Target Health is pleased to announce that eCliniqa (http://www.ecliniqua.com/2009/05/26/ferring-target-health.html) has a feature article entitled “EDC Co-Development a Win-Win for Ferring, Target Health.” The article, written by Deb Borfitz (26 May 2009), interviewed Dr. Per Cantor, Senior VP of Clinical and Non-Clinical R&D at Ferring Pharmaceuticals in Copenhagen. Dr. Cantor summarized Ferring’s 10 year relationship with Target Health which includes 4 NDAs, 3 of which used Target e*CRF®. The article emphasized the true partnership between the 2 companies and the rationale for partnering to develop an EDC system. 

Target e*CRF® has been used in over 160 studies, 4 approved NDAs, 1 approved BLA, 10 approved PMAs and 1 approved 510k, as well as for approvals in Canada and Europe. One NDA was approved this year as well as 1 PMA. We expect another European approval this year. In addition, two NDAs will be submitted this year which used Target e*CRF® for the pivotal trials. Target Health will do a full eCTD submission for one of the NDAs and will prepare Module 1 for the second NDA. 

For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com

Creating a Mouse With a Human Gene For Language

The gene, FOXP2, was identified in 1998 as the cause of a subtle speech defect in a large London family, half of whose members have difficulties with articulation and grammar. All those affected inherited a disrupted version of the gene from one parent. FOXP2 quickly attracted the attention of evolutionary biologists because other animals also possess the gene, and the human version differs significantly in its 1) ___ sequence from those of mice and chimpanzees. Researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, have now genetically 2) ___ a strain of mice whose FOXP2 gene has been swapped out for the human version. The study is reported in the journal Cell. Svante Paabo, in whose laboratory the mouse was engineered, promised several years ago that when the project was completed, “We will speak to the mouse.” He did not promise that the mouse would say anything in reply, doubtless because a great many genes must have undergone 3) ___ change to endow people with the faculty of language, and the new mouse was gaining only one of them. So it is perhaps surprising that possession of the human version of FOXP2 does in fact change the sounds that mice use to communicate with other mice, as well as other aspects of brain function. FOXP2, a gene whose protein product switches on other 4) ___, is important during embryonic development and plays an active part in constructing many tissues, including the lungs, stomach and brain. The gene is so vital that mice in which both copies of the gene are disrupted die after a few weeks. Despite the mammalian body’s dependence on having its two FOXP2 genes work just right, it was found that the human version of FOXP2 seemed to substitute perfectly for the mouse version in all the mouse’s tissues except for the 5) ___. In a region of the brain called the basal ganglia, known in people to be involved in language, the humanized mice grew nerve cells that had a more complex structure. Baby mice utter ultrasonic whistles when removed from their mothers. The humanized baby mice, when isolated, made whistles that had a slightly lower pitch, among other differences. Dr. Enard proposed that putting significant human genes into mice is the only feasible way of exploring the essential differences between people and chimps. There are about 20 million DNA differences between the 6) ___ of humans and chimps, but most make no physical difference. To understand which DNA changes are important, the genes must be put into another species. There is no good way of genetically engineering chimps, even if it were 7) ___ acceptable, so the mouse is the test of choice. Dr. Joseph Buxbaum, an expert on the molecular basis of psychiatric disease at Mount Sinai Medical Center, said Dr. Enard’s team had taken a good first step toward understanding the role of FOXP2 in the development of the brain. “The most surprising finding, and cause for great optimism, is that the gene does seem to have a great effect on pathways of 8) ___ development in mice,” he said. Dr. Gary Marcus, who studies language acquisition at New York University, said the study showed lots of small effects from the human FOXP2, which fit with the view that FOXP2 plays a vital role in language, probably with many other genes that remain to be discovered. “People shouldn’t think of this as the one language gene but as part of a broader cascade of genes,” he said. “It would have been truly spectacular if they had wound up with a talking mouse.” Source: NY Times 29 May 2009 

ANSWERS

1) DNA; 2) engineered; 3) evolutionary; 4) genes; 5) brain; 6) genomes; 7) ethically; 8) neural

The oldest known skeleton showing signs of leprosy has been found in India and may help solve the puzzle of where the disease originated. The skeleton, about 4,000 years old, was found at the site of Balathal, near Udaipur in northwestern India. Historians have long considered the Indian subcontinent to be the source of the leprosy that was first reported in Europe in the fourth century BCE, shortly after the armies of Alexander the Great returned from India. The skeleton is described in the journal PLoS One by Gwen Robbins, an anthropologist at Appalachian State University, and colleagues in India. The authors say the skull shows signs of erosion typical of leprosy. The authors say their find confirms that a passage in the Atharva Veda, a set of Sanskrit hymns written around 1550 BCE, indeed refers to leprosy, a reading that had been doubted because until now the oldest accepted written accounts of the disease were from the sixth century BCE. It was reported three years ago that the bacterium that causes leprosy seemed to have spread worldwide from a single clone. But for lack of sufficient samples, they could not tell whether the bacterium was disseminated when modern humans first left Africa about 50,000 years ago, or spread from India in more recent times. Other biologists have contended that because the bacterium is not very transmissible, requiring prolonged intimate contact between people, it would not have started to spread until around the third millennium BCE., when people started living in dense populations in cities and long-distance trade sprang up. Helen D. Donoghue, an infectious disease specialist at University College London, said the new finding was fascinating and fit in with the theory that Alexander’s army had brought leprosy back from its campaigns in India. This was the right period for leprosy to have spread from India to Europe, Samuel Mark, an anthropologist at Texas A&M, argued in an article in 2002. But he doubted that Alexander’s troops were the mode of transmission. More likely, in his view, is the possibility that leprosy arrived with women imported as slaves by ship from India to Egypt. Dr. Robbins said she planned to extract ancient bacterial DNA from the Indian skeleton and hoped it might resolve how the disease originated. Source: The New York Times, May 27, 2009

Inflammation is an immune response that helps facilitate the healing process and is part of the body’s natural defense against harmful elements, such as pathogens, damaged cells, or other irritants, and. Inflammation can be classified as either acute or chronic. Acute inflammation is the short-term, beneficial response to harmful stimuli. Chronic inflammation is a disease in which the inflammatory state persists and may result in tissue damage. C-reactive protein (CRP) and serum amyloid A (SAA), accumulate in the blood in response to inflammation. CRP is produced by the liver, as well as by fat cells, and has several immune-related functions. SAA, which is also secreted by the liver, is involved in both the transport of cholesterol from the liver to the bile, and the recruitment of immune cells to sites of inflammation. Both proteins are found in higher concentrations in the blood of people with low-grade chronic inflammation, which is believed to contribute to the development and spread of breast cancer. Breast cancer survivors with chronic inflammation may be at a higher risk of recurrence. Elevated CRP is also linked to increased risk of heart disease. According to an article published online in the Journal of Clinical Oncology (May 26, 2009), an association has been found between breast cancer survival and two proteins that, when present in the blood in high levels, are indicators of inflammation. Using data from the Health, Eating, Activity and Lifestyle (HEAL) study, it was shown that breast cancer patients with elevated levels of CRP and SAA were approximately two to three times more likely to die sooner or have their cancer return than those patients who had lower levels of these proteins, regardless of the patient’s age, tumor stage, race, body mass index, or history of previous cardiovascular issues. The Heal study joins an increasing body of research indentifying CRP and SAA as indicators of reduced survival from cancer. Previous studies have shown an association between elevated levels of CRP and poor survival outcomes in metastatic prostate cancer, as well as gastroesophageal, colorectal, inoperable non-small-cell lung, and pancreatic cancers. In other studies, a similar association was shown for SAA and gastric cancer and renal cell carcinoma. Although research has indicated that inflammation may play a role in the progression of cancer, the exact mechanism by which this happens has been unclear. For the study, 1,183 women with early-stage breast cancer were recruited from three cancer centers. Participants completed a lifestyle questionnaire when they joined the study and the researchers collected blood samples (which were analyzed for CRP and SAA levels) and height and weight measurements at a subsequent visit two years later (approximately 2.5 years after their initial diagnosis). The women will be followed for a total of 10 years. Because the biomarkers were measured approximately 31 months after diagnosis, enough time had passed to accurately assess the effect of chronic inflammation, as opposed to acute inflammation that may have been a result of the breast cancer treatments each patient received. The study examined the relationships between the inflammation biomarkers and both overall survival and disease-free survival. Overall survival was defined as the amount of time from the follow-up appointment until the patient died (from any cause) or the study period ended. Disease-free survival was defined as the amount of time from the follow-up appointment until the patient’s breast cancer returned, a new cancer was diagnosed, the patient died, or the study period ended. Results showed that women with high levels of SAA were three times as likely to die sooner, and women with high levels of CRP were two times as likely to die sooner. They found similar, but weaker, associations with disease-free survival, in that women with high levels of SAA were two times as likely to die or have their cancer return, and women with high levels of CRP were more than 1.5 times as likely to die or have their cancer return. This suggests that SAA and CRP may be more closely related to overall survival than disease-free survival.

The health of our skin – one of the body’s first lines of defense against illness and injury – depends upon the delicate balance between our own cells and the millions of bacteria and other one-celled microbes that live on its surface. To better understand this balance, NIH researchers have set out to explore the skin’s microbiome, which is all of the DNA, or genomes, of all of the microbes that inhabit human skin. Their initial analysis, published in the journal Science (May 29, 2009: 1166-1168), reveals that human skin is home to a much wider array of bacteria than previously thought. The study also shows that at least among healthy people, the greatest influence on bacterial diversity appears to be body location. For example, the bacteria that live under your arms likely are more similar to those under another person’s arm than they are to the bacteria that live on your forearm. The study involved taking skin samples from 20 sites on the bodies of 10 healthy volunteers. DNA was then extracted from each sample and the 16S ribosomal RNA genes, a type of gene that is specific to bacteria, were sequenced. More than 112,000 bacterial gene sequences were identified, which were classified and compared. The analysis detected bacteria belonging to 19 different phyla and 205 different genera, with diversity at the species level being much greater than expected. There was considerable variation in the number of bacteria species at different sites, with the most diversity being seen on the forearm (44 species on average) and the least diversity behind the ear (19 species on average). The study also generated information that may prove useful in efforts to combat the growing problem of methicillin-resistant Staphylococcus aureus (MRSA), a bacterium that can cause serious, even life-threatening, infections. While it is known that a significant proportion of people have colonies of S. aureus inside their noses, the NIH team checked to see where else on the body surface that these bacteria thrive. They found that the crease of skin outside the nose is the site with the microbial community most similar to that found inside the nose. According to the authors, not only does this work shed new light on understanding an important aspect of skin biology, it provides yet another example of how genomic approaches can be applied to study important problems in biomedical research. NIH recently launched the Human Microbiome Project, a part of the NIH Roadmap for Medical Research, to discover what microbial communities exist in different parts of the human body and to explore how these communities change with disease. In addition to skin and nose, that project is sampling the digestive tract, the mouth, and other parts of the body. The skin sites selected for the Science study represent three microenvironments: oily, moist and dry. The oily sites included between the eyebrows, beside the nose, inside the ear, back of the scalp, and upper chest and back. Moist areas were inside the nose, armpit, inner elbow, webbed area between the middle and ring fingers, side of the groin, top fold of the buttocks, behind the knee, bottom of the foot and the navel. Dry areas included the inside surface of the mid-forearm, the palm of the hand and the buttock. Researchers found that dry and moist skin had a broader variety of microbes than did oily skin. Oily skin contained the most uniform mix of microbes. To look for changes that may occur in the skin microbiome over time, the study sampled some volunteers twice, with the samples being taken about four to six months apart. Most of the resampled volunteers were more like themselves over time than they were like other volunteers. However, the stability of the microbial community was dependent on the site surveyed. The greatest stability was found in samples from inside the ear and nose, and the least stability was found in samples from behind the knee.

There is a general concern and curiosity about the cardiovascular health implications of large size among professional football players and those players who aspire to professional status. As a result, a study published in the Journal of the American Medical Association (2009;301:2111-2119), was performed to assess cardiovascular disease (CVD) risk factors in active National Football League (NFL) players and to compare these findings with data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. The investigation was a cross-sectional study of 504 active, veteran football players from a sample of 12 NFL teams at professional athletic training facilities between April and July 2007. Data were compared with men of the same age in the general US population (CARDIA study, a population-based observational study of 1,959 participants aged 23 to 35 years recruited in 1985-1986). The main outcome measures were the prevalence of CVD risk factors (hypertension, dyslipidemia, glucose intolerance, and smoking). Results showed that the NFL players were less likely to smoke when compared with the CARDIA group (0.1% vs. 30.5%; P < .001). Despite being taller and heavier, NFL players had significantly lower prevalence of impaired fasting glucose (6.7% vs. 15.5%; P < .001). The groups did not differ in prevalence of high total cholesterol and low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), or high triglycerides. Hypertension (13.8% vs 5.5% and prehypertension (64.5% vs. 24.2% were significantly more common in NFL players than in the CARDIA group (both P < .001). Large size measured by body mass index (BMI) was associated with increased blood pressure, LDL-C, triglycerides, and fasting glucose, and decreased HDL-C. According to the authors, compared with a sample of healthy young-adult men, a sample of substantially larger NFL players had a lower prevalence of impaired fasting glucose, less reported smoking, a similar prevalence of dyslipidemia, but a higher prevalence of hypertension. Increased size measured by BMI was associated with increased CVD risk factors in this combined population.

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Once arthritis or injury destroys the cartilage that cushions the ankle bone, the joints can become painful enough to warrant total ankle replacement. The FDA has just approved a total ankle replacement system for arthritic or deformed ankles that may preserve some range of motion in the joint. The new prosthesis is a mobile-bearing device, which relies on bearings that move across a surface of polyethylene, a flexible plastic. The device is the first of its type. The Scandinavian Total Ankle Replacement (STAR) System is an alternative to fusion surgery and may allow for greater rotation and movement in the joint. Fusion surgery involves cementing the shin bone (tibia) – the thicker of the two bones in the lower leg – to the talus bone in the ankle. While the procedure stabilizes the ankle, it significantly decreases the ability to move the foot up and down. The FDA has already cleared several fixed-bearing ankle devices, which are also options to fusion surgery. In fixed-bearing ankle system, the articulating surface is molded, locked or attached to one of its metallic components. To support approval, a clinical trial followed a subgroup of a 224-patient clinical study and found that the STAR system demonstrated similar rates of adverse events, surgical interventions and major complications as fusion surgery. As a condition of FDA approval, the company will evaluate the safety and effectiveness of the device during the next eight years. The STAR Ankle is owned by Small Bone Innovations Inc. of Morrisville, Pa.

Work Starting on Flu Vaccine

Companies are starting preliminary work on a vaccine for the H1N1 flu, or swine flu, and should begin clinical trials soon, but the new vaccine will not be ready for widespread use until October, United States health officials said. Dr. Anne Schuchat of the federal Centers for Disease Control and Prevention said the agency shipped virus samples for making vaccines to manufacturers several days ago. Dr. Schuchat said that in coming weeks companies would start making “candidate lots” of vaccine that will be used for clinical trials over the summer.  Source: GoogleNew.com, NYTimes.com