Target Health is pleased to announce that it will again be exhibiting at the annual DIA meeting which is being held in San Diego between June 21-25, 2009. Besides our strong capabilities in Regulatory Affairs, Clinical Trials Management, Data Management, Biostatistics and Medical Writing, our booth will feature our Paperless Clinical Trial Toolbox including: 

1.      Target e*CRF® (16 FDA approvals, with 2 in 2008 and 2 in 2009)

2.      Target Document® (paperless TMF)

3.      Target Encoder® (MedDRA and WHO DRUG)

4.      Target e*CTMSTM (Clinical Trial Management)

5.      Target e*PharmacovigilanceTM (Form 3500A and CIOMS out of Target e*CRF®)

6.      Target Newsletter® (ongoing communications with data derived from Target e*CRF®)

7.      Target Time Management (tracks hours)

Let us know if you will be attending and please visit us at booths 2232-2234.

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

Biologists have long wondered why the embryonic heart begins beating so early, before the tissues actually need to be infused with 1) ___. Two groups of researchers from Children’s Hospital Boston, Brigham and Women’s Hospital, and the Harvard Stem Cell Institute (HSCI) – presenting multiple lines of evidence from zebrafish, mice and mouse embryonic stem cells – provide an intriguing answer: A beating heart and blood flow are necessary for development of the blood system, which relies on mechanical stresses to cue its formation. Their studies, published online by the journals Cell and Nature, respectively, on May 13, together offer clues that may help in treating blood diseases such as leukemia, immune deficiency and sickle cell 2) ___, suggesting new ways scientists can make the types of blood cells a patient needs. This would help patients who require marrow or cord blood transplants, who do not have a perfect donor match. One team used zebrafish, whose 3) ___ embryos allow direct observation of embryonic development. The team discovered that compounds that modulate blood flow had a potent impact on the expression of a master regulator of blood formation, known as Runx1, which is also a recognized marker for the blood 4) ___ ___ that give rise to all the cell types in the blood system. Confirming this observation, a strain of mutant embryos that lacked a heartbeat and blood circulation exhibited severely reduced numbers of blood stem cells. Further work showed that nitric oxide, whose production is increased in the presence of blood flow, is the key biochemical regulator: Increasing nitric oxide production restored blood stem cell production in the mutant fish embryos, while inhibiting nitric oxide production led to reduced stem cell number. Suppression of nitric oxide production in mice, by either genetic or chemical means, similarly reduced the number of functional Runx1-expressing blood stem cells. Nitric oxide appears to be a critical signal to start the process of blood stem cell production. This finding connects the change in blood flow with the production of new blood cells. The second team, was intrigued by the appearance of blood progenitors in the wall of the developing aorta soon after the heart starts 5) ___. They investigated the effects of mechanical stimulation on blood formation in cultured mouse embryonic stem cells. They showed that shear stress – the frictional force of fluid flow on the surface of cells lining the embryonic aorta – increases the expression of master regulators of blood formation, including Runx1, and of 6) ___ markers found in blood stem cells. Shear 7) ___ also increased formation of colonies of progenitor cells that give rise to specific lineages of blood cells (red cells, lymphocytes, etc.). These findings demonstrate that biomechanical forces promote blood formation. The researchers also studied mouse embryos with a mutation that prevented initiation of the heartbeat. These embryos had a sharp reduction in progenitor blood cell colonies, along with reduced expression of genetic markers of blood stem cells. When specific cells from the mutant embryos were exposed in vitro to shear stress, markers of blood stem cells and numbers of blood cell colonies were restored. Finally, the team showed that when nitric oxide production was inhibited, in both cell cultures and live mouse embryos, the effects of shear stress on blood progenitor colony formation were reduced. These observations reveal an unexpected role for biomechanical forces in 8) ___ development. This work highlights a critical link between the formation of the cardiovascular and hematopoietic systems. The authors of the two papers speculate that drugs that mimic the effects of embryonic blood flow on blood precursor cells, or molecules involved in nitric oxide signaling, might be therapeutically beneficial for patients with blood diseases. For example, nitric oxide could be used to grow and expand blood stem cells either in the culture dish or in patients after transplantation. (The studies were supported by the National Institutes of Health, the NIH Director’s Pioneer Award, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the Howard Hughes Medical Institute.)

ANSWERS

1) blood; 2) anemia; 3) transparent; 4) stem cells; 5) beating; 6) genetic; 7) stress; 8) embryonic

The first crusaders set out for Jerusalem in 1096. The crusades could be said to be the most fascinating events of the medieval world. The mass migration in sequential waves of tens of thousands of people from Europe to the eastern Mediterranean for such a disparate number of reasons created a complex and unique society. For thousands of crusaders this journey was a major challenge. The overland and sea journeys could lead to malnutrition, frostbite, drowning and the potential for the spread of communicable conditions from fleas to tuberculosis. An individual with a culture and an immune system developed for cooler northern Europe might have been at considerable risk migrating to the Middle East. First, he would encounter new diseases to which he might have little immunity, such as the parasites dracunculiasis and schistosomiasis. Moreover, a culture developed for a different region would have increased a crusader’s risk of succumbing to conditions resulting from conditions such as heat stroke or food poisoning. Soldiers involved in a long siege would have faced the risk of death or wounds from weapon injuries. The fact that siege conditions necessitated staying in the same place for so long, significantly increased the risk of ill health from other causes. Dysentery was well described in the chronicles and we would expect such gastrointestinal diseases to have resulted from contamination of drinking water supplies. Fevers and epidemics were often mentioned by those recounting life in army encampments. In many cases we will never know exactly which infections occurred in any particular epidemic, but there are a number of possibilities. Malarial parasites have been found in Egyptian mummies and this confirms their presence in the region well before the time of the crusades. Some Frankish written sources mention when a fever was periodic in nature and the time period at which the fever returns. In malaria, this is a classic sign of the disease. If an army was encamped close to marshes for a long period of time, we might expect a significant proportion of the troops to have been bitten by mosquitoes and run the risk of contracting malaria. Trachoma, also known in the past as ophthalmia, is an infection of the eyes which is spread by flies. Trachoma may have a protracted and chronic course which can end in blindness. Trachoma is also believed to have been present in the eastern Mediterranean well before the crusades and was probably endemic in ancient Egyptian times. This disease was still debilitating in more recent military expeditions to the Levant in the 19th and 20th centuries. Scurvy is the nutritional deficiency that results from insufficient intake of vitamin C in the diet. While the loss of teeth is perhaps the best-known consequence in severe cases, an individual may die from spontaneous bleeding if scurvy continues for a long enough time. Scurvy is clearly described in the troops of a number of Frankish sieges. In a medieval army it must have been very difficult to maintain personal hygiene, eat an adequate diet or live a lifestyle that would have minimized the risk of contracting any one of the wide range of diseases that existed. In consequence, thousands appear to have died from such diseases in the Latin East. (This is the first book to be published on any aspect of medicine in the crusades. Cambridge University Press 052184455X – Medicine in the Crusades: Warfare, Wounds and the Medieval Surgeon Piers D. Mitchell Excerpt)

The European Helicobacter Study Group has recently issued the current concepts in the management of Helicobacter pylori infection (Maastricht III Consensus Report, 2005). As a result, a study published in the American Journal of Gastroenterology (2009;104:21-25), was performed to examine the cumulative H. pylori eradication rates that can be achieved in clinical practice by adopting first and second regimens as proposed by the Maastricht III consensus and a third-line empirical levofloxacin-based regimen. For the study, H. pylori-positive patients were treated initially with a first-line eradication triple regimen consisting of omeprazole, amoxicillin, and clarithromycin and subsequently with a second-line quadruple regimen consisting of omeprazole, bismuth, metronidazole, and tetracycline. Finally, after two previous H. pylori eradication failures, patients received omeprazole, amoxicillin, and levofloxacin, as a third-line empirical strategy. The success rate was calculated by both intention-to-treat (ITT) and per protocol (PP) analyses. In total, 540 consecutive H. pylori-positive patients received first-line treatment (omeprazole, amoxicillin, and clarithromycin). H. pylori were eradicated in 380 patients and 40 patients were withdrawn (ITT, 70.3%; PP, 76%). The remaining 120 H. pylori-positive patients received second-line treatment (omeprazole, bismuth, metronidazole, and tetracycline). H. pylori were eradicated in 83 patients and 7 patients were withdrawn (ITT, 69.1%; PP, 73.45%). Finally, the remaining 30 H. pylori-positive patients received third-line treatment (omeprazole, amoxicillin, and levofloxacin). H. pylori were eradicated in 21 patients and 0 patients were withdrawn (ITT, 70%; PP, 70%). Thus, out of 540 patients initially included in the study, H. pylori were eradicated in 484 patients, 47 were withdrawn, and only 9 remained positive. These results give 89.6% ITT and 98.1% PP cumulative H. pylori eradication rates. According to the authors, by adopting first- and second-line regimens, as proposed by the Maastricht III consensus and a third-line levofloxacin-based empirical regimen, high cumulative H. pylori eradication rates can be achieved. As a result, a substantial number of cultures to determine sensitivity to antibiotics can be avoided with beneficial consequences concerning cost.

The Global Project on Anti-Tuberculosis Drug Resistance has been gathering data since 1994. A study, published online in The Lancet (16 April 2009), provides the latest data on the extent of drug resistance worldwide. For the study, data for drug susceptibility were gathered from 90,726 patients in 83 countries and territories between 2002 and 2007. Standardized collection of results enabled comparison both between and within countries. Where possible, data for HIV status and resistance to second-line drugs were also obtained. Laboratory data were quality assured by the Supranational Tuberculosis Reference Laboratory Network. The median prevalence of resistance to any drug in new cases of tuberculosis was 11.1%. The prevalence of multidrug resistance in new tuberculosis cases ranged from 0% in eight countries to 7% in two provinces in China, 11.1% in Northern Mariana Islands (although reporting only two cases), and between 6.8% and 22.3% in nine countries of the former Soviet Union, including 19.4% in Moldova and 22.3% in Baku, Azerbaijan (median for countries surveyed 1.6%). Trend analysis showed that between 1994 and 2007, the prevalence of multidrug-resistant (MDR) tuberculosis in new cases increased substantially in South Korea and in Tomsk Oblast and Orel Oblast, Russia, but was stable in Estonia and Latvia. The prevalence of MDR tuberculosis in all tuberculosis cases decreased in Hong Kong and the USA. Thirty seven (37) countries and territories reported representative data on extensively drug-resistant (XDR) tuberculosis. Five countries, all from the former Soviet Union, reported 25 cases or more of XDR tuberculosis each, with prevalence among MDR-tuberculosis cases ranging between 6.6% and 23.7%. According to the authors, MDR tuberculosis remains a threat to tuberculosis control in provinces in China and countries of the former Soviet Union. Data on drug resistance are unavailable in many countries, especially in Africa, emphasizing the need to develop easier methods for surveillance of resistance in tuberculosis.

Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF. As a result, a study published in the Journal of the American Medical Association (2009;301:1892-1901), was preformed to examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF). The investigation was a prospective observational study at 2 tertiary cardiology centers in Poland of 501 men with an average age of 58 years. Study participants had chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4. Cohorts was divided into quintiles of serum estradiol (quintile 1, <12.90 pg/mL; quintile 2, 12.90-21.79 pg/mL; quintile 3, 21.80-30.11 pg/mL; quintile 4, 30.12-37.39 pg/mL; and quintile 5, 37.40 pg/mL). Quintile 3 was considered prospectively as the reference group. Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays. During the study, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio [HR], 4.17; and, 2.33; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6%, 65.8%, 82.4%, 79.0%, and 63.6%; respectively (P < .001). According to the authors, among men with chronic HF and reduced LVEF, high and low concentrations of estradiol compared with the middle quintile of estradiol are related to an increased mortality.

Fun Express, Inc. recalls children’s face paint associated with adverse events 

The FDA is advising consumers to stop using certain cosmetic “Face Paint” items labeled as distributed by Oriental Trading Co., Omaha, Neb., due to adverse event reports of skin reactions in children. These items were distributed nationwide. The FDA has learned of a cluster of adverse events in children exposed to various colors of the face paint. All exposures occurred on the same day at an organized event and included rashes, itchiness, burning sensation, and swelling where the face paints were applied. Significant microbial contamination was indicated in most of the products in testing by an FDA laboratory. The following Face Paints manufactured by Shanghai Color Art Stationery Company Limited, Shanghai, China, are being voluntarily recalled by Fun Express Inc., a wholly-owned subsidiary of Oriental Trading Co. Fun Express Inc. is recalling the face paints from the market and FDA advises consumers to stop use of these products and discard them or return them to the retailer. The FDA encourages consumers and health care providers to report any adverse events from face paints to the FDA as well as to state and local health authorities.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.