treatment with satraplatin,” said Martine George, MD, Senior Vice President, Drug Development and Chief Medical Officer at GPC Biotech. “We are pleased to be working with the NCI to conduct this potentially ground-breaking study.”

About Satraplatin

Satraplatin, an investigational drug, is a member of the platinum family of compounds. Platinum-based drugs are a critical part of modern chemotherapy treatments and are used to treat a wide variety of cancers. All platinum drugs currently on the market require intravenous administration. Satraplatin is an oral compound that clinical trial patients are able to take at home. A Marketing Authorization Application for satraplatin in combination with prednisone is currently under review in Europe for the treatment of hormone-refractory prostate cancer patients whose prior chemotherapy has failed. A decision on the filing by the European regulators is expected in the second half of 2008.

About GPC Biotech

GPC Biotech AG is a publicly traded biopharmaceutical company focused on anticancer drugs. GPC Biotech’s lead product candidate is satraplatin, an oral platinum compound. The Company has various anti- cancer programs in research and development that leverage its expertise in kinase inhibitors. GPC Biotech AG is headquartered in Martinsried/Munich (Germany) and has a wholly owned U.S. subsidiary in Princeton, New Jersey. For additional information, please visit GPC Biotech’s Web site at www.gpc-biotech.com.

This press release contains forward-looking statements, which express the current beliefs and expectations of the management of GPC Biotech, including statements about the efficacy and safety of satraplatin. Such statements are based on current expectations and are subject to risks and uncertainties, many of which are beyond our control, that could cause future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Actual results could differ materially depending on a number of factors, and we caution investors not to place undue reliance on the forward-looking statements contained in this press release. Satraplatin may not be approved for marketing in a timely manner, if at all. We direct you to GPC Biotech’s Annual Report on Form 20-F for the fiscal year ended December 31, 2006 and other reports filed with the U.S. Securities and Exchange Commission for additional details on the important factors that may affect the future results, performance and achievements of GPC Biotech. Forward- looking statements speak only as of the date on which they are made and GPC Biotech undertakes no obligation to update these forward- looking statements, even if new information becomes available in the future.

Satraplatin has not been approved by the FDA in the U.S., the EMEA in Europe or any other regulatory authority and no conclusions can or should be drawn regarding its safety or effectiveness. Only the relevant regulatory authorities can determine whether satraplatin is safe and effective for the use(s) being investigated.

Taxotere(R) is a registered trademark of Aventis Pharma S.A.

(c) 2008 BUSINESS WIRE. Provided by ProQuest Information and Learning. All rights Reserved.

VANCOUVER, BRITISH COLUMBIA–(Marketwire – June 24, 2008) – Perceptronix is pleased to announce two (2) new distribution partnerships signifying an important third party validation of LungSign(TM) and its value in the market place. IRS (Independent Respiratory Services) and Medpro Respiratory Care have agreed to add the LungSign(TM) test kit to their list of offerings allowing physicians to now order the test directly through these service providers. Patients will receive a test kit, with a physician’s requisition, from our distributors’ office in their geographic area and then mail the specimen to the Perceptronix laboratory for analysis.

The addition of LungSign(TM) to the IRS and Medpro offerings expands their current scope of services to include detection for lung cancer, which is seen as the leading category of cancer causing death among men and women. The provision of LungSign(TM) through IRS and Medpro enables patients to access the most up to date technology in respiratory health. The partnership also allows more geographic areas to be reached putting LungSign(TM) in the hands of all physicians throughout BC and more people who need it.

The partnership will engage both Perceptronix and the distributors in co-promotion of the LungSign(TM) test. Perceptronix will provide technical support to the distributors as all parties continue to work together to serve the needs of a broad client base.

IRS will cover the Okanagan Valley while Medpro will cover the greater Vancouver area (including Vancouver Island).

“This is a very exciting time for our company,” said Bojana Turic, President and CEO of Perceptronix. “Partnerships with companies like IRS and Medpro, who are recognized expert providers of respiratory services, reflect the increasing need for the LungSign(TM) test in this critical market.”

“This partnership with Perceptronix brings a valued added service to our portfolio,” said Keith Houghton president and CEO of IRS. “The team at Perceptronix have delivered an early cancer detection technology to a market that is in desperate need of a test like LungSign(TM).”

“The ability for CareStream to broaden its marketing capacity with a cancer test like LungSign(TM), provides us with state-of-the- art technology with which to enter the Lung Cancer markets,” said George Louvros, BC Manager of Medpro Respiratory Services.

In North America, overall cancer rates, and related deaths, have been declining in recent years. Lung cancer incidence and death rates, however, continue to climb. Every year, over 230,000 North Americans are told they have lung cancer. It is the second leading category of cancer death in men, and has even surpassed breast cancer as the leading category of cancer death in women. On a yearly basis, more people die of lung cancer than of breast, colon and prostate cancers combined.

About IRS Independent Respiratory Services Inc. (IRS)

Located in the interior of BC, IRS Independent Respiratory Services Inc. is a BC-owned and operated full service respiratory company. Founded in 1996, IRS services Interior hospitals and clinics throughout BC. They are known for their commitment to excellence in respiratory care, quality service, timely and accurate reporting of results, and commitment to patient care.

About Medpro Respiratory Services (division of CareStream Medical Ltd.)

Medpro Respiratory Services is a division of CareStream Medical Ltd., which was founded in 1997 and has been serving our customer’s respiratory and anesthesia needs for over 10 years. Medpro Respiratory Care is a respiratory equipment and service provider serving the British Columbia respiratory homecare market for the past 10 years under the Carestream Medical Ltd. banner. MedPro was recently awarded the provincial Home Oxygen Contract in 4 of the 5 Health Regions in BC making it one of the largest home oxygen providers in BC. Carestream is in the 200 fastest growing companies in Canada based on the previous five fiscal years.

About Perceptronix Medical Inc.

Perceptronix Medical Inc. is a Vancouver-based, privately-owned cancer detection company founded in June 1999 as a spin off of the BC Cancer Agency. The mission of Perceptronix is to commercialize effective technologies to improve the early detection, localization, diagnosis and follow-up of cancer, with an initial focus on lung cancer. Perceptronix’ products and services offer an improvement over existing detection and localization technologies and provide physicians with increased options for prolonging and improving the quality of patients’ lives.

(c) 2008 Marketwire. Provided by ProQuest Information and Learning. All rights Reserved.

By John Rentoul

Old Labour practices live on in the cruel rule that prevents NHS patients paying for extra cancer treatment

Once upon a time, at the very beginning of New Labour, before it was even called New Labour, Neil Kinnock made the speech of his life that would change politics. He spoke of impossible promises – he meant those of the Trotskyist left, but he could have been talking of any utopianism. “They are then pickled into a rigid dogma, a code, and you go through the years sticking to that, out-dated, misplaced, irrelevant to the real needs.” And anyone who was politically conscious at the time can tell you what happens next. You end in grotesque chaos.

So it was with all those changes that were needed to make Labour electable again. There was the closed shop, for example. It was one of those codes of old trade unionism that arose out of a desire for fairness. In order to prevent free riders gaining the benefits of union membership without paying their dues, some unions made deals with employers that everyone at a place of work was required to be a union member. The original motive of justice became pickled into a rigid dogma, and the Labour Party stuck to it, mistaking form for content, long after the countervailing injustices became obvious, of workers being sacked if they fell out with their union. Then some lightweight opposition spokesman called Tony Blair came along and ditched the party’s support for what was now an infected appendix of history.

It might be thought that there aren’t any dangerous appendices left on New Labour’s thoroughly modernised body, not after 25 years of almost continuous revisionism. Indeed, there are many people who think that this is one of Labour’s problems: that it has been so pasteurised and homogenised that all its distinctive values have been cleaned out, leaving a centrist husk that cannot compete with the fresher centrism of Cameron’s Conservatives. How wrong they are.

There is one out-dated, misplaced dogma to which the Labour Government clings, which is irrelevant to the real needs. It is certainly distinctive, redolent of an old idealism – and utterly repellent to the voters. It is the rule, recently reinvented by Alan Johnson, the Secretary of State for Health, that if you pay for drugs in addition to National Health Service treatment, then your NHS treatment is withdrawn.

Last week the case of Linda O’Boyle was reported. She paid for a cancer drug in the hope that it would extend her life. It is difficult to know whether it did or not – her husband believes that it gave her an extra three months before she died, aged 64. She had to pay because the drug is not approved for use on the NHS. Her doctor told her that, if she wanted to take it, she would have to pay for all the other drugs that she was getting on the NHS. So that, of course, is what she did.

But what an absurd state of affairs. Alan Johnson tried to defend it in December, when two other cancer patients sued their NHS trusts for refusing them NHS care if they bought their own top-up drugs. He told the House of Commons that it was “a founding principle” of the NHS that “someone is either a private patient or an NHS patient”. A patient “cannot, in one episode of treatment, be treated on the NHS and then allowed, as part of the same episode and the same treatment, to pay money for more drugs. That way lies the end of the founding principles of the NHS.”

The original motive is just about visible through the cloudy mixture of meaning-starved utopianism and bureaucratic authoritarianism. When the NHS was established, it was important to keep private and public medicine separate, mainly for fear of doctors using their NHS practice as a source of private business. That became confused with what really was the founding principle of the NHS in 1948, namely that everyone would be entitled to medical treatment regardless of their ability to pay. And this in turn became pickled into the idea that everyone had to be treated the same. Hence the older theological dispute about pay beds.

And hence today’s refusal to treat NHS patients on the NHS if they pay for any pills themselves. To allow public and private to be mixed in “one episode of treatment” – the Department of Health’s code of practice actually says “for the treatment of one condition during a single visit to a NHS organisation” – would, according to the Department’s press office, “risk creating a two-tier health service”.

Here we are, therefore, in the grotesque chaos of a Government that will pay 140m to let over-60s swim for free, but which will take away free life-saving or life-extending treatment from people who top up NHS treatment with drugs that the NHS won’t let them have.

The Government’s policy is like telling parents that if they pay for a private tutor, their children won’t be allowed to continue to attend a state school. In other words, if everyone cannot have something, then no one can. Not unless they are really rich in which case there’s nothing we can do about it, although – the implication seems to be – we wish we could.

Where is the Johnson who was a moderniser at Education, reforming student finance by ditching the rigid dogma of a supposedly egalitarian system that had become elitist? Can he not see that the game is up? Already, Doctors for Reform, the pressure group for patient choice, is preparing a legal challenge to his policy. If they can find the right test case, the weak legal base of the Health Department’s guidelines is likely to be exposed.

Nor will the changes that have brought the issue to the fore in the past two years go away. On the contrary, they will intensify. Medical science is developing new, expensive drugs that control or limit cancers.

The only fair way for a state healthcare system to contain these cost pressures is for an independent body, in our case the National Institute for Clinical Excellence, to decide which drugs offer the greatest benefit for their price. That means that more and more drugs that are safe and potentially beneficial will not be available on the NHS, or not within the abbreviated lifetimes of many cancer patients.

One reason that Johnson has not come under more pressure to ditch an indefensible policy is that the Conservatives support it. David Cameron understands, in the way that Kinnock once did, the power of history in poisoning attitudes to an opposition party.

However unfair the Tory reputation for being hostile to the NHS might be, he cannot say anything that might be characterised as favouring the better-off within the NHS. So he said he was “tempted” to ditch the ban on top-up drugs, while Andrew Lansley, his health spokesman, keeps up the old “no two-tier” tune. That is an opportunity for Johnson, though, not an excuse for doing nothing, especially after a little-reported revolution last week. On Wednesday, the British Medical Association, the most successful and conservative trade union in the country, changed its policy. Its consultants’ conference voted overwhelmingly that NHS patients should be allowed to top up their treatment.

Funny how doctors as consumers of health care turn out to think differently from doctors as providers of it. The conference heard from Gordon Matthews, an orthopaedic surgeon whose wife has terminal cancer. There were non-NHS drugs that cost 20,000 a year that “might buy her a few months”, but if she used them her NHS treatment, worth “tens and tens of thousands of pounds”, would be withdrawn.

With the doctors, public opinion and common sense on his side, it is only “out-dated, misplaced dogma” that is holding Alan Johnson back.

(c) 2008 Independent on Sunday, The. Provided by ProQuest Information and Learning. All rights Reserved.

Health Net of California:

 WHAT:    Health Net of California and the Central Valley Health Network will illustrate the looming financial crisis facing the state's safety-net health clinics and launch an emergency loan program to help clinics keep their doors open and serving patients during the state's continuing budget negotiations.  WHEN:    Thursday, June 26, 10:30 a.m.  WHO:     Presenters are: David Quackenbush - Central Valley Health Networks Ana Andrade - Health Net of California Luisa Medina - Central California Legal Services and chair of Children's Health Initiative, Fresno County  WHY:     Without a state budget in place, the bulk of the clinics' funding will be halted effective July 1. Many clinics do not have the financial reserves needed to continue meeting payroll and expenses during the crunch. Many, therefore, face the prospect of temporary closure until state funding is restored.  Studies repeatedly have shown that the "medical home" provided by the clinics provides better utilization of health services and health outcomes, including reduced reliance on expensive and maxed-out emergency rooms, fewer hospitalizations, lower overall costs and better preventive care.  WHERE:   Kerman Health Care Center 517 South Madera Avenue Kerman, California 93630  VISUALS: Interview and photo opportunities with health clinic medical professionals, community supporters and patients.  CALL-IN  A conference call has been established for media outlets INFO:    unable to attend in person: 1-800-768-6570. Passcode: 8419811. Conference ID: Health Net of California. 

By The Tribune, Seymour, Ind.

Jun. 24–An 87-year-old Columbus woman was hospitalized in critical condition at an Indianapolis hospital Monday after she was injured in a wreck in the Cortland area earlier in the day.

According to a report from Jackson County Officer Adam Nicholson, Mary M. Yeadon underwent surgery for a broken femur at Methodist Hospital in Indianapolis after the wreck, reported in the 6000 block of East County Road 800N at 11 a.m. Monday.

Yeadon was flown from the scene to Indianapolis by Dunn Flight Helicopter Service after she was freed by Hamilton Township volunteer firefighters, using the jaws of life, from the pickup she had been driving.

Yeadon’s 12-year-old and 14-year-old great-granddaughters also were in the vehicle. They were treated by Jackson County Emergency Medical Services personnel and taken to Schneck Medical Center in Seymour. They were later released.

Nicholson was assisted by county Detective Bob Lucas and county Lt. Darin Downs.

Nicholson also investigated a wreck earlier in the day that left a 26-year-old Norman woman complaining of “severe” neck and shoulder pain. That wreck, which involved a Honda passenger car driven by Jane Bair, occurred in the 9300 block of West County Road 750N (Buffalo Pike) in Salt Creek Township.

Bair told police she was driving east on County Road 750N when she swerved to avoid a deer. The vehicle then hit a tree. Two juveniles riding in the vehicle with Bair were not injured in the wreck, reported at 8:41 a.m. Monday, Nicholson said.

Jackson County EMS treated Bair and took her to Schneck Medical Center for treatment. Pershing Township volunteer firefighters also assisted at the scene.

—–

To see more of The Tribune or to subscribe to the newspaper, go to http://www.tribtown.com/.

Copyright (c) 2008, The Tribune, Seymour, Ind.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

SEATTLE, June 24 /PRNewswire/ — A Place for Mom (http://www.aplaceformom.com/) announced today that Breslin Longstreth joined the company as Vice President of Finance. Longstreth will oversee the financial performance of the company, help drive planning, reporting, analysis and company strategy, as well as evaluate new business opportunities to grow revenue.

“Breslin is a seasoned entrepreneur with a strong accounting, finance and technology background,” said Pamala Temple, president and founder of A Place for Mom. “He has lead finance teams at both the Fortune 500 level and the early-stage start-up level. As such he brings broad perspective from the roll-up-your-sleeves requirements of a start up to the strategic and systems work of large-cap companies. Breslin will be instrumental in helping us continue the phenomenal growth of A Place for Mom.”

Longstreth began his career with Arthur Andersen working in the tax, audit and company valuation practices. He received his MBA with honors from the University of Virginia’s Darden Graduate School of Business. He received his bachelor of arts from the University of Washington with a double major in business and accounting and has a CPA. Longstreth spent four years at Oracle as a senior consultant in enterprise software and later joined the start-up company Everyday Wireless, LLC where he held the roles of CFO for four years in addition to acting as Interim CEO.

“A Place for Mom has created a national industry out of helping baby-boomers find appropriate senior care for their aging parents,” said Longstreth. “The hundreds of thousands of families they’ve already helped find assisted living, nursing homes and senior housing is a testament to value of this service. I’m very excited to help A Place for Mom grow and scale this service to meet the needs of the millions of baby-boomers and seniors whose lives will be improved by finding the right senior care solution.”

About A Place for Mom

A Place for Mom is the nation’s largest elder care referral network serving families who are searching for care options for elderly loved ones. A Place for Mom has over 13,000 long-term care communities in its referral network such as assisted living (http://assisted-living.aplaceformom.com/), nursing homes (http://nursing-homes.aplaceformom.com/), Alzheimer’s care (http://alzheimers.aplaceformom.com/), residential care homes (http://residential-care-homes.aplaceformom.com/), retirement communities (http://retirement-communities.aplaceformom.com/), and home care (http://home-care.aplaceformom.com/) providers. Families can review detailed information about their local elder care providers online, and get free personal, professional assistance by telephone from one of 300 local eldercare advisors. A Place for Mom’s referral network of long-term care providers covers more than 3,000 cities in the U.S. For more information, visit http://www.aplaceformom.com/ or call 1-866-333-3110.

A Place for Mom

CONTACT: Sarah Bentz, Marketing Director of A Place for Mom,+1-206-802-1512, mobile, +1-412-225-2310

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

MEDRAD, INC., announced today that its Multi Vendor Service was added to MEDRAD’s ISO 13485:2003 certification, making it one of only two major providers of ultrasound transducer and MRI coil repair services with the certification.

Multi Vendor Service achieved this new certification by demonstrating to the International Organization for Standards (ISO) that it has quality systems in place to ensure high-quality product and repair service.

“This certification, paired with over 40 years of commitment to quality at MEDRAD, affirms our Multi Vendor Service organization’s first-rate repair process to our customers,” said Diane Watson, executive director of Multi Vendor Service. “We are able to accomplish this while providing significant cost savings over OEM offerings.”

ISO 13485:2003, which is closely related to the ISO 9000 standards for quality management systems, is the international standard for the medical device industry. It specifies requirements for quality systems that demonstrate a company’s ability to provide medical devices and related services that consistently meet customer needs and regulatory requirements.

MEDRAD’s Multi Vendor Service team provides OEM-quality repairs for all brands of MRI coils, ultrasound transducers and ultrasound parts in locations around the world. Multi Vendor Service repairs nearly 400 different makes and models of MRI coils and 300 types of ultrasound probes, in addition to providing comprehensive replacement and sourcing capabilities.

About MEDRAD, INC.

MEDRAD, INC., is a worldwide leading provider of medical devices and services that enable and enhance imaging procedures of the human body. Used in diagnostic imaging, MEDRAD’s product offerings include a comprehensive line of vascular injection systems, magnetic resonance (MR) surface coils and patient care products, and equipment services. Total 2007 revenues were $525 million. MEDRAD is a 2003 recipient of the Malcolm Baldrige National Quality Award, the top honor a U.S. company can receive for quality and business excellence. The company’s world headquarters is near Pittsburgh, Pennsylvania, in the United States. MEDRAD is an affiliate of Bayer AG. More company information is available at www.medrad.com.

The Bayer Group is a global enterprise with core competencies in the fields of healthcare, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business operates under the name Bayer Schering Pharma AG. Bayer HealthCare’s aim is to discover and manufacture products that will improve human and animal health worldwide. Find more information at www.bayerhealthcare.com.

Cautionary statement regarding forward-looking statements.

Certain statements in this press release that are neither reported financial results nor other historical information are forward-looking statements, including but not limited to, statements that are predictions of or indicate future events, trends, plans or objectives. Undue reliance should not be placed on such statements because, by their nature, they are subject to known and unknown risks and uncertainties and can be affected by other factors that could cause actual results and MEDRAD’s plans and objectives to differ materially from those expressed or implied in the forward-looking statements. MEDRAD, INC. undertakes no obligation to update publicly or revise any of these forward-looking statements, whether to reflect new information or future events or circumstances or otherwise.

 For additional information contact: Bill Kollitz MEDRAD Multi Vendor Service 412-767-2400 ext. 5060 Email Contact  Dan Dieter MEDRAD Marketing Services 724-940-6949 Email Contact

SOURCE: MEDRAD, INC.

Allscripts, a provider of clinical software, has announced that it will offer qualified medical staff members of Hoag Memorial Hospital Presbyterian in Newport Beach, California, preferred pricing on the company’s Electronic Health Record and Practice Management solutions.

Hoag Hospital, in its commitment to enable better quality care and services, is leveraging the recent Stark and Anti-kickback reforms to assist Orange County physicians in the adoption of Electronic Health Records in their private practices. Hoag believes it is important to promote open, interconnected, interoperable Electronic Health Record applications that help improve the quality of patient care and efficiency in the delivery of health care to patients. To facilitate this, Hoag has signed an agreement with

Allscripts to subsidize its Electronic Health Record and Practice Management (EHR-PM) solutions for independent members of its medical staff, a major step in the hospital’s community-wide initiative to electronically link hospital services, physicians and other healthcare providers to offer truly integrated patient care.

Allscripts Electronic Health Record and Practice Management for small and medium-sized physician practices are easy-to-deploy, physician-centric solutions that improve the delivery of safe, cost-effective, high-quality care by automating common tasks such as prescribing and refilling medications, ordering and viewing tests, and documenting care.

Kemeta, LLC, an innovative, palm-sized breath sensor company, today announced the successful completion of the first clinical testing of their Fat Burn Monitor. In a single exhaled breath, an individual can simply and cost-effectively monitor their rate of fat metabolism using the Kemeta palm-sized breath analyzer. The clinical testing was performed in collaboration with Dr. John Hernried at the Obesity Treatment Center Medical Group (OTCMG) in Sacramento, Calif.

The 11-week IRB-approved study showed that individuals can receive an immediate indication of their fat burn rate by simply blowing into the Kemeta device. The device functions by measuring the concentration of the chemical acetone in the breath. Acetone is produced as fat is metabolized in the body. The simple non-invasive acetone measurement allows the user to track the success of their weight management program.

Dr. Barb Landini, Kemeta VP of RD & Clinical Testing, said, “This initial study with the OTCMG indicates the efficacy of our technology. The ability to successfully measure breath acetone using a simple palm-sized device is a significant achievement.”

“We were pleased with the success of this study. The Kemeta product allows our patients to monitor their daily progress, providing the needed immediate feedback to keep them motivated to continue their weight management regimen,” stated Dr. John Hernried, OTCMG Medical Director and Principal.

The study also showed greater than 90% correlation of the Fat Burn Monitor to the Gas Chromatograph, an industry standard bench-top tool used for breath analysis. The Kemeta product will be available in 2009.

About The Kemeta Company

Kemeta is a privately held business headquartered in Mesa, Ariz. Kemeta is focused on the commercialization of palm-sized analyzers for detection and monitoring of biomarkers in the breath. Visit www.kemeta.com for more information.

About The Obesity Treatment Center Medical Group

OTCMG is a privately held business headquartered in Sacramento, Calif., with three offices in Northern California. OTC uses long-term behavioral therapy combined with a medically supervised diet to help obese patients lose and maintain their weight, treating obesity as a chronic disease of abnormal energy storage and not a lack of willpower. Visit www.keepitoff.com for additional information.

RIDGEFIELD, Conn., June 24 /PRNewswire/ — Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) granted approval of Aptivus(R) (tipranavir) capsules/oral solution with dosing information for treatment-experienced pediatric patients between the ages of 2-18 infected with HIV-1. The oral solution formulation, which is a new dosage form of APTIVUS, was also approved for treatment-experienced adults. The oral solution formulation will be available in the U.S. beginning in mid-September. The FDA granted full (traditional) approval to APTIVUS capsules for treatment-experienced adults in October 2007.

“Due to significant advances in HIV therapy and care, many perinatally infected children are growing into young adulthood and beyond. Most of these children have received multiple courses of anti-HIV medications and many have evidence that their HIV strains have developed resistance to the majority of currently approved antiretrovirals. An unmet need remains for pediatric indications and new formulations of antiretroviral therapies,” said Dr. Juan Salazar, Associate Professor in Pediatrics, University of Connecticut’s Department of Pediatrics, Division of Pediatric Infectious Diseases, and Director of the Pediatric and Youth HIV Program at the Connecticut Children’s Medical Center. “This approval is an important development for treatment-experienced children and teenagers who may have limited therapeutic options.”

APTIVUS Indications and Usage

APTIVUS, a protease inhibitor co-administered with ritonavir (APTIVUS/r), is indicated for combination antiretroviral treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/r of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients age 2 to 18 years. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with APTIVUS/r:

— The use of APTIVUS/r in treatment-naive patients is not recommended.

— The use of other active agents with APTIVUS/r is associated with a greater likelihood of treatment response.

— Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/r. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/r.

— Use caution when prescribing APTIVUS/r to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment.

— Liver function tests should be performed at initiation of therapy with APTIVUS/r and monitored frequently throughout the duration of treatment.

— The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use.

— Use caution when prescribing APTIVUS/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding.

— The risk-benefit of APTIVUS/r has not been established in pediatric patients less than 2 years of age.

There are no study results demonstrating the effect of APTIVUS/r on clinical progression of HIV-1.

APTIVUS/r does not cure HIV or help prevent passing HIV to others.

According to Centers for Disease Control and Prevention (CDC) data for 33 states, an estimated 8,545 children and adolescents under the age of 20 were living with HIV/AIDS in the U.S. at the end of 2006.(1) The estimated number of 13 to 19-year-olds living with HIV/AIDS increased by 28 percent from 2003 to 2006.(1)

APTIVUS/r has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naive patients), with baseline HIV-1 RNA of at least 1,500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs.

All patients initially received APTIVUS oral solution. Pediatric patients who were 12 or older and received the maximum dose of 500/200 mg twice daily could subsequently change to APTIVUS capsules at day 28. The trial primarily compared two doses for safety and tolerability based on adverse events and laboratory findings, and secondarily evaluated pharmacokinetics and virologic and immunologic response and time to treatment failure at 48 weeks.

Based on the results, the recommended pediatric dose of APTIVUS for both capsules and oral solution is 14 mg/kg with 6 mg/kg ritonavir, or 375 mg/m2 co-administered with ritonavir 150 mg/m2, taken twice daily. A greater proportion of patients receiving this dose achieved a viral load of less than 400 copies/mL. For children who develop intolerance or toxicity and cannot continue with the higher dose, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir, or APTIVUS 290 mg/m2 co-administered with 115 mg/m2 ritonavir, taken twice daily, provided their virus is not resistant to multiple protease inhibitors.

Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily.

At 48 weeks, 40 percent of patients had a viral load of less than 400 copies/mL. The proportion of patients with viral load less than 400 copies/mL tended to be greater (70 percent) in the youngest group of patients, who had less viral resistance at baseline, compared to the older groups (37 percent and 31 percent). Agents approved by the FDA in the past five months were not included in the trial.

The most frequent adverse reactions in pediatric patients were similar to those in adults. Fever, vomiting, cough, rash, nausea and diarrhea were most frequently reported, and rash was reported more frequently in pediatric patients than in adults. The most frequent treatment-emergent laboratory abnormalities were increases in CPK, ALT and amylase.

Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).

“The approval of a new formulation and the pediatric indication demonstrates Boehringer Ingelheim’s commitment to the community and patients with advanced stage HIV,” said Dr. Thor Voigt, Senior Vice President, Medicine and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “APTIVUS oral solution provides physicians and patients with an important treatment option in the fight against HIV/AIDS.”

Important Safety Information for APTIVUS

— APTIVUS/r has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation.

— APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).

— All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/r, and frequently throughout the duration of treatment.

— Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In the RESIST trials, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3 percent (10.9/100 PEY) of patients receiving APTIVUS/r through week 48. In a study of treatment-naive patients, 20.3 percent (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/r through week 48.

— APTIVUS/r is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment.

— The drug-drug interaction potential of APTIVUS/r when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/r use.

— APTIVUS/r is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, midazolam (oral) and triazolam due to the potential for serious and/or life-threatening events or loss of efficacy.

— A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of APTIVUS/r and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing’s syndrome and adrenal suppression. APTIVUS/r should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk.

— Caution should be used when prescribing sildenafil, tadalafil, and vardenafil with APTIVUS/r because concentrations of these drugs may increase. Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations.

— Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentrations.

— Use caution when prescribing APTIVUS/r in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E.

— Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).

— Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in patients receiving APTIVUS/r. In some, rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10 percent of females and in 8 percent of males receiving APTIVUS/r through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5 percent. In an uncontrolled compassionate use program (n=3,920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21 percent. Most of these patients had mild rash and 5 percent had moderate rash. Overall, 3 percent interrupted APTIVUS treatment due to rash and the discontinuation rate for rash was 0.9 percent. Discontinue and initiate appropriate treatment if severe skin rash develops.

— APTIVUS should be used with caution in patients with a known sulfonamide allergy.

— New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

— Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS/r.

— Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. A causal relationship has not been established.

— Treatment with APTIVUS/r has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during APTIVUS/r therapy.

— Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in APTIVUS/r-treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors.

— APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

— Please refer to the complete ritonavir prescribing information for a description of ritonavir contraindications and additional information on precautionary measures.

— In adults, the most frequent adverse reactions (incidence greater than 4 percent) were diarrhea, nausea, fever, vomiting, fatigue, headache, and abdominal pain. In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric patients than in adults.

Please see full Prescribing Information, including boxed WARNINGS, for APTIVUS at http://www.aptivus.com/.

APTIVUS is also approved for the treatment of adult patients in Argentina, Australia, Canada, Finland, Switzerland, Mexico, Iceland, Taiwan and the European Union.

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 135 affiliates in 47 countries and approximately 39,800 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2007, Boehringer Ingelheim posted net sales of US $15.0 billion (10.9 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

   For more information, please visit http://us.boehringer-ingelheim.com/.    References:  

(1) Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2006: Table 8 – Estimated numbers of persons living with HIV/AIDS, by year and selected characteristics, 2003-2006-33 states and 5 U.S. dependent areas with confidential name-based HIV infection reporting. April 1, 2008. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2006report/table8 .htm (due to the length of this URL, please copy and paste into browser). Accessed 21 April 2008.

Boehringer Ingelheim Pharmaceuticals, Inc.

CONTACT: Anna Moses, Communications & Public Relations, BoehringerIngelheim Pharmaceuticals, Inc., +1-203-798-4638, Fax: +1-203-791-6442,[email protected]

Web site: http://us.boehringer-ingelheim.com/http://www.aptivus.com/

Reportlinker.com announces that a new market research report related to the Biotechnologies and Genetics industry is available in its catalogue.

World Molecular Diagnostics Market

http://www.reportlinker.com/p090566/World-Molecular-Diagnostics-Market.html

This report analyzes the worldwide markets for Molecular Diagnostics in Millions of US$. The specific product segments analyzed are Infectious Disease Testing, Pharmacogenomics, and Cancer Screening. The report provides separate comprehensive analytics for the US, Canada, Japan, Europe, Asia-Pacific, and Rest of World. Annual forecasts are provided for each region for the period of 2000 through 2015. The report profiles 103 companies including many key and niche players worldwide such as Abbott Laboratories, Abbott Molecular, Applera Corporation, Celera, Biomerieux, CytoCore Inc., GE Healthcare, Gen-Probe Inc., Genzyme Corporation, Genzyme Genetics, MiraiBio, Inc., Nanogen, Novartis Vaccines & Diagnostics, Inc., QIAGEN N. V, Digene Corporation, Quest Diagnostics Incorporated, Roche Diagnostics, Siemens Healthcare Diagnostics, and Tecan Group Ltd. Market data and analytics are derived from primary and secondary research. Company profiles are mostly extracted from URL research and reported select online sources.

MOLECULAR DIAGNOSTICS MCP-1226

A GLOBAL STRATEGIC BUSINESS REPORT

CONTENTS

I. INTRODUCTION, METHODOLOGY & PRODUCT DEFINITIONS

Study Reliability and Reporting Limitations I-1

Disclaimers I-2

Data Interpretation & Reporting Level I-2

Quantitative Techniques & Analytics I-3

Product Definitions and Scope of Study I-3

Infectious Diseases Testing I-3

Pharmacogenomics I-4

Cancer Screening I-4

II. EXECUTIVE SUMMARY

1. Industry Overview II-1

Global Market Outlook II-1

Molecular Diagnostics – The Fastest Growing Medical

Diagnostic Technology II-1

New Applications Hold Promising Potential II-1

Automated Systems – Prime Target II-2

Infectious Disease Testing Drives the Diagnostics Market II-2

The Future in Store II-3

2. A Review of Medical Diagnostics Market II-4

Clinical Diagnostics Industry – Trends and Tendencies II-4

Table 1: Worldwide In Vitro Diagnostics (IVD) Market (2005 &

2006)- Percentage Breakdown by Value Sales for

Immunochemistry, Diabetes, Clinical Chemistry, Point-of-care

testing, Molecular Diagnostics, Hematology, Coagulation,

Urinalysis, and Others (includes corresponding Graph/Chart) II-5

Table 2: Leading Players in the Worldwide In Vitro

Diagnostics (IVD) Market (2005) – Percentage Breakdown by

Value Sales for Roche Diagnostics, Abbott Laboratories,

Johnson & Johnson, Bayer Diagnostics, Beckman Coulter, Dade

Behring, and Others (includes corresponding Graph/Chart) II-5

Table 3: Leading Players in the Worldwide Molecular

Diagnostics Market (2006) – Percentage Breakdown by Value

Sales for Roche Diagnostics, Chiron, Bayer Diagnostics,

GenProbe, Abbott Laboratories, Becton Dickinson, and Others

(includes corresponding Graph/Chart) II-6

Diagnostic Tests – Classification II-6

Table 4: Leading Players in the Worldwide Genetic Testing

Market (2006) – Percentage Breakdown by Value Sales for Roche

Diagnostics /Affymetrix, Abbott Laboratories, Bio-Rad

Laboratories, and Others(includes corresponding Graph/Chart) II-7

Nucleic Acid Diagnostics Market – An Overview II-7

Molecular Diagnostics – Growth Drivers II-8

Molecular Diagnostics – A Replacement and Enabling Technology II-9

Molecular Diagnostics for Lymphoid Malignancies II-9

3. Competitive Dynamics in the Molecular Diagnostics Market II-10

Key Players and Their Technologies II-10

The Top Tier II-10

Mid-Sized and Small Companies II-10

4. Market Trends & Issues II-12

Market Consolidations on the Way to Integrate in Vivo andin

Vitro Diagnostics II-12

Global Molecular Diagnostics on High Growth Curve II-12

Pharmaceutical Firms Carving Their Niche in Molecular

Diagnostic Market II-12

Towards Tailoring the Right Treatment for the Right Disease II-12

Disease-Specific Molecular Diagnostics to Deliver Improved

Clinical Outcomes II-13

Molecular Diagnostics and Intellectual Property II-13

Business Opportunities in the Offing II-13

Challenges Facing the Molecular Diagnostic Market II-14

Medical Training and Practice Challenges II-14

Shortcomings to Overcome II-14

Limited Reimbursements by Third Party Payers – A Stumbling Block II-15

Hurdles All the Way for Companies Eyeing Molecular Diagnostics II-15

Product Marketing – Key to Commercial Success II-16

Integration of Molecular Diagnostics into Therapeutics II-16

Molecular Diagnostics – Moving from Centralization to

Decentralization II-17

Migrating to Decentralized Format II-17

Going Ahead with Decentralization II-17

5. Product & Technology Overview II-19

Molecular Diagnostics – Definition & Scope II-19

Molecular Diagnostics – Impact on Healthcare II-19

Utility of Molecular Diagnostic Tests II-20

Background of Molecular Diagnostics II-20

Major Molecular Diagnostics Company Products II-20

Major Test Launches in Molecular Diagnostics II-21

Unabated Developments in Molecular Diagnostics Technology II-21

Signal Amplification Technologies II-21

PCR – New Developments II-21

Major Applications of Real-Time PCR II-22

Quantitative Real-Time PCR for Molecular Diagnostics II-22

Signal Detection and Quantification II-22

Quantitative Real-Time RT-PCR Analysis II-23

Applications of Quantitative Real-Time PCR Analysis II-23

Non-PCR Methods II-23

Other Signal Amplification Technologies II-23

DNA Probe Based Products II-23

Direct Detection of Specific Nucleic Acid Sequences II-24

Nucleic Acid Amplification and Detection II-24

DNA Sequencing and Gene Detection II-25

Arrays of Immobilized Probes (DNA Chips) in Gene Detection II-25

RNA Diagnostics II-26

Complementary Molecular Diagnostic Technologies II-26

Fluorescent in situ hybridization (FISH) II-26

DNA Biochips / Microarrays II-26

Biosensors II-27

Proteomic Technologies for Molecular Diagnostics II-28

Nanotechnology for Molecular Diagnostics II-28

Technologies on the Anvil II-29

Haplotype Analysis – A Distant Possibility II-29

Chronic Multi-Gene Defects Now Diagnosable II-29

6. An Insight into Applications of Molecular Diagnostics II-30

Infectious Diseases Testing II-30

Activity in the Field II-30

Identifying Multidrug Resistance II-31

Infectious Disease Treatment Monitoring II-31

Other Infectious Diseases Applications II-31

Genetic Disease Testing Applications II-31

Pharmacogenomics – Prognosis Based on Genomics II-32

Cancer Screening & Diagnosis II-32

Molecular Tests Lead the Way for Cancer IVD Market Growth II-33

Table 5: Worldwide Cancer Diagnostic Testing Market (2006):

Percentage Breakdown of Value Sales for Immunoassays,

Histology (IHC/ISH), Pap Testing, Flow Cytometry,

Prostate-Specific Antigen, Molecular Assays, and Fecal

Occult Blood Test (includes corresponding Graph/Chart) II-34

Other Testing Applications II-34

7. Product Developments/Introductions II-35

TMD Launches Test for K-ras Mutations in Colorectal Cancer

Patients II-35

CombiMatrix Releases Updated Version of Constitutional

Genetic Array Test II-35

Myriad Introduces TheraGuide 5-FU II-35

CMDX Unveils First HemeScan(TM) Prognostic II-35

CombiMatrix Introduces HemeScan(TM) MDS II-35

Genzyme Rolls Out Two New Molecular Tests II-36

Dade Behring Launches The Quadriga BeFree II-36

BD Diagnostics Introduces The BD Viper System II-36

Genzyme Introduces P53 Mutation Analysis II-36

CombiMatrix Molecular Diagnostics Rolls Out A New Melanoma Test II-36

Qiagen Launches Fast Cycling PCR Product Line II-36

Genzyme Releases Molecular Assay for Colorectal Cancer Patients II-36

Roche Diagnostics Launches LightCycler 480 System II-37

Roche Diagnostics Introduces AmpliChip CYP450 Test II-37

SEQUENOM Unveils iPLEX(TM) II-37

SEQUENOM Develops a Novel Process II-37

Cerner Corp Develops Cerner Millennium(R) PathNet Helix(TM) II-37

Roche Diagnostics Launches Amplicor HPV Test II-37

Gen-Probe Launches Procleix Ultrio Assay in Europe II-37

Gen-Probe Launches TIGRIS(R)DTS(TM) System II-38

BD Biosciences Introduces BD QZyme(TM) Assay II-38

Epoch Biosciences Releases MGB Eclipse(TM) II-38

QIAGEN Unveils BioRobot MDx DSP Device II-38

Digene Unveils DNAwithPap II-38

Exact Sciences Launches Non-Invasive Test for Colorectal Cancer II-38

TDT Introduces GCC-B1 Blood Test to Detect Colorectal Cancer II-38

AcroMetrix Joins Hands with Nabi to Introduce ViroSure II-39

Orchid Cellmark Introduces DNA Express Service II-39

Roche Develops New IVD Real-Time PCR Instrument II-39

Nanogen Rolls Out First Ever ASR II-39

Digene Introduces Hybrid Capture II-39

Digene’s Hybrid Capture 2 HPV DNA Test to Effectively

Identify Cervical Cancer II-39

PGD to Eliminate Human Eggs Affected with Alzheimer’s Disease II-40

Esoterix Introduces New HCV Testing Program II-40

Gen-Probe Releases New APTIMA Combo 2 Assay II-40

Nycomed’s NeoSpect to Identify Suspected Lung Cancer II-40

DNAPrint Introduces New Services to Assist Forensic Market II-40

IMBG Develops an Efficient Procedure to Treat Diseases II-41 8. Recent Industry Activity II-42

Vermillion, Johns Hopkins Ink Agreements to Develop Molecular

Diagnostic Tests II-42

Beckman Coulter Inks Licensing Agreements with National

University of Ireland II-42

Roche Takes over BioVeris II-42

Siemens Acquires Dade Behring II-42

DiagnoCure Acquires Catalyst Oncology II-42

Burrill & Co Takes over Expression Diagnostics II-43

Solis Acquires Bertrand II-43

ParagonDx LLC Purchases Gentris Diagnostics II-43

Beckman Collaborates to Discover CVD Symptoms II-43

Exiqon to Take over Oncotech II-43

Roche to Acquire Ventana II-43

Qiagen Merges with Digene II-44

Qiagen & Bio One Capital Collaborates II-44

AGT & MAL Signs MoU II-44

Qiagen Obtains Licenses to Real-Time PCR II-44

Cepheid Purchases Sangtec II-44

Source MDx Collaborates with Pfizer II-45

Nanosphere Receives FDA Clearance for Second Molecular

Diagnostic Test II-45

QIAGEN Acquires eGene II-45

Quest Diagnostics Acquires AmeriPath II-45

Mayo and ILMN Team up to Develop Molecular Diagnostics for

Complex Diseases II-45

CHEO and ILMN Team up to Develop Molecular Diagnostics for

Newborn Screening II-45

Siemens Medical Solutions USA Sets Up Siemens Medical

Solutions Diagnostics II-46

Novartis Acquires Chiron II-46

Quest Diagnostics Acquires Focus Diagnostics II-46

Becton Dickinson Acquires GeneOhm II-46

Iris International Acquires Leucadia Technologies II-46

Predicant Biosciences Acquires Pathwork Informatics II-46

AmeriPath Acquires Rose Pathology Associates II-46

Nanogen Acquires Amplimedical’s Diagnostics Division II-47

Nanogen Acquires Immunoassay Test Business of Spectral

Diagnostics II-47

Fisher Scientific Acquires Athena II-47

Qiagen Acquires Genaco II-47

Bio-Rad Acquires Blackhawk BioSystems II-47

IRIS International Acquires Leucadia Technologies II-47

Qiagen Acquires Shenzhen PG Biotech II-47

Qiagen Acquires Artus GmbH II-48

Nanogen and Fisher Increases Agreement Tenure II-48

Qiagen Signs An Agreement with Gentra II-48

Qiagen Inks an Agreement with VLA II-48

Stratagene Signs an Agreement with AROS II-48

Bayer Inks an Agreement with Hamilton Company II-48

Prodesse and Invitrogen Sign a Pact II-49

Illumina Forms Collaboration with ReaMetrix II-49

PerkinElmer Signs an Agreement with Jacobi Medical II-49

UniPath and Roche Diagnostics Sign an Accord II-49

Qiagen Alliances with Eppendorf II-49

Olympus and Cangen Extends their Research Collaboration II-49

Toppan, Shimadzu and Third Wave Collaborate to Develop A POC

Molecular Diagnostic Instrument II-50

Focus Diagnostics Signs an Agreement with Stratagene II-50

Innogenetics Inks an Agreement with Roche Diagnostics II-50

The University of Goettingen, Bruker Daltonik and PANATecs

Collaborate to Develop New Molecular Diagnostic Assays for

Rheumatoid Arthritis II-50

Focus Diagnostics Enters into an Agreement with Luminex II-50

QIAGEN Expands Strategic Alliance with Protedyne II-51

Specialty Laboratories Teams Up with SEQUENOM and Siemens II-51

Gen-Probe Enters into a Licensing Agreement with Corixa II-51

Gen-Probe Inks a Supply and Purchase Agreement with F.

Hoffmann-La Roche II-51

Gen-Probe Enters into a Licensing Agreement with AdnaGen II-51

Roche Establishes New Polymerase Chain Reaction (PCR)

Manufacturing Center II-52

Ambion Establishes a Subsidiary in Japan II-52

Gen-Probe Gains FDA Approval for APTIMA(R) II-52

Blood Center of Southeastern Wisconsin Adopts Ambion’s

Signature(TM) CF 2.0 ASR II-52

Orchid Biosciences, Inc. Becomes Orchid Cellmark Inc II-52

Roche Acquires IGEN International II-52

GE Takes Over Amersham Plc II-52

Nanogen Acquires SYNX PHARMA II-53

Nanogen Merges with Epoch Biosciences II-53

Sequenom Enters into Collaboration with Siemens II-53

TMD Joins Hands with University of Texas II-53

GE Global and Two other Companies Enters into a Joint

Research Collaboration II-53

Third Wave and BML Extend Partnership to Promote Molecular

Diagnostic Tests II-53

ViroLogic Signs an Agreement with ACLARA II-53

Abbott and BioGenex Sign an Agreement II-54

Novation Signs a Pact with Bayer Diagnostics II-54

Osmetech Enters into a Licensing Agreement with LGC Limited II-54

Licensing Agreement between DxS Ltd and Sangtec Molecular

Diagnostics II-54

EraGen Biosciences Strikes a Deal with Inter Medico II-54

Nanogen Bags Patent for Molecular Diagnostics and Optical

Waveguides Systems II-54

Gen-Probe Secures Regulatory Approval for PROCLEIX (R) ULTRIO(TM)

Assay II-55

Gen-Probe Bags FDA Approval to Use TIGRIS DTS System for STD

Testing II-55

Gen-Probe Acquires Majority Stake in MLT II-55

AmeriPath in Strategic Alliance with Roche II-55

Abbott and Promega to Offer Nucleic Acid Extraction Products II-55

Ambion RNA to Offer Services Through BBI II-55

STMicroelectronics Inks an Agreement with Mobidiag II-56

BBI Contracts with IDS II-56

Focus to Assist FDA in Evaluation of Antimicrobial Resistance II-56

Bayer Acquires Rights to Detect HCV and HIV Antibodies II-56

Cenetron in Strategic Alliance with Roche II-56

Saint Luke’s Health System in Alliance with Roche II-56

US LABS Adds Gene Expression Profiling Capabilities on (FFPE)

Tissue II-57

Bayer Acquires Visible Genetics II-57

Qiagen Enters into an Agreement with RMS II-57

Dabur Starts a New Molecular Diagnostic Lab II-57

Roche Gains Rights for Cervical-Cancer Testing Market II-57

Ventana Acquires License From MDI II-58

Genzyme Genetics Gains Rights for Genzyme Molecular’s Cancer

Diagnostics II-58

Abbott in Strategic Alliance with Celera II-58

MDI and DiagnoCure Join Hands to Integrate ImmunoCyt/uCyt

with InPath II-58

MDI and PMI to Jointly Promote Lung Cancer Detection System II-58

MDI in Agreement with Esoterix II-59

MDI to Expand Product Base in China II-59

Abbott and Tecan to Offer Devices for Molecular Diagnostic

Assays II-59

Invirion Extends Licensing Agreement with MDI II-59

Ambion RNA Grants License to Celera II-59

Morewood and IT&M to Introduce New Micro Array System II-59

Ambion RNA Constructs New Manufacturing Facility II-60

LabCorp Teams up with Celera II-60

Athena Launches New DNA Testing for TSC II-60

Genezyme Genetics Expands Cancer Testing Services II-60

Promega Teams Up with Abbott II-60

ChromaVision and Ventana Join Hands to Market Testing Process

that Identifies HPV II-60

OraSure in Agreement with Abbott II-61

Nanogen and Bionomics to Jointly Develop IVD for Epilepsy II-61

DiagnoCure and Compugen Join Hands to Develop Tests to

Identify Epithelial Cancers II-61

OraSure Gets FDA Approval for OraQuick Rapid HIV-1 Test II-61

Ampersand and Accumed Merged to Form MDI II-61

Abbott Acquires Vysis II-61

Millennium and Abbott Forge 5-Year Drug Deal II-62

Bode Enters into Agreement to Undertake DNA Testing II-62

BD Contracts with TriPath to Develop Molecular Diagnostics II-62

TriPath Installs New Interactive System II-62

Archemix in Strategic Alliance with RPI II-62

AmeriPath Strengthens Relationship with Genomics Collaborative II-63

Cepheid and Infectio Join Hands to Form Aridia II-63

Myriad Enters into Agreement with NCI II-63

Nanogen Gains Further Rights for Electronic Microarray Technology II-63

9. Focus on Select Global Players II-64

Abbott Laboratories (US) II-64

Abbott Molecular II-64

Applera Corporation (US) II-64

Celera (US) II-64

Biomerieux (France) II-65

CytoCore Inc (US) II-65

GE Healthcare (US) II-66

Gen-Probe Inc (US) II-66

Genzyme Corporation (US) II-66

Genzyme Genetics (US) II-67

MiraiBio, Inc. (US) II-67

Nanogen (US) II-67

Novartis Vaccines & Diagnostics, Inc. (US) II-67

QIAGEN N. V (The Netherlands) II-68

Digene Corporation (USA) II-68

Quest Diagnostics Inc. (US) II-69

Roche Diagnostics (Switzerland) II-69

Siemens Healthcare Diagnostics (US) II-69

Tecan Group Ltd. (Switzerland) II-70

10. Global Market Perspective II-71

Table 6: World Recent Past, Current & Future Market Analysis

for Molecular Diagnostics by Geographic Region – US, Canada,

Japan, Europe, Asia-Pacific (excluding Japan) and Rest of

World Independently Analyzed with Annual Sales Figures in US$

Million for Years 2000 through 2010 (includes corresponding

Graph/Chart) II-71

Table 7: World Long-term Projections for Molecular Diagnostics

by Geographic Region – US, Canada, Japan, Europe, Asia-Pacific

(excluding Japan) and Rest of World Independently Analyzed

with Annual Sales Figures in US$ Million for Years 2011

through 2015 (includes corresponding Graph/Chart) II-72

Table 8: World 10-Year Perspective for Molecular Diagnostics

by Geographic Region – Percentage Breakdown of Dollar Sales

for US, Canada, Japan, Europe, Asia-Pacific (excluding Japan)

and Rest of World Markets for Years 2003, 2008 & 2012(includes

corresponding Graph/Chart) II-73

Table 9: World Recent Past, Current & Future Market Analysis

for Molecular Diagnostics (Infectious Disease Testing) by

Geographic Region – US, Canada, Japan, Europe, Asia-Pacific

(excluding Japan), and Rest of World Independently Analyzed

with Annual Sales Figures in US$ Million for Years 2000

through 2010 (includes corresponding Graph/Chart) II-74

Table 10: World Long-term Projections for Molecular

Diagnostics (Infectious Disease Testing) by Geographic Region – US, Canada, Japan, Europe, Asia-Pacific (excluding Japan),

and Rest of World Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2011 through 2015 (includes

corresponding Graph/Chart) II-75

Table 11: World 10-Year Perspective for Molecular Diagnostics

(Infectious Disease Testing) by Geographic Region – Percentage

Breakdown of Dollar Sales for US, Canada, Japan, Europe,

Asia-Pacific (excluding Japan), and Rest of World Markets for

Years 2003, 2008 & 2012 (includes corresponding Graph/Chart) II-76

Table 12: World Recent Past, Current & Future Market Analysis

for Molecular Diagnostics (Pharmacogenomics) by Geographic

Region – US, Canada, Japan, Europe, Asia-Pacific (excluding

Japan), and Rest of World Independently Analyzed with Annual

Sales Figures in US$ Million for Years 2000 through 2010

(includes corresponding Graph/Chart) II-77

Table 13: World Long-term Projections for Molecular

Diagnostics (Pharmacogenomics) by Geographic Region – US,

Canada, Japan, Europe, Asia-Pacific (excluding Japan), and

Rest of World Independently Analyzed with Annual Sales Figures

in US$ Million for Years 2011 through 2015 (includes

corresponding Graph/Chart) II-78

Table 14: World 10-Year Perspective for Molecular Diagnostics

(Pharmacogenomics) by Geographic Region – Percentage Breakdown

of Dollar Sales for US, Canada, Japan, Europe, Asia-Pacific

(excluding Japan), and Rest of World Markets for Years 2003,

2008 & 2012 (includes corresponding Graph/Chart) II-79

Table 15: World Recent Past, Current & Future Market Analysis

for Molecular Diagnostics (Cancer Screening) by Geographic

Region – US, Canada, Japan, Europe, Asia-Pacific (excluding

Japan), and Rest of World Independently Analyzed with Annual

Sales Figures in US$ Million for Years 2000 through 2010

(includes corresponding Graph/Chart) II-80

Table 16: World Long-term Projections for Molecular

Diagnostics (Cancer Screening) by Geographic Region – US,

Canada, Japan, Europe, Asia-Pacific (excluding Japan) and

Rest of World Independently Analyzed with Annual Sales Figures

in US$ Million for Years 2011 through 2015 (includes

corresponding Graph/Chart) II-81

Table 17: World 10-Year Perspective for Molecular Diagnostics

(Cancer Screening) by Geographic Region – Percentage Breakdown

of Dollar Sales for US, Canada, Japan, Europe, Asia-Pacific

(excluding Japan), and Rest of World Markets for Years 2003,

2008 & 2012 (includes corresponding Graph/Chart) II-82

III. MARKET

1. United States III-1

A.Market Analysis III-1

A Precursor to the Molecular Diagnostics Market in the US III-1

Molecular Diagnostics Heavily Tied to Proteomics and Genomics III-1

Burgeoning Potential for Genetic Testing III-1

Regulatory Environment III-2

Regulations Out for Molecular Diagnostic Testing of HPV III-2

Limited Reimbursements – A Major Hindrance III-3

Key Players III-3

Product Launches III-7

Strategic Developments III-12

B.Market Analytics III-29

Table 18: US Recent Past, Current & Future Analysis for

Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-29

Table 19: US Long-term Projections for Molecular Diagnostics

by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets Independently

Analyzed with Annual Sales Figures in US$ Million for Years

2011 through 2015 (includes corresponding Graph/Chart) III-29

Table 20: US 10-Year Perspective for Molecular Diagnostics

by Product Segment – Percentage Breakdown of Dollar Sales

for Infectious Disease Testing, Pharmacogenomics, andCancer

Screening Markets for 2003, 2008 & 2012(includes

corresponding Graph/Chart) III-30

2. Canada III-31

A.Market Analysis III-31

Strategic Developments III-31

B.Market Analytics III-32

Table 21: Canadian Recent Past, Current & Future Analysis

for Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-32

Table 22: Canadian Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart III-32

Table 23: Canadian 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-33

3. Japan III-34

A.Market Analysis III-34

Strategic Developments III-34

B.Market Analytics III-35

Table 24: Japanese Recent Past, Current & Future Analysis

for Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-35

Table 25: Japanese Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets Independently

Analyzed with Annual Sales Figures in US$ Million for Years

2011 through 2015 (includes corresponding Graph/Chart) III-35

Table 26: Japanese 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-36

4. Europe III-37

A.Market Analysis III-37

Insight into Molecular Diagnostics Markets in Europe III-37

Table 27: European Molecular Diagnostics Market (2006) –

Market Shares of Leading Players by Value Sales for Roche

Diagnostics, Abbott Diagnostics, Bayer Diagnostics, Becton

Dickinson, Digene Diagnostics, BioMerieux and Others

(includes corresponding Graph/Chart) III-38

Product Launches III-38

B.Market Analytics III-39

Table 28: European Recent Past, Current & Future Analysis

for Molecular Diagnostics by Geographic Region – France,

Germany, Italy, UK, and Rest of Europe Markets Independently

Analyzed with Annual Sales Figures in US$ Million for Years

2000 through 2010 (includes corresponding Graph/Chart) III-39

Table 29: European Long-term Projections for Molecular

Diagnostics by Geographic Region – France, Germany, Italy,

UK, and Rest of Europe Markets Independently Analyzed with

Annual Sales Figures in US$ Million for Years 2011 through

2015 (includes corresponding Graph/Chart) III-40

Table 30: European Recent Past, Current & Future Analysis

for Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-40

Table 31: European Long-term Projections for

Molecular(includes corresponding Graph/Chart) Diagnostics by

Product Segment -Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart) III-41

Table 32: European 10-Year Perspective for Molecular

Diagnostics by Geographic Region – Percentage Breakdown of

Dollar Sales for France, Germany, Italy, UK, and Rest of

Europe Markets for 2003, 2008 & 2012 (includes

corresponding Graph/Chart) III-41

Table 33: European 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-42

4a. France III-43

A.Market Analysis III-43

bioMerieux – A Key French Player III-43

Strategic Development III-43

B.Market Analytics III-44

Table 34: French Recent Past, Current & Future Analysis for

Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-44

Table 35: French Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart) III-44

Table 36: French 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-45

4b. Germany III-46

Market Analysis III-46

Table 37: German Recent Past, Current & Future Analysis for Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-46

Table 38: German Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart) III-47

Table 39: German 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-47

4c. Italy III-48

Market Analysis III-48

Table 40: Italian Recent Past, Current & Future Analysis for

Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-48

Table 41: Italian Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart) III-49

Table 42: Italian 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-49

4d. United Kingdom III-50

A.Market Analysis III-50

Product Launch III-50

Strategic Development III-50

B.Market Analytics III-51

Table 43: UK Recent Past, Current & Future Analysis for

Molecular Diagnostics by Product Segment – Infectious

Disease Testing, Pharmacogenomics, and Cancer Screening

Markets Independently Analyzed with Annual Sales Figures in

US$ Million for Years 2000 through 2010 (includes

corresponding Graph/Chart) III-51

Table 44: UK Long-term Projections for Molecular Diagnostics

by Product Segment – Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes corresponding

Graph/Chart) III-51

Table 45: UK 10-Year Perspective for Molecular Diagnostics

by Product Segment – Percentage Breakdown of Dollar Sales

for Infectious Disease Testing, Pharmacogenomics, and

Cancer Screening Markets for 2003, 2008 & 2012 (includes

corresponding Graph/Chart) III-52

4e. Rest of Europe III-53

A.Market Analysis III-53

Key Players III-53

Product Launches III-54

Strategic Developments III-55

B.Market Analytics III-58

Table 46: Rest of Europe Recent Past, Current & Future

Analysis for Molecular Diagnostics by Product Segment –

Infectious Disease Testing, Pharmacogenomics, and Cancer

Screening Markets Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2000 through 2010

(includes corresponding Graph/Chart) III-58

Table 47: Rest of Europe Recent Past, Current & Future

Analysis for Molecular Diagnostics by Product Segment –

Infectious Disease Testing, Pharmacogenomics, and Cancer

Screening Markets Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2011 through 2015

(includes corresponding Graph/Chart) III-58

Table 48: Rest of Europe 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-59

5. Asia-Pacific III-60

A.Market Analysis III-60

Indian Diagnostic Market III-60

Strategic Developments III-60

B.Market Analytics III-61

Table 49: Asia-Pacific Recent Past, Current & Future

Analysis for Molecular Diagnostics by Product Segment –

Infectious Disease Testing, Pharmacogenomics, and Cancer

Screening Markets Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2000 through 2010

(includes corresponding Graph/Chart) III-61

Table 50: Asia-Pacific Recent Past, Current & Future

Analysis for Molecular Diagnostics by Product Segment –

Infectious Disease Testing, Pharmacogenomics, and Cancer

Screening Markets Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2011 through 2015

(includes corresponding Graph/Chart) III-62

Table 51: Asia-Pacific 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-62

6. Rest of World III-63

Market Analysis III-63

Table 52: Rest of World Recent Past, Current & Future

Analysis for Molecular Diagnostics by Product Segment –

Infectious Disease Testing, Pharmacogenomics, and Cancer

Screening Markets Independently Analyzed with Annual Sales

Figures in US$ Million for Years 2000 through 2010

(includes corresponding Graph/Chart) III-63

Table 53: Rest of World Long-term Projections for Molecular

Diagnostics by Product Segment – Infectious Disease

Testing, Pharmacogenomics and Cancer Screening Markets

Independently Analyzed with Annual Sales Figures in US$

Million for Years 2011 through 2015 (includes

corresponding Graph/Chart) III-64

Table 54: Rest of World 10-Year Perspective for Molecular

Diagnostics by Product Segment – Percentage Breakdown of

Dollar Sales for Infectious Disease Testing,

Pharmacogenomics, and Cancer Screening Markets for 2003,

2008 & 2012 (includes corresponding Graph/Chart) III-64

IV. COMPETITIVE LANDSCAPE

To order this report:

World Molecular Diagnostics Market

http://www.reportlinker.com/p090566/World-Molecular-Diagnostics-Market.html

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 Contacts: Reportlinker.com Nicolas (718) 887-3024 Email: [email protected]

SOURCE: Reportlinker.com

Crown Philanthropic Solutions, LLC (www.crownps.com), an innovative provider of technology solutions for the financial services and nonprofit space, is pleased to announce it has been selected to provide the Web-based interface and administrative solution for the Renaissance Charitable Giving Fund (www.rcgf.org), a $160 million donor advised fund sponsored by the Renaissance Charitable Foundation.

This comes on the heels of Crown Philanthropic Solutions’ recent introduction of a totally new approach to traditional donor-advised fund (DAF) technology, and one that for the first time empowers donors and sponsors with the expanded functionality and engagement capabilities that donors have been looking for. “We are excited to be selected by Renaissance and consider it a tribute to our corporate vision of enhanced donor engagement that an organization with their experience in the charitable planning space has elected to provide our program to their donors,” remarked Crown CEO Ephy Torenberg.

“I believe that our adoption of the Crown DonorFirst(TM) platform for our donor advised fund program will provide our advisors and donors with the type of leading edge solutions and service they have come to expect from Renaissance,” noted Elizabeth Packer Bassett, CEO of Renaissance. “The DonorFirst(TM) platform offers a highly efficient workflow capability and an integrated Guidestar charity verification for our staff; the online technology our advisors need to guide their clients from financial success to personal significance. The system also supports levels of family collaboration previously available only within private foundation sponsors.”

Recognized as the fastest growing charitable instrument in the country today, donor advised funds (DAFs) have historically been limited in their ability to support the levels of family collaboration, donor-grantee communication, and investment flexibility traditionally demanded by the high net-worth audience. Crown Philanthropic Solutions is the first player in the Internet philanthropic space with an approach that can truly help mobilize the vast amounts of social capital that exist within the nation today.

DAFs enable individuals with philanthropic interests to efficiently manage their charitable giving by allowing them to make an irrevocable contribution of a variety of personal assets (cash, appreciated stocks, bonds, mutual funds, and real estate) at the most advantageous time; claim a tax deduction for the gifts, and then direct contributions from their account to the charity or charities of their choice by recommending a grant distribution from the foundation sponsoring their account.

Crown’s DonorFirst(TM) platform provides a true open architecture capability that was designed to serve a wide range of investment options and donor/advisor preferences. “Coupled with a powerful, private, and secure relationship and collaboration environment, Crown has introduced a solution that supports high net worth donors as they move toward a new, broad-based form of philanthropy, enhancing the overall engagement experience for donors and their families, while simultaneously providing a simple, efficient system for managing basic charitable contributions,” said William H. Hewitt, Crown Philanthropic Solutions’ National Marketing Director. “This evolution from charity to philanthropy is a process that all donors go through as they mature, and as they acquire the kind of wealth which carries with it increased responsibility. The Crown platform not only supports both ends of the continuum, but makes the donors’ path smoother and more accessible than ever before.”

Renaissance, an independent trust administrator with over $2 billion in assets under administration, has been the leader in expanding the concept of social capital since 1987, and has helped design, draft and administer more than 5,000 planned charitable gifts and has even accepted a roller coaster, boats and cattle as charitable donations during their 20 plus years. The organization has trained and supported thousands of donor advisors to help its clients recognize the existence of social capital, and understand how to best put it to use for society and themselves. “We are excited about the potential the Crown DonorFirst(TM) platform offers to support the mobilization of philanthropic capital in the United States,” continued Bassett.

About Crown Philanthropic Solutions, LLC

Crown Philanthropic Solutions, LLC was established in 2005 for the primary purpose of creating a donor advised fund (DAF) solution that is responsive to the expanding needs of the philanthropic and financial services communities. Crown recognized the pressure on both these groups to respond to demands for increased transparency, functionality, and informational flow in their charitable gifting tools and by leveraging advancements in Web technology Crown has created a bridge between the nonprofit and foundation community, financial organizations and donors. The DonorFirst(TM) platform supports both a pooled or mutual fund style investment chassis as well as individually managed accounts, and introduces levels of communication and collaboration within each donor’s account dashboard that have been unavailable in any existing DAF program. To learn more about Crown Philanthropic Solutions, LLC and their DonorFirst(TM) Program please visit (www.crownps.com).

 Media Contact: Carol Graumann JC Public Relations Email Contact 973-784-0064  

SOURCE: Crown Philanthropic Solutions, LLC

To: STATE EDITORS

Contact: Marcel Blanchet of Connecticut Hospice, +1-203-315-7556

BRANFORD, Conn., June 24 /PRNewswire-USNewswire/ — Kristen Michelle Masterson is this year’s Miss Fairfield County. The Connecticut Hospice, birthplace of hospice in America, has supervised Kristens volunteer patient care activities over these last two years, as she been preparing to become a nurse. Her compassion for those that are suffering has been extraordinary, whether she is attending to one of our pediatric patients or to our young or mature adults, said Soozi Flannigan, RN, MSN, Director of Hospice and Co-Director of Education.

(Photo: http://www.newscom.com/cgi-bin/prnh/20080624/DC25950)

This weekend she will be competing in the Miss Connecticut Scholarship Pageant 80th Year Jubilee,June 27th, 2008, which will be held at theGarde Arts Centre325 State St, in New London,Connecticut. Kristens platform is the Connecticut Hospice Program and how important the quality of care is to the patients and their families – – volunteering is her way of giving back to her community, offering a smile, but most importantly holding patients hands. Kristen will tell you that volunteering brings her a great sense of satisfaction. The power of one person to make someones life just a little bit better through kindness, time, and a listening ear is something all of us can do. Kristen knows first hand the importance of quality care for terminally ill patients and their families and what the Connecticut Hospice has to offer not only in Connecticut, but the world.

As Miss Fairfield County, Kristen will continue to educate the public on Hospice Awareness and promote volunteerism. There is a growing need for medical professionals and families to understand what happens during the last weeks, days, and hours of life and what kind of action, or inaction is most likely to bring a comfortable, peaceful, even beautiful, end.

Kristen is a cum laude graduate of the University of Connecticut in Storrs and is currently studying for her masters degree in nursing. The fact that Kristen has chosen the medical field would be of no surprise to anyone who knows her. All her life she has been a people person and centered on the community. From a very young age, Kristen understood the necessity of giving back. As a six year old, she helped feed the homeless and less fortunate at soup kitchens. The seed of volunteerism was planted. As Kristen became older, her involvement grew and took off into a variety of community organizations.

Kristen has also had the privilege of participating in a medical mission trip with the Greenfield Hill Congregational Church. A medical team of 4 doctors along with others traveled to Khammam, India. The village was warm and welcoming, the peoples smiles traversed the language barrier that some had. The team worked in an antiquated hospital where the only air conditioned place was in the operating room. The anesthesia equipment was a relic from the 1930s, the conditions crowded, mosquitoes innumerable, but still miracles happened. The team performed an average of 15 surgeries a day repairing cleft lips and palates, removing tumors, helping burn victims with skin grafts, and other surgeries that the western world often takes for granted. This trip helped solidify Kristens future aspirations in the medical field.

Kristen believes in staying fit and eating healthfully. She is an avid runner and enjoys walking her dog daily. She played competitive soccer for 7 years including varsity soccer at Fairfield High School. She is quite proud of the fact that she ran for the first time in Fairfields Turkey Trot (5 Miles) on Thanksgiving Day, 2007 along with 20,000 other runners from all over. She enjoys Mexican food, a good laugh, and loves to take on new challenges. She is very excited to be a representative for the Miss America Organization because she knows how important it is to have a positive role model in todays society. She is equally prepared to advocate for something she is genuinely passionate about, and will forever hold dear to her heart, hospice awareness.

SOURCE The Connecticut Hospice

(c) 2008 U.S. Newswire. Provided by ProQuest Information and Learning. All rights Reserved.

By John Trumbo, Tri-City Herald, Kennewick, Wash.

Jun. 24–The fall of the gavel and cry of “sold” will mark the end of a family history at the Sal-Jo Ranch in Kennewick this week.

The historic George Austin Jr. home overlooking the Tri-Cities is being offered to the highest bidder at an auction Thursday evening.

Bidding for the 2,963-square-foot brick and timber ranch house where Sallie McMillin and Joan Bell grew up on 17.2 acres will begin at $100,000 but is expected to climb to many times that.

“The nice thing about an auction is there is no ceiling,” said Scott Musser of Kennewick-based Musser Bros. Auction, which is handling the sale. He said the family decided an auction would be the best way to sell one of the most unique properties in the Tri-Cities because there is no easy way to estimate a selling price.

The house is being offered for sale for the first time since it was built on the banks of the Columbia River 75 years ago. As of Wednesday, it had attracted 58 potential buyers, Musser said.

The great flood of 1948 prompted Austin and his wife, Johanna, to move the home a few years later to its current perch above 45th Avenue at Ely Street. The seven-mile move cost $6,000, which was double what it cost to build the place in the mid-1930s.

The original home has been enlarged over the years to have four bedrooms, 3.75 baths, a large recreation room, a spacious living room with picturesque windows and a four-car garage. There’s also a swimming pool, a 10-stall horse barn and a wide-angle view that sweeps from the Blue Mountains on the east to the western horizon somewhere beyond the Hanford reservation.

McMillin told the Herald last year that the house hasn’t seen much activity since her mother, twice-widowed Johanna Colby, died in September 2006.

She’d like to see the property sell for a good price — $2 million would be nice — but tries not to think about what will happen to the house that has provided so many memories.

“With mom and dad gone, it’s not a home anymore. It’s just a house,” she said.

The accompanying 17 acres are prime real estate for development, so it wouldn’t surprise her to see the family home razed for new construction.

Musser said anyone interested in bidding should bring a $50,000 bank check.

Bidder registration for the auction will begin at 5 p.m. Thursday, with the sale to start at 7 p.m.

—–

To see more of the Tri-City Herald, or to subscribe to the newspaper, go to http://www.tri-cityherald.com.

Copyright (c) 2008, Tri-City Herald, Kennewick, Wash.

Distributed by McClatchy-Tribune Information Services.

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By de Seny, Dominique Fillet, Marianne; Ribbens, Clio; Maree, Raphael; Meuwis, Marie-Alice; Lutteri, Laurence; Chapelle, Jean-Paul; Wehenkel, Louis; Louis, Edouard; Merville, Marie-Paule; Malaise, Michel

BACKGROUND: SELDI-TOF mass spectrometry (MS) is a high- throughput proteomic approach with potential for identifying novel forms of serum biomarkers of arthritis. METHODS: We used SELDI-TOF MS to analyze serum samples from patients with various forms of inflammatory arthritis. Several protein profiles were collected on different Bio-Rad Laboratories ProteinChip arrays (CM10 and IMAC- Cu^sup 2+^) and were evaluated statistically to select potential biomarkers.

RESULTS: SELDI-TOF MS analyses identified several calgranulin proteins [S100A8 (calgranulin A), S100A9 (calgranulin B), S100A9*, and S100A12 (calgranulin C)], serum amyloid A (SAA), SAA des-Arg (SAA-R), and SAA des-Arg/des-Ser (SAA-RS) as biomarkers and confirmed the results with other techniques, such as western blotting, immunoprecipitation, and nano-LC-MS/MS. The S100 proteins were all able to significantly differentiate samples from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from those of patients with inflammatory bowel diseases used as an inflammatory control (IC) group, whereas the SAA, SAA-R, and SAA-RS proteins were not, with the exception of AS. The 4 S100 proteins were coproduced in all of the pathologies and were significantly correlated with the plasma calprotectin concentration; however, these S100 proteins were correlated with the SAA peak intensities only in the RA and IC patient groups. In RA, these S100 proteins (except for S100A12) were significantly correlated with the serum concentrations of C-reactive protein, matrix metalloproteinase 3, and anti-cyclic citrullinated peptide and with the Disease Activity Score (DAS^sub 28^).

CONCLUSIONS: The SELDI-TOF MS technology is a powerful approach for analyzing the status of monomeric, truncated, or posttranslationally modified forms of arthritis biomarkers, such as the S100A8, S100A9, S100A12, and SAA proteins. The fact that the SELDITOF MS data were correlated with results obtained with the classic calprotectin ELISA test supports the reliability of this new proteomic technique.

(c) 2008 American Association for Clinical Chemistry

Members of the S100 protein family are acidic proteins of low molecular mass characterized by cell type-specific production and the presence of 2 EF-hand calcium-binding domains (1). Of these proteins, S100A8 (also known as myeloid-related protein 8 and calgranulin A), S100A9 (myeloid-related protein 14, calgranulin B), and S100A12 (calgranulin C) have prompted particular interest among rheumatologists because they are valuable markers of phagocyte activation (2). The secretion of S100A8 and S100A9 by neutrophils and macrophages is stimulated during these cells’ interaction with activated endothelial cells (3, 4). A hallmark of the S100A8 and S100A9 proteins is to form dimers, with a heterodimer-homodimer ratio of about 10:1 (5,6). The S100A8/(S100A9)2 heterotrimer, better known as calprotectin, has a mass of 36.5 kDa, although trimer formation has never been confirmed by nuclear magnetic resonance analysis (5, 7). Nevertheless, the term calprotectin continues to be used to refer to the S100A8/S100A9 heterocomplex, and the ELISA technique has almost been used almost exclusively to quantify calprotectin status in disease states. Finally, tetramers (S100A8/ S100A9)^sub 2^ have also been described (8). In inflammatory conditions, S100A8 and S100A9 are produced independently; however, only S100A9 is found in acute inflammatory conditions such as gingivitis, with the production of S100A8 being restricted to chronic inflammation (9). Increased production of S100A8 and S100A9 has been observed in serum, synovial fluid, and synovium samples for many inflammatory rheumatic diseases, including rheumatoid arthritis (RA),6 psoriatic arthritis (PsA), and ankylosing spondylitis (AS) (10-13), and in the serum of individuals with nonrheumatic inflammatory diseases, such as inflammatory bowel diseases (IBDs) (14). The serum concentration of calprotectin has been correlated with many variables associated with disease activity in RA, PsA, and AS, including such clinical variables as the number of swollen joints (15), the Ritchie index (10), the Disease Activity Score (DAS^sub 28^) (16), and such biological variables as C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (10, 15, 16).

S100A12 is produced mainly by granulocytes upon inflammatory activation and acts independently of S100A8 and S100A9 (17). Its interaction with the receptor for advanced glycation end products (RAGE) induces proinflammatory signals in endothelium and in cells of the immune system (18). Increased S100A12 concentrations have been found in the serum, synovium, and synovial fluid of patients with RA (11, 19), PsA (19), and AS (19), as well as in the serum of IBD patients (20). Serum amyloid A (SAA), a key promoter of inflammatory events in RA and shown to be produced by inflamed synovial tissue, also induces RAGE activation (21).

The identification of the S100 and SAA groups of proteins as biomarkers is therefore challenging. In the absence of ELISAs specific for the monomeric forms of S100A8 and S100A9 and of a commercially available test for S100A12, we have hypothesized that mass spectrometry (MS) might be a possible approach for detecting these proteins (22). S100A8 has already been identified by 2- dimensional gel electrophoresis to be present in synovium (13), but not in serum (12). Two-dimensional liquid chromatography-coupled tandem MS has also been used successfully to identify several S100 proteins, including S100A8, in serum samples from a few RA patients (11); however, the labor-intensive nature of these 2 proteomics technologies allow the investigation of only small numbers of biological samples. Accordingly, we postulated SELDI-TOF MS technology to be a more appropriate proteomic approach for detecting low molecular weight proteins (

Patients and Methods

PATIENTS

Blood samples were prospectively collected from 139 Caucasian patients after they had provided informed consent. The study protocol was approved by the ethics committee of our academic hospital (CHU de Liege). Beginning in 2002, we collected blood samples into 10-mL serum separator Vacutainer Tubes (BD Medical Systems). We allowed the blood to clot for 30 min at room temperature and centrifuged the samples at 700g for 10 min. All serum samples were aliquoted and immediately frozen at -80 [degrees]C until thawed for SELDITOF MS analysis. We defined 5 sets of patients: (a) a noninflammatory control (NIC) group of 36 individuals (16 healthy individuals and 20 osteoarthritis patients), (b) 34 RA patients, (c) 22 PsA patients, (d) 19 AS patients, and (e) an IC group of 28 patients with IBD (14 with Crohn disease and 14 with ulcerative colitis).

The epidemiologic characteristics of the patient groups are summarized in Table 1. RA patients fulfilling the 1987 American College of Rheumatology criteria (26) had a median DAS^sub 28^ of 6.3 (range, 3.5-8.8), with 86% of the scores >5.1 (high disease activity). PsA patients had active disease with at least 3 tender and swollen joints. The AS patients [modified New York criteria (27)] had active disease, as indicated by a median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 6/10 (range, 4/10-10/ 10). Diagnosis of IBD patients was made according to validated criteria (28). Active Crohn disease was defined by a Harvey- Bradshaw index >/=7, and active ulcerative colitis was defined by both clinical and endoscopic signs of activity.

Table 1. Epidemiologic characteristics of the patients and controls.a

The preparation and reproducibility of Protein-Chip arrays (Vermillion/Ciphergen Biosystems) are described in the supplemental methods in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol54/ issue6.

ANALYSIS OF SELDi-TOF MS DATA

Peaks were detected with ProteinChip Biomarker Wizard software (version 3.0; Bio-Rad Laboratories). We analyzed the data by 2 approaches, nonparametric Mann-Whitney U tests and a machine- learning algorithm called random forests (29), after we had completed various preprocessing steps (24). Random forests is a decision-tree multivariate analysis that estimates the relevance or relative contribution of each peak to the classification of 2 groups (29). The latter approach allows m/z values to be ranked according to their relevance for differentiating the 2 groups based on quantitative estimates of the percentage of information (% of info) supplied. P values

SlOOAS, S100A9, S100A12, and SAA were assessed by Western blot (WB) analysis. In brief, 2 [mu]L of serum was run on 12% NuPAGE Bis- Tris polyacrylamide gels (Invitrogen), transferred, and incubated with antiS100A8 monoclonal antibody (20 [mu]L diluted in 10 mL; BMA Biomedicals), anti-S100A9 polyclonal antibody (10 [mu]L diluted in 10 mL; Santa Cruz Biotechnology), anti-S100A12 polyclonal antibody (20 [mu]L diluted in 10 mL: Santa Cruz Biotechnology), or anti-SAA monoclonal antibody (5 [mu]L diluted in 10 mL; Abeam). We then incubated with a mouse secondary antibody (2 [mu]L diluted in 10 mL; GE Healthcare/Amersham Biosciences) to specifically detect S100A8 and SAA, with a rabbit secondary antibody (2 [mu]L diluted in 10 mL; Dako) to detect S100A9, or with a goat secondary antibody (2 [mu]L diluted in 10 mL; Santa Cruz Biotechnology) to detect S100A12. Proteins were revealed with an enhanced chemiluminescence detection method according to the manufacturer’s instructions (GE Healthcare/ Amersham Biosciences).

The supplemental methods in the online Data Supplement describe the immunoprecipitation and 1-dimensional gel electrophoresis methods as well as LC-MS/MS identification of SAA.

Table 2. Discriminatory power of selected peaks as assessed with the Mann-Whitney U test and represented as P values.

ELISA TESTS

We carried out ELISAs for anti-cyclic citrullinated peptide 2 (anti-CCP2) antibody (cutoff, 5 000 relative units/L; Euroimmun), calprotectin (range, 1.6-100 [mu]g/L; Hyeult biotechnology), and matrix metalloproteinase 3 (MMP-3) (range, 1.25-20 [mu]g/L; BioSource) (30) as recommended by the respective manufacturers. We used serum samples or, in the case of calprotectin assays, the corresponding plasma samples.

CORRELATION ANALYSIS

We used ranked data to calculate Spearman correlation coefficients and used the chi^sup 2^ test to compare qualitative data. P values

Results

ANALYSIS OF SELDI-TOF MS DATA

We loaded 139 serum samples in duplicate on weak cation-exchange ProteinChip (CM10) arrays and collected 278 spectra. We first compared the spectra for the RA and NIC groups. The Bio-Rad software resolved 200 peaks. Four peaks detected at m/z values of 10 444, 10835, 12688, and 13 272 were differentiated with high statistical significance (P values

We also loaded the 139 serum samples in triplicate onto immobilized metal affinity capture ProteinChip (IMAC-Cu^sup 2+^) arrays and collected 417 spectra. Both statistical approaches detected 3 peaks as significantly increased in RA patients compared with the NIC group. These peaks had m/z values of 11 438 (P

IDENTIFICATION OF S100 FAMILY PROTEINS

We confirmed the identities of the S100A8, S100A9, and S100A12 proteins by comparing WB and SELDITOF MS results for the serum samples (Fig. 2). The WB analysis was performed with 8 serum samples (posilions 1-8) from each of the 5 sets of patients (NIC, RA, PsA, AS, and IC). The same RA sample was run in position 9 on each gel as a positive control. SELDI-TOF MS spectra for the same serum samples were monitored at m/z values of 10 835, 13 272, and 10 444 and compared with the corresponding WB results. We obtained similar profiles in the WB and SELDI analyses for each protein tested (Fig. 2, A-C). These data suggest that the peaks at 10 835,13 272, and 10 444 m/z values are the SlOOAS, S100A9, and S100A12 proteins, respectively. According to these 2 semiquantitative approaches, some RA, PsA1 AS> and, to a lesser extent, IC serum samples were positive for the 3 S100 proteins. We detected 2 S100A9 variants. The m/z value of 13 272 agreed well with the calculated mass for an oxidized form of S100A9 (13 242 Da plus 32 Da), and the 12 688 m/z value likely represents an S100A9 variant known as S100A9*, which has previously been characterized by ultraviolet MALDI MS (31 ). S100A9* results from translation beginning at amino acid residue 5 and acetylation of amino acid residue 6 (a Ser residue), yielding a calculated mass of 12 691 Da.

Fig. 1. Protein mass spectra collected on CM10 and IMAC-Cu^sup 2+^ ProteinChip arrays with serum samples from 5 patients with arthritis (2 RA, 2 AS, and 1 PsA) and 5 NIC individuals.

(A), S100A8 and S100A12 peaks are detected on CM10 arrays at m/z values of 10 835 and 10 444, respectively. S100A9 (m/z = 13 272) and the S100A9* variant (m/z = 12 688) are also present on these arrays. (B), Detection of SAA (m/z = 11 680), SAA-R (m/z = 11 528), and SAA- RS (m/z – 11 438) on IMAC-Cu^sup 2+^ ProteinChip arrays.

We also confirmed the identities of the S100A8 and S100A9 proteins by eluting the 2 proteins from their immunocomplexes on NP20 arrays after immunodepletion of a serum sample from an RA patient (see Fig. 1 in the online Data Supplement). We also detected a slight cross-reactivity with S100A12, S100A9*. and S100A9 on the NP20 spectra after eluting S100A8 (the sequence homologies of the S100A8, S100A9, and S100A12 proteins are around 40%) (32). We were unable to immunoprecipitate the S100A12 protein.

IDENTIFICATION OF SAA PROTEINS

To identity the proteins responsible for the 11 438, 11 528, and 11 680 m/z peak values in the RA spectra on IMAC-Cu^sup 2+^ arrays, we collected serum samples from a healthy control individual and an RA patient, depleted the samples of albumin and IgG, and ran them on a !-dimensional SDS-PAGE gel (see Fig. 2 in the online Data Supplement). After silver staining, we excised a band from the RA sample on the gel with an apparent molecular weight of 11 kDa and subjected it to LC-MS/MS analysis (see Fig. 2 in the onJine Data Supplement). We also excised another band from the gel at the same position for the serum sample from the healthy control individual. We digested these bands with trypsin and analyzed the resulting peptides by tandem MS (see Fig. 2 in the online Data Supplement). Sequencing analysis of 4 major tryptic fragments (sequence coverage, 51%; total score, 186) revealed the excised protein to be SAA.

Fig. 2. Analysis of S100A8, S100A9, S100A J 2, and SAA by WB and SELDI-TOF MS.

Comparison of 8 serum samples (1-8) for each of the 5 sets of serum samples (NIC, RA, PsA, AS, and IC) with both techniques. Serum sample 9 from an RA patient was used as a positive control in each WB analysis to normalize the experiment. SELDI-TOF MS results are presented in both electrophoresis gel and spectrum views. Shown are spectrum regions near m/z values of 10 835, 13 272, 10 444, and 11 680, which correspond to the S100A8, S100A9, S100A12, and SAA proteins, respectively.

We confirmed the identity of SAA by comparing the WB results with the SELDI-TOF MS results for the serum samples (Fig. 2D). Each set of patient samples (but not those of the NIC group) was positive for SAA in the WB analysis. This result confirmed the identity of the peak at m/z 11 680 to be the SAA protein (calculated mass, 11 682 Da). The peaks at m/z values of 11 438,11 528, and 11 680 were clustered on each spectrum. We therefore hypothesized that the 11 438 and 11 528 m/z peak values represented 2 variants of the original SAA protein. The 11 528 m/z value corresponds to the calculated mass for the SAA protein without its first N-terminal Arg residue ( – 156 Da); this peak represents the SAA-R protein (calculated mass, 11 526 Da). Similarly, the 11 438 m/z value corresponds to the calculated mass of the SAA protein truncated at the N-terminal end by 2 residues, Arg and Ser (-243 Da); this peak represents the SAA-RS protein (calculated mass, 11 439 Da). We also confirmed the identities of these proteins by eluting them from their immunocomplexes on NP20 after immunodepleting a serum sample from an RA patient (see Fig. 1 in the online Data Supplement).

THE DISTRIBUTION OF PEAK INTENSITIES AMONG PATIENT GROUPS

The discriminatory power of the peaks at m/z values of 10 835 (S100A8), 12 688 (S100A9*), 13 272 (S100A9), 10444 (S100A12), 11680 (SAA), 11528 (SAA-R), and 11 438 (SAA-RS) detected in the spectra of samples from each of the arthritis groups was assessed with the Mann- Whitney U test (Table 2). In brief, S100 proteins were found to be highly significantly effective (P

We next analyzed the percentages of serum samples that were positive for the 7 biomarkers. These percentages were calculated according to the peak intensities measured at tn/z values of 10444 (S100A12), 10 835 (S100A8), 13 272 (S100A9),and 12 688 (S100A9*) on CM10 arrays, and at m/z values of 11 680 (SAA), 11 528 (SAA-R), and 11 438 (SAA-RS) on IMAC-Cu^sup 2+^ arrays. Peak intensity values were averaged. The cutoff value was defined as the highest peak intensity of the corresponding m/z values in the spectra for the NIC serum samples. Similarly, the percentages of plasma samples positive for calprotectin were calculated with the cutoff defined as the highest calprotectin concentration observed in the NIC group. Increased S100 protein peak intensities and increased calprotectin concentrations were detected in 43%-89% and 33%-56% of arthritis serum samples, respectively, and in 15%34% and 33% of IC patients, respectively (Table 3). The positivity rates among the 4 S100 proteins were significantly linked [chi^sup 2^ (9) = 84; P

Statistically significant correlations were found petween the various S100 proteins, SAA, calprotectin, and other evaluated variables in the RA, PsA, AS, and IC patient groups (Table 4). In brief, values for the 4 SlOO proteins were both highly intercorrelated and correlated with plasma calprotectin concentration in all of the patient groups. S100 protein peaks were also correlated with SAA peaks, but only in the RA and IC groups. In the RA group, S100 protein peaks and the calprotectin concentration were correlated with CRP, log MMP-3, and anti-CCP2 antibody (except for S100A12) serum concentrations and with the DAS^sub 28^, but not with the number of tender or swollen joints (data not shown). RA patients who produced S100 proteins or calprotectin had longer disease durations than SlOO-negative and calprotectin-negative patients (132 months vs 17 months and 117 months vs 16 months, respectively; P

Table 4. Correlation coefficients for S100 proteins, SAA, and clinical variables for serum samples collected from RA, PsA, AS, and IC patients.a

SAA was correlated with the serum concentration of CRP in all patient groups and with DAS28 and logarithm MMP-3 serum concentration in the RA patient group. The plasma calprotectin concentration was correlated with log MMP-3 serum concentration in the RA, PsA, and IC patient groups and with the SAA protein in the RA, AS, and IC patient groups.

Discussion

In this study, we used the SELDI-TOF MS approach to detect S100A8, S100A9, an S100A9 variant (S100A9*), S100A12, SAA, SAA-R, and SAA-RS, and we identified^ these proteins by WB, immunodepletion, and nanoLC-MS/MS. In a previous study, we had already demonstrated by WB analysis that the peak at m/z 10 835 in one RA serum sample was S100A8 (24). We confirmed the identity of this peak in the present study, not only in serum samples from RA patients but also in samples from patients with other inflammatory diseases. The mass of the protein for the peak identified as S100A9* was in good agreement with that of a truncated form of S100A9, a variant that has already been detected by ultraviolet MALDI MS in human buffy coats (31), in head and neck sauamous cell carcinoma (33), and in neutrophils from pediatric cystic fibrosis patients (34). The SAA variants had previously been identified in renal cancer, but not in arthritis or in patients with IBD. SELDI-TOF MS is therefore a very efficient technology for detecting such arthritis biomarkers as S100 and SAA proteins in their monomeric, truncated, or posttranslationally modified forms.

The highly significant linear correlations between the peak intensities for the S100 proteins and the calprotectin plasma concentration as measured by ELISA confirm the reliability of this new proteomic approach for investigating these inflammation-related proteins. We conclude that these proteins are up-regulated in each of the diseases we studied because the S100 proteins and calprotectin are correlated both qualitatively, as shown by the strong concordance between WB positivity and SELDI-TOF MS positivity, and quantitatively, as shown by the significant linear correlations in peak intensities. Furthermore, the peak intensities of S100A8, SIOOA9, S100A9*, and S100A12, as well as the calprotectin concentration, are correlated with variables that reflect the biological and clinical activity of RA, such as the DAS^sub 28^ and serum concentrations of CRP, MMP-3, and anti-CCP2 antibody. These results provide strong support for the clinical relevance of proteomic detection of calgranulins. The anti-CCP2 antibody may also be related to radiologically observed structural damage in RA because antiCCP antibodies have been demonstrated to be independent predictors of joint damage (35 ), as is the serum concentration of calprotectin (16). We could not address this question directly because we conducted no x-ray-imaging studies; however, we did find that patients with increased SlOO protein or calprotectin concentrations had significantly longer disease durations, which are expected to be associated with greater radiographically detectable damage.

We observed a discrepancy between RA patients and PsA and AS patients in that the 4 S100 proteins were significantly correlated with CRP and MMP-3 concentrations in RA patients, but not in the other 2 groups of patients. We attribute this finding to the fact that AS and PsA patients exhibit abnormal CRP and MMP-3 concentrations less frequently than RA patients (30). The strong correlation between the 4 S100 proteins and the serum concentration of MMP-3 in the IC group agrees with findings of abundant production of both types of proteins in inflamed intestinal tissue (36).

We also observed that the 4 S100 proteins distinguished arthritis conditions from nonarthritis conditions (NIC and IC groups), whereas SAA patterns distinguished inflammatory diseases (RA, PsA, and IC groups) from noninflammatory conditions (the NIC group). It is also interesting that within the arthritis groups the peak intensities for the 4 S100 proteins were correlated with the SAA peak intensities in the RA group but not in the AS and PsA groups. These results mimic what we had already observed with the CRP and MMP-3 variables. We therefore conclude that the arthritis process is correlated with the inflammatory process in RA, in which the acute- phase response is well developed, but not in AS or PsA, in which it is weaker. This conclusion thus suggests that the regulatory pathways at the sites of inflammation and the patterns of local production of S100 and SAA proteins in RA patients are different from those in AS and PsA patients (37).

SELDI-TOF MS is a unique method for distinguishing SlOO monomers from multimeric forms and for detecting SAA variants, which are not possible with current ELISAs. The identification of the various SAA forms may be important because they may have different pathophysiological roles. The recent identification via SELDI-TOF analysis of several truncated forms of S100A8 and S100A12 in cystic fibrosis patients suggests that C-terminal truncations affect protein function (34). The presence of S100A8 and S100A12, but not calprotectin, have been found to be characteristic of intra- amniotic inflammation (22), and SAA variants with different properties, such as differential susceptibility to matrix metalloproteinase digestion, have been described (38). These findings demonstrate the relevance of developing new proteomic approaches sufficiently powerful for investigating proteins in their modified or monomeric forms.

In conclusion, we have used SELDI-TOF MS technology to identify several relevant arthritis biomarkers that are correlated with several biological or clinical variables associated with disease activity. We could not address the functional role of these biomarkers in the pathophysiology of arthritis, because we selected serum samples from individuals with the respective dis ease characteristics and not from individuals at different stages of each disease. Studies that take advantage of the SELDI-TOF MS technology to evaluate the effects of disease stage on these biomarkers may shed light on this question. Grant/Funding Support: This research was supported by the National Fund for Scientific Research (FNRS, Belgium) and the Fonds d’Investissement pour la Recherche Scientifique (FIRS), CHU de Liege, Belgium.

Financial Disclosures: None declared.

Acknowledgments: The authors thank Aline Desoroux and Gael Cobraiville for their expert technical assistance. M.F. is a Research Associate, and E.L. and M.P.M. are Senior Research Associates at FNRS (National Fund for Scientific Research).

6 Nonstandard abbreviations: RA, rheumatoid arthritis; PsA, psoriatic arthritis; AS, ankylosing spondylitis; IBD, inflammatory bowel disease; DAS28, Disease Activity Score; CRP, C-reactive protein; RAGE, receptor for advanced gtycation end products; SAA, serum amyloid A; MS, mass spectrometry; IC, inflammatory control; NIC, noninflammatory control; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; WB, western blot anti-CCP2, anti-cyclic citrullinated peptkie 2; MMP-3, matrix metalloproteinase 3; CMIO, weak cation-exchange ProteinChip; % of info, percentage of information; IMAC-Cu^sup 2+^. immobilized metal affinity capture ProteinChip; SAA-R, SAA des-Arg; SAA-RS, SAA des-Arg/ des-Ser.

References

1. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007;81:28-37.

2. De Rycke L, Baeten D, Foell D, Kruithof E, Veys EM, Roth J, et al. Differential expression and response to anti-TNFalpha treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J Pathol 2005;206:17-27.

3. Frosch M, Strey A, Vogl T, Wulffraat NM, Kuis W, Sunderkotter C, et al. Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum 2000;43:628-37.

4. Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, et al. The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther 2006;8:R69.

5. Hunter MJ, Chazin WJ. High level expression and dimer characterization of the S100 EF-hand proteins, migration inhibitory factor-related proteins 8 and 14. J Biol Chem 1998;273:12427-35.

6. Cropper C, Huang X, Roth J, Sorg C, Nacken W. Analysis of the MRP8-MRPH protein-protein interaction by the two-hybrid system suggests a prominent role of the C-terminal domain of S100 proteins in dimer formation. J Biol Chem 1999; 274:183-8.

7. Strupat K, Rogniaux H, Van Dorsselaer A, Roth J, Vogl T. Calcium-induced noncovalentty linked tetramers of MRPS and MRP14 are confirmed by electrospray ionization-mass analysis. J Am Soc Mass Spectrom 2000;11:780-8.

8. Komdorfer IP, Brueckner F, Skerra A. The crystal structure of the human (S100A8/S100A9)^sub 2^ heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteins, J Mol Biol 2007;370:887-98.

9. Zwadlo G, Bruggen J, Gerhards G, Schlegel R, Sorg C. Two calcium-binding proteins associated with specific stages of myeloid cell differentiation are expressed by subsets of macrophages in inflammatory tissues. Clin Exp Immunol 1988;72: 510-5.

10. Kane D, Roth J, Frosch M, Vogl T, Bresnihan B, FitzGerald O. Increased perivascular synovial membrane expression of myeloid- related proteins in psoriatic arthritis. Arthritis Rheum 2003;48: 1676-85.

11. Liao H, Wu J, Kuhn E. Chin W, Chang B, Jones MD, et al. Use of mass spectrometry to identify protein biomarkers of disease severity in the synovial fluid and serum of patients with rheumatoid arthritis. Arthritis Rheum 2004;50: 3792-803.

12. Sinz A, Bantscheff M, Mikkat S, Ringel B, Drynda S, Kekow J, et al. Mass spectrometric proteome analyses of synovial fluids and plasmas from patients suffering from rheumatoid arthritis and comparison to reactive arthritis or osteoarthritis. Electrophoresis 2002;23:3445-56.

13. Tilleman K. Van Beneden K, Dhondt A. Hoffman I, De Keyser F, Veys E, et al. Chronically inflamed synovium from spondyloarthropathy and rheumatoid arthritis investigated by protein expression profiling followed by tandem mass spectrometry. Proteomics 2005;5:2247-57.

14. Lugering N, Stoll R, Kucharzik T, Schmid KW, Rohlmann G, Burmeister G, et al. Immunohistochemical distribution and serum levels of the Ca^sup 2+^-binding proteins MRP8, MRP14 and their heterodimeric form MRP8/14 in Crohn’s disease. Digestion 1995;56:406- 14.

15. Brun JG, Jonsson R, Haga HJ. Measurement of plasma calprotectin as an indicator of arthritis and disease activity in patients with inflammatory rheumatic diseases. J Rheumatol 1994;21:733-8.

16. Hammer HB, Odegard S, Fagerhol MK, Landewe R, van der Heijde D, Uhlig T, et al. Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis 2007;66:1093-7.

17. Vogl T, Propper C, Hartmann M, Strey A, Strupat K, van den Bos C, et al. S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. J Biol Chem 1999; 274:25291- 6.

18. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/ calgranulin polypeptides. Cell 1999;97:889-901.

19. Foell D, Kane D, Bresnihan B, Vogl T, Nacken W, Sorg C, et al. Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology (Oxford) 2003; 42:1383-9.

20. Foell D, Kucharzik T, Kraft M, Vogl T, Sorg C. Domschke W, et al. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut 2003;52:847- 53.

21. Cai H, Song C, Endoh I, Goyette J, Jessup W, Freedman SB, et al. Serum amyloid A induces monocyte tissue factor. J Immunol 2007;178: 1852-60.

22. Buhimschi IA, Buhimshi CS, Weiner CP, Kimura T, Hamar BD, Sfakianaki AK, et al. Proteomic but not enzyme-linked immunosorbent assay technology detects amniotic fluid monomeric calgranulins from their complexed calprotectin form. Clin Diagn Lab Immunol 2005;12:837-44.

23. Tang N, Tomatore P, Weinberger SR. Current developments in SELDI affinity technology. Mass Spectrom Rev 2004;23:34-44.

24. de Seny D, Fillet M, Meuwis MA, Geurts P, Lutteri L, Ribbens C, et al. Discovery of new rheumatoid arthritis biomarkers using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry ProteinChip approach. Arthritis Rheum 2005;52:3801-12.

25. Meuwis MA, Fillet M, Geurts P, de Seny D, Lutteri L, Chapelle JP, et al. Biomarker discovery for inflammatory bowel disease, using proteomic serum profiling. Biochem Pharmacol 2007;73: 1422-33.

26. Amett FC Edworthy SM, Bloch DA, MacShane DJ, Fries JF, Cooper N. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315- 24.

27. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-27.

28. Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation, Gastroenterology 2004;126:1518-32.

29. Geurts P, Fillet M, de Seny D, Meuwis MA, Malaise M, Merville MP, et al. Proteomic mass spectra classification using decision tree based ensemble methods. Bioinformatics 2005;21: 3138-45.

30. Ribbens C, Martin y Porras M, Franchimom N, Kaiser MJ, Jaspar JM, Damas P, et al. Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment. Ann Rheum Dis 2002;61: 161-6.

31. Vogl T, Roth J, Sorg C, Hillenkamp F, Strupat K. Calcium- induced noncovalently linked tetramers of MRP8 and MRP14 detected by ultraviolet matrix-assisted laser desorption/ionization mass spectrometry. J Am Soc Mass Spectrom 1999;10: 1124-30.

32. Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 2004;50:3762-71.

33. Roesch Ely M, Nees M, Karsai S, Magele I, Bogumil R, Vorderwulbecke S, et al. Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma. Eur J Cell Biol 2005;84:431-44.

34. McMorran BJ, Ouvry Patat SA, Carlin JB, Grimwood K, Jones A, Armstrong DS, et al. Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients. Clin Chem 2007;53:1782-91.

35. Syversen SW, Gaarder PI, Goll GL, Odegard S, Haavardsholm EA, Mowinckel P, et al. High anti-CCP levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum 2008; 2008;67: 212-7.

36. Louis E, Ribbens C, Godon A, Franchimom D, De Groote D, Hardy N, et al. Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. Clin Exp Immunol 2000;120:241-6.

37. Mullan RH, Bresnihan B, Golden-Mason L, Markham T, O’Hara R, FitzGerald O, et al. Acute-phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF-kappaB-dependent signal transduction pathway. Arthritis Rheum 2006;54:105-14.

38. Stix B, Kahne T, Sletten K, Raynes J, Roessner A, Rocken C. Proteorysis of AA amyloid fibril proteins by matrix metalloproteinases-1, -2, and -3. Am J Pathol 2001;159:561-70.

Dominique de Seny,1* Marianne Fillet,2 Clio Ribbens,1 Raphael Maree,3 Marie-Alice Meuwis,2 Laurence Lutteri,2 Jean-Paul Chapelle,2 Louis Wehenkel,4 Edouard Louis,5 Marie-Paule Merville,2 and Michel Malaise1 1 Laboratory of Rheumatology, GIGA Research, CHU, University of Liege;2 Laboratory of Clinical Chemistry, GIGA Research, University of Liege; 3 GIGA Bioinformatics Platform, University of Liege; 4 Bioinfomiatics and Modeling Unit Department of Electrical Engineering & Computer Science, GIGA Research, University of Liege;5 Laboratory of Hepato-Gastroenterology, CHU, University of Liege, Liege, Belgium.

* Address correspondence to this author at: Laboratory of Rheumatology, Tour GIGA +2, CHU. 4000 Liege, Belgium. Fax (32) 4 366 45 34; e-mail ddeseny@ chu.ulg.ac.be.

Received November 6, 2007; accepted March 28, 2008.

Previously published online at DOI: 10.1373/clindwm.2007.099549

Copyright American Association for Clinical Chemistry Jun 2008

(c) 2008 Clinical Chemistry. Provided by ProQuest Information and Learning. All rights Reserved.

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“This new program for Hannaford’s associates effectively complements our ongoing efforts to provide our customers and associates with innovative programs and resources that promote healthy lifestyles,” said Peter Hayes, Director of Associate Health and Wellness. “RedBrick Health executives were at the forefront of the consumer-driven health movement, and we are thrilled to work with them as they advance the health care industry’s efforts to manage costs by motivating, educating and supporting consumers to take ownership of their health.”

About Hannaford Bros. Co.

Hannaford Bros. Co., based in Scarborough, Maine, operates 165 stores in the Northeast. Stores are located in Maine, New York, Massachusetts, New Hampshire, and Vermont. All Hannaford stores feature Guiding Stars, America’s first storewide nutrition navigation system. Hannaford employs more than 27,000 associates. The company is owned by Delhaize Group of Brussels, Belgium. For more information visit www.hannaford.com.

About RedBrick Health

RedBrick Health, headquartered in Minneapolis, is a health services company that was founded in 2006 to lead the transition from employer-sponsored health care to Consumer-Owned Health. RedBrick Health uses financial tools and incentives, a customized Personal HealthMap(SM) and independent customer service advocacy to establish greater individual responsibility, long-term lifestyle changes, and substantial return on investment. An independent advocate that works with all employer-sponsored health plans, RedBrick Health focuses its services on both Fortune 1000 companies and their employees. For more information visit: www.redbrickhealth.com.

LAGUNA HILLS, Calif., June 24 /PRNewswire/ — In response to increasing demand for convenient, tasty, satisfying foods that help people prevent and manage Diabetes and heart disease, WatchDog Nutrition(TM) today announced availability of its snack bars in over 200 Southern California Ralph’s grocery stores. Invented by doctors, nutritionists and fitness experts, WatchDog Nutrition snack bars are formulated with nutrients and ingredients scientifically proven to help people maintain heart-healthy lifestyles or diabetic diets.

(Logo: http://www.newscom.com/cgi-bin/prnh/20080624/LATU514LOGO)

“Ralph’s is an ideal partner for WatchDog Nutrition’s line of functional foods and the first of several retail chains that you’ll be able to buy them in,” said Dr. Rajeev Saggar, CEO and one of the three founders of WatchDog Nutrition. “Demand for snack foods properly formulated for whole health is increasing, and the addition of WatchDog bars to Ralph’s adult nutrition products section magnifies their commitment to providing convenient, healthy, great tasting foods.”

WatchDog Heart Healthy bars are a satisfying healthy snack. These low-calorie functional food bars contain several proven natural ingredients such as fiber, plant sterols, oats, and beta-glucans that may help reduce the risk of high blood pressure, high cholesterol, and other heart-related conditions when consumed as part of a diet low in salt, total fat, and saturated fat. With no trans fats or high-fructose corn syrup, the bars contain only what’s good for you — and don’t have common bar ingredients many consumers prefer to avoid.

The Diabetic Healthy functional food bars are not only low in simple sugars and glycemic index, which is important for maintaining an optimal diabetic diet, but they are formulated to help reduce the medical problems commonly associated with diabetes such as heart disease, high blood pressure, and high cholesterol. These diabetic snacks also provide only the essential vitamins and minerals that are most critical to the diabetic diet.

In addition to the Heart Healthy and Diabetes Healthy snack bars, WatchDog Nutrition will introduce a Joint Healthy bar this summer and has plans to introduce a children’s snack bar and a line of healthy beverages.

About WatchDog Nutrition

WatchDog Nutrition(TM), an innovator in today’s growing functional food industry, creates and distributes nutritional snack foods that inspire consumers to take control of their health so they can live healthier, more active, more vital lives. WatchDog Nutrition products provide consumers with food items that may help prevent or slow down the onset of diseases or may help reduce the progression of diagnosed medical conditions. Created by doctors, nutritionists and fitness experts, every WatchDog Nutrition snack contains vitamins and minerals with scientifically proven health benefits geared towards specific medical conditions such as Diabetes, heart disease or joint/bone disease.

For more information about WatchDog Nutrition, please visit watchdognutrition.com.

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20080624/LATU514LOGOAP Archive: http://photoarchive.ap.org/PRN Photo Desk, [email protected]

WatchDog Nutrition

CONTACT: Nicole Bellemare of Sol Marketing Concepts, +1-408-843-8441,for WatchDog Nutrition; or Sonny Singh, COO and Co-founder of WatchDogNutrition, +1-949-632-4833

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

By Robert Boyer, Times-News, Burlington, N.C.

Jun. 24–A county official has revealed key details in an ongoing controversy at the Alamance County Health Department.

Commissioner Bill Lashley said Monday he was the public official who asked Sheriff Terry Johnson to call in the SBI to investigate the department’s record-keeping and use of patient-provided aliases in work-excuse notes.

Last Wednesday, Dr. Kathleen Shapley-Quinn, the health department’s medical director, and Karen Saxer, a nurse practitioner, were suspended with pay pending the outcome of the State Bureau of Investigation inquiry.

Word of Saxer’s suspension came from a memo from Interim Health Director Tim Green.

In memos to Shapley-Quinn and Saxer, Green wrote that each is “on investigatory suspension with pay until further notice.

“The investigation is related to possible performance or conduct deficiencies,” Green concluded.

Lashley, who also serves on the health board, said Monday that Shapley-Quinn should be charged if Bureau investigators find that laws were broken.

“She’s no better than anybody else. If she breaks the law, she should be prosecuted.” Lashley and health board Chairman Keith Whited say the department’s handling of aliases related to medical records and work notes violates federal HIPAA laws concerning patient privacy and other state and federal laws covering identity theft.

At the June 17 meeting of the county Board of Health, members, at Whited’s urging, approved policy changes giving the board stronger oversight concerning patient records and required the release of all names and identifying information in a patient’s file to “non-medical third parties,” among other things.

The flap over the aliases surfaced on May 20, when Nursing Director Marilyn Burns reported to a health board subcommittee that health department medical staffers, at the request of some patients, had been issuing the work notes using alias names. The names were kept separate from the patients’ medical files.

Patients asked for work notes with aliases two or three times a month, department officials say. Most of them were Hispanic, Burns has said.

At the health board meeting on June 17, Shapley-Quinn confirmed that the practices had continued until about a month ago, when she instructed the medical staff to discontinue writing notes with aliases until she had received guidance on whether to continue the practice.

Shapley-Quinn said the issue first came up in the summer of 2007, when the medical staff asked for guidance on the “complex” issue to balance department policy with the agency’s primary goal of maintaining public health.

By law, health departments are required to treat all county residents who seek care, regardless of whether the are legal U.S. residents.

JILL MOORE, AN associate professor at the UNC School of Government, specializes in public health law and said she is an expert on HIPAA, the federal guidelines covering patient privacy.

“There is nothing in HIPAA that requires where you put your records,” she said. “HIPAA regulates what you do with your records once you have them.” Writing aliases in work notes also squares with HIPAA, provided the patient authorized the use of the name and the medical worker gives the note to the patient, not the employer, Moore said.

Records, like aliases, can be kept apart from a patient’s file, provided there are “reasonable safeguards” against unauthorized disclosure.

On the issue of whether health department staffers who write such “aliases” help their patients break the law in some cases, Moore said she is still consulting with criminal law experts to get a better handle on what she refers to a “new frontier in the law.” There are no reported cases in North Carolina of health care workers being charged with a crime by including an alias in a work note, Moore said.

The issue of criminality revolves around whether health care providers know a person is using a false name to commit a crime and whether they know they are helping the person break the law.

“Do you have a duty to ask?” she said. “How would a health provider know?” People have a number of reasons for using alternate names, Moore said. Some women go by their maiden and married names.

Some, like prominent or famous people, use false names when seeking care.

The first case is an example of a legitimate use, she said. The second is an illegitimate, but also legal use she added.

Dr. Leah Devlin, the state’s health director, said there is no statewide policy when it comes to such issues.

Local health boards set policies for their health departments.

Citing the SBI investigation, Devlin declined to talk about the controversy in Alamance County. But in general, Devlin said public heath agencies “need to do whatever we can to serve every individual we can, because that’s in the communities’ health interest.

“It really important for us to eliminate barriers to care when we can,” she added.

Whited and Lashley are running for office in the November election — Whited for a district court judgeship, Lashley for another term as commissioner. In his bid against incumbent judge Tom Lambeth, Whited has taken a strong stand against illegal immigration.

Whited has said that as health board chairman, his stance on the issue is about protecting the department and its employees and has nothing to do with politics.

ALSO ON MONDAY, Lashley provided this additional background on how the SBI became involved: Whited told him about the issue on May 21, the day after Burns’ report to the Personal Health Committee.

Lashley said he then consulted with County Manager David Smith, who asked if he had spoken with the sheriff about the issue.

After the June 16 county commissioners’ meeting, Lashley consulted with Johnson and Smith. The sheriff, Lashley said, told him he would contact the SBI.

On Monday, Lashley produced a memo from Green detailing Shapley-Quinn’s and Saxer’s suspension.

In the memo, Green wrote that last Wednesday, Johnson, Assistant County Attorney Clyde Albright and County Human Resources Director Joyce Graves-Hinton held a conference call with him to discuss the situation.

On Wednesday, Graves-Hinton asked Green to instruct Shapley-Quinn “to turn in her keys” Thursday morning, “and that County (Management Information Systems) would be locking her computer.””I told her she was not being dismissed but that she would be suspended with pay,” Green wrote. “We are in the process of arranging for temporary coverage of her duties as medical director,” Green continued. “I do not know how long she could be on leave — possibly several weeks pending results of the investigation.” To comment on this or any Times-News story online go to TheTimesNews.com, find the story, go to the bottom and follow the directions

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To see more of the Times-News, or to subscribe to the newspaper, go to http://www.thetimesnews.com.

Copyright (c) 2008, Times-News, Burlington, N.C.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

The first scorecard ranking U.S. hospitals on the value of care they provide their patients found the vast majority of hospitals offer high quality healthcare, but the price for essentially the same care varies widely across the country and even across the same community.

The 2008 Hospital Value Index was unveiled today at the Healthcare Financial Management Association’s annual conference in Las Vegas.

The study – which includes in-depth analysis and national and local market rankings of America’s best value hospitals – is available without charge at www.HospitalValueIndex.com.

Findings

In its analysis of 1,500 hospitals, the 2008 Hospital Value Index(TM) also found that:

— A number of hospitals with a reputation for offering high quality care do not necessarily provide high value care. Conversely, a number of lesser known hospitals – including several public or “safety-net” hospitals – provide high value care.

— High value care can be offered by hospitals regardless of ownership, size, teaching status, geography or demographics. The Hospital Value Index(TM) found none of these are guarantees of high value care – or of poor value care.

— If all of the 1,500 hospitals studied were to perform at levels consistent with those ranked as “best value hospitals,” then approximately $273 billion in excess charges would be removed from the healthcare delivery system by hospitals alone.

Hospital Value Index(TM)

The study was developed by Data Advantage, LLC (www.data-advantage.com) in anticipation of the Centers for Medicare and Medicaid Services’ (CMS) Value-Based Purchasing initiative, which proposes to financially reward a hospital based on the value of its care beginning next year. It also recognizes the growing influence of consumers shopping for the best hospital values in their communities.

“Given the federal government’s new Value-Based Purchasing initiative, it is essential for hospital leaders to look beyond quality and outcomes to define their value to the community,” said Hal Andrews, Chief Executive Officer at Data Advantage, which developed the scorecard.

“CMS has proposed rewarding both excellent performance and also improvements from a baseline score. With the Hospital Value Index(TM), hospitals will have an all-encompassing score to understand where they excel and where they can improve.”

The Hospital Value Index(TM) is also a resource for healthcare consumers to compare the value of hospitals, Andrews said. Where the quality of care between hospitals is relatively equal, the Hospital Value Index(TM) will identify the hospital that is more affordable. Where the price between hospitals is the same, the Hospital Value Index(TM) will reveal the one with better quality.

The Hospital Value Index(TM) analyzed more than 1,500 general acute-care hospitals in America’s 100 largest cities, serving approximately 180 million consumers. It defines a hospital’s “value” by its success in four critical areas:

— Quality of its care, including core processes and patient safety;

— Efficiency of its care and affordability, including the prices it charges;

— Experience encountered by its patients as measured by patient satisfaction; and

— Comprehensive reputation of a hospital as measured by local public perception.

“In an environment in which consumers – including patients, employers and payers – shoulder an increasing burden of the cost of healthcare, it is important to recognize those hospitals that deliver outstanding value,” said John R. Morrow, a founder of 100 Top Hospitals: Benchmarks for Success, and a senior advisor to Data Advantage.

“These consumers increasingly want a score that considers everything we publicly know – and they care about – when choosing a hospital. The Hospital Value Index(TM) provides the first go-to source for that complete analysis.”

Behind the Hospital Value Index(TM)

The Hospital Value Index(TM) uses the latest objective, publicly available data to specifically measure the key elements that healthcare consumers consider when choosing a hospital. As a dynamic scorecard, the Hospital Value Index(TM) will be continually updated as new data and resources become available.

“The Hospital Value Index(TM) was born of our shared interests in making sense of the overwhelming amounts of healthcare measurement and information available today,” said David Potash M.D., MBA, Data Advantage’s Chief Medical Officer.

“We want to recognize the great efforts and value that hospitals already deliver and provide hospitals the information they need to make improvements.”

For a complete list of findings, market-by-market hospital scores, and more information on the Hospital Value Index(TM), please visit www.HospitalValueIndex.com.

About Data Advantage, LLC

Data Advantage, LLC is a healthcare information company that specializes in providing the healthcare and business communities with independent and objective information resources for improved business intelligence. Since 1992, more than 1,000 hospitals and other businesses have looked to Data Advantage for information solutions. For more information, please visit www.data-advantage.com or call (502) 779-4990.

Editor’s note: Representatives of the media are invited to attend a conference call (1-800-860-2442) with the founders of the Hospital Value Index(TM) at 10 a.m. PDT/1 p.m. EDT on June 24.

JACKSONVILLE, Fla., June 24, 2008 (PRIME NEWSWIRE) — BodyTel Scientific Inc. (OTCBB:BDYT), a developer of wireless telemedical devices, announces today that it has, through its wholly owned subsidiary BodyTel Europe GmbH, entered into an exclusive distribution agreement with Diabetes Supplies Ltd. (DSL), a well known distributor of medical supplies in New Zealand. Beginning in the third quarter of 2008, BodyTel’s new partner, Diabetes Supplies, intends to begin offering BodyTel’s blood glucose monitoring and diabetes management system, GlucoTel(tm), in New Zealand (the “Territory”). Pursuant to the terms of the distribution agreement, BodyTel granted DSL the right to exclusively market the GlucoTel in the Territory for a term of one year. Diabetes Supplies Ltd. is also responsible for all distribution, compliance and marketing costs relating to the sale of the products in the Territory.

Walter Stahl, CEO of Diabetes Supplies Ltd., stated, “DSL has a tremendous reach in the New Zealand diabetes community, extending to patients and caregivers. We are delighted and excited to begin distributing the GlucoTel system in New Zealand, which we believe represents the future of glucose testing globally. Comprehensive knowledge and complete access to disease related data and information are the keys to effective disease management. The BodyTel approach is a giant step forward in this regard.”

Diabetes Supplies Ltd. is a specialist distributor in New Zealand (www.diabetessupplies.co.nz) focused entirely on diabetes related products. Through this focus, DSL strives to achieve maximum penetration in the market and to reach every person with diabetes directly, offering a comprehensive range of products and services, including dispensing of prescriptions of glucose test strips and meters.

“We continue to add high quality distributors, and Diabetes Supplies Ltd. is no exception,” said Stefan Schraps, CEO of BodyTel. “We chose DSL due to their extensive knowledge of diabetes management. As we begin our sales and marketing efforts, it is especially important to have knowledgeable distributors with extensive territorial reach.”

BodyTel’s first market-ready product is the GlucoTel(tm) blood glucose meter. It is part of the GlucoTel(tm) system, a complete telemedical blood glucose monitoring and diabetes management system, supporting patients and doctors in the treatment of diabetes and its corollary diseases. GlucoTel(tm) electronically measures the blood sugar level and then sends it via Bluetooth to the patient’s cell phone. After that, the data is automatically transmitted to an online database via internet connection and stored on a long-term basis. To facilitate better diabetes management, the patient and any authorized persons, e.g. healthcare professionals or caregivers, can access the data via internet at any time using a secure login.

About BodyTel

BodyTel is a German-American telehealth company that specializes in telemedical monitoring and management systems for chronic diseases. The company combines its know-how in telecommunications, internet and medical technology/diagnostics to create new products and services for the changing needs of global health. BodyTel products are designed not only to simplify home monitoring by patients, but also to ease the communication of ‘measured body values’ to healthcare professionals or other caregivers by bridging the gap between the patient and the caregivers instantaneously and in real-time. BodyTel’s products — GlucoTel, PressureTel and WeightTel — are each at different stages of development and approval processes. BodyTel holds a 50% interest in GlucoTel Scientific Inc., which holds the rights to the GlucoTel(tm) blood glucose meter technology.

Further information can be found at www.bodytel.com.

Forward Looking Statements

Statements in this news release that are not historical are forward-looking statements. Forward-looking statements are statements that are not historical facts and are generally, but not always, identified by the words “expects,””plans,””anticipates,””believes,””intends,””estimates,””projects,””aims,””potential,””goal,””objective,””prospective,” and similar expressions, or that events or conditions “will,””would,””may,””can,””could” or “should” occur. Forward-looking statements in this news release include: that Beginning in the third quarter of 2008, BodyTel’s new partner, Diabetes Supplies, intends to begin offering BodyTel’s blood glucose monitoring and diabetes management system, GlucoTel(tm), in New Zealand, and that as we begin our sales and marketing efforts, it is especially important to have knowledgeable distributors with extensive territorial reach. It is important to note that the Company’s actual outcomes may differ materially from those statements contained in this press release. Factors which may delay or prevent these forward looking statements from being realized include but are not limited to those concerning the timing of regulatory approval or commercialization of its products or the achievement of any other clinical, regulatory or product development milestones or other risk factors and matters set forth in the Company’s Annual Report on Form 10-KSB for the year ended February 28, 2007 and the Company’s periodic reports filed with the SEC. These reports are available on our investor relations website at www.bodytel.com and on the SEC’s website at http://www.sec.gov. BodyTel undertakes no obligation to update publicly any forward-looking statements to reflect new information, events or circumstances after the date they were made, or to reflect the occurrence of unanticipated events.

This news release was distributed by PrimeNewswire, www.primenewswire.com

 CONTACT:  BodyTel Europe GmbH           Michaela Klinger           +49 (0)5621 96776 11           [email protected]            Chain Relations           Torsten Herrmann           06192/96 166 80           [email protected]            ZA Consulting Inc.           US Investor Relations           David Zazoff           212-505-5976 

PatientFlow Technology (www.patientflowtech.com), the leading provider of patient flow management tools and services for hospitals, today announced that the first four months of the patient flow improvement project at WellStar Health System’s Kennestone Hospital Cardiac Catheterization Laboratory has produced dramatic results. The cardiac cath lab project is coordinated with the patient flow project currently underway in the main OR (see Press Releases of 3/25/08 and 06/16/08). Since the plan was implemented in late January, waiting times for urgent cardiac catheterization cases have dropped by more than 50%, and patients and physicians are getting into the cath lab more quickly. Emergency cases continue to get into the cath lab in less than 90 minutes, as before. Kennestone Hospital, WellStar’s 633-bed flagship hospital, is located in Marietta, Georgia.

On January 28, 2008, Kennestone Hospital implemented a plan specifically aimed at improving patient flow in the cardiac cath lab. Cardiac cath labs care for a mix of patients, some of whom are having elective procedures, but many of whom are admitted to the hospital with chest pain or in the midst of a heart attack and need quick attention. Because of the mix of scheduled and unscheduled cases, days can be hectic and long.

Using rigorous data analysis and queuing theory — an operations management tool developed in industry and adapted for the hospital environment — PatientFlow Technology developed a plan that calls for setting aside one or two of the existing four labs, depending on the day of the week, for urgent and emergent cases. This ensures that these patients are cared for in a timely manner, without causing delays or cancellations in the day’s elective cases. The plan was approved and adopted by the medical director of the cath lab, the project team and hospital administration.

Since the plan was implemented in late January, average waiting times for urgent cases have dropped 50 – 60%. These are cases that cardiologists determined should be cared for within 24 hours. At the same time, emergency cases continue to get into the cath lab in less than 90 minutes, the “gold standard” for cardiac care.

“By performing non-elective cases in designated rooms starting in the morning, and implementing other operational improvements, we have seen a decrease in waiting time. This has helped to improve the quality of care that we provide to our patients, and has decreased the amount of time that our patients need to fast,” said Dr. Arthur Reitman, Medical Director of Kennestone’s cath lab.

“The staff is pleased with the new design. Their days are much more predictable, and they more regularly go home on time or earlier. I am delighted about the ongoing projects with PatientFlow Technology, and the results we are achieving here,” added Dr. Reitman. The average amount of time that the lab has had to stay open past regular hours on a daily basis has dropped from about 55 minutes to less than 10 minutes.

“The project has measurably improved the cath lab efficiency and provided a framework that all the physicians are comfortable with,” said Pat Jansen, Vice President of Cardiac Services. “And the sicker patients are getting into the lab more quickly,” concurred Brenda Adams and Susan Wheaton, cath lab flow coordinators at Kennestone. Notably, waiting times decreased even as the volume of cases increased 15% over the first three months of the project and the utilization rate of the cath lab rooms increased by 10%.

Dr. Diosdado Irlandez, Cardiologist at Kennestone, commented, “I do not feel as busy, although we are doing more cases. We used to bump patients from day to day; it was very embarrassing to bump a patient who had been fasting from midnight the day before.””Now, we don’t have to do that anymore,” added Dr. Scott McKee, Cardiologist at Kennestone.

“Kennestone is pioneering an extensive operational improvement effort. Word has spread quickly about the tremendously successful results we are seeing in the OR, ER and now the cardiac cath lab,” said Candice Saunders, SVP and hospital administrator, WellStar Kennestone. “Although they are different, each successive project is running more smoothly and with better collaboration. Staff and physicians want to become a part of the process and improve not only their own workflow, but also the quality of care they offer our patients. Without a doubt, these enhancements are also paying big dividends in the form of patient satisfaction and a more balanced life for our staff and physicians.”

“Kennestone continues on a successful path with its operational improvement projects by moving into the cardiac cath lab. This unique and bold move illustrates the hospital’s true world-class colors,” said Richard Siegrist, President and CEO of PatientFlow Technology. “The cath lab is one of the most stressful and complex areas of the hospital to manage, and Kennestone has seen outstanding results in terms of decreasing wait times for urgent/emergent cases and improving the utilization rate of the cath lab rooms. All levels of the hospital are seeing the benefits.”

About WellStar Health System

The vision of WellStar Health System is to deliver world-class healthcare through our hospitals, physicians and services. WellStar Health System includes Cobb, Douglas, Kennestone, Paulding and Windy Hill hospitals; WellStar Physicians Group; Urgent Care Centers; Health Place; Homecare; Hospice; Atherton Place; Paulding Nursing Center; and WellStar Foundation. For more information, call 770-956-STAR or visit www.wellstar.org.

About PatientFlow Technology, Inc.

PatientFlow Technology provides tools and services for hospitals to address problems such as emergency room overcrowding, long wait times, bumped or delayed surgeries, and lack of available ICU and routine hospital beds, while concurrently improving quality of care. The company’s headquarters are in Boston, Massachusetts. For more information, visit www.patientflowtech.com or call 617-358-5060.

 Contact: PatientFlow Technology Osnat Levtzion-Korach 617-358-5060 [email protected]  Schwartz Communications Davida Dinerman/Wendy Mejia 781-684-0770 [email protected]

SOURCE: PatientFlow Technology

Taro Pharmaceutical Industries has received final approval from the FDA for its abbreviated new drug application for prescription cetirizine hydrochloride syrup, 1mg/1ml.

Taro had received tentative approval for this abbreviated new drug application in October 2007. The company plans to market the product through its US affiliate, Taro Pharmaceuticals USA.

Taro’s Cetirizine syrup is bioequivalent to McNeil Consumer Healthcare’s Zyrtec syrup. Cetirizine syrup is a prescription medication used for the relief of symptoms associated with perennial allergic rhinitis in children six to 23 months of age, and for chronic urticaria in children six months to five years of age.

By Denise Allabaugh, The Citizens’ Voice, Wilkes-Barre, Pa.

Jun. 24–WILKES-BARRE — With no job and no health insurance, Agnes Barberio came to the Volunteers in Medicine free medical clinic Monday seeking relief for a variety of health problems after being turned away at other places.

The 49-year-old Larksville resident formerly worked at Lord & Taylor until 2004 when she got sick. Her husband is disabled and does not work.

Barberio was one of several uninsured people who sought medical attention at the clinic, which opened Monday at 190 N. Pennsylvania Ave., Wilkes-Barre. The volunteer-based medical center will provide a wide range of medical services, including primary health care for the uninsured and the underinsured in Luzerne County, services Barberio said she needs.

“I’m always in constant pain,” Barberio said, while bursting into tears in a treatment room in the new clinic while waiting to see Dr. Susan Sordoni, the only doctor volunteering Monday. “We have been calling trying to get some kind of insurance off TV and I can’t afford it.”

Sordoni, the clinic’s founder, was busy on opening day seeing 10 patients who scheduled appointments and three others who walked in seeking medical care.

“This is a sign that people have been waiting and need the care,” Sordoni said. “Primary health insurance is extremely costly. People have jobs and their employers cannot supply the insurance because they cannot afford to supply the insurance. If people don’t have a clinic like this, they will go to the emergency room and pay 10 times the cost or more.”

According to figures provided by Volunteers in Medicine, more than 35,000 residents in Luzerne County do not have access to or cannot afford health insurance. While the clinic was set up to serve the working poor who don’t have health insurance, Sordoni said everyone who walks in the door would be seen. If they cannot be helped at the clinic, volunteers will direct them to the right services.

“If people don’t have jobs and don’t have primary care insurance, they become our patients,” Sordoni said. “If they qualify as a patient for this medical center, we will see they have all they need. Others have access to other insurance and we will help them find it.”

Sordoni plans to maintain her practice in Kingston and will recruit other doctors to volunteer at the free clinic. Renovations are still being completed. The clinic has two treatment rooms and will eventually offer additional treatment rooms as well as dental and eye care and a pharmacy, said Kelly Ranieli, executive director for the clinic.

“We’re in the process of organizing all the volunteer physicians,” Ranieli said. “The nurses will be volunteers.”

The clinic also will employ a paid medical director, who has not yet been hired, a nursing director and an administrative assistant, Ranieli said. Corporate donations and foundation grants are funding the clinic, which was planned for more than three years, she said.

Sister Lucille Brislin of Mercy Services, who works with low-income families and who accompanied an uninsured woman Monday, credited Sordoni for opening the free clinic.

“She has been committed for years to the establishment of this clinic, which serves a desperate need for health care,” Brislin said. “Without people like Dr. Sordoni and her co-workers and the volunteers, the health care crisis would be far more intensified than it already is.”

[email protected], 570-821-2115

Info box: Volunteers in Medicine free health clinic at 190 N. Pennsylvania Ave. in Wilkes-Barre will be open Mondays through Fridays from 9 a.m. to 4 p.m. The volunteer-based clinic will provide a wide range of services, including primary and preventative health care and eventually dental and eye care to the uninsured and underinsured in Luzerne County. To schedule an appointment or to volunteer, call 970-2864.

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To see more of The Citizens’ Voice or to subscribe to the newspaper, visit http://www.citizensvoice.com/.

Copyright (c) 2008, The Citizens’ Voice, Wilkes-Barre, Pa.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

By Tim Moran, The Modesto Bee, Calif.

Jun. 24–Where there’s smoke, there’s fire — and vice versa. Wildfires are raging throughout Northern California, and that’s why the air in the Northern San Joaquin Valley is hazy to downright smoky.

The fires are to blame for the unhealthy air quality throughout the region.

A fire in Napa and Solano counties is generating significant amounts of smoke, which is carried into the valley on delta breezes.

To the east of Modesto, a 600-acre fire in the Stanislaus National Forest is contributing to the smoky sky. Air tankers and helicopters are dumping retardant on the blaze, but firefighters are having to hike miles through rugged terrain without trails to get to it, forest spokesman Jerry Snyder said.

Oakdale has been engulfed in smoke from the fires, and San Joaquin Valley Air Pollution Control District monitors are picking up smoke particles in Stockton and Modesto, according to Shawn Ferreria, senior air quality specialist with the district.

The district doesn’t have monitors in Oakdale, but a resident reported heavy smoke in town Monday morning. A spokeswoman for Oak Valley Hospital in Oakdale said Monday evening that the emergency room there has not experienced an increase in patients because of the air quality.

A staff member in the emergency room at Doctors Medical Center said that as of 7:30 p.m. Monday there had not been an increase in ER patients because of the dirty air although he expected to get a few extra patients.

Residents with asthma or other respiratory problems are urged to stay indoors. The small particles in the smoke are capable of getting deep into the lungs, Ferreria said, causing health problems.

Exposure to the particle pollution can aggravate lung disease, cause asthma attacks and acute bronchitis and increase the risk of respiratory infections, according to the air district.

Short-term exposure to particle pollution also has been linked to heart attacks and arrhythmia in people with heart disease, according to the Environmental Protection Agency.

Older adults and children should avoid prolonged exposure and strenuous activities, and everyone else should reduce exposure and heavy exertion, air district officials warn.

Air quality might get worse

If the conditions persist today, Ferreria predicted that San Joaquin County air will be declared unhealthy and Stanislaus County as unhealthy for sensitive groups. That would move Stanislaus County from a yellow air quality status to orange in the alert system.

“Those are very important triggers to us,” said Dr. John Walker, Stanislaus County’s public health officer.

“At orange, we seek to notify the at-risk groups, and we have several groups of concern,” he said. Those include asthmatics, adults with chronic lung disease and those with heart disease.

The air quality is rated on a six-point scale: good, moderate, unhealthy for sensitive groups, unhealthy, hazardous and very unhealthy.

The thunderstorm system that came through California on Saturday generated 5,000 to 6,000 lightning strikes and sparked more than 700 fires, said Daniel Berlant, a spokesman for the California Department of Forestry and Fire Protection.

Many of those were small and were controlled at less than a few acres, he said. But some, fanned by wind, have grown much larger. In addition to the Tuolumne fire, Cal Fire is fighting blazes in Solano, Calaveras, Mendocino, Lassen and Modoc counties, Berlant said.

Fire crews might take a few more days to get all the fires under control, Berlant said. Air quality problems are likely to persist until the fires are out, Ferreria said.

Bee staff writer Emilie Raguso contributed to this report.

Bee staff writer Tim Moran can be reached at [email protected] or 578-2349.

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To see more of The Modesto Bee, or to subscribe to the newspaper, go to http://www.modbee.com/.

Copyright (c) 2008, The Modesto Bee, Calif.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

ROLLA, Mo., June 24 /PRNewswire/ — As hospitals struggle to staff their floors in the face of an ongoing shortage of hospitalists, one company has introduced a cost-effective way for hospitals to maintain safe continuity of care. Night Hospitalist Company, LLC (NHC, http://www.nighthospitalist.com/) provides nighttime hospital coverage by telephone — and demand is so great the service will soon be available nationwide.

Hospitalists — physicians working full-time in hospitals, instead of dividing their time between private practice and hospital rounds — are in such short supply, many daytime hospitalists are being overworked. Hiring a full-time nocturnist, or nighttime doctor, is expensive.

NHC, by comparison, provides reliable telephonic care from 7 p.m. to 7 a.m. for a fraction of the cost of hiring a staff physician. All NHC physicians are Board-certified or Board-eligible internal medicine M.D.s or D.O.s with extensive hospital experience. Each is qualified to handle emergency room calls, floor calls and stable ICU admissions. The NHC solution is seamless and designed to free hospitals up to concentrate their resources on patient care: NHC covers its own physicians’ malpractice insurance and documents all patient-related activity overnight using a web-based proprietary software called MDHandOff (http://www.mdhandoff.com/). All overnight changes in medical management are transmitted to the correct hospital floors for insertion into patients’ medical records. The company contracts directly with hospitals for ease of billing.

“NHC is the first solution of its kind,” stated company founder Dr. Yomi Olusanya. “We exist to give hospitals a viable way to provide high-quality patient care at night at a cost far lower than that of hiring on-site physicians. Our clients are not only weathering the hospitalist shortage and unexpected physician absences, they’re actually finding NHC to be a real alternative to full-time nocturnists.”

NHC physicians are also available to cover night calls for physicians in private practice as well as for nursing homes and acute care facilities. The company is currently evaluating telemedicine vendors, with an eye to remotely examining and evaluating patients via video telemetry. NHC serves facilities in Missouri but will soon have night hospitalists practicing across the U.S. To learn more, visit http://www.nighthospitalist.com/.

   Contact:    Yomi Olusanya, M.D.   Night Hospitalist Company, LLC   800-750-8952   [email protected]   http://www.nighthospitalist.com/    

This release was issued through eReleases(TM). For more information, visit http://www.ereleases.com/.

Night Hospitalist Company, LLC

CONTACT: Yomi Olusanya, M.D., of Night Hospitalist Company, LLC,+1-800-750-8952, [email protected]

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

By MARIE LEVY

TEESSIDE parents today welcomed the unveiling of plans for the North-east’s first specialist children’s hospital – a pounds 100m facility set to revolutionise children’s care in the region.

Due for completion in 2010, the state-of-the-art hospital at the Royal Victoria Infirmary (RVI) in Newcastle is being dubbed a Great Ormond Street for the North.

Children like Acklam teenager Cameron Gibb, who suffers from a one-in-a-million bone condition, will benefit from the groundbreaking facility. Cameron’s mum Claire said having all the specialist services under one roof will be “very valuable” for parents.

The hospital will bring together all the region’s groundbreaking children’s services, including the heart transplant team from the Freeman Hospital, Newcastle General’s “bubble baby” unit – one of only two in the UK – and cancer experts from the RVI. The centre of excellence will house the widest range of children’s services outside of London and is designed to be as far removed from a traditional hospital environment as possible.

Every bedroom will let in maximum natural light while coloured, curved corridors will eradicate the feeling of long walkways.

It will accommodate 245 in-patients with 75% of its bedrooms designed for single occupancy and equipped with en-suite bathrooms and guest beds to allow parents to rest close to their child when they are most needed. The rooftop will feature a penthouse for teenage cancer patients and there will also be an atrium, outside courtyard, play area and a 50-seat cinema.

Georgina Curtis, 27, of Nunthorpe, whose daughter Emily, seven, is fighting germ cell cancer and has to travel to Newcastle for chemotherapy, said: “It sounds brilliant. I just wish it was open now.

“We have just spent a week on ward 16 in a cubicle because there are not enough separate rooms.”

Karen Harrison, 32, of NewMarske, lost her daughter Jessica to kidney cancer last year. The seven-year-old spent many weeks at the RVI during her brave two-year battle. She said: “It will be fantastic for the kids. The hospitals do look like hospitals at the moment so anything that brightens them up and makes them more comfortable is a good thing.”

Samantha Smith, 34, of Marton Grove, watched her daughter Louisa McGregor-Smith become the youngest baby ever to survive on an artificial heart machine last year when the tiny tot’s heart failed at just three months old and she was rushed to the Freeman Hospital. She said: “It’s a fantastic idea. It will be more child friendly.”

Dr Stephen Singleton, chairman of The Children’s Foundation and regional director of public health, said: “The new children’s hospital will be a fantastic resource for the whole region.”

Dr Mohammed Kibirige, consultant paediatrician at the James Cook University Hospital, said: “This is excellent news. We have finally agreed that children need to be seen in an environment designed for their specific needs.”

Join in the name game

TEESSIDERS are being asked to help pick a name for the new children’s hospital.

The three shortlisted names are:

The Greenhouse Children’s Hospital

Northern Lights Children’s Hospital

The Great North Children’s Hospital

To vote, visit www.hospitalvote.co.uk or text “HOSPITAL” to 60999 followed by the keyword of your favourite name: GREENHOUSE, LIGHTS or GREAT. Alternatively votes can be posted to PO Box 2YB, Queen Victoria Road, Newcastle upon Tyne, NE9 92Y. Votes close at midnight on July 2.

Voters are also urged to make donations via the same website to The Children’s Foundation. Donations will be used to fund a range of facilities at the new hospital from special interactive therapies to creative play schemes.

(c) 2008 Evening Gazette – Middlesbrough. Provided by ProQuest Information and Learning. All rights Reserved.

By Erin Wisdom, St. Joseph News-Press, Mo.

Jun. 24–Nursing home pageant names queen

The Ms. Missouri Nursing Home Pageant was held recently at Terrible’s Frontier Casino in St. Joseph.

The pageant is sponsored every year by the Missouri Health Care Association. The association’s second district, in Northwest Missouri, has approximately 35 member facilities. There were 13 queen candidates in attendance.

The winner was Lucille Benne from Tiffany Heights nursing home in Mound City, Mo. First runner-up was Vernace Gott of Oregon Care Center in Oregon, Mo. The winners will compete in August at the statewide pageant in Branson, Mo.

Auxiliary awards scholarships

The Hedrick Medical Center Auxiliary recently awarded $500 scholarships to Sarah McCumber, Amy Patel and Amber Parker, all of Chillicothe, Mo., Sadie Jones, Taylor Cox and Alana Tolle of Trenton, Mo., Deanna Peck of Newtown, Mo., and Elizabeth McMahon of Gilman City, Mo.

Auxiliary scholarships are awarded once a year with a May 15 application deadline. The Auxiliary scholarship program began in June of 1998. To date, 90 $500 scholarships have been awarded for a total of $45,000.

The HMC Auxiliary Scholarship Fund was established for the purpose of encouraging qualified individuals to pursue or to enrich a career in the health care field. For information on scholarships, contact the Hedrick Medical Center Human Resources department at (660) 646-1480.

Donations will help St. Joseph man in need of lung transplant

Good health is something often taken for granted until it becomes threatened. Joe Campbell of St. Joseph knows this, as that is what happened to him.

In 2004, Joe developed respiratory problems. Many tests later, he was diagnosed with bronchiectasis. To make matters worse, doctors discovered the bottom portion of his left lung was not functioning. This led him to being placed on numerous medications and requires him to use oxygen 24 hours a day.

Working with his doctors to find a solution, a lung transplant became the focus of his future. After a weeklong evaluation at Barnes Jewish Hospital in St. Louis, the determination was that Joe required a double lung transplant.

To help defray those expenses not covered by insurance, a fundraising campaign has been established in Joe’s honor with the National Transplant Assistance Fund (NTAF).

NTAF is a nonprofit organization that has been assisting the transplant community for over 20 years. All donations are tax-deductible and are administered for transplant expenses only. If you wish to make a donation, make checks payable to NTAF and note in the memo section “In Honor of Joe Campbell.” Please send to NTAF, 150 N. Radnor Chester RD, Suite F-120 Radnor, PA 19087.

St. Joseph woman to walk in mother’s memory

Allison (Fernelius) Smothers of St. Joseph, whose mother, Kathleen, lost her life to breast cancer, is raising funds to participate in the Breast Cancer 3 Day in Minneapolis, Minn., Sept. 19-21.

Participants in this event walk an average of 20 miles each day to reach their goal of 60 miles total and have to raise $2,200 each in order to do the walk. Allison and her teammates will be walking in memory of her mother.

Anyone interested in donating to Allison’s fund to help her reach this goal can contact her at (816) 341-1639. To learn more about the event, visit www.the3day.org.

Car wash will benefit Cliff Akins

A car wash will be held from 9 a.m. to 7 p.m. June 29 at Auto Zone, 520 S. Belt Highway, to raise money for the Cliff Akins cancer fund, which has been established to pay for chemotherapy for the area resident. Payment will be by donation only, and volunteers are needed to help wash cars.

Donations also may be made to the fund at all area Nodaway Valley Bank locations. For more information, call 324-0322 or 244-1236.

Fundraisers will help Hayden Wion

Upcoming fundraisers to benefit Hayden Wion include a car wash and garage sale.

His family continues to seek donations, which can be made by contacting Tommie Haeberle at 617-3084, by contributing to donation buckets at Speedy’s No. 7, Barbosa’s Castillo and Blockbuster or by giving money at any Nodaway Valley Bank. The trust is under Larry and Hayden Wion.

Hayden’s family thanks everyone who has helped them raise $7,500 so far.

Lifestyles reporter Erin Wisdom can be reached at [email protected].

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To see more of the St. Joseph News-Press or to subscribe to the newspaper, go to http://www.stjoenews-press.com/.

Copyright (c) 2008, St. Joseph News-Press, Mo.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

NYSE:BBI,

By Bill Chronister, The Columbus Dispatch, Ohio

Jun. 24–Greg Ubert and Armando Escobar have a long history with Ohio State University and will be going back this fall, but not to study.

The founders of CrimsonCup, who met 18 years ago when Escobar was working at the old student union, will be providing products and training coffee-shop managers and employees at several venues on OSU campuses.

The new contracts will make CrimsonCup the brew you buy at the cafe in the new Thompson Library when it opens in 2009, as well as the Science and Engineering Laboratory, the OSU MarketPlace at 1578 Neil Ave. and the new Warner Library and Student Center on the Newark campus.

“Our mission is to roast the best coffee in the world and teach others how to be successful in the business of brewing and selling it,” Ubert said.

That mission dovetails nicely with several initiatives that OSU dining services tries to meet, said Thom Stevenson, director of food-service operations.

“OSU’s Eat Global, Buy Local campaign — by which we do as much as we can with local industry to support the Ohio economy –ensures that we give operations such as CrimsonCup a look,” Stevenson said. “They provide a lot of value in a number of ways.”

One is that the facilities remain in OSU’s control. CrimsonCup provides training through its sole proprietary store, at 4541 N. High St. And Ubert and his company have gone out of their way to provide special services for OSU, including creating a private-label coffee blend for the Blackwell Inn on campus.

And it doesn’t hurt that the product tastes good. The bidding process involves blind taste tests for staff, professors and students, which Stevenson said CrimsonCup’s brews regularly win.

Vito, Vito, Vito

First, there was Vito’s Italian Pub, the brainchild of John Magnacca, on Broadway in Grove City and then on Scioto-Darby Road in the Hilliard area.

For partnership reasons, Magnacca let that go so he could focus on Vito’s Italian Express on Grandview Avenue, near W. 5th Avenue. But he wasn’t pleased with the way things were running there, either.

Now, for those craving Italian Twisty Rolls or a Spaghetti Sangwich, there’s Don Vito’s Italian Bistro, which opened recently at 4015 Parkmead Dr. in Grove City.

Magnacca is the owner, but he’s installed his son Christian as executive chef, entrusting him with Magnacca’s inventions as well as the recipes for lasagna and Italian wedding soup that Magnacca’s mom used to make at Cenci’s Restaurant on W. 5th Avenue near Marble Cliff.

“I don’t care if it’s got a Don before it and Bistro instead of pub, people see the word Vito’s and they know what to expect,” Magnacca said. “All these other imitations out there are just trying to catch a ride on what we have developed.”

Don Vito’s opens at 11 a.m. Tuesday through Saturday, closing at 10 p.m. on weeknights and “later” on Friday and Saturday, Magnacca said. It’s open from 1 to 10 p.m. on Sundays. Lunch is about $8 per person and dinner about $13-$14.

Eggs at your door

Jon and Pete Nowak, owners of Cafe Corner at 1105 Pennsylvania Ave., near W. 3rd Avenue, have seen a need, and they’re frying to fill it.

Realizing that eggs — and other breakfast foods — hadn’t yet been offered for delivery, the two last week began EGGS Breakfast Delivery in the University District and nearby.

“I know people enjoy breakfast food at night,” Jon Nowak said. And now you can order a meal to be delivered to your door between 8 p.m. and 3 a.m.

“We’re trying to open quietly right now; we’re still trying to work the kinks out before school resumes in fall,” Jon Nowak said.

Pete Nowak remains in charge of the cafe, a breakfast-and-lunch operation. Jon has taken on the new venture.

The delivery menu includes some breakfast specialties, including the Horseshoe, with hash browns, eggs, meat and gravy or cheese sauce for $8.99.

Food, wine event

The Columbus Food & Wine Affair is preparing for its fifth run as a fundraiser by the Central Ohio Restaurant Association. The gala features food from 25 local restaurants, a silent auction and live music and will take place from 6:30 to 10 p.m. Sept. 5 at the Franklin Park Conservatory.

The event benefits CORA, the WBNS-TV Family Fund, Arthur G. James Cancer Hospital, United Way of Central Ohio, Adventures for Wish Kids and the Ian Adams VanHeyde Scholarship Fund.

Tickets are $100 per person and go on sale starting July 1 on the charity’s Web site, www.foodandwineaffair.com.

Bar adds new twists

New to the bars at central Ohio’s four Hyde Park Prime Steakhouses: a nitrogen-charged process that allows bartenders to add a light foam garnish to many drinks, and additions to the drink menu, including sirloin “sliders” and bacon-wrapped scallops and calamari, $5 each.

Minty fresh

Dairy Queen’s Blizzard flavor of the month for July is Girl Scout Thin Mints.

On Restaurants is a weekly column about the restaurant industry. Send tips, information and news releases to: [email protected].

[email protected]

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To see more of The Columbus Dispatch, or to subscribe to the newspaper, go to http://www.columbusdispatch.com.

Copyright (c) 2008, The Columbus Dispatch, Ohio

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

St. David’s Community Health Foundation (SDCHF) announced today that they have awarded $2.3 million in grants to area nonprofit organizations to help address mental health needs in the Central Texas region.

“In our third year of making grants in the mental health sector, we have increased our grants by more than 56 percent, an increase we support as we have seen the value of integrating mental health care with other health resources at the clinical level,” said Earl Maxwell, CEO of St. David’s Community Health Foundation. “As part of our mission of increasing access to health care, we are gratified to see the positive benefits of providing mental health grants along with the grants we make toward physical good health.”

SDCHF provides grants to selected organizations on a twice-yearly schedule: physical health grants, grants for aging adults, and grants for special populations in December of each year; and mental health grants in June.

The 2007 grants provided funds for mental health care to accompany physical health care at two Central Texas safety net clinics, Lone Star Circle of Care in Williamson County and People’s Community Clinic in Austin. A year-long study showed the medical benefits of integrated care, and the 2008 grants continue to support those clinics’ integrated mental health care programs.

“The vast majority of the 975 patients we have treated since starting this program in 2006 are uninsured and have had little access to mental health services,” said Dr. Lucius Ripley, psychiatrist at Lone Star Circle of Care. “By integrating psychiatric and primary care services, daily consultations between myself and our primary care providers are routine, making psychiatric treatment both more efficient and effective. None of the success we have experienced would have been possible without the significant support of the St. David’s Community Health Foundation, and we are grateful for the Foundation’s continued support of LSCC’s adult and our new child and adolescent mental health programs.”

“We have seen incredible results with our patients who participate in the integrated behavioral health program,” said People’s Community Clinic clinical care manager Megan Zesati. “Funding for the program allows us to provide a continuum of care in the complex lives of our patients, who might otherwise not seek help for their emotional issues. Very often, helping alleviate their emotional burdens has helped the patient and their doctor better cope with their physical or chronic illness.”

A complete listing follows of the grants announced today by St. David’s Community Health Foundation.

For more information on St. David’s Community Health Foundation, visit www.sdchf.org.

 St. David's Community Health Foundation Mental Health Grant Totals 2006-2008  Year                Amount ---------------------------------------------------------------------- 2006                $811,000 ---------------------------------------------------------------------- 2007                $1,347,417 ---------------------------------------------------------------------- 2008                $2,309,632(a) ---------------------------------------------------------------------- 

(a) includes $20,000 for ongoing program evaluation

 St. David's Community Health Foundation Grant Totals 2004-2008  Year                Amount ---------------------------------------------------------------------- 2004                $1,188,000 ---------------------------------------------------------------------- 2005                $2,016,908 ---------------------------------------------------------------------- 2006                $4,101,131 ---------------------------------------------------------------------- 2007                $5,222,150 ---------------------------------------------------------------------- 2008                $7,072,310 ---------------------------------------------------------------------- 

 St. David's Community Health Foundation 2008 Mental Health Grant Recipients 

 St. David's Community Health Foundation Mental Health Grants for Psychiatric Bed Crisis $266,961 -- 166% increase over 2007 total of $100,000 

Austin Recovery: Grant for one detox bed and three residential treatment beds for existing patients at ATCMHMR, as part of overall strategy dealing with emergency room crowding by mental health patients.

 St. David's Community Health Foundation Mental Health Grants for Care $1,862,671 -- 54% increase over 2007 total of $1,207,417 

Any Baby Can: Grant supports No Estas Solo, in-home counseling for clients in any of ABC’s programs; will serve an additional 85 clients per year.

Austin Child Guidance Center: Grant supports further expansion of psychological assessment unit; will allow more assessments, more individual counseling, and more group counseling.

Breakthrough: Grant supports Project Safety Net; provides mental health evaluation, counseling, and treatment services for middle and high school students participating in Breakthrough programs.

Communities in Schools: Grant supports salary increases for campus program managers in middle-school programs and operational support.

Easter Seals-Central Texas: Grant supports salary for a counselor; will provide free counseling to clients in the Transitions Project who have mental health issues, physical disabilities, and substance abuse issues.

FamilyConnections: Grant supports Parents of Newborns project, whose staff provides counseling and support for women identified with post-partum depression at hospitals.

Family Crisis Center: Grant supports the school-based counseling program and provides an additional component of partial funding for group counseling for anger management in teens.

Hays-Caldwell Women’s Center: Grant supports continued funding for sexual assault and family violence programs.

Helping Hand Home for Children: Grant supports psychiatric services for 35 children staying in HHH foster care homes; supports training for foster parents.

Interagency Support Council of East Williamson County: Supports East Williamson County school-based mental health project; provides counseling, therapy, and case management for students.

Leander ISD: Grant supports school-based counseling services at five schools; will allow a 5 percent increase in number of students served.

LifeWorks: Grant supports additional counselor for Youth and Adult Counseling Program.

Lone Star Circle of Care: Grant supports additional child psychiatrist for clinic’s child and adolescent program.

People’s Community Clinic: Grant supports clinical social worker staff.

SafePlace: Grant supports a broad range of counseling services for children and adults; will address the waiting-list issue and allow SafePlace to serve more clients.

Samaritan Center for Pastoral Care: Grant supports fee assistance for low-income uninsured families.

SIMS Foundation: Grant supports funding for counseling, psychiatric, and addiction intervention for local musicians.

Waterloo Counseling: Grant supports Project Counselor staff, Clinical Director position, and project supervision.

 St. David's Community Health Foundation Mental Health Grants for Capital Funds $160,000 -- 700% increase over 2007 total of $20,000 

Capital Area Mental Health Center: Grant supports facility expansion; will lead to a 25 percent increase in number of clients served.

People’s Community Clinic: Grant supports expansion/renovation of space for Integrated Behavioral Health Care Initiative.

Samaritan Center for Pastoral Care: Grant supports capital campaign.

Tybee, a 10-year-old rough-coat Jack Russell terrier, has lymphoma, a cancer that affects the immune system.

“(Having cancer) really hasn’t affected him except the big treatments, which make him nauseous,” said his owner, Kathy Maschka.Tybee’s normally long hair fell out when he began treatment six months ago, giving him a freshly trimmed look.Friday he went for his last round of chemotherapy in Charleston. After his treatment, he nibbled on his favorite meal — chicken and Special K cereal.

And he missed only one day of work in those six months. Ironically, Tybee is one of five dogs registered by Therapy Dogs International Inc. that volunteer at Beaufort Memorial Hospital, visiting patients.

Tybee has been visiting patients at Beaufort Memorial for at least five years, giving him seniority in the therapy dog pack.

The hospital hopes that having dogs visit will improve patients’ experience, as well as lower their blood pressure, stress, anxiety and emotional pain. Many studies assert that being around companion animals has that effect on people.

Maschka said Tybee looks forward to his job, even if it means he has to take a bath, something he despises.

When Tybee enters a patient’s room, he picks up on the patient’s mood. If the patient is subdued, he remains calm and sits in the patient’s lap, content to be petted. If the patient is happier, he has more energy and wiggles around, Maschka said.

Sometimes Tybee’s role is a little more complex.

On one occasion, hospital staff members told a patient they had a surprise for her, but she had to get off her ventilator first. The incentive worked. A visit from Tybee was the surprise.

Another time, a woman told Maschka that Tybee’s visit to her mother when she was in the hospital lifted her mother’s spirits and she spoke of the visit until she died a few days later.

To become a therapy dog, Tybee went through a rigorous behavioral test and evaluation that includes walking past an open cheeseburger on the floor.

The five therapy dogs visit people in the mental health, rehabilitation, mammography and administration departments, said Jamie McMahon, the hospital’s volunteer coordinator.

JoAnn Graham, the owner of Bonnie, a white golden retriever therapy dog, shadowed Maschka and Tybee before she and Bonnie started their rounds.

Graham said there is an automatic connection between humans and animals.

Having a dog visit while a patient is in the hospital can bring back fond memories of a childhood pet and that makes it easier to be in the hospital, Maschka said.

“It’s so good to bring a smile to people’s faces,” she said.

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To see more of The Beaufort Gazette or to subscribe to the newspaper, go to http://www.beaufortgazette.com.

Copyright (c) 2008, The Beaufort Gazette, S.C.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected], call or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.