Science Weekly: Extrasolar planets and dark energy

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Our podcast this week is dedicated to the Year of Astronomy, and Ardi, our oldest human-like ancestor

Target e*CRF® and Stimulus Funding From NIH

Target Health is pleased to announce that it is part of a clinical trial program now being supported by Federal Stimulus Funds. The clinical trial, Trial of Early Aggressive Therapy in Juvenile Idiopathic Arthritis (TREAT in JIA; ClinicalTrials.gov Identifier – NCT00443430; PI, Carol A. Wallace, MD.), was started in 2007 and is using Target e*CRF® for electronic data capture (EDC). Original funding was by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and most recently by Amgen. The study is a multicenter, randomized, parallel, double blind study evaluating methotrexate, etanercept, and prednisolone, versus methotrexate plus placebo etanercept and placebo prednisolone, in newly diagnosed subjects with polyarticular juvenile idiopathic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, extended oligoarthritis juvenile idiopathic arthritis. The additional funding will allow for 1) the extension of the clinical trial enrollment period and thus the ability to obtain the full complement of study subjects, and 2) the creation of a biorespository with precious biologic samples from the subjects at key time points in their treatment.

Target Health Inc. is committed to working with academia in early stage development programs and anticipates additional stimulus funding with programs at Rutgers/UMDNJ and SUNY Stony Brook. There is an ongoing EDC program with the Cleveland Clinic, and an EDC program in jaundice in the newborn was recently completed with Stanford University.

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

New Mathematical Model Suggests How Brain Might Stay In Balance

The human brain is made up of 100 billion 1) ___ – live wires that must be kept in delicate balance to stabilize the world’s most magnificent computing organ. Too much excitement and the network will slip into an apoplectic, uncomprehending 2) ___. Too much inhibition and it will flatline. A new mathematical model describes how the trillions of interconnections among neurons could maintain a stable but dynamic relationship that leaves the brain sensitive enough to respond to stimulation without veering into a blind seizure. Marcelo O. Magnasco, head of the Laboratory of Mathematical Physics at The Rockefeller University, and his colleagues developed the model to address how such a massively complex and responsive network such as the brain can balance the opposing forces of excitation and inhibition. His model’s key assumption: Neurons function together in localized groups to preserve 3) ___. “The defining characteristic of our system is that the unit of behavior is not the individual neuron or a local neural circuit but rather groups of neurons that can oscillate in synchrony,” Magnasco says. “The result is that the system is much more tolerant to faults: Individual neurons may or may not fire, individual connections may or may not transmit information to the next neuron, but the 4) ___ keeps going.” Magnasco’s model differs from traditional models of neural networks, which assume that each time a neuron fires and stimulates an adjoining neuron, the 5) ___ of the connection between the two increases. This is called the Hebbian theory of synaptic plasticity and is the classical model for learning. “But our system is anti-Hebbian,” Magnasco says. “If the connections among any groups of neurons are strongly oscillating together, they are weakened because they threaten 6) ___. Instead of trying to learn, our neurons are trying to forget.” One advantage of this anti-Hebbian model is that it balances a network with a much larger number of degrees of freedom than classical models can accommodate, a flexibility that is likely required by a computer as complex as the brain. In work published this summer in Physical Review Letters, Magnasco theorizes that the connections that balance excitation and inhibition are continually flirting with 7) ___. He likens the behavior to an indefinitely large number of public address systems tweaked to that critical point at which a flick of the microphone brings on a screech of feedback that then fades to quiet with time. This model of a balanced neural network is abstract – it does not try to recreate any specific neural function such as learning. But it requires only half of the network connections to establish the homeostatic balance of exhibition and inhibition crucial to all other brain activity. The other half of the network could be used for other functions that may be compatible with more traditional models of neural networks. Developing a systematic theory of how neurons 8) ___ could provide a key to some basic questions in biology. Adapted from materials provided by Rockefeller University.

ANSWERS: 1) neurons; 2) chaos; 3) stability; 4) system; 5) strength; 6) homeostasis; 7) instability; 8) communicate

Did Science Kill Off the Werewolf?

For much of recorded history, humans have reserved their greatest fears for dog-human hybrids like the werewolf. These beasts were once thought to be real, hiding behind every tree waiting for the unsuspecting traveler. According to Brian Regal, assistant professor of the history of science at Kean University in Union, New Jersey, the publication of Charles Darwin’s On the Origin of Species 150 years ago focused minds on a different kind of monster – ape-men such as the Yeti, Bigfoot and Sasquatch. From the late 19th century onwards, stories of werewolf encounters tailed away significantly. The spread of the idea of evolution helped kill off the werewolf because a canid-human hybrid makes no sense from an evolutionary point of view. However, the ape-human hybrid, however, is not only evolutionarily acceptable, it is the basis of human evolution. Today, in Darwin’s bicentenary year, werewolves have been relegated to films, while when it comes to the actual monster scene, it is Bigfoot that now dominates. Adapted from materials provided by British Society for the History of Science,

ONCOLOGY

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Drug That Crosses Blood-Brain Barrier Reduces Formation of Brain Metastases in Mice

While various therapies are improving the survival of breast cancer patients, the incidence of breast cancer metastases to the brain is increasing. These brain metastases have proven to be largely untreatable because the blood-brain barrier, which arises from the specialized structure of blood capillaries in the brain, severely limits drug access to the brain while at the same time actively transports drugs out of brain. Consequently, the one-year survival estimate for breast cancer patients after a diagnosis of brain metastasis is only about 20%. Vorinostat (Zolinza, Merck) is approved by the FDA for the treatment of cutaneous T-cell lymphoma. Previous studies have suggested that Vorinostat can be taken up by the brain, although little was known about its effects on metastatic tumors. Therefore, a study, published online in Clinical Cancer Research. (29 September 2009), used a mouse model of human breast cancer to study the effect of vorinostat on the formation of brain metastases. For the study, human breast cells were cultured in the laboratory and then injected into mice with compromised immune systems. Results showed while vorinostat was absorbed readily into normal mouse brains, it accumulated up to three-fold higher in some metastases when compared to surrounding brain tissue. Vorinostat reduced the development of tiny tumors (micrometastases) in mice by 28% when compared with mice that did not receive this therapy. The ability of vorinostat to reduce metastatic lesions in the brain was linked to a novel double-barreled mechanism: 1) the drug can cause breaks in both strands of a DNA helix and can also lower the activity of a DNA repair gene called Rad52. This inability of the cancer cells to repair DNA damage slows the rate of tumor cell metastasis. In June of this year, a study published in Molecular Cancer Therapeutics (2009;8:1589-1595) showed that vorinostat could enhance the effect of radiation therapy in mice with brain cancer metastasis. Mice that received implants of human breast tumors in their brains lived the longest after treatment with both vorinostat and radiation.

Treating Mild Gestational Diabetes Reduces Birth Complications

Gestational diabetes occurs when pregnant women who did not have any signs or symptoms of diabetes before they were pregnant develop high blood sugar levels. The condition affects from 1% to 14% of all U.S. pregnancies. Gestational diabetes is not well understood, but is thought to occur when hormones produced during pregnancy interfere with the body’s ability to use insulin to absorb sugar from the blood. In most cases, treatment for gestational diabetes consists of lowering blood sugar levels through proper diet and exercise. If diet and exercise alone fail to lower blood sugar levels, women may be treated with drugs that increase the body’s ability to use insulin, or may be prescribed insulin itself. Although treatment is routinely prescribed for all women with gestational diabetes, there was no evidence to show whether treating the mild form of the condition benefited, or posed risks for, mothers or their infants. As a result, according to an article published in the New England Journal of Medicine (2009; 361:1339-1348), treating pregnant women who have even the mildest form of gestational diabetes can reduce the risk of common birth complications among infants, as well as blood pressure disorders among mothers. The study found that, compared to the women’s untreated counterparts, women treated for mild gestational diabetes had smaller, leaner babies which were less likely to be overweight or abnormally large. In addition, there were fewer cases of shoulder dystocia, an emergency condition in which the baby’s shoulder becomes lodged inside the mother’s body during birth. Treated mothers were also less likely to undergo cesarean delivery, to develop high blood pressure during pregnancy, or to develop preeclampsia, a life-threatening complication of pregnancy that can lead to maternal seizures and death. The study enrolled 958 women with mild gestational diabetes. Roughly half were treated for their diabetes and half were not, receiving only standard pregnancy care. 

Specifically, compared to women who did not receive treatment, those who did were: 

  • half as likely to have an unusually large baby,
  • half as likely to experience shoulder dystocia during childbirth,
  • four-fifths as likely to give birth by cesarean section, and
  • three-fifths as likely to develop high blood pressure or preeclampsia.

SLEEP

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Weight Loss and Obstructive Sleep Apnea Among Obese Diabetics

The belief that weight loss improves obstructive sleep apnea (OSA) has limited empirical support. As a result, a study published in the Archives of Internal Medicine (2009;169:1619-1626) was performed to assess the effects of weight loss on OSA over a 1-year period. The study included 264 participants with type 2 diabetes and a mean age of 61.2 years, weight of 102.4 kg, body mass index (BMI) of 36.7, and an apnea-hypopnea index (AHI) of 23.2 events per hour. The participants were randomly assigned to either a behavioral weight loss program developed specifically for obese patients with type 2 diabetes: 1) intensive lifestyle intervention (ILI), 2) 3 group sessions related to effective diabetes management (diabetes support and education; DSE). Results showed that the ILI participants lost more weight at 1 year than did DSE participants (10.8 kg vs 0.6 kg; P < .001). Relative to the DSE group, the ILI intervention was associated with an adjusted decrease in AHI of 9.7 events per hour (P < .001). At 1 year, 1) more than 3 times as many participants in the ILI group than in the DSE group had total remission of their OSA, and 2) the prevalence of severe OSA among ILI participants was half that of the DSE group. Initial AHI and weight loss were the strongest predictors of changes in AHI at 1 year (P < .01). Participants with a weight loss of 10 kg or more had the greatest reductions in AHI. According to the authors, physicians and their patients can expect that weight loss will result in significant and clinically relevant improvements in OSA among obese patients with type 2 diabetes.

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 Issues Draft Guidance on Risk Evaluation and Mitigation Strategies (REMS)

The FDA has announced the availability of the first draft guidance for industry on Risk Evaluation and Mitigation Strategies or REMS, which are required for certain drugs or biologics. The Food and Drug Administration Amendments Act of 2007 (FDAAA) granted the FDA the authority to require the submission and implementation of a REMS if the FDA determines a REMS is necessary to ensure that a drug’s benefits outweigh its risks. REMS components include medication guides; patient package inserts; a communication plan for health care providers; elements to ensure safe use including requirements for those who prescribe, dispense, or use the drug; and a timetable for REMS submission. The draft guidance for industry titled “Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications“:

  • Provides FDA’s current thinking on the format and content that industry should use for submissions of proposed REMS
  • Describes each potential element
  • Includes preliminary information on the content of assessments and proposed modifications of approved REMS
  • Describes REMS policies for certain regulatory situations
  • Informs industry about who to contact within FDA about a REMS
  • Indicates FDA Web sites where documents about approved REMS will be posted
  • Provides an example of what an approved REMS might look like for a fictitious product.

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