Target Health is pleased to announce that it will again be attending the annual BioMed meeting in Tel Aviv (June 15-17) and exhibiting at DIA in San Diego (June 21-24). Please get in touch with Dr. Mitchel if you will be attending so we can plan a get together. 

At DIA, please visit us at BOOTH 2322 (as always near the lunch area). We will be featuring our paperless software suite as well as our capabilities in regulatory affairs, clinical research, data management, biostatistics and medical writing. Please also come by for your complimentary and eco-friendly fan to cool you down in the hot California sun. 

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. Visit www.targethealth.com

Antidepressant Bacteria 

Bacteria found in the soil have been shown to activate a group of neurons that produce the brain chemical serotonin. Treatment of mice with a “friendly” bacteria, normally found in the soil, altered their behavior in a way similar to that produced by 1) ___ drugs. These findings aid the understanding of why an imbalance in the immune system leaves some individuals vulnerable to mood disorders like 2) ___. Dr Chris Lowry, from Bristol University and lead author on the paper, said: “These studies help us understand how the body communicates with the brain and why a healthy 3) ___ system is important for maintaining mental health. They also leave us wondering if we shouldn’t all be spending more time playing in the dirt.” Interest in the project arose after human cancer patients being treated with the bacteria Mycobacterium vaccae unexpectedly reported increases in their quality of life. Lowry and his colleagues reasoned that this effect could be caused by activation of 4) ___ in the brain that contained serotonin. When the team looked closely at the brains of mice, they found that treatment with M. vaccae activated a group of neurons that produce serotonin. The lack of serotonin in the brain is thought to cause depression in people, thus M. vaccae’s effects on the behavior of mice may be due to increasing the release of 5) ___ in parts of the brain that regulate mood. The new research supports this hypothesis. Early online edition of the Journal of Neuroscience, April 29, 2009. 

ANSWERS

  • 1) antidepressant; 2) depression; 3) immune; 4) neurons; 5) serotoni

Functioning Prostheses

20090608-1 

Photo: Jacky Finch – The prosthetic toe is shown in the Cairo Museum.

An artificial big toe found on the foot of a 3000+ year-old Egyptian mummy could prove to be the world’s earliest functioning prosthetic body part. Volunteers who have lost their right big toe are now being recruited to see how effective replicas of the prosthesis are. The fake toe from the Cairo museum in Egypt was found in 2000 in a tomb near the ancient city of Thebes. Archaeologists speculated that the prosthesis came from a 50 to 60-year-old woman who might have lost her toe due to complications from diabetes. The wood and leather prosthesis dates from 1069 to 664 BCE, based on artifacts it was found with in the mummy’s burial chamber. This means it predates what was previously thought of as the earliest known functioning prosthesis, the Roman Capua Leg, a bronze artifact dating from about 300 BCE. The leg was once at the Royal College of Surgeons in London but was destroyed by bombing during World War II. Replicas of a second false Egyptian right big toe on display at the British Museum in London, albeit without its mummy, will also be tested. This artifact, named the Greville Chester Great Toe after the collector who acquired it for the museum in 1881, is made from cartonnage, a sort of paper mache made using linen, glue and plaster. Based on the way the linen threads were spun, it dates from 1295 to 664 BCE. “If either prosthesis aids walking or balance then the history of prosthetic medicine will be pushed back some 600 to 700 years and credited to the ancient Egyptians,” said researcher Jacky Finch at the University of Manchester’s KNH Centre for Biomedical Egyptology in England. “If either one is functional it may be interesting to manufacture it with modern materials and trial it for use on people with missing toes.” The Cairo toe is the most likely of the two to be functional, as it is jointed in three places “and shows signs of wear,” Finch said. The amputation site is also well healed. The Greville Chester Great Toe also shows signs of wear, suggesting that it may have been worn by its owner in life and not simply attached to the foot during mummification for religious or ceremonial reasons. However, unlike the Cairo specimen, the Greville Chester Great Toe does not bend and so is likely to have been more cosmetic. The ancient Egyptians often restored artificial body parts to corpses, which means what might appear to be useful prosthetics actually were not. “The theology of Osiris, the god of the dead, stated that the body, in order to be effective during the afterlife, should be complete,” Finch explained. Osiris himself, according to myth, was cut up and his body parts scattered and later reunited. Scientists have found a variety of artificial body parts restored on mummies, including feet, legs, noses, and ears. For the next 1500 years or so, most artificial limbs were worn for cosmetic, rather than functional purposes, and made of very heavy materials, like iron. Then in the early 16th century, Ambroise Pare, revolutionized the field, developing limbs that many consider to be the foundation of modern prosthetics, featuring knee-lock control, advanced harnesses, and other improvements. Amputations became more common in the 19th century, encouraging a wave of advancements. They included an arm that could be moved by using straps affixed to the opposite shoulder and the successful attachment of a lower-body prosthetic using a suction-socket. Both of these methods were refined in the 20th century. Advanced versions are still used today. Another surge in prosthetic technology followed WW2, as researchers worked to create more functional limbs for veterans. A mechanical hand covered with flesh-colored rubber, was developed during this time. A wide range of prosthetic devices is available today, including those made from lightweight aluminum and carbon-fiber. Some are controlled by other body movements via cables or by external motors and switches. More advanced prostheses interpret muscle signals through electrodes, producing movement, like an intact biceps muscle might signal to move a prosthetic hand. This is called myoelectric control.

Use of Canakinumab in the Cryopyrin-Associated Periodic Syndrome (CAPS) 

The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab (Novartis) is a human anti-interleukin-1 beta monoclonal antibody. According to a study published in the New England Journal of Medicine, (2009;360:2416-2425), a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab was performed in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. Therapeutic responses were evaluated using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA). Results showed that in part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In terms of safety, in part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo. According to the authors, treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.

The Cognitive Impact of Anticholinergics: A Clinical Review

The cognitive side effects of medications with anticholinergic activity have been documented among older adults in a variety of clinical settings. However, there has been no systematic confirmation that acute or chronic prescribing of such medications lead to transient or permanent adverse cognitive outcomes. As a result, a study published online in the May 2009 issue of the Journal of Clinical Interventions in Aging, was performed to evaluate the existing evidence regarding the effects of anticholinergic medications on cognition in older adults. For the study, the MEDLINE, OVID, and CINAHL databases were searched from January, 1966 to January, 2008 for eligible studies. Studies were included if the anticholinergic activity was systematically measured and correlated with standard measurements of cognitive performance. Studies were excluded if they reported case studies, case series, editorials, and review articles. For the study, the method used to determine anticholinergic activity of medications and its association with cognitive outcomes were extracted from each eligible publication. There were 27 studies that met the inclusion criteria where serum anticholinergic assay was the main method used to determine anticholinergic activity. Interestingly, all but two studies found an association between the anticholinergic activity of medications and either delirium, cognitive impairment or dementia. According to the authors, medications with anticholinergic activity negatively affect the cognitive performance of older adults and that recognizing the anticholinergic activity of certain medications may represent a potential tool to improve cognition.

New Genetic Immune Disorder Discovered In Children

One’s immune system plays an important function in health in that it protects you against viruses, bacteria, and other toxins that can cause disease. In autoinflammatory diseases, however, the immune system goes awry, causing unprovoked and dangerous inflammation. Now, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered a new autoinflammatory syndrome, a rare genetic condition that affects children around the time of birth. The findings appear in the current issue of the New England Journal of Medicine (2009;360:2426-2437). The new autoinflammatory syndrome was been termed DIRA (deficiency of the interleukin-1 receptor antagonist). Children with the disorder display a constellation of serious and potentially fatal symptoms that include swelling of bone tissue; bone pain and deformity; inflammation of the periosteum (a layer of connective tissue around bone); and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient’s body. Most of the children begin to have symptoms from birth to 2 weeks of age. According to Stephen I. Katz, M.D., Ph.D., NIAMS director and immunodermatologist, “The beauty of this discovery is that the symptoms of this devastating disease can now be treated.” Dr. Katz added that “The abnormal inflammatory pathways seen in this disease may also help us understand other common diseases that share clinical features, such as psoriasis, as well as other autoinflammatory disorders.” All the children had inherited mutations in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as the inflammatory protein interleukin-1, and acts as a brake on this inflammatory protein. Without IL-1Ra, the children’s bodies cannot control systemic inflammation that can be caused by interleukin-1. The team identified nine patients from six families with DIRA in the Canadian province of Newfoundland, the Netherlands, Lebanon, and Puerto Rico. Those who were alive at the time of diagnosis, six were treated with anakinra, a drug made by Amgen, that is normally used for rheumatoid arthritis. Anakinra is a synthetic form of human IL-1Ra. Although the patients were resistant to other medications such as steroids, most responded successfully and immediately to anakinra. “Our first patient had been unresponsive to several treatments, and his health care team had almost given up. But with anakinra, he was out of the hospital in 10 days and his symptoms resolved,” Dr. Goldbach-Mansky said. Although the mutation that causes DIRA is rare, as many as 2.5% of the population of northwest Puerto Rico are carriers. Since DIRA is recessively inherited, these data suggest that it may be present in about 1 in 6,300 births in this population. Because the mutation was found in three independent Dutch families, newborn screening for DIRA in this population, as well as that of northwest Puerto Rico, may be warranted. “The DIRA discovery can be attributed to an innovative and collaborative effort between clinicians and laboratory researchers at NIAMS and an international team of dedicated investigators,” said NIAMS Clinical Director and coauthor Daniel L. Kastner, M.D., Ph.D. “Moreover, the unveiling of this novel autoinflammatory syndrome provides us with a tool to further dissect the role of interleukin-1 in human biology and disease.”

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available. 

FDA Forms Transparency Task Force 

The FDA today has formed a task force to develop recommendations for enhancing the transparency of the agency’s operations and decision-making process. To support the efforts of the task force, the FDA issued a Federal Register notice announcing a June 24, 2009, public meeting to solicit recommendations on how the agency can make more available, useful and understandable information on its activities and decisions. The task force will be chaired by Principal Deputy Commissioner Joshua Sharfstein, M.D., and will include center directors, the associate commissioner for regulatory affairs, chief scientist, and the chief counsel. The Transparency Task Force will:

Seek public input on issues related to transparency;

Recommend ways that the agency can better explain its operations compatible with the appropriate protection of confidential information;

Identify information the FDA should provide about specific agency operations and activities, including enforcement actions and product approvals;

Identify problems and barriers, both internal and external, to providing useful and understandable information about FDA activities and decision-making to the public;

Identify appropriate tools and new technologies for informing the public;

Recommend changes to the FDA’s current operations, including internal policies and guidance, to improve the agency’s ability to provide information to the public in a timely and effective manner;

Recommend legislative or regulatory changes, if appropriate, to improve the FDA’s ability to provide information to the public; and

Submit a written report to the commissioner on the Transparency Task Force’s findings and recommendations.

The establishment of the task force follows President Obama’s Jan. 21, 2009 memorandum directing executive agencies to find new ways of making information available to the public rapidly and in a form that is easily accessible and user-friendly. For more information, go to: FDA Transparency Task Force, and Transparency and Open Government: President Obama’s Memorandum for the Heads of Executive Departments and Agencies