Health Meaning

Since November 29, not a single new case of Ebola was reported in Guinea, Sierra Leone or Liberia. If no new cases pop up, the world will be able to declare January 14 as 2 years Ebola epidemic has ended at the end, after more than 28,0 cases and 11,300 deaths.

The victory also mean the end of an unprecedented era in the search for Ebola. The tragedy provided a unique opportunity: Never had the disease affected enough people to allow researchers to test drugs and Ebola vaccines in a real context. As the number of cases exploded in mid-2014, they initiated a broad research program that runs at breakneck speed.

But the harvest of this massive effort is thin.

The greatest success to date is a vaccine produced by Merck. A July 31 report to The Lancet documented remarkable effectiveness in a real-world test in Guinea. But all other results have yet to appear in the scientific literature. And careful consideration of the data so far supported by dozens of interviews with leaders of the study and other experts Ebola clearly shows that almost every other trial seems destined to end questionable results or total failure . The results of those who have completed are proving difficult to publish in high-level journals.

The reasons are varied and complex. Even under the best circumstances, clinical trials may not provide satisfactory results. In this case, many studies have begun too late, when the epidemic was already down, and ran out of patients. Others had ideas which from the beginning were unlikely to provide a clear answer. A pharmaceutical company abandoned a trial for reasons he never specified, and the fate of another trial remains obscure, even to the World Health Organization.

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(Click image to enlarge.)

"thin harvest", explains where the Ebola clinical trials in Guinea, Sierra Leone and Liberia stand today and what they are most likely to yield

• brincidofovir :. A test purposes without explanation

• TKM-Ebola: Negative results prove difficult to publish

• favipiravir: A large study fails to give solid answers

• Interferon: A test that few believed in

• zmapp: the front-runner is fading

• the blood of survivors A trial whose fate is not known

• plasma Cloudy results filtered blood

• vaccines: The only real success story so far

for more science news and research coverage of the Ebola epidemic to visit our collection "files Ebola." For more coverage, see the January 1 issue of Science.

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brincidofovir

a trial ends without an explanation

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On January 30, Chimerix Durham, North Carolina, has pulled the plug on a clinical trial of its experimental drug brincidofovir patients Ebola. The drug, which mimics a DNA building block is active against many viruses in test tube experiments and in human studies to treat cytomegalovirus and adenovirus. But the Ebola test began on 1 January by researchers working with Médecins Sans Frontières (MSF) in a clinic Ebola in Monrovia, was canceled after only four registered patients.

The announcement surprised even the scientists running the trial. "The press knew before me," says Stephen Kennedy, a Liberian investigator on the study's principal investigator Peter Horby of Oxford University in the UK said the reasons Chimerix not be told;. In a statement press the company has simply noted that the number of new cases in Liberia had "decreased significantly."

Horby said he doubts the decision was related to how the drug made in the first four patients. Instead, he believes Chimerix decided he did not want to continue bringing to market brincidofovir Ebola after discussions with the US Food and Drug Administration (FDA) has raised questions about the interpretation of studies animals. As chief scientist of the FDA, Luciana Borio in Silver Spring, Maryland, says she can not comment. "We have asked the company to disclose the facts surrounding the case and we could not." (FDA does not oversee the trial of Liberia itself.)

"Someone should call Chimerix and ask them," said Marie-Paule Kieny of the World Health Organization in Geneva Switzerland, who coordinated the international research effort on the Ebola virus. Science did this, but a spokesman for the company declined to comment.

Whatever motivation, "it was frustrating," said Horby. "We have invested a huge amount of resources, time, effort, in very difficult circumstances, such as MSF. it must not have been arrested at least it was for a very good reason. "With so few patients enrolled, the study results are" uninterpretable "said Horby, which nevertheless still hopes to publish a paper on the subject

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TKM-Ebola

negative results prove difficult to publish

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at the peak of the Ebola outbreak in September 2014, the World health Organization (WHO) gathered experts in Geneva, Switzerland, to discuss the myriad potential treatments and help identify the most promising. The group has given priority to interventions that have proven successful in monkeys experimentally infected with Ebola and a drug called TKM-Ebola ended at the front of the pack. Made by Tekmira Pharmaceuticals Corporation of Vancouver, Canada, TKM-Ebola interferes with RNA of the Ebola virus.

But the company has had precious few doses, and a formal clinical trial was slow to start. Some researchers also frowned upon because the study was launched March 11 in Sierra Leone, has not had a randomized controlled design. But Peter Horby, a respected researcher from the University of Oxford in the UK, led the study, and the Wellcome Trust funded. Hopes ran high that it would at least give an indication of whether the encouraging results monkey would be supported in humans.

On June 19, however, Tekmira ended suddenly the study, without fully explaining why. Horby said after testing the drug on 14 patients, the study had reached a predefined "border futility." This means entering other patients was "unlikely to show that the drug was significantly beneficial," he said.

The absence of a clear advantage was "disappointing," Horby said, but he noted that it is not unusual for drugs to work in monkeys and humans fail. A problem may have been that animals were treated early in their illness; most Ebola patients seek care very late, he said.

next disappointment came when Horby The New England Journal of Medicine ( NEJM ) rejected a paper describing the results. He speculates that scientific publications are losing interest in Ebola, and the fact that this study lacked a randomized design and clear results have worked against her as well.

"Newspapers have published large amounts of anecdotal evidence on one or two cases and hundreds and hundreds of opinion and comment pieces, but we struggled to publish final data information but no trial, "said Horby. Although he understands that negative studies are less exciting," you have to balance this against the enormous difficulty of these tests and the almost complete absence of any data on the effects of treatment. "

WHO Assistant Director-General Marie Paule Kieny shares her frustration." it is problematic because it is very important that these results are in the open, "she said. A spokesman NEJM says she can not comment because the journal publication process is confidential. Horby said the document is currently being studied in another paper

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favipiravir

A large study fails to give solid answers

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The largest study on the treatment done in the favipiravir tested Ebola epidemic, drug against influenza. The trial ended after the listing of more than 0 people, and its results could soon appear in a scientific journal. But the study may not give a clear answer to the key question: he works

favipiravir that inhibits viral enzyme called RNA polymerase critical and is developed by Fujifilm in Japan, has shown activity Ebola virus in test tubes and in mice. At the beginning of the epidemic, there was a big advantage over other drug candidates: He was generous and had proven safe when administered to healthy volunteers in Phase trials. Researchers at the National Institute of France for Health and Medical Research (INSERM) began a collaboration with researchers in Guinea, French-speaking countries, to test favipiravir four Ebola treatment units.

In February, the INSERM researchers presented what they said were encouraging preliminary results based on the first 69 patients. The drug appeared to save the lives of people who came to clinics with low levels of Ebola, they said. French President Francois Hollande welcomed the results in a press release and invited leading research Ebola at the Elysee Palace in Paris. Since then, all patients Ebola in Guinea were offered favipiravir.

Many researchers were less impressed. INSERM team has not used a randomized controlled trial (RCT) design, but gave all eligible patients of the drug; their results were compared to a group of Ebola patients who fell ill before the start of the trial. The problem is that the mortality greatly depends on the quality of care Ebola, which varies considerably over time and from one to another treatment facility. This makes such comparisons difficult. The drug also worked only in people without treatment have a much better chance of surviving Ebola because when they first sought care, they had relatively low levels of virus in their blood.

An RCT would have been impossible, says researcher INSERM Denis Malvy; it was unacceptable for the local population, already distrustful of the government and foreign workers Ebola. He said building research collaborations was hard enough without the added stress of asking local employees to refuse treatment to a control group. "It is easy to criticize a study," he said. "We decided to look for a signal, not a formal proof of efficacy."

But now, nobody is sure favipiravir should be used in the next Ebola outbreak. That's the bottom line, says Luciana Borio of the US Food and Drug Administration, and it shows that uncontrolled studies can cause more harm than good. "The result was that the nebula data area we were so scared about," said Borio. "We left not knowing if the product help, hurt, or does nothing."

The study design was also one of the reasons why the New England Journal of Medicine (NEJM) rejected an article on the results, said Malvy; instead of the newspaper offered him a letter of 300 words to the publisher, he said was laughable. (A NEJM spokesman declined to comment.) The study is now under review at PLOS Medicine Malvy said

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Interferon

A trial that few believed in

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When Ebola spiral out of control in the summer of 2014, immunologist Eleanor Fish, University of Toronto in Canada thought it had some thing that could save lives. Since no treatment was available, Fish said it was logical to try interferon, a group of biochemicals with antiviral activity she had long studied.

Many scientists Ebola disagreed.

Fish sent the World Health Organization (WHO) study showing that interferon-α, delivered by an adenovirus and combined with a cocktail of antibodies, has an efficacy in monkeys infected with Ebola virus. But other researchers noted that has not been shown only interferons do anything. A panel requested by WHO to prioritize drugs for testing interferons considered "problematic". Side effects such as fever and muscle aches, which are similar to Ebola symptoms-could create problems in the Ebola treatment centers, the group said. "Basically, all interferons do not work," Peter Jahrling, a researcher Ebola veteran at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, told a WHO meeting, summarizing the evidence animal therapies for Ebola. "I do not know why you want to do a clinical trial with them."

given the lack of alternatives at the time, Fish pushed forward with a test of the interferon-β, including in vitro studies suggested was the most effective way to counteract the replication of the Ebola virus, she said. she teamed with Guinean epidemiologist Mandy Kader Konde set up a clinical trial in the Ebola treatment center in Coyah, about 2 hours northeast of the capital, Conakry. But it was not until March 2015 to write the protocol and get the study approved by Guinean regulators. D by then, the number of Ebola cases had fallen sharply. Because interferons may make things worse if taken at the end of the infection, the trial enrolled patients within 6 days after onset of symptoms, which still has limited enrollment.

Ultimately, only nine patients participated in the study. All received interferon-β; having a placebo arm was unacceptable in Guinea, Fish said, that patient outcomes were compared with those of 21 untreated patients, matched for age, who were seen in the same center in the same period. Given the study design and small size, "I do not think there will be something out of this," said Marie-Paule Kieny WHO.

But fish disagrees. "Statistical analyzes indicate that [interferon] offered a therapeutic advantage," she wrote in an email to Science . "We have a number of measures that we evaluated that support this." Fish declined to elaborate, but said the data will soon be submitted for publication

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zmapp

A front- fane runner

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zmapp, cocktail three artificial Ebola antibodies, has been the darling of the world of research and the media since missionary Kent Brantly and Nancy Writebol received treatment in the summer of 2014. CNN has described as a "secret serum that probably saved" their lives . CNN reporter Sanjay Gupta, a medical doctor said one source describes how Brantly had a "sudden deterioration" in Liberia and "thought he was going to die," but after receiving zmapp, "within 20 minutes to an hour" it was "a nearly complete reversal of symptoms. "However, from individual cases for statistical data that the drug really works in people was difficult.

zmapp worked brilliantly in monkey experiments, even save the animals in advanced stages of infection. When the antibody cocktail was administered to animals up to 5 days after infection with Ebola virus, each of them survived, scientists reported in Nature in August 2014. veteran Ebola researcher Thomas Geisbert of the University of Texas Medical Branch in Galveston called the result a "monumental achievement." But zmapp made by Mapp biopharmaceutical in San Diego, California, was so rare that by the mid-February 2015, only nine people had received and some were dead, adding that whatever its potential, there were limits.

it took until 27 February for a formal trial randomized controlled zmapp to start in Liberia, conducted by the US National Institute of allergy and infectious diseases (NIAID). But by then, the epidemic in Liberia was practically over. the team expanded the study Sierra Leone and hit a collaboration with french researchers working in Guinea to recruit patients there. (One patient in the US has also been included in the trial.)

But time was not on the side of the study. To date, the trial has enrolled about 70 patients, said lead researcher Clifford Lane NIAID in Bethesda, Maryland. Complicating the study is that patients also receive favipiravir Guinea, based on a French study inconclusive in this country that suggested he was an anti-Ebola effect. The team will zmapp a subset of country analysis to see if the effects of the two drugs can be untangled.

What the forerunner of the past will be shown to work remains the big question. The study safety data independently and the Supervisory Board (DSMB) that looks at the results once a month or more. "They have not yet stopped the trial, so we know he must at least do something," said Marie-Paule Kieny of the World Health Organization, which is still hopeful that zmapp become second story clinical success of the Ebola outbreak, after Merck

vaccine. But Lane's safer. "it is very difficult to read between the lines of a DSMB recommendation," he said. However, "I am hopeful that, although the data do not reach statistical significance, there could be at least a tendency to effectiveness of humans who support animal data."

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the blood of survivors

A trial whose fate is not known

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whole blood of Ebola survivors has been given to people with the disease as an experimental treatment. This tarpaulin hung outside of Liberia treatment center when closing

The people who survive an infection like Ebola have a powerful weapon in their blood. Antibodies that conquered the invading microbe. In principle, a surviving blood infusion could be a lifeline for people newly infected. But an initial study in Sierra Leone test this concept remained unpublished and nobody seems to know what happened with the data.

The World Health Organization (WHO) has pushed for therapies studies based on blood early in the Ebola epidemic as the most promising drug candidates were rare, while the number of survivors was growing. These studies can be performed with either whole blood or its plasma, which has removed the cells; it is much more difficult technically because it requires so-called plasmapheresis machine to separate the plasma and cells.

Gevao Sahr, a hematologist at the University of Sierra Leone in Freetown and consultant to the Ministry of Health of the country and sanitation, decided to try the simplest option from the start. A study of whole blood transfusion began in the fall of 2014 in the hospital 34 military in Freetown. But at the same time, an international consensus has emerged that the use of plasma was the way forward, and collaborations have been set up to ship plasmapheresis machines and West Africa to test this strategy in Ebola three affected countries.

The whole blood study in Sierra Leone seems to have ended at the end of 2014; Gevao became the principal investigator for the plasma study of the country, in collaboration with the University of Liverpool in the UK and other partners.

But data from the whole blood study were published. Some press reports have suggested that he was successful, and Wiltshire Johnson Pharmacy Board of Sierra Leone to oversee clinical trials in the country, said Science 33 patients out of 44 who received transfusion survived. These are much higher survival rates than were reported at the time to untreated Ebola. But scientists warn that it is unclear how patients were selected for the trial, or if their care differed in other ways that made them more likely to survive.

Gevao did not respond to emails from Science . Scientists working on plasma studies say they do not know what happened with the whole study of blood. Neither is WHO. "I have not yet seen the results," said WHO Assistant Director-General Marie-Paule Kieny. "We have to chase it, we need to know what happened"

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Plasma

Cloudy results filtered blood

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the blood of Ebola survivors contains antibodies that could help sick people with the disease, but blood is a precious commodity: donors can not be bled frequently, and the product must be used within a few months. .

A person is brain dead and five others were hospitalized after a phase I clinical trial in France went horribly wrong turned. At least three of the patients may suffer from irreversible brain damage if they survive, a doctor treating said today.

The patients were previously healthy volunteers who participated in a study by Biotrial, a private company in the city of Rennes, to test the tolerance of a drug candidate. French officials have not announced any drug, and it is still not clear why many others who participated in the study since it began in July has apparently not experienced similar serious side effects.

details of the accident have been slow to emerge. Biotrial, a research organization known contract established in 1989, has notice of a paragraph on its website today said, without providing details, that in a first study in men, the events "serious adverse in relation to test drug occurred in some subjects." (A few hours later, the company issued another statement saying: "Our thoughts are with the volunteers and their families, we work hand in hand with the health authorities to understand the cause of this. accident. ")

at a press conference in Rennes this afternoon, the French health Minister Marisol Touraine said Biotrial testing a compound acting on the system endocannibanoid body, a group receptor proteins that meets the naturally made compounds in the body as well as components of cannabis. The drug temporarily for multiple disorders, including neurodegenerative diseases and anxiety, was developed by the Portuguese pharmaceutical company Bial. Contacted by Science today, a spokesman Bial said she could not comment, but the company will issue a press release about it later today.

Speculation on the Internet focuses on a compound named BIA 10-2474, which, according to the website of Bial, is a candidate drug for the "neurological and psychiatric pathologies," which is currently in Phase I test.

Speaking of the news France info radio stations today, neurologist Gilles Edan of Rennes University hospital Centre said the first patient in the study arrived Sunday with symptoms very severe than the team initially thought Edan could be caused by a stroke. the patient soon deteriorated further and is now brain dead, Edan said. Four other patients have neurological symptoms of varying severity, he added, but not in a coma. "of these four, three already have a pretty table severe clinical danger that even in the best situation, there will be an irreversible disability," said Edan. Because the effects of drugs on humans are not known, patients should be closely monitored, he said. "We can not make a definitive prognosis." The sixth patient has no symptoms, but is under surveillance.

Touraine, who visited the hospital today, said the six are men aged between 28 and 49 years. She said the drug had been tested on animals, including chimpanzees, and the National Agency of France for medicine and safety of health products (ANSM) approved the trial on June 26, 2015. The plan was to enroll 128 volunteers aged between 18 and 55; the trial should first test a single dose and multiple doses, and finally the combination of medication with a meal. So far, 0 people received doses ranging drug while others received a placebo, Touraine said. (Phase I studies are generally not a placebo ;. We do not know why it did)

The six volunteers who were hospitalized all received multiple daily doses, the first that was given on January 7. The first symptoms on 10 January, Touraine said, and the trial was halted the next day

Touraine did not speculate on why the symptoms only appeared in this group and not in the previous voluntary . it is possible that the six were the first to receive multiple doses of the drug, or drug lot was contaminated in some way. (All six were "in the same test group," said Edan.) Each volunteer who took the drug for the trial will be contacted, Touraine says, presumably to be checked for any adverse events have gone unnoticed.

Touraine said that prosecutors are investigating Rennes and ANSM will investigate as well. Meet with victims and their families now was "an intense moment of emotion," said Touraine. "The shock is even greater because the people involved [in phase I trials] are healthy, not sick, and they obviously do not expect to face such accidents."

Phase I studies are designed to test the safety and tolerability of a drug, and how and how fast the chemical is processed by the human body. Most of these studies are performed by specialized companies of research contracts; the subjects are generally healthy volunteers who receive a modest compensation.

Serious incidents in Phase I studies are rare, but they can never be completely excluded because the behavior of a drug in animals are not always a good predictor of its effects in the man. The last similar incident known to the public occurred in 06 when six men in the UK suffered a severe organ dysfunction after receiving small doses of a monoclonal antibody called TGN1412.

With reporting by Tania Rabesandratana .

There are less than a year, Zika seemed too trivial for anyone with hard measures against developing. The virus spread by mosquitoes has been racing across the countries of the southern hemisphere, but, at worst, it seemed to cause a mild fever and a rash. No more: On 1 February the World Health Organization (WHO) said cluster "extraordinary" microcephaly and other neurological complications that have now been linked to Zika "international scope of public health emergency." and vaccinemakers large and small, began the race to head off. they have a good chance of success, many experts say, but they cautioned that vaccine development requires years of testing.

isolated in 1947, Zika caused the first serious concern in May 2015 after arriving in South America and suspicions grew that the infection during pregnancy could be the cause of microcephaly harmful brain in babies. the link, the WHO Director-General Margaret Chan in Geneva, Switzerland, the stresses, is "strongly suspected but not yet scientifically proven," as a potential link to Guillain-Barre syndrome, can cause temporary paralysis in adults. With viral propagation increasingly, a vaccine is now a priority.

Vaccine pioneer Stanley Plotkin of the University of Pennsylvania predicted "a single development path" for a vaccine. He noted that Zika belongs to the flavivirus family, and vaccines exist for many of his relatives, including dengue fever, yellow fever and Japanese encephalitis. "I see no technical issues such as those that obviously exist for vaccines against HIV, tuberculosis, and many other agents," said Plotkin, who consults several vaccinemakers.

However, "there are a lot of puzzles," said Thomas Monath, a virologist who studied Zika in wild monkeys in Nigeria in the 1970s and is now chief scientist in chief to NewLink Genetics in Devens, Massachusetts, contributed to the development of a promising Ebola vaccine. For Zika, an unknown is whether the infection leads to life protection, a key feature of diseases for which vaccines are most effective, such as yellow fever. Another question is whether the natural immunity or induced by the vaccine against other related viruses, including yellow fever could offer a measure of "cross-protection", which could confuse efforts to assess vaccine Zika . have not yet researchers developed a monkey model much needed to allow comparisons of candidate vaccines.

The approaches have proliferated. Monath, who developed vaccines against several flaviviruses, said NewLink pursue a traditional strategy that inactivates or kills the virus with a chemical so it can not replicate in the body. He thinks an inactivated vaccine has the best chance to win regulatory approval for a product that pregnant women can use.

At nonprofit Butantan Institute in Sao Paulo, Brazil, however, immunologist and director Jorge Kalil is betting that weakened, live vaccine can be safe and potentially more effective than the killed virus. His team plans to exploit a technology that researchers from the US National Institute of Allergy and Infectious Diseases (NIAID) used to make a vaccine against dengue fever, which Butantan licensed and is currently being tested in a test 'efficiency. To weaken the virus, the researchers deleted genes so it can copy but not cause illness. "Maybe we can mitigate the Zika virus using the same cuts of the same sites," Kalil said, noting that Butantan likely would partner with NIAID to develop its vaccine. The Brazilian Institute has a key advantage: Unlike almost all other non-profit in the world who does research on vaccines, it has a year of manufacture on an industrial scale plants last, the institute cranked 40 million doses of flu vaccine, so it might be able to provide enough product for Brazil without needing help from big pharma.

NIAID Director Anthony Fauci in Bethesda, Maryland, said his institute has a "head start" with a different technology, used to make an experimental vaccine for West Nile, another flavivirus. The manufacturing process begins with a "plasmid" circular DNA which contains the essential viral genes. When inserted in bacterial cells, they produce "particles" viruslike that are similar to an inactivated vaccine, because they can not replicate. (The West Nile vaccine worked well in early human studies, but NIAID could not find a commercial partner to advance it.)

Inovio Pharmaceuticals Plymouth Meeting, Pennsylvania, boasts that it already has an experimental vaccine Zika nothing containing a plasmid made Zika genes. With the help of an electric zap the skin, plasmid goes directly into human cells, which then Zika of proteins that stimulate the immune system. CEO Joseph Kim says his team has already started tests on mice. But although researchers can quickly make such simple DNA vaccines, they lost their luster over the past 20 years because it did not trigger strong immune responses against other diseases. "There are very good people in the field who have lost faith in this technology," admits Kim. "I want to prove that this technology is viable and perhaps the best option for these types of homes."

The small Jenner Institute in Oxford, UK, is to Zika the surface protein of adenovirus innocuous chimpanzee, which serve as a "vector" -an approach similar to that used in the Ebola vaccine GlaxoSmithKline, which was tested during the outbreak in West Africa. Protein Sciences Vaccinemakers Meriden, Connecticut and Hawaii Biotech Honolulu, both of which specialize in the production of viral proteins in insect cell lines also have ongoing projects.

predict when a vaccine will be marketed is the game of a cup, but Fauci NIAID think animal studies could be completed in a few months and small human studies to evaluate the safety and immune responses could start the end of 2016. While promising candidate surfaces, large-scale efficacy trials are probably years away, he said. Getting a vaccine approved and provide millions of doses could take a large manufacturer resources. Among the four major pharmaceutical companies that make vaccines, only Sanofi Pasteur of Lyon, France, which produces all three existing vaccines-a flavivirus Zika launched a program, although others say they are closely monitoring the field.

As an emergency measure for pregnant women, Kalil said Butantan hopes to produce a protective serum that the institute already for several diseases, injecting Zika virus in horses and harvesting antibodies animals do. "It will take a little over a year," says Kalil. "This is the best course of time, if you are very, very optimistic."

A sleep bad night is enough to put everyone in a bad mood, and although scientists have long suspected a link between mood and sleep, molecular basis of this connection has remained a mystery. Now, new research has found several rare genetic mutations in the same gene that permanently connect the two.

sleep goes hand in hand with the mood. People suffering from depression and mania, for example, have frequently changed sleep patterns, such as those with seasonal affective disorder (SAD). And although no one knows exactly how these changes come about, in people with SAD are affected by changes in light exposure, the time to cue keeping the brain. But the mood affects sleep, sleep affects mood, or is it a third factor influencing both? Although a number of tantalizing leads have linked the circadian clock in the mood, there is "no definitive factor that prove causality or indicates the direction of the relationship," said Michael McCarthy, a neurobiologist at the Medical Affairs Center San Diego veterans and the University of California (UC), San Diego.

to see if they could establish a link between the circadian clock, sleep and mood, scientists in the new study examined the genetics of a family that suffers from abnormal sleep patterns and mood disorders, including SAD and something called advanced sleep phase, a condition in which people wake up early and sleep earlier than normal. the scientists screened the family of mutations in key genes involved in circadian clock, and identified two rare variants of PERIOD3 ( PER3 ) gene in members suffering from SAD and advanced sleep phase. "We found a genetic change in people who have both seasonal affective disorder and the morning lark trait," said lead researcher Ying-Hui Fu, a neuroscientist at UC San Francisco. When the team tested for these mutations in DNA samples from the general population, they found that they were extremely rare, occurring in less than 1% of samples.

Fu and his team then created mice that carried the gene variants novel. These transgenic mice showed an unusual sleep-wake cycle and struggled less when handled by the researchers, a typical sign of depression. They also had lower levels of PER2, a protein involved in circadian rhythms, the mice not mutated, providing a molecular explanation possible for unusual sleeping habits in the family. Fu said this supports the link between PER3 changes and both sleep and mood. " PER3 'role in the regulation of mood has never been demonstrated directly before," she said. "Our results indicate that PER3 might work to help us adjust to seasonal changes," altering the body's internal clock.

To further investigate, the team studied mice lacking a functional PER3 gene. They found that these mice showed symptoms of SAD, with a more severe depression when the duration of the simulated natural light in the laboratory has been reduced. Because SAD affects between 2% and 9% of people in the world, the new variants can not fully explain. But understanding the function of PER3 could provide insight into the molecular basis of a wide range of sleep disorders and mood, Fu said.

Together, these experiments show that PERIOD3 gene likely plays a key role in regulating the sleep-wake cycle, influencing the mood and regulation of the relationship between depression and seasonal changes in light availability, the team reports today in the Proceedings of the national Academy of sciences . "The identification of a mutation in PER3 with such an effect on mood is remarkable," McCarthy said. "It suggests an important role for the circadian clock in determining mood. "

the next step will be to analyze these results generalize to other people with mood and sleep disorders." It will be interesting to see if other rare variants in PER3 are, or SAD is constantly observed in other carriers, "McCarthy said. This could eventually lead to new drugs that selectively target the gene, McCarthy said," could be a strategy to deal mood or sleep disorders. "

les scientifiques ont découvert une nouvelle méthode de ruse pour éviter les amas de protéines qui obstruent les neurones dans les personnes souffrant de la maladie d'Alzheimer. En se liant un petit médicament pour une grande protéine, ils peuvent garder les touffes de se former. La technique est prometteuse pour le traitement de nombreuses maladies impliquant des interactions protéine-protéine.

Dans la maladie d'Alzheimer, de grands amas anormaux d'une amyloïde β surround peptide appelé et étouffer l'intérieur des neurones. Dans l'espoir de retarder la maladie, les chercheurs ont essayé d'utiliser des médicaments pour bloquer cette agglutination, mais avec peu de succès. En utilisant des molécules de médicaments lilliputiens comme bloqueurs des peptides amyloïdes relativement massives est comme essayer d'empêcher des bandes de Velcro d'adhérer en les saupoudrant de sel.

biologiste moléculaire Isabella Graef, chimiste Jason Gestwicki, et biologiste Gerald Crabtree de l'Université de Stanford adapté une stratégie de blocage trouvée dans la nature pour créer un médicament qui semble fonctionner. Gestwicki attaché chimiquement un ligand synthétique pour FKBP - une grande protéine de liaison que les bactéries du sol utilisent pour paralyser enzymes bactériennes ennemis - au Congo rouge, un colorant qui colle à la ß-amyloïde. La petite molécule résultante peut saisir FKBP à une extrémité et β-amyloïde à l'autre et ainsi ouvrir la voie de la protéine volumineuse entre les deux peptides amyloïdes. Lorsqu'il est ajouté à tester des tubes de β-amyloïde avec FKBP, les composés soit considérablement retardée ou complètement empêché de grosses touffes de β-amyloïde de se former. Sans FKBP, cependant, le médicament a tenu aucun avantage, montrant que la grande protéine est essentielle à son mode de fonctionnement. Les touffes de peptides plus petits qui se sont formés également apparu moins toxiques pour les neurones. Le médicament, ainsi que FKBP, a également empêché l'amyloïde β de tuer des neurones de rat les plus cultivés, les chercheurs rapport dans le 29 numéro d'Octobre de Science.

La forme actuelle du médicament n'a pas clinique utilité dans la maladie d'Alzheimer, comme le rouge Congo ne traverse pas la barrière sang-cerveau, mais la technique pourrait être utile pour le traitement de nombreuses maladies, y compris la maladie d'Alzheimer et de Parkinson, qui impliquent des interactions protéine-protéine. "Nous pensons que l'idée de la lutte contre la protéine en vrac avec des protéines en vrac va être général», dit Gestwicki. "Il est comme la lutte contre le feu avec le feu."

"Ils ont joué un truc chimique créatif qui clairement pourrait être pratique», dit Peter Lansbury, chimiste à la Harvard Medical School à Boston, "mais le chemin de cette à la drogue d'Alzheimer va être extrêmement difficile ". Un énorme problème, Lansbury dit, sera de trouver une alternative au rouge Congo qui cible l'amyloïde β.

Sites connexes
Le document Science
Gerald la page de laboratoire de Crabtree

Les médicaments contrefaits sont devenus un problème majeur de santé publique dans de nombreux pays en développement. Mais ces régimes mortels peuvent être déjoués si les responsables de la santé publique, les scientifiques et la police se donnent la main à travers les frontières, un article dans le numéro actuel de PloS Medicine montre. La recherche a conduit à l'arrestation de deux personnes en Chine en 06 et peut-être aidé à proximité ligne de médicaments antipaludiques contrefaits en Asie du Sud-Est l'un d'approvisionnement

Le groupe -. Sous les auspices de l'Organisation internationale de police criminelle (INTERPOL ) et de l'Organisation mondiale de la santé (OMS) bureau régional à Manille - étudié les contrefaçons d'artésunate, un médicament contre le paludisme produit par Guilin Pharmaceutical en Chine et largement vendues dans les pharmacies privées en Asie du Sud-est. Les chercheurs ont achetés ou recueillis 391 échantillons de ce qui a été vendu comme l'artésunate de Guilin au Vietnam, Cambodge, Laos, Myanmar, et les zones frontalières de la Thaïlande. Une inspection de l'emballage a révélé que beaucoup étaient contrefaits: Dans presque la moitié des échantillons, le petit hologramme Guilin utilise pour garantir l'authenticité avéré être un faux. (Certains étaient «terrible», dit Paul Newton de l'hôpital Mahosot de Vientiane, au Laos, le premier auteur du papier, d'autres étaient si convaincantes que même les experts du paludisme ne peuvent pas les distinguer à l'oeil nu.)

Analyse chimique a montré toutes les pilules avec des hologrammes faux pour être faux. Certains ne contenaient un peu d'artésunate, jusqu'à 12 milligrammes par comprimé, alors que les comprimés authentiques ont 50 milligrammes. Ces faibles doses, peut-être ajoutés pour contrecarrer les tests d'authenticité simples, sont particulièrement dangereux, Newton note, car ils peuvent provoquer une résistance chez le parasite du paludisme. D'autres pilules contenaient aucune artésunate du tout, mais un large éventail d'autres composés actifs -. De paracétamol et de la chloroquine, un vieux médicament contre le paludisme qui est désormais inutile en Asie du Sud-Est, à safrole, un précurseur cancérogène pour l'ecstasy du parti

laboratoires participants ont également analysé des quantités infimes de pollen et de composés minéraux non actifs présents dans les pilules, ce qui les a amenés à conclure qu'ils ont été très probablement produites quelque part dans le sud de la Chine. Tous les éléments de preuve ainsi suggéré qu'il y avait au moins deux producteurs de faux artesunates: celui qui a fait un «groupe ouest» de contrefaçons se trouve principalement au Myanmar, le long de la frontière entre la Thaïlande / Myanmar et le nord du Laos et une autre production du «groupe l'est" trouvé au Vietnam , le Cambodge et le sud du Laos. Après INTERPOL a présenté les données au gouvernement chinois en Mars 06, une enquête criminelle a conduit à deux arrestations tard cette année. Une des personnes arrêtées était originaire de la province du Yunnan qui aurait acheté 240.000 paquets de faux artésunate, dont la plupart il a vendu au Myanmar. L'autre était le vendeur des médicaments; le producteur est considéré comme toujours.

Que les arrestations ont réduit la quantité de médicaments contrefaits sur les marchés du sud-est incertaine. Pour commencer, les chercheurs pensent que la police chinoise ne peuvent ont pris la route commerciale ouest. Il peut y avoir beaucoup plus de producteurs ou de routes que ces deux, dit Valerio Reggi, un expert en contrefaçon de médicaments au siège de l'Organisation mondiale de la Santé qui n'a pas participé à l'opération. Pourtant, les collaborations internationales comme celui-ci sont essentiels pour lutter contre le problème, dit Reggi. Son succès a contribué à inspirer l'OMS pour lancer l'International Medical Products Anti-Counterfeiting Taskforce en 06.

Même si, dit le chercheur du paludisme Nicholas White de l'Université Mahidol à Bangkok, beaucoup plus doit être fait pour arrêter le flot de faux médicaments . Les gouvernements nationaux devraient être plus agressifs, par exemple, et les sociétés pharmaceutiques devraient être tenus de dire aux autorités drogue régulation quand ils découvrent leur drogue est truqué; actuellement, beaucoup ne le font pas par peur il ternir l'image du produit.

La plupart des spécialistes du paludisme conviennent que même le véritable artésunate produit par Guilin devrait sortir sur le marché dès que possible. Bien efficace contre le paludisme, l'OMS dit artésunate doit être vendu que dans soi-disant thérapies combinées pour retarder ou empêcher l'apparition d'une résistance chez le parasite du paludisme.

Sites connexes

• Le document
• Le site Web d'IMPACT
• Une présentation par l'expert de l'holographie David Pizzanelli, co-écrit par Paul Newton, sur hologrammes trouvés sur les paquets de faux artésunates

For most cancer patients, it is not the original tumor that poses the greatest risk. It is the metastases that invade the lung, liver and other tissues. Now, researchers have developed an approach that tricks these tumors derived by swallowing poison. So far, the strategy has been tested in mice, where it has proven very effective. But the results are promising enough that the researchers plan to launch clinical trials in cancer patients within a year.

The new work is "very innovative stuff," says Steven Libutti, a geneticist and cancer surgeon at the Albert Einstein College of Medicine in New York, who was not involved in the study. The treatment, he explains, works in three steps to place a conventional chemotherapeutic agent near the core (or cores) of a metastatic cancer cell where the drug molecules are the deadliest. "It's almost like a multistage rocket" which lifts the astronauts out of Earth, sends them to the moon and return safely, he said.

At the heart of the new therapy is a chemotherapy drug called doxorubicin (Dox). the drug has been a mainstay of cancer treatment for years, because it blocks the DNA in the cell nucleus and prevents tumor cells from dividing. But when it is injected into the circulation blood, the drug can also kill cells of the heart muscle and cause heart failure, which often requires oncologists or reconstruct the dose or stop completely. Delivering dox only to tumor cells is highly desirable, but it was a challenge major.

hoping to provide such cell specificity, researchers led by Mauro Ferrari, an expert in nanomedicine, and president and CEO of the Houston Methodist Research Institute in Texas, spent years developing porous silicon particles as drug carriers. the micrometric scale particles and disc-like shape allows them to travel freely throughout the normal blood vessels. But when they hit the blood vessels around tumors, which are typically malformed and leaking, the particles fall out of traffic and the pool near the tumor. This was the first step in delivering chemotherapy drugs to their target. But just fill these particles with dox does not do much good, says Ferrari. Even if a small amount of the drug finds its way inside tumor cells, cells often have membrane proteins that act as tiny pumps to push the drug back out of the cell before they can do damage.

To obtain large amounts of dox within the metastatic tumor cells, and then past the protein pumps, Ferrari and colleagues linked many molecules of Dox molecules called polymers rope. They then perfused polymers bearing Dox in their micro-particles of silicon and injected into mice who had been implanted with tumors of the liver and metastatic human lung. As in previous studies, the researchers found that the silicon particles gathered in and around the tumor sites, and once there, the particles slowly degraded over 2 to 4 weeks.

As they did, the silicon particles released dox -carrying polymer strands. In the aquatic environment surrounding the tumor cells, wound strands in tiny balls, each only 20-80 nanometers. This size, Ferrari said, is ideal, since it is the same size as the tiny vesicles which are routinely exchanged between neighboring cells as part of their normal chemical communication. In this case, the dox-polymer beads were readily taken up by tumor cells. Once there, much was done in Internal away pumps dox exporters cell membrane to the nucleus. Ferrari said at the time that his team does not know exactly why dox loaded balls are transported to the nucleus, although that is exactly what they wanted.

Not only is the region around the core devoid of dox- removing pumps, but it typically has a more acidic environment near the cell membrane. And the Ferrari team used to their advantage as well. They designed chemical bonds between the molecules of Dox and the polymer to dissolve in acidic conditions. This frees the dox where its destructive power of the cells is higher.

Up to 50% of cancer-bearing mice given the treatment showed no evidence of metastatic tumor eight months later, the researchers report today in Nature Biotechnology . In humans, Ferrari said, this is equivalent to being cancer free for 24 years. "If this research involves humans and we see even a fraction of that time to survive, we talk yet greatly extend life for many years," said Ferrari. "This essentially provides a cure in a population of patients now says there is not. "

the new treatment is not the first nanomedicine to show promise. According to a recent study of nanotechnology working group published in the Lancet , more than 50 Nanomedicine compounds are now in clinical trials. However, the new work is promising, Libutti said, because the silicon microparticles tend to target liver tumors and lung tumor cells of common destinations metastatic.

the new work holds the hope of improving the effectiveness of other chemotherapy drugs as well, Libutti said. "There is no reason to believe that you could not make a version of these particles with a chemotherapeutic agent. "

A special commission of inquiry to the US House of Representatives this week stepped up its investigation of the use of fetal tissue in the biomedical research with a dozen new assignments for researchers and abortion providers. This second series of questions, two of them directed to the members of individual faculty at the University of New Mexico (UNM) in Albuquerque, deepens concerns among some education groups and scientists that personal information revealed in survey researchers could make the target of extremist violence.

Select the Panel Room infant Lives survey, launched last October and led by Marsha Blackburn representative (R-TN), born Republican game on published secret videos last summer by the Center for Medical Progress, an antiabortion group that accused the organization Planned Parenthood to profit illegally from the sale of abortions tissue. The panel has sent more than 30 requests for information to universities, businesses and abortion clinics before issuing three formal assignments in February to the provider of abortion southwest of women's options (SWO) the tissue procurement StemExpress UNM and society, including science center includes health laboratories that work with the fetal tissue from abortions performed by SWO. The application included "identity, name, people who participated in each study" involving fetal tissue, as well as those who were transferred from the fabric to the university.

At first hearing panels in March, his Democratic members moved unsuccessfully to cancel the assignments, citing security concerns following a shootout that killed three people in a clinic Colorado Planned Parenthood last fall. Jerrold Nadler (D-NY) is concerned that the panel would be "complicit" in the murder of researchers if their names were revealed. UNM said it has so far provided the panel with some 3,000 pages of documents, but refused to reveal the identity of teachers and students involved in research.

This answer did not satisfy Blackburn. "[S] ome of these organizations so redacted document even after being assigned, it is impossible for us to get a complete picture of what is actually happening. Others refused to produce documents required under previous assignments, and threatened to withhold assigned additional information, "she said in a statement on March 30.

the new assignments include requests for documents from the institutional review board of Biomedical Research Institute America and Ganogen, an old company recently converted into a research institute funded by the private sector, working to develop fetal organs aborted animals for transplantation in humans. the online publication STAT yesterday identified Eugene Gu researcher from Vanderbilt University in Nashville as the founder of Ganogen. Gu noted that it has not received the summons and was not sure what would be his reply. But it seemed a note to the challenge, said STAT "It feels like living in North Korea or something ... we continue to pursue our research, and we do not go away ... despite intimidation by Republicans. "

Four other subpoenas were sent to people whose names redacted panel in published documents, but UNM confirmed that two of them are faculty members . assignments require details on the exchange of tissue samples between UNM and SWO, and the names of people involved in these transactions. another, apparently intended for an affiliate UNM clinician documentation of patient demand or referred to SWO other abortion providers.

"[W] e simply can not comply safely demand accompanying the subpoenas for documents that identify the staff and students who have worked in the laboratory where the research was conducted, "the university in a given statement to science Insider. "This disclosure would expose our employees and at serious risk of harm students."

Several research organizations have come to the University of Defence in a letter published yesterday in Blackburn. The Association of American Medical Colleges (AAMC), the Association of American Universities (AAU) and the Association of Public Universities and Land-Grant (Aplu) jointly urged the panel to establish clear rules on how including personally identifiable information would be used and protected.

A spokesman for Blackburn argues that personal information will be handled with care, but would not comment on who would have access to all names provided. "It is important for the president to be responsible for the use of these names," Mike Reynard, director of communications for the Investigation Committee said Science Insider, "but it is impossible for the panel to complete our investigation without full knowledge and understanding of the people involved in the operations and practices. "

assignments give beneficiaries until April 11 to provide requested documents, and more demand for deposits they appear in April.

Materials scientists would kill to be able to produce such incredible material as the biological muscle, which can retract on command, stretch of about 70% without damage, and heal his own cuts and tears. Now researchers say they are closer to a synthetic material that can do all these things, but not as well as natural muscle. The advance could one day be useful in robotics and prosthetic.

The concept of an artificial muscle back decades. Researchers have proposed many different starting materials, from carbon nanotubes thick carbon tubes called to ceramics to metal alloys. In 00, scientists have shown that certain rubbery polymers called elastomers can be stretched reversibly to a maximum of three times their length by applying a voltage across them. Like almost all synthetic materials, however, these elastomers needed someone to repair them if they are damaged. Working separately, other scientists used elastomers such as basic self-healing polymers, materials that can repair tears, seal holes and even joining the cut edges. However, most of them were quite small and lacked elasticity, making them poor artificial muscles. And nobody has produced an artificial muscle that can be repaired.

Until now, that is. Materials chemist Zhenan Bao of Stanford University in Palo Alto, California, and colleagues reveal today Nature Chemistry a group of elastomers called Fe-Hpdca PDMS. The material comprises long chain and randomly entangled polymer containing silicon, oxygen, nitrogen and carbon atoms in admixture with an iron salt. The chemical bonds of forms of iron with oxygen and nitrogen atoms in the polymer, linking the polymer chains to both themselves and to each other, such as strings attached with elastic bands at the crossing points. These crosslinks do not prevent the polymer chains to move altogether, so that the material can stretch. But do not stop crosslinks the chains to slide completely freely. For the form change material, the crosslinks must be stretched, distorted, and sometimes broken and rearranged. When the material is made of stretch, the cross-links return to their original shape, giving both the material strength and elasticity.

Next, there is self-healing. If a hole is drilled in the material, iron atoms on a side of the hole are attracted by oxygen atoms and nitrogen on the other hand, reforming atomic bonds and the closing of the orifice in the 72 hours. Even when the researchers cut the polymers into two separate pieces, the ends of the cutting edges almost perfectly joined if they have been contacted, recovering almost all of their strength and 0% of their scalability, even at temperatures as lower than -20 ° C.

When the researchers applied an electric field across the polymer (similar to how muscle tissue is activated), the length of the material rapidly increased approximately 2% . When the field was switched off, the material is returned to its original size

A notable weakness of the matter is that the size change after the electric field is applied is still low. Even if the material can normally be stretched up to 45 times its original length and still return to its original shape, size change when the field was turned on was much smaller than the real muscle (which can shorten up 40%). This would mean that the robotic legs could not bend nearly as well as natural.

"In our case, the goal was not to make the best artificial muscle, but rather to develop new design rules for stretchable materials and self-healing materials," says Bao. "Artificial Muscle is a potential application for our material." The Bao team is currently planning further work on increasing the effects of electric fields.

"It is very interesting and extremely elegant work, "says Marek Urban polymer chemist at Clemson University in South Carolina. He said the polymer could possibly be used to make synthetic muscles needed to move artificial limbs or to replace missing for disabled people or to allow robots to move things as a human can. He also said the material could have other applications. Materials that expand and contract in response to an electric field are often used as pressure or strain sensors, sometimes self-correction. Self-healing may be useful when the sensors should be placed in extreme conditions such as in space, where repair is difficult or impossible. "If a material is to be placed in an environment where there is a risk of damage [and] as self-repairing material, which is a huge advantage," says Urban.