Science Weekly: Evolution’s greatest hits, and ancient Muslim science

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Sex, death and consciousness are among author Nick Lane’s top 10 evolutionary breakthroughs. Plus: Islamic science; the elixir of life; and dangerous sofas

Target Health Software Now Supporting Other CROs

Target Health is pleased to announce that it is now working closely with four CROs who are using our software suite including Target e*CRF®, Target Document®, Target e*CTMS® and Target Encoder®.  There are 5 pluses that support these collaborations:

1.      Target Health software was designed by clinical people and not techies

2.      The CROs are using software developed by another CRO which understands and speaks their language

3.      Staff at Target Health can interact with both the CRO and potential sponsors and add value to the project if Target Health can provide services that the partnering CRO does not have, e.g. data management and eCTD submissions

4.      When there is a good idea coming from a partner, all the partners share in the new feature

5.      Costs are reasonable

More information about the Target Health Global Partnership and how to participate will be available soon.

For more information about Target Health and 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

Antibiotic Delayed Aging in Experiments With Mice

A new star has appeared in the field of drugs that delay aging in laboratory animals, and are therefore candidates for doing the same in 1) -___. The drug is an antibiotic, rapamycin, already in use for suppressing the immune system in transplant patients and for treating certain 2) ___. Rapamycin treatment had the remarkable effect of extending life even though it was not started in the right dose until the mice had lived 600 days – equivalent to a person at age 60. Most interventions that prolong life in mice, including a very low-calorie diet, need to be started early in life to show any effect. Experts warn that this should not be tried at home. No one knows yet if rapamycin slows aging in people or at what dose it might be effective. And any drug that suppresses the 3) ___ system is not to be trifled with. The researchers do not know how 4) ___ secures its anti-aging effect. It could be just halting 5) ___ rather than delaying the aging process in general. The three teams were sponsored by the National Institute on Aging as part of a program to test possible anti-aging drugs much more rigorously. One of the nasty secrets of the field is that most mouse 6) ___ experiments are done only once in one lab on one genetic background, said Steven Austad, an expert on aging at the University of Texas Health Science Center, who was not involved in the research. The National Institute on Aging program includes a test of two doses of resveratrol, the ingredient of red 7) ___ that is thought to mimic the effects of caloric restriction on longevity. The results have not been published, but Christoph Westphal, chief executive of Sirtris, a company exploring the health effects of resveratrol and similar chemicals, said the tests are seeing quite modest effects of resveratrol.  The effectiveness of rapamycin in extending the life of elderly mice was discovered by accident. The researchers found that the mice fed rapamycin were not getting the proper dose in their bloodstream. They reformulated the drug in the form of capsules that fed slow doses to the 8) ___, but by that time the mice were elderly. Nonetheless, 9) ___ span increased by 14 percent in the females and 9% in the males. Concrete evidence is still needed before claims can be made for a drug that can slow 10) ___ down.

ANSWERS: 1) people; 2) cancers; 3) immune; 4) rapamycin; 5) tumors; 6) longevity; 7) wine; 8) intestine; 9) life; 10) aging

Genome Study Provides a Census of Early Humans

Did everyone alive today descend from just 18,500 people? From the composition of just two human genomes, geneticists have computed the size of the human population 1.2 million years ago from which everyone in the world is descended. They put the number at 18,500 people, but this refers only to breeding individuals, the “effective“ population. The actual population would have been about three times as large, or 55,500. Comparable estimates for other primates then are 21,000 for chimpanzees and 25,000 for gorillas. In biological terms, it seems, humans were not a very successful species, and the strategy of investing in larger brains than those of their fellow apes had not yet produced any big payoff. Human population numbers did not reach high levels until after the advent of agriculture. Geneticists have long known that the ancestors of modern humans numbered as few as 10,000 at some time in the last 100,000 years. The critically low number suggested that some catastrophe, like disease or climate change induced by a volcano, had brought humans close to the brink of extinction. If the new estimate is correct, however, human population size has been small and fairly constant throughout most of the last million years, ruling out the need to look for a catastrophe. The estimate, reported this past Tuesday 19 January 2010, in The Proceedings of the National Academy of Sciences, was made by a team of population geneticists at the University of Utah led by Chad D. Huff and Lynn B. Jorde. The human population a million years ago was represented by archaic species like Homo ergaster in Africa and Homo erectus in East Asia. The Utah team says its estimate of 18,500 implies “an unusually small population for a species spread across the entire Old World.“ But that estimate would apply to the worldwide population only if there were inbreeding between the humans on the different continents. If not, and if modern humans are descended from just one of these populations, like Homo ergaster in Africa, then the estimate would apply only to that. Richard G. Klein, a paleoanthropologist at Stanford, said it was hard to believe the population from which modern humans are descended was as small as 18,500 “unless they were geographically restricted to Africa or a small part of it.“ There is no independent way of assessing a genetics-based estimate of population size at this period, Dr. Klein said, although archaeologists have developed ways of assessing ancient populations of more recent times. The Utah team based its estimate on the genetic variation present in two complete human genomes, one prepared by the government’s human genome project and the other by J. Craig Venter, the genome sequencing pioneer. The government decoded a single copy of a mosaic genome derived from a medley of people, apparently of European and Asian origin. Dr. Venter decoded both copies of his own genome, the one inherited from his father and the one from his mother. The Utah team thus had three genomes to work with and looked at ancient elements known as Alu insertions, the youngest class of which appeared in the human genome around a million years ago. The amount of variation seen in the DNA immediately surrounding the Alu insertions gave a measure of the size of human population at that time. Their estimate agrees almost exactly with an earlier one, also based on Alu insertions but with sparser data. The insertions tag ancient regions of the genome that are unaffected by the recent growth in population, Dr. Huff said. Source: The New York Times, January 19, 2010, by Nicholas Wade

GENETICS

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New Gene Discovered For Recessive Form of Brittle Bone Disease

Osteogenesis imperfecta (OI), sometimes known as Brittle Bone Disease, or Lobstein syndrome, is a genetic bone disorder. The NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases estimates that in the United States a minimum of 20,000 and possibly as many as 50,000 people are affected by OI. About 85% of all OI cases are caused by mutations in the genes that contain the information needed to make collagen. Collagen functions as molecular scaffolding that holds together bone, tendons, skin and other tissues. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. The deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagen triple helix structure. The larger amino acid side-chains create steric hindrance that creates a “bulge“ in the collagen complex. This in turn influences both the molecular nanomechanics as well as the interaction between molecules, which are both compromised. OI weakens bones, results in frequent fractures and is sometimes fatal. Most types of OI result from a dominant mutation in collagen itself, requiring only one copy of the mutated gene to bring about the disorder. OI involving the Cyclophilin B gene is a recessive trait, requiring two defective copies of the gene to cause the disorder. According to an article published online in the New England Journal of Medicine (20 January 2010), a third gene in a sequence of genes has been discovered that accounts for previously unexplained forms of OI. The newly identified gene contains the information needed to make the protein Cyclophilin B. This protein is part of a complex of three proteins that modifies collagen, folding it into a precise molecular configuration, before it is secreted from cells. Previously it was established that OI could also be caused by defects in two protein complexes 1) cartilage associated protein, or CRTAP, and 2) prolyl 3-hydroxylase 1 (P3H1), resulting in severe forms of OI. Individuals with mutations in CRTAP have all died in childhood, while mutations in P3H1 are sometimes fatal in early life. In the current study, it was determined that a 12-year-old boy and his 4-year-old sister had mutations in the gene for Cyclophilin B. Although the children’s bones were brittle and highly susceptible to fracturing, they did not have shortening of the upper portion of limbs (rhizomelia) seen in the children with mutations in CRTAP and P3H1. It was found that the collagen from the two children was folded into its usual configuration, strongly suggesting that Cyclophilin B is not uniquely involved in its role in collagen folding, and that another, currently unknown, protein must also be involved.

Molecule Repairs Alcohol Metabolism Enzyme

After alcohol is consumed, it is first metabolized, or broken down, into acetaldehyde, a toxic chemical that causes DNA damage. Aldehyde dehydrogenase 2 (ALDH2) is the main enzyme responsible for breaking down acetaldehyde into acetate, a nontoxic metabolite in the body. It also removes other toxic aldehydes that can accumulate in the body. About 40% of the East Asian population, and many people of East Asian descent throughout the world, carry a genetic mutation that produces an inactive form of ALDH2. When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea, and rapid heartbeat. In addition to its link to increased cancer risk, the inactive form of ALDH2 also reduces the effectiveness of nitroglycerin. Nitroglycerin is a drug to treat angina, chest pain that occurs when the heart doesn’t get enough oxygen-rich blood. According to an article published in the advance online edition of Nature Structural and Molecular Biology (10 January 2010), an experimental compound has been shown to repair a defective alcohol metabolism enzyme that affects an estimated 1 billion people worldwide. The findings suggest the possibility of a treatment to reduce the health problems associated with the enzyme defect. For the study, in a series of experiments that examined the interaction between Alda-1 and the defective ALDH2 enzyme, it was found that Alda-1 restored the structure of the inactive enzyme. The normal, active form of ALDH2 creates a catalytic tunnel, a space within the enzyme in which acetaldehyde is metabolized. In the defective enzyme, the tunnel does not function properly. Alda-1 binds to the defective enzyme in a way that effectively reopens the catalytic tunnel and thus allows the enzyme to metabolize acetaldehyde. According to the authors, the manner in which Alda-1 binds to the structure of ALDH2 provides with powerful insight into the relationships between activators and inhibitors of this crucial detoxifying enzyme. The authors added that this insight will lead to the modification of Alda-1 to improve its potency, and also opens up the possibility of designing new analogs that can selectively affect the metabolism of other molecules that are detoxified by aldehyde dehydrogenase.

Humoral Responses After Influenza Vaccination Are Severely Reduced In Patients With Rheumatoid Arthritis Treated With Rituximab

For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab (Rituxan,MabThera) is unknown. As a result, a study published in Arthritis and Rheumatism (2010;62:75-81) was performed to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. The study also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination. For the study, trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4-8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6-10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity. Results showed that following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX-treated group and in healthy controls, but for no strains in the rituximab-treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab-treated group than in the MTX-treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab-treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab-treated group, previously vaccinated patients in the rituximab-treated group had higher pre- and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination. According to the authors, rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6-10 months after rituximab administration, and that previous influenza vaccination in rituximab-treated patients increases pre- and postvaccination titers. RA activity was not influenced.

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 Approves Left Ventricular Assist System for Severe Heart Failure Patients

Heart assist devices are surgically implanted mechanical pumps that help the heart’s ventricle pump blood to the rest of the body. HeartMate II consists of a small, lightweight blood pump implanted in a patient’s chest just below the heart. An electrical cable that powers the blood pump passes through the patient’s skin to an external controller worn around the patient’s waist. A physician designates the pump’s speed based upon clinical need. The device is designed to sound an alarm upon malfunction or other potentially drastic changes that could impact the pump’s operation. The FDA has approved the HeartMate II, a continuous-flow, left ventricular assist system as a support for severe heart failure patients who are not acceptable candidates for heart transplantation. The HeartMate II is already FDA-approved for use in patients awaiting further, perhaps more complex treatment, such as transplants. In a randomized clinical study of 200 participants at 38 centers, 46% of 134 participants with the HeartMate II were still living after two years with no disabling stroke or need for a reoperation for device replacement or repair compared with 11% of 66 participants in the control group. In addition, data collected in a separate registry of smaller stature women and men indicated that the device worked well in this specific population. As a condition of the FDA’s approval, the company will conduct a post-approval study to further evaluate the device’s performance. The data will be recorded in the Interagency Registry of Mechanical Assisted Circulatory Support (INTERMACS) and made available when the post-approval study is concluded. The INTERMACS is a clinical outcomes registry managed by the FDA, the National Heart, Lung and Blood Institute at the National Institutes of Health, the Centers for Medicare & Medicaid Services and participating hospitals and companies. HeartMate II is manufactured by Thoratec Corp. based in Pleasanton, Calif.

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

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMS™, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTR™ (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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