Science Weekly: Will our oceans ever recover?

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Protecting the oceans; how stray dogs helped Russia in the space race; Tutankhamun goes online; and the Guardian’s ‘climategate’ debate

Target Health and LifeOnKey EHR and EDC Collaboration

 

Target Health Inc., and LifeOnKey Inc., are pleased to announce the development of an alliance to provide an innovative fully integrated information system for Phase 1 to Phase IV clinical research services to the biopharmaceutical and device industry, including the electronic health record (EHR), Personal Health Record (PHR), and Registries fully integrated with electronic data capture (EDC) software. This partnership takes advantage of the extensive expertise in the development of innovative information systems residing in both companies in order to successfully and efficiently move products to the market.

“We are very enthusiastic about building a comprehensive solution for the integration of clinical trial software and EHRs for the industry,” comments Target Health Inc. President Dr. Jules Mitchel. “With over 17 years of clinical trial and clinical trial information systems developed and implemented at Target Health, coupled with the state-of-the-art Health Management Platform offered by LifeOnKey, this partnership is the first of its kind in the field of Clinical Trials and Post Marketing Surveillance.”

“LifeOnKey is joining forces with Target Health to bring to the market the first integrated system to enable clinical research to be part of the revolution in health information systems, and that LifeOnKey’s vast experience and know-how in health information systems compliments the outstanding product development expertise of Target Health,” explains Dr. Linda Harnevo, CEO of LifeOnKey.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel 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

Nature’s Insect Repellents Discovered

Backpedaling. Mosquitoes flee when they detect chemicals emitted by their predator, the N. maculata backswimmer. (Credit: Image courtesy of Rockefeller University)

In the battle between insect predators and their prey, chemical signals called kairomones serve as an early-warning system. Pervasively emitted by the predators, the compounds are detected by their 1) ___, and can even trigger adaptations, such as change in body size or armor, that help protect the prey. But as widespread as kairomones are in the insect world, their chemical identity has remained largely unknown. New research by Rockefeller University’s Joel E. Cohen and colleagues at the University of Haifa in Israel has identified two compounds emitted by mosquito predators that make the mosquitoes less inclined to lay eggs in pools of 2) ___.

The findings, published in the July issue of Ecology Letters, may provide new environmentally friendly tactics for repelling and controlling disease-carrying insects. Many animals use 3) ___ to communicate with each other. Pheromones, which influence social and reproductive behaviors within a particular species, are probably the best known and studied. Kairomones are produced by an individual of one species and received by an individual of a different 4) ___, with the receiving species often benefiting at the expense of the donor.

Cohen and his Israeli colleagues focused on the interaction between two 5) ___ species found in temporary pools of the Mediterranean and the Middle East: larvae of the mosquito C. longiareolata and its predator, the backswimmer N. maculata. When the arriving female mosquitoes detect a chemical emitted by the backswimmer, they are less likely to lay eggs in that pool.

To reproduce conditions of temporary pools in the field, the researchers used aged tap water with fish 6) ___ added as a source of nutrients. Individual backswimmers were then placed in vials containing samples of the temporary pools, and air samples were collected from the headspace within the vials. The researchers used gas chromatography-mass spectrometry to analyze the chemicals emitted by the backswimmers. Cohen and his colleagues identified two chemicals, hydrocarbons called n-heneicosane and n-tricosane, which repelled egg-laying by mosquitoes at the concentrations of those compounds found in nature. Together, the two chemicals had an additive effect.

Since the mosquitoes can detect the backswimmer’s kairomones from above the water’s 7) ___, predator-released kairomones can reduce the mosquito’s immediate risk of predation, says Cohen. But they also increase the female mosquito’s chance of dying from other causes before she finds a pool safe for her to lay her 8) ___ in. “That’s why we think these chemicals could be a useful part of a strategy to control the population size of 9) ___,” says Cohen, who is the Abby Mauze Rockefeller Professor and head of the Laboratory of Populations. “We started this work from very basic curiosity about how food webs and predator-prey interactions work, but we now see unexpected practical applications. These newly identified compounds, and others that remain to be discovered, might be effective in controlling populations of disease-carrying insects. It’s far too soon to say, but there’s the possibility of an advance in the battle against infectious 10) ___.”

 

ANSWERS: 1) prey; 2) water; 3) chemicals; 4) species; 5) insect; 6) food; 7) surface; 8) eggs; 9) mosquitoes; 10) disease 

A Case That Shook Medicine

A DAUGHTER LOST After Libby Zion died in a hospital at age 18, her father’s crusade led to changes in work hours and supervision of medical residents.

History shows how one man’s rage over his daughter’s death sped reform of doctor training. Many people have vowed to avenge the untimely death of a relative. Lawyer and journalist Sidney Zion actually did so to the benefit of patients and doctors-in-training nationwide. After his 18-year-old daughter Libby died within 24 hours of an emergency hospital admission in 1984, Zion learned that her chief doctors had been medical residents covering dozens of patients and receiving relatively little supervision. His anger set in motion a series of reforms, most notably a series of work hour limitations instituted by the Accreditation Council on Graduate Medical Education (ACGME), that have revolutionized modern medical education. Just about everyone involved in the Libby Zion case – her father, her doctors and the people who testified at the trial that eventually resulted – has a different account of what happened. But there are some undisputed facts.

Libby was a college freshman with an ongoing history of depression who came to New York Hospital in Manhattan on the evening of Oct. 4, 1984, with a fever, agitation and strange jerking motions of her body. She also seemed disoriented at times. Unable to diagnose her condition definitively, the emergency room physicians admitted her for hydration and observation. The physician of record, a senior clinician who had treated several members of the Zion family, approved the decision by phone. On the hospital ward where she was sent, Libby was evaluated by two residents: an intern eight months out of medical school, and another intern who had one additional year of training. They, too, were not quite certain of Libby’s diagnosis. One of the interns termed it a “viral syndrome with hysterical symptoms,” suggesting that Libby was overreacting to a relatively mild illness. The doctors prescribed a shot of meperidine, a painkiller and sedative, to control her shaking. The family doctor approved the plan by phone.

At about 3 in the morning, the intern went off to care for some of the 40 other patients she was covering. The other intern went to sleep in an adjacent building, where he would be available, if necessary, by beeper. After the doctors left, Libby became more agitated. The nurses contacted the intern at least twice. The intern ordered physical restraints to hold the patient down and prevent her from hurting herself. She also prescribed an injection of haloperidol, another medication aimed at calming her down. Busy with other patients, the intern did not reevaluate Libby. Libby finally fell asleep, according to the nurses, but when a nurse’s aide took her temperature at 6:30 a.m., it was 107, dangerously high. The intern was called and emergency measures were tried to lower the temperature. But Libby Zion suffered a cardiac arrest and died. The intern called her parents, telling them doctors had done everything they could.

To the doctors at the hospital, the case was an inexplicable “bad outcome’ in which a healthy young woman had died of a mysterious infection. But the more Sidney Zion learned of the circumstances of Libby’s death, the more he rejected this assertion. He became convinced his daughter’s death was due to inadequate staffing at the teaching hospital. And he grew determined to ensure that others not fall victim to the same gaps in the teaching hospital system that he blamed for his daughter’s death.

First, there was a question as to whether the meperidine, known to cause fatal interactions with phenelzine – Libby Zion’s antidepressant  had produced the high fever. Second, Sidney Zion questioned the use of restraints and shots for an increasingly agitated patient. “They gave her a drug that was destined to kill her,” Zion later stated, “then ignored her except to tie her down like a dog.” Zion’s anger was exacerbated by what he learned about the hospital’s staffing on the night Libby died. In addition, the intern assigned to Libby, was covering a large number of patients; the other doctor on call, was never awakened; and the supervising physician, wasn’t called when Libby deteriorated.

Over time, the image of the bedraggled, unsupervised intern wreaking damage in hospitals would be featured in the pages of The Washington Post, the New York Times and Newsweek.

In May 1986 Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges. Although it declined to indict, the jury issued a report strongly criticizing “the supervision of interns and junior residents at a hospital in New York County.” In response, New York State Health Commissioner David Axelrod established a blue-ribbon panel of experts headed by Bertrand M. Bell, an outspoken primary care physician at the Albert Einstein College of Medicine in the Bronx, to evaluate the training and supervision of doctors in the state. Bell had long criticized the lack of supervision of physicians-in-training. In 1989, New York state adopted the Bell Commission’s recommendations that residents could not work more than 80 hours a week or more than 24 consecutive hours and that senior physicians needed to be physically present in the hospital at all times. Hospitals instituted so-called night floats, doctors who worked overnight to spell their colleagues, allowing them to adhere to the new rules.

Still, some physicians resisted reform efforts. Many institutions essentially disregarded the new regulations. Until 2003. In that year, the ACGME made reduced work hours mandatory for the accreditation of residency training programs across the country. The new ACGME standards look remarkably similar to those of the Bell Commission. Now it is commonplace to see chief residents at medical centers charting the numbers of hours worked by their staffs. Residents who wish to stay longer at work are at times sent home to sleep, a development that would have been inconceivable in the past. As might be expected, the new requirements are a work in progress. A study published in the Sept. 6, 2006, issue of the Journal of the American Medical Association found that 80% of interns nationwide still sometimes work excessive hours. Data measuring whether work hour limits have improved patient care are just coming in. One study published in the New England Journal of Medicine in 2004 did find that eliminating extended work shifts improved the attention span of interns.

Historians these days tend to distrust the idea that the actions of specific people truly cause large-scale change. Rather, many argue, change more commonly results from a complex interplay of cultural and political factors. In the case of Libby Zion, however, it is possible to trace a straight line from her death to Sidney Zion’s campaign to the Bell Commission to the ACGME regulations. To be sure, it took the social changes of the 1960s and 1970s to make graduate medical education susceptible to reform from the outside. But Sidney Zion sped things up considerably, ensuring that Libby had not died in vain.

In the winter of 1994, Zion v. New York Hospital finally went to trial. Court TV avidly covered the proceedings, which were full of vitriol on both sides. The jury hedged, attributing responsibility to both the doctors and the patient. Sidney Zion still calls the $375,000 jury award to him a travesty of justice. There is one other legacy of Zion’s crusade. By championing the cause of patients and families who believed they had been harmed by the medical profession, Zion helped set the stage for the medical-errors movement that began in the 1990s. To aggrieved patients and their families, Zion became a sort of folk hero.

Throughout his crusade, Sidney Zion’s anger was paramount. Indeed, it is quite possible that without this rage, he might not have accomplished what he did. Zion was “aggressive, narcissistic, self-indulgent, pushy, persistent and paranoid,” psychiatrist Willard Gaylin memorably wrote in the Nation, “but that is precisely the stuff successful reformers are made of.”

Barron H. Lerner is the Angelica Berrie-Gold Foundation Associate Professor of Medicine and Public Health at Columbia University’s Mailman School of Public Health. This essay, from the Washington Post, draws on his book, “When Illness Goes Public: Celebrity Patients and How We Look at Medicine” (Johns Hopkins, 2006).

“I left her there with an earache and a fever,” he has said, “and they sent her home in a box.”  Sidney Zion, heartbroken father.

The Libby Zion Law –

Major Shift in Doctor’s  Hours

New York State Department of Health Code, Section 405, also known as the Libby Zion Law, is a regulation that limits the amount of resident physicians‘ work in New York State hospitals to roughly 80 hours per week.  The law was named after Libby Zion who died at the age of 18 under the care of overworked resident physicians and intern physicians.  In July 2003 the Accreditation Council for Graduate Medical Education (ACGME) adopted similar regulations for all accredited medical training institutions in the United States.

Genes and Behcet’s Disease

 

Although the Greek physician Hippocrates described Behcet’s disease (pronounced BET-chet’s) more than 2,000 years ago, the condition existed in relative obscurity until the early 20th century. Named for the Turkish physician who first classified it in 1937, Behcet’s disease is found almost exclusively in populations with origins along the Silk Road, a trading route that stretched from Europe to the Far East. Marco Polo was among the most famous travelers along the Silk Road. Today, despite advances in genetics and genomics research, the diagnosis of Behcet’s disease is still determined by the clinical picture, characterized by painful ulcers affecting the mouth and genitals and inflammation of the skin and eyes. Recurrent inflammatory attacks affecting the eyes may result in permanent loss of vision, and inflammation of the brain and large blood vessels may be associated with increased mortality. In addition, treatments for the disease target individual symptoms rather than addressing an underlying mechanism.

Just recently, an study published online in the Nature Genetics (11 July 2010) showed that susceptibility to Behcet’s disease was associated with genes involved in the body’s immune response. Further investigation of the interleukin 10 (IL10) gene associated with immune response, showed that people with two copies of the Behcet’s disease IL10 gene, produced significantly lower levels of IL-10 protein than people with only one or no IL10 disease gene.

In the current study, the NIH researchers from NIAMS, in collaboration with Professor Ahmet Gul’s group at Istanbul University, performed the first large genome-wide association study (GWAS) of Behcet’s disease in a Turkish population. They looked at the genomes of more than 1,200 Behcet’s patients and 1,200 people without the disease in an effort to identify places where the two groups differed. These places, called single nucleotide polymorphisms (SNPs), could point to genes that are associated with the disorder. Both groups of people were from Turkey, which has the highest prevalence rate for the disease, 4 cases per 1,000 individuals. Previous genetic studies have shown a strong association of Behcet’s disease to the major histocompatibility complex (MHC), a section of the genome on chromosome 6 containing a large number of immune-related genes. The highest association is with the human leukocyte antigen (HLA)-B51 region of the MHC. However, since it accounts for less than 20% of the disease’s genetic risk, other genetic factors had to be involved.

In addition to conducting their own GWAS, the NIAMS group exchanged data with an independent group of investigators that concurrently performed a large GWAS for Behcet’s disease in a Japanese population. The Japanese results reconfirmed a strong association of Behcet’s disease with the HLA-B51 region of the MHC and identified an independent association area within the MHC. The researchers also identified associations on chromosome 1 with a known variant of the IL10 gene and with a variant located between the genes for the IL-23 receptor (IL23R) and a component of the IL-12 receptor (IL12RB2). Interestingly, the genetic variants found to be associated with Behcet’s disease in the Turkish population were identical to those independently identified in the Japanese population, lending credence to a genetic link between two disparate populations separated by thousands of miles, but tied together by the ancient trading route.

The most encouraging finding resulted from an analysis of the function of the IL10 gene variant. They found that cells from blood donors who had two copies of the IL10 gene variant produced significantly lower levels (approximately one-third) of IL-10 protein compared to people with one or two normal IL10 genes. Since the function of IL-10 is to decrease inflammation, the results suggested that low levels of IL-10 protein, in conjunction with external triggers, might be a risk factor for Behcet’s disease. Additionally, IL10 has an extensive disease history, with different variants of IL10 having been associated with other autoimmune and autoinflammatory diseases, including ulcerative colitis, type 1 diabetes, systemic lupus erythematosus, and severe juvenile rheumatoid arthritis. These findings suggest that there may be possible therapeutic targets that can be examined in future studies.

After 40 Years, Possible New Treatment For Severe Vasculitis

 

Patients with ANCA-associated vasculitis make antibodies that attack immune cells called neutrophils, causing inflammation in small- to medium-sized blood vessels. This leads to organ damage, particularly in the airways, lungs and kidneys. There are two main forms of this type of autoimmune vasculitis, microscopic polyangitis and Wegener’s granulomatosis. These are rare, so-called orphan, diseases with approximately 6,000 newly diagnosed cases in the United States each year.

The current standard of care for ANCA-associated vasculitis combines a 3- to 6-month course of daily cyclophosphamide plus steroids, followed by long-term daily azathioprine (AZA) plus steroids. This regimen was originally developed by NIAID Director Anthony S. Fauci, M.D., and his colleagues in the early 1970s. Before this treatment regimen became available, about 80% of people died within two years of disease onset from kidney failure or bleeding in the lungs. The nearly 40-year-old therapy has been lifesaving for many patients.

Investigators have made a major advance in treating people with a severe form of vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, a rare but devastating disease of blood vessels. In a six-month study, a new treatment strategy provided the same benefits as the current standard of care used for more than 40 years but required less frequent treatments. Early results also suggest that patients with disease relapses-typically recurrences of fever, fatigue, kidney damage, or bleeding in the lungs-respond better to the new regimen. The study, appears online in the New England Journal of Medicine (DOI:10.1056/NEJMoa0909905(2010))

Dr. Fauci’s earlier research had shown that cyclophosphamide worked by suppressing the function of B cells, an immune cell that produces the self-destructive antibodies. However, long-term, repeated use of cyclophosphamide puts patients at increased risk of infection, cancer and infertility as well as other side effects. In search of an alternative therapy for patients with ANCA-associated vasculitis, ITN investigators turned to rituximab, a synthetic antibody that selectively reduces the number of B cells circulating in the blood. Rituximab currently is licensed to treat some B-cell lymphomas, chronic lymphocytic leukemia and rheumatoid arthritis.

In the study, one group received intravenous rituximab therapy once a week for one month, plus steroids. The other group received 3 to 6 months of daily cyclophosphamide therapy plus steroids, followed by daily AZA. Neither the investigators nor the patients knew the treatment assignments. After a 6-month treatment period, the investigators found that 64% of participants in the rituximab group and 53% in the cyclophosphamide group had no disease activity and were able to completely discontinue the use of steroids. According to the authors, the study has successfully demonstrated that rituximab provided comparable benefits as standard therapy for ANCA-associated vasculitis. Moreover, in patients with relapsing disease, the new treatment worked even better. The investigators found that 67% of participants with relapsing disease in the rituximab group had no disease activity and were able to discontinue all steroid use after therapy, compared with only 42% in the cyclophosphamide group.

Mental Decline Thwarted In Aging Rats – Perhaps Good New for Alzheimer’s Disease Sufferers

 

Physical activity, social, or other enriching experiences promote neurogenesis – the birth and maturation of new neurons. This growth takes place in the dentate gyrus, a key area of the brain’s memory hub, the hippocampus. But even in the normal adult brain, most of these newborn neurons die during the month it takes to develop and get wired into brain circuitry. To survive, the cells must run a gauntlet of challenges. Newborn hippocampus neurons fare much worse in aging-related disorders like Alzheimer’s disease, marked by runaway cell death.

According to an article published online in Cell (9 July 2010), a compound has been discovered that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain’s memory hub. The research, funded in part by the National Institutes of Health, has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer’s disease.

In hopes of finding compounds that might protect such vulnerable neurons during this process, more than 1000 small molecules were tested in living mice. One of the compounds, designated P7C3, corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells – normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40%. Among clues to the mechanism by which P7C3 works, it was discovered that it protects the integrity of machinery for maintaining a cell’s energy level.

To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the compound was given to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.

The study also pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer’s cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer’s disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the authors are now searching for the molecular target of P7C3 — key to discovering the underlying neuroprotective mechanism.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA Approves First Implantable Miniature Telescope to Improve Sight in Patient with Age-Related Macular Degeneration

Age-related macular degeneration (AMD) a condition that mainly affects older people, damages the center of the retina (macula) and results in a loss of vision in the center of the visual field. About 8 million people in the United States have AMD and nearly 2 million of them already have significant vision loss, according to the National Eye Institute. AMD can make it difficult or impossible to recognize faces or perform daily tasks such as reading or watching television.

The FDA has announced the approval of the Implantable Miniature Telescope (IMT) to improve vision in some patients with end-stage AMD. Surgically implanted in one eye, the IMT is a small telescope that replaces the natural lens and provides an image that has been magnified more than two times. The IMT is available in two models: one that provides 2.2 times magnification and another 2.7 times magnification. The IMT is designed to magnify and project images onto a healthy portion of the retina. The IMT is intended to be implanted in only one eye; the non-implanted eye is used for peripheral vision. The IMT is used in patients ages 75 years and older with stable severe to profound vision impairment (when vision impairment has not changed over time) caused by blind spots (bilateral central scotoma) associated with end-stage AMD. These patients also have evidence of a visually significant cataract.

Patients must undergo training with an external telescope with a low vision specialist prior to implantation to determine whether adequate improvement in vision with the external telescope can be obtained and to verify if the patient has adequate peripheral vision in the eye that would not be implanted. Patients must also agree to participate in a post-operative visual training program.

In a 219-patient, multi-center clinical study of the IMT, 90% of patients achieved at least a 2-line gain in either their distance or best-corrected visual acuity, and 75% of patients improved their level of vision from severe or profound impairment to moderate impairment. Because the IMT is a large device, implantation can lead to extensive loss of corneal endothelial cells (ECD), the layer of cells essential for maintaining the clarity of the cornea, and chronic endothelial cell loss. The chronic rate of endothelial cell loss is about 5% per year. Significant losses in ECD may lead to corneal edema, corneal decompensation, and the need for corneal transplant. In the study, 10 eyes had unresolved corneal edema, with five resulting in corneal transplants. The calculated five-year risk for unresolved corneal edema, corneal decompensation, and corneal transplant are 9.2%, 6.8% and 4.1%, respectively.

To ensure that the risks of IMT implantation are sufficiently and consistently communicated to patients, the FDA and the manufacturer created detailed labeling, including an Acceptance of Risk and Informed Decision Agreement, which patients must complete prior to IMT implantation. The agreement provides a guide for patients and their physicians to discuss the risks associated with IMT implantation. Patients should be given adequate time to review all of the information regarding the IMT. As a condition of FDA approval, the manufacturer, VisionCare Ophthalmic Technologies Inc. of Saratoga, Calif., must conduct two post-approval studies. In one study, VisionCare must continue follow-up on the subjects from its long-term follow-up cohort for an additional two years. Another study of 770 newly enrolled subjects will include an evaluation of the endothelial cell density and related adverse events for five years after implantation.

For more information about our expertise in Medical Affairs, contact Dr. Mark Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen ParkTARGET HEALTH INC.

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, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

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2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).

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