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New research suggests that people who are exposed to low levels of sunlight coupled with a history of having a common virus known as mononucleosis（单核细胞增多症） may be at greater odds of developing multiple sclerosis (MS多发性硬化) than those without the virus. The research is published in the April 19, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology. “MS is more common at higher latitudes, farther away from the equator,” said George C. Ebers, MD, with the University of Oxford in the United Kingdom and a member of the American Academy of Neurology. “Since the disease has been linked to environmental factors such as low levels of sun exposure and a history of infectious mononucleosis, we wanted to see whether the two together would help explain the variance in the disease across the United Kingdom.”Infectious mononucleosis is a disease caused by the Epstein-Barr virus, which is a Herpes virus that is extremely common but causes no symptoms in most people. However, when a person contracts the virus as a teenager or adult, it often leads to infectious mononucleosis. The body makes vitamin D when exposed to ultraviolet B (UVB) light.For the study, researchers looked at all hospital admissions to National Health Service hospitals in England over seven years. Specifically, they identified 56,681 cases of multiple sclerosis and 14,621 cases of infectious mononucleosis. Scientists also looked at NASA data on ultraviolet intensity in England.The study found that adding the effects of sunlight exposure and mononucleosis together explained 72 percent of the variance in the occurrence of MS across the United Kingdom. Sunlight exposure alone accounted for 61 percent of the variance.”It’s possible that vitamin D deficiency may lead to an abnormal response to the Epstein-Barr virus,” Ebers said.He noted that low sunlight exposure in the spring was most strongly associated with MS risk. “Lower levels of UVB in the spring season correspond with peak risk of MS by birth month. More research should be done on whether increasing UVB exposure or using vitamin D supplements and possible treatments or vaccines for the Epstein-Barr virus could lead to fewer cases of MS.”

Women who choose among different breast cancer treatment options make smarter choices when getting the information and making decisions in small doses rather than all at once, as is customary, a University of Michigan study found. It’s long been known that people who aren’t good with numbers have a harder time understanding the risk information they need to make good medical decisions, says Brian Zikmund-Fisher, assistant professor at the U-M School of Public Health and a research assistant professor at the U-M Health System.Zikmund-Fisher and co-authors Peter Ubel and Andrea Angott of Duke University tested whether asking women to make a series of simpler choices rather than one complex decision would help them understand when aggressive post-surgery therapies, such as chemotherapy, actually yield larger benefits.The researchers found that the group of women in the study who weren’t good with numbers became confused when faced with as few as four treatment options at once, and chose chemotherapy regardless of whether their benefit would be 1 percent or 5 percent.A different group of women in the study received the same treatment options divided into two separate decisions. They first decided whether to take hormonal therapy, and if they said yes, they then decided whether or not to add chemotherapy. More of the women who made decisions incrementally（递增地） chose the chemotherapy only if it gave them a large benefit.”It’s obvious that you should be more interested in chemotherapy if you’re going to get a 5 percent benefit versus only a 1 percent benefit,” Zikmund-Fisher said. “That wasn’t always true for people who got all of the risk information at once. But, when we let women make their hormonal therapy choices separately from chemotherapy choices, more people wanted the treatment if it was a 5 percent benefit.”Zikmund-Fisher says the findings send a clear message about physician-patient communication.”What that tells me is that it doesn’t take very much information to be too much, especially with patients who have trouble with numbers,” he said. “When we try to provide patients with full and complete information, we often end up overwhelming them.”Even women who are good with numbers benefit from having information presented piece-by-piece because they can better understand how much benefit comes from each treatment option, Zikmund-Fisher says.He says that parceling out（分派） information to make decision-making simpler doesn’t necessarily mean more work for doctors or longer visits.”I believe that having patients make decisions one at a time might make doctors’ visits shorter rather than longer,” Zikmund-Fisher said. “When you make things simpler, you don’t have to explain it again and again.”

A duo of drugs, each targeting a prime survival strategy of tumors, can be safely administered and are potentially more effective than either drug alone for advanced, inoperable melanomas（黑素瘤） , according to a phase 1 clinical trial led by Dana-Farber Cancer Institute investigators. The findings (abstract 8511), will be presented in an oral session at the annual meeting of the American Society of Clinical Oncology on Saturday, June 4, 3 p.m. CT, Arie Crown Theater, McCormick Place.The drugs — ipilimumab and bevacizumab — are both monoclonal antibodies, intensified formulations of natural disease-fighting proteins. Ipilimumab spurs the immune system to attack diseased cells, including tumor cells. Bevacizumab, also known by the trade name Avastin, blocks the growth of blood vessels that provide tumors with nourishment. Ipilimumab has extended the lives of metastatic melanoma patients in previous clinical trials, and bevacizumab is often used to treat tumors of the colon, lung, and kidney.The trial involved 22 patients with metatastic melanoma that was not treatable by surgery.F. Stephen Hodi, MD, the study’s lead author and director of the melanoma treatment center at Dana-Farber, said the trial is the first to explore whether the two agents enhance each other’s effectiveness. Most of the participants didn’t experience serious adverse side effects, although some did experience inflammation of artery walls, the liver, thyroid gland, colon, or uvea（葡萄膜） (the middle layer of the eye). Five patients required steroid treatment for these problems and were removed the trial.Positron emission tomography (PET正电子成像术) scans showed a prompt immune system response to many of the melanoma tumors, and computed tomography (CT) scans showed decreased blood flow to the tumors. Eight of the participants had partial responses — showing some tumor shrinkage — to the dual treatment, and six had stable disease. All the responses lasted at least six months. Biopsies performed after the treatment showed a more vigorous immune system response than would be expected with ipilimumab alone.”Our findings indicate that ipilimumab and bevacizumab can be safely administered with careful management of side effects,” said Hodi. “The results of lab tests suggest that the two agents may work synergistically（协同地） , with 14 of 21 evaluable patients experiencing a clinical benefit. This approach merits exploration in further clinical trials.”

Scientists from The Scripps Research Institute have identified a class of compounds that could be a boon（恩德，福利） to basic research and drug discovery. In a new study, published online in Nature Chemical Biology on May 15, 2011, the researchers show the new compounds powerfully and selectively block the activity of a large and diverse group of enzymes known as “serine（丝氨酸） hydrolases.” Previously discovered serine hydrolase-blocking compounds have been turned into drugs to treat obesity, diabetes, and Alzheimer’s disease, and are currently in testing as treatments for pain, anxiety, and depression.”There are more than 200 serine hydrolases in human cells, but for most we’ve lacked chemical inhibitors of their activity,” said team leader Benjamin F. Cravatt III, professor and chair of the Department of Chemical Physiology at Scripps Research and a member of its Skaggs Institute for Chemical Biology, “so we’ve had only a limited ability to study them in the lab or to block them to treat medical conditions. This new research allows us to greatly expand our list of these inhibitors.”A Scaffold on Which to BuildHints from previous work by the Cravatt lab and other groups led the team to investigate a group of molecules known as ureas（尿素酶） for their ability to inhibit serine hydrolase activity. In initial tests using recently advanced techniques for measuring enzyme-inhibition strength and specificity, the Scripps Research scientists found that molecules known as 1,2,3-triazole ureas could powerfully inhibit some serine hydrolases without affecting other enzymes.In the next set of tests, the team synthesized a basic “scaffold” of 1,2,3-triazole urea, and found that it inhibited many more serine hydrolases – still without affecting other enzyme classes – than did an existing broad inhibitor known as a carbamate（氨基甲酸酯） . The team then began modifying the scaffold compound to refine its inhibitory activity to specific serine hydrolase targets. This chemical tweaking would once have been a lengthy and burdensome task, but in this case it was done using simple “click chemistry” techniques developed at Scripps Research by Nobel laureate Professor K. Barry Sharpless and his colleague Associate Professor Valery Fokin.”We can make these modifications in just two chemical steps, which is a great advantage,” said Alexander Adibekian, a postdoctoral fellow in the Cravatt lab and first author of the new paper. “And despite this technical simplicity, we were able to generate compounds that were extremely potent and selective.”From the 20 compounds the scientists generated this way, they found three with powerful and highly specific inhibitory effects on individual serine hydrolases with many unknown characteristics.Most of the study’s enzyme-inhibition tests were conducted in mouse cell cultures, a more realistic biochemical environment than traditional “test-tube” biochemical preparations; but for one of the group’s inhibitor compounds, AA74-1, the scientists extended their inhibition-measurement techniques to animal models, showing that the compound potently blocked the activity of its target serine hydrolase, acyl-peptide hydrolase, or APEH, without significantly affecting other enzymes.Not much had been known about APEH, but with its inhibitor AA74-1, the team was able to illuminate the enzyme’s normal role in the chemical modification of proteins, showing the levels of more than two dozen proteins dropped sharply when APEH was inhibited.”This was unexpected and unusual,” said Adibekian. “But it’s what one wants to see with these compounds— strong enzyme-inhibiting activity in different tissues, at a low dose. And it’s the first time this kind of evaluation has been done in both cultured cells and animal tissues.”The Cravatt lab is now using the expanding number of inhibitors that team members have generated so far to study serine hydrolases（水解酶） with previously unknown or uncertain biological functions.”We’re also using the techniques described in this paper to try to systematically generate more of these inhibitor compounds,” said Cravatt. “We see these compounds as basic tools that enable us to determine the roles of serine hydrolases in health and disease. As we understand these enzyme roles better, we expect that some of their inhibitors could become the bases for medicines.”

UT Southwestern Medical Center scientists are shedding new light on why the anesthetic（麻醉的） drug ketamine produces a fast-acting antidepressant response in patients with treatment-resistant depression. The drug’s robust effect at low doses as a fast-acting antidepressant potentially has use in emergency rooms with high-risk patients.”Ketamine produces a very sharp increase that immediately relieves depression,” said Dr. Lisa Monteggia, associate professor of psychiatry at UT Southwestern and senior author of the study published June 15 in Nature.Typical antidepressant medications – one of the most widely prescribed classes of drugs in the U.S. each year – often take several weeks to relieve symptoms of depression. If they are not successful within 12 weeks, physicians must prescribe a different antidepressant to produce a response.”Ketamine produces a fast-acting antidepressant effect, and we hope our investigation provides critical information to treat depression effectively sooner,” Dr. Monteggia said.”We now have a novel pathway to explore that may provide potential for the development of faster-acting and longer-lasting antidepressants,” Dr. Monteggia said.The next step, Dr. Monteggia said, is to investigate further the short- and long-term effects of the changes that occur when the brain cells communicate with each other.

Sleep deprivation is an issue that affects practising physicians and not only medical residents, and we need to establish standards for maximum work and minimum uninterrupted sleep to ensure patient safety, states an editorial in CMAJ (Canadian Medical Association Journal) (pre-embargo link only) http://www.cmaj.ca/embargo/cmaj110402.pdf. A recent study indicated that lack of sleep can result in higher rates of surgical complications（并发症） if a surgeon had less than six hours of sleep the preceding（在前的） night. Doctors practising post-call may not be at optimal levels as fatigue can effect mental acuity.”The problem may only be getting worse,” write CMAJ editors Drs. Noni MacDonald, Paul Hébert, Ken Flegel and Matthew Stanbrook. “Medical care today is more complex than in decades past….Increasing complexity of care at the bedside or in the operating theatre places unprecedented cognitive and physical demands on doctors who oversee and deliver care in these environments.”However, there are barriers to limiting physicians’ work hours, including increased costs and the need to increase the number of doctors and residents in the system. As well, ensuring that physicians comply with restrictions on work hours may be a challenge.”We doctors ourselves are part of this problem,” write the authors. “We need to shift our professional culture. Long periods on call should not be accepted as routine or a source of pride.”They suggest that “licensing, accreditation（委派，相信） , insurance and government institutions need to establish minimum best practice standards for maximum work and minimum uninterrupted sleep hours.”

High epidermal growth factor receptor (EGFR表皮发展因子受体) expression was a good predictor of which lung cancer patients would survive longer when cetuximab (Erbitux) was added to first-line chemotherapy, according to research presented at the 14th World Conference on Lung Cancer in Amsterdam, hosted by the International Association for the Study of Lung Cancer (IASLC). “The new analysis of the Phase III FLEX study has allowed us to identify which non-small cell lung cancer patients are most likely to benefit from treatment with Erbitux in the first-line setting,” said principal investigator Dr. Robert Pirker of the Medical University of Vienna in Austria. “By demonstrating that high EGFR expression is the first predictive biomarker for improved overall survival in advanced NSCLC, we have taken a major step towards a more personalized approach in this difficult-to-treat disease.”Based on a new analysis of all FLEX patients (1,121 out of 1,125 FLEX study patients), researchers found that patients with high tumor EGFR expression (200 and above on a scale of 0-300) consistently benefited from the addition of cetuximab to chemotherapy（化学疗法） regardless of histology（组织学） . Within this group, overall survival averaged 12 months, compared with 9.6 months for patients receiving chemotherapy alone.In patients with low EGFR expression, no difference in overall survival was seen between patients receiving chemotherapy plus cetuximab, compared to those receiving chemotherapy alone.

The quality of interactions among married couples is affected by wives’ inability to fall asleep at night, but not by husbands’ sleep problems, suggests new research that will be presented Monday, June 13, in Minneapolis, Minn., at SLEEP 2011, the 25th Anniversary Meeting of the Associated Professional Sleep Societies LLC (APSS). Results show that, among wives, taking longer to fall asleep at night predicted their reports of more negative and less positive marital（婚姻的） interactions the next day, and it also predicted their husband’s reports of less positive marital interaction ratings the following day. In contrast, husbands’ sleep did not affect their own or their wife’s report of next day’s marital interactions.”We found that wives’ sleep problems affect her own and her spouse’s marital functioning the next day, and these effects were independent of depressive symptoms,” said principal investigator Wendy M. Troxel, PhD, assistant professor of psychiatry（精力病学） at the University of Pittsburgh School of Medicine in Pittsburgh, Pa. “Specifically, wives who took longer to fall asleep the night before reported poorer marital functioning the next day, and so did their husbands.”The relationship between nightly sleep and next day’s marital interactions was stronger than the association between daily marital interactions and subsequent sleep. Curiously, however, husbands’ reports of higher levels of positive marital interactions predicted their own shorter sleep duration the next night.The study involved 32 healthy, married couples with an average age of 32 years. Participants were free of clinically relevant sleep, psychiatric or medical disorders. Sleep latency, wakefulness after sleep onset, and total sleep time were measured by actigraphy（体动记录仪） for 10 nights. The quality of marital interactions was assessed daily over the 10-day assessment using electronic diaries to evaluate positive marital interactions such as feeling supported or valued by spouse, as well as negative marital interactions such as feeling criticized or ignored by spouse. Dyadic, time series analyses helped determine the direction of the relationship between sleep and marital interactions.According to the authors, the findings show that sleep disorders such as insomnia（掉眠） can have a negative impact on marital relationships.”These results highlight the importance of considering the interpersonal consequences of sleep and sleep loss,” said Troxel.The study was supported by the National Institutes of Health through the National Heart, Lung, and Blood Institute; and the Clinical & Translational Science Awards.The SLEEP 2011 abstract supplement is available for download on the website of the journal Sleep at http://www.journalsleep.org/ViewAbstractSupplement.aspx.In previous studies, Troxel found that the stable presence of a husband or cohabiting partner predicted better sleep quality and continuity in women (SLEEP – July 2010); and women who were happy in their marriage reported fewer sleep disturbances (Behavioral Sleep Medicine – 2009).

A new study by scientists from Maryland and Colorado using American kestrels（美洲隼） , a surrogate（代办代理的） test species for raptorial birds, suggests that they are at greater risk from poisoning from the rodenticide（灭鼠剂） diphacinone than previous believed. The research, published in Environmental Toxicology and Chemistry, considers the threat posed by diphacinone as its usage increases following restrictions on the use of similar pesticides. “Recent restrictions on the use of some rodenticides may result in increased use of diphacinone,” said lead author Dr. Barnett Rattner from the US Geological Survey. “Very few controlled studies have examined its toxicity in birds so it is important to determine how lethal this chemical is to wildlife.”Surveillance programs have reported detection of rates of rodenticide in birds of prey across France, Great Britain and Western Canada, revealing that several second-generation rodenticides can result in non-target deaths, with possible population-level implications.However, the global magnitude of non-target poisoning through the routine use of rodenticide, or through targeted eradication programs remains unknown, partly because the indirect fatalities go largely unnoticed and unreported.The team tested kestrels and discovered the effects of diphacinone and the quantity required for a lethal dose. The results showed that birds that had ingested greater than 300 mg per kilogram of body weight died within 8 to 23 hours, while those ingesting a dose of 118.6 mg/kg survived 27 to 47 hours. At lower doses, nearly all of the birds survived.Poisoned birds displayed some evidence of internal bleeding, although histological（组织学的） examination of internal organs revealed hemorrhaging（出血） over a wide range of doses. The results demonstrate that doses that reach or exceed 79 mg/kg body weight are lethal for kestrels.”Our study, combined with previous research in hawk and owl species show that birds of prey are considerably more sensitive to diphacinone compared to species such as bobwhite（美洲鹑） quails and mallards,” said Rattner. “Their protection requires more substantial safety margins than are afforded to species of game birds traditionally used in pesticide registration studies.”Using their results the team estimated how much poisoned prey a hawk or owl would need to consume before ingesting a lethal dose. Using a probabilistic（概率的） risk approach, the team estimated that an endangered hawk or owl would be at risk if it consumed as little as 3 to 4 grams of liver from a poisoned rodent.”Diphacinone was found to be considerably more toxic to American kestrels than previously reported in tests of other wildlife test species”, concluded Rattner. “These data, in combination with similar measurements in Northern bobwhites, will assist in the development of a pharmacodynamic（药效的） model and a more complete risk assessment of diphacinone for birds.”