Avian Flu Viruses Which Are Transmissible Between Humans Could Evolve in Nature

It might be possible for human-to-human airborne transmissible avian H5N1 influenza viruses to evolve in nature, new research has found.

Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green) [Credit: CDC/Courtesy of Cynthia Goldsmith; Jacqueline Katz; Sherif R. Zaki]

The findings, from research led by Professor Derek Smith and Dr Colin Russell at the University of Cambridge, were published June 22 in the journal Science.

Currently, avian H5N1 influenza, also known as bird flu, can be transmitted from birds to humans, but not (or only very rarely) from human to human. However, two recent papers by Herfst, Fouchier and colleagues in Science and Imai, Kawaoka and colleagues in Nature reveal that potentially with as few as five mutations (amino acid substitutions), or four mutations plus reassortment, avian H5N1 can become airborne transmissible between mammals, and thus potentially among humans. However, until now, it was not known whether these mutations might evolve in nature.

The Cambridge researchers first analysed all of the surveillance data available on avian H5N1 influenza viruses from the last 15 years, focusing on birds and humans. They discovered that two of the five mutations seen in the experimental viruses (from the Fouchier and Kawaoka labs) had occurred in numerous existing avian flu strains. Additionally, they found that a number of the viruses had both of the mutations.

Colin Russell, Royal Society University Research Fellow at the University of Cambridge, said: "Viruses that have two of these mutations are already common in birds, meaning that there are viruses that might have to acquire only three additional mutations in a human to become airborne transmissible. The next key question is 'is three a lot, or a little?' "

The scientists explored this key question using a mathematical model of how viruses replicate and evolve within a mammalian host and assessed the influence of various factors on whether the remaining three mutations could evolve in a single host or in a short chain of transmission between hosts

The factors that increased the likelihood of mutations evolving are:

1. Random mutation. The replication mechanisms of influenza viruses don't make perfect copies. On average, every time an influenza virus replicates itself it makes approximately one mutation somewhere in the genome of each new virus. In each infected human there will be billions of viruses, and thus with many viruses replicating, multiple mutations can accumulate within a single host.

2. Positive selection. If some of the remaining mutations help the avian virus to adapt to mammals, then those mutations will make the viruses more fit and thus will be positively selected and preferentially accumulate.

3. Long infection. The longer someone is infected and producing new viruses, the more time there is for mutations to accumulate.

4. Functionally equivalent substitutions. The sets of substitutions identified by Fouchier and Kawaoka are unlikely to be the only combinations of substitutions capable of producing an aerosol transmissible virus. The probability of emergence increases with the number of combinations.

5. Diversity in the within-bird virus population. Given all of the mutations there are likely to be within a host due to random mutation, it is possible that the viruses from a bird that infect a human might have a mutation that would not be detected by routine surveillance. For example, if 100 virus particles from a bird infect a human and one of those particles had a key mutation, it would increase the probability of the mutation reaching high levels within a host even though routine sequencing would not detect it.

6. Transmission between mammals. If mammals are capable of transmitting viruses that have some but not all of the necessary substitutions it could increase the probability of an airborne transmissible virus evolving.

The factors that decreased the likelihood of mutations evolving are:

1. An effective immune response. An effective immune response would shorten the length of an infection and thus decrease the time available to accumulate mutations.

2. Deleterious substitutions. If any of the substitutions necessary for airborne transmission were harmful to the virus it would, on average, slow the accumulation of mutations.

3. Order of acquiring mutations. It is not currently known if the mutations for airborne transmissibility need to be acquired in a specific order. If they do, it would, on average, slow the accumulation of mutations.

"With the information we have, it is impossible to say what the exact risk is of the virus becoming airborne transmissible among humans. However, the results suggest that the remaining three mutations could evolve in a single human host, making a virus evolving in nature a potentially serious threat," said Derek Smith, Professor of Infectious Disease Informatics at the University of Cambridge. "We now know that it is in the realm of possibility that these viruses can evolve in nature, and what needs to be done to assess the risk more accurately of these mutations evolving in nature."

The scientists recommend the following activities be considered high priority for estimating and ameliorating the risk of emergence of aerosol transmissible H5N1 viruses.

First, additional surveillance in regions where viruses with airborne transmission enabling substitutions have been observed and in regions connected to those regions by bird migration and trade. Also, increased surveillance for mutations that might have the same function as those found by the Fouchier and Kawaoka labs.

Second, related to surveillance, some targeted sequencing of H5N1 viruses should be done by "deep sequencing" where the lab sequences many viruses from an individual host to look for viruses that might have accumulated the critical mutations, even if those viruses are just a small proportion of the viruses within an animal.

Third, further investigations are needed to determine which substitutions and combinations of substitutions that are not the same as, but have the same function as, the substitutions identified by the Fouchier and Kawaoka labs are capable of making viruses airborne transmissible between mammals.

Fourth, further studies are needed to elucidate the changes in within-host fitness and between-host transmissibility associated with each airborne transmission enabling substitution and combination of substitutions.

Professor Smith added: "The situation is similar to assessing the risk of an earthquake or tsunami. We don't know exactly when and where, but by increasing monitoring and research -- some of which is already underway -- scientists and public health officials will be able to increase the accuracy with which the risk can be assessed and to minimise those risks."

The research was funded by multiple sources including the European Commission through framework 7 grants EMPERIE and ANTIGONE, the Royal Society, the Human Frontiers Science Program, the Wellcome Trust, and the National Institutes of Health.

Source: University of Cambridge [June 21, 2012]

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The Power of Suggestion: What We Expect Influences Our Behavior, for Better or Worse

A lucky rabbit foot. A glass of wine. A pill. What do these things all have in common? Their effects -- whether we do well on a test, whether we mingle at the cocktail party, whether we feel better -- all depend on the power of suggestion.

In a new article, psychological scientists Maryanne Garry and Robert Michael of Victoria University of Wellington, along with Irving Kirsch of Harvard Medical School and Plymouth University, delve into the phenomenon of suggestion, exploring the intriguing relationship between suggestion, cognition, and behavior. The article is published in the June issue of Current Directions in Psychological Science, a journal of the Association for Psychological Science.

Over their research careers, Garry and Kirsch have both studied the effects of suggestion on cognition and behavior. Kirsch focused mostly on suggestion in clinical psychology, while Garry, whose work is supported by the Marsden Fund of New Zealand, was interested in the effects of suggestion on human memory. When the two got to talking, "we realized that the effects of suggestion are wider and often more surprising than many people might otherwise think," says Garry.

Across many studies, research has shown that deliberate suggestion can influence how people perform on learning and memory tasks, which products they prefer, and how they respond to supplements and medicines, which accounts for the well-known placebo effect.

But what can explain the powerful and pervasive effect that suggestion has in our lives? The answer lies in our 'response expectancies,' or the ways in which we anticipate our responses in various situations. These expectancies set us up for automatic responses that actively influence how we get to the outcome we expect. Once we anticipate a specific outcome will occur, our subsequent thoughts and behaviors will actually help to bring that outcome to fruition.

So, if a normally shy person expects that a glass of wine or two will help him loosen up at a cocktail party, he will probably feel less inhibited, approach more people, and get involved in more conversations over the course of the party. Even though he may give credit to the wine, it is clear that his expectations of how the wine would make him feel played a major role.

But it's not just deliberate suggestion that influences our thoughts and behaviors -- suggestions that are not deliberate can have the very same effects. As the authors point out, "simply observing people or otherwise making them feel special can be suggestive," a phenomenon termed the Hawthorne effect. As a result, people might work harder, or stick to a task for longer. And this case is more worrying, says Garry, "because although we might then give credit to some new drug or treatment, we don't realize that we are the ones who are actually wielding the influence."

It is for precisely this reason that the issue of unintentional suggestion has important implications for academic researchers. "In the scientific community, we need to be aware of -- and control for -- the suggestions we communicate to subjects," says Garry. The authors note that some recent failures to replicate previous research findings may ultimately be explained by such unintentional suggestion. "Recent research suggests that some of psychological science's most intriguing findings may be driven, at least in part, by suggestion and expectancies," Garry observes. "For example, a scientist who knows what the hypothesis of an experiment is might unwittingly lead subjects to produce the hypothesized effect -- for reasons that have nothing to do with the experiment itself."

And the unintended effects of suggestion aren't just restricted to the laboratory -- they cut across many real world domains, including the fields of medicine, education, and criminal justice. For example, converging evidence on eyewitness identification procedures demonstrates that the rate of false identifications is significantly higher when lineups are conducted by people who know who the suspect is than when the lineups are conducted by people who don't.

While research has provided clear evidence for the phenomenon of suggestion, there is still much more to learn about the underlying relationship between suggestion, cognition, and behavior. As the authors point out, researchers still don't know where the boundaries and limitations of these effects lie. "And, if a 'real' treatment and a 'suggestion' lead to a similar outcome, what differentiates between the two?" says Garry. Understanding these issues has important real world implications. "If we can harness the power of suggestion, we can improve people's lives."

Source: Association for Psychological Science [June 06, 2012]

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Statistical Model Attempting to Estimate Level of Alcohol Consumption That Is 'Optimal' for Health

Cutting the amount we drink to just over half a unit a day could save 4,600 lives a year in England, according to a modelling study by Oxford University researchers published in the journal BMJ Open.

Half a unit of alcohol is as little as a quarter of a glass of wine, or a quarter of a pint [Credit: © G.G. Lattek / Fotolia]

Scientists have carried out a complex analysis in an attempt to determine the "optimal" level of alcohol consumption that is associated with the lowest rates of chronic disease in the UK. They conclude that the intake of about one-half of a typical drink per day would result in the healthiest outcomes, and the authors conclude that the recommended alcohol intake for the UK should be reduced from the current advised level of drinking.

Half a unit of alcohol is as little as a quarter of a glass of wine, or a quarter of a pint. That's much lower than current government recommendations of between 3 to 4 units a day for men and 2-3 units for women.

The researchers set out to find the optimum daily amount of alcohol that would see fewest deaths across England from a whole range of diseases connected to drink. Previous studies have often looked at the separate effects of alcohol on heart disease, liver disease or cancers in isolation.

'Although there is good evidence that moderate alcohol consumption protects against heart disease, when all of the chronic disease risks are balanced against each other, the optimal consumption level is much lower than many people believe,' says lead author Dr Melanie Nichols of the BHF Health Promotion Research Group in the Department of Public Health at Oxford University.

The team used a mathematical model to assess what impact changing average alcohol consumption would have on deaths from 11 conditions known to be at least partially linked to drink.

These included coronary heart disease, stroke, high blood pressure, diabetes, cirrhosis of the liver, epilepsy, and five cancers. Over 170,000 people in England died from these 11 conditions in 2006, and ill health linked to alcohol is estimated to cost the NHS in England £3.3 billion every year.

The researchers used information from the 2006 General Household Survey on levels of alcohol consumption among adults in England. They combined this with the disease risks for differing levels of alcohol consumption as established in large analyses of published research.

They found that just over half a unit of alcohol a day was the optimal level of consumption among current drinkers.

They calculate this level of drinking would prevent around 4,579 premature deaths, or around 3% of all deaths from the 11 conditions.

The number of deaths from heart disease would increase by 843, but this would be more than offset by around 2,600 fewer cancer deaths and almost 3,000 fewer liver cirrhosis deaths.

'Moderating your alcohol consumption overall, and avoiding heavy-drinking episodes, is one of several things, alongside a healthy diet and regular physical activity, that you can do to reduce your risk of dying early of chronic diseases,' says Dr Nichols.

She adds: 'We are not telling people what to do, we are just giving them the best balanced information about the different health effects of alcohol consumption, so that they can make an informed decision about how much to drink.

'People who justify their drinking with the idea that it is good for heart disease should also consider how alcohol is increasing their risk of other chronic diseases. A couple of pints or a couple of glasses of wine per day is not a healthy option.'

Although this study in BMJ Open did not look at patterns of drinking, Dr Nichols says: 'Regardless of your average intake, if you want to have the best possible health, it is also very important to avoid episodes of heavy drinking ("binge drinking") as there is very clear evidence that this will increase your risks of many diseases, as well as your risk of injuries.'

Source: University of Oxford [June 06, 2012]

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To Quit Smoking, Try Eating More Veggies and Fruits

If you're trying to quit smoking, eating more fruits and vegetables may help you quit and stay tobacco-free for longer, according to a new study published online by University at Buffalo public health researchers.

If you're trying to quit smoking, eating more fruits and vegetables may help you quit and stay tobacco-free for longer [Credit: © taviphoto / Fotolia]

The paper, in the journal Nicotine and Tobacco Research, is the first longitudinal study on the relationship between fruit and vegetable consumption and smoking cessation.

The authors, from UB's School of Public Health and Health Professions, surveyed 1,000 smokers aged 25 and older from around the country, using random-digit dialing telephone interviews. They followed up with the respondents fourteen months later, asking them if they had abstained from tobacco use during the previous month.

"Other studies have taken a snapshot approach, asking smokers and nonsmokers about their diets," says Gary A. Giovino, PhD, chair of the Department of Community Health and Health Behavior at UB. "We knew from our previous work that people who were abstinent from cigarettes for less than six months consumed more fruits and vegetables than those who still smoked. What we didn't know was whether recent quitters increased their fruit and vegetable consumption or if smokers who ate more fruits and vegetables were more likely to quit."

The UB study found that smokers who consumed the most fruit and vegetables were three times more likely to be tobacco-free for at least 30 days at follow-up 14 months later than those consuming the lowest amount of fruits and vegetables. These findings persisted even when adjustments were made to take into account age, gender, race/ethnicity, education, household income and health orientation.

They also found that smokers with higher fruit and vegetable consumption smoked fewer cigarettes per day, waited longer to smoke their first cigarette of the day and scored lower on a common test of nicotine dependence.

"We may have identified a new tool that can help people quit smoking," says Jeffrey P. Haibach, MPH, first author on the paper and graduate research assistant in the UB Department of Community Health and Health Behavior. "Granted, this is just an observational study, but improving one's diet may facilitate quitting."

Several explanations are possible, such as less nicotine dependence for people who consume a lot of fruits and vegetables or the fact that higher fiber consumption from fruits and vegetables make people feel fuller.

"It is also possible that fruits and vegetables give people more of a feeling of satiety or fullness so that they feel less of a need to smoke, since smokers sometimes confuse hunger with an urge to smoke," explains Haibach.

And unlike some foods which are known to enhance the taste of tobacco, such as meats, caffeinated beverages and alcohol, fruits and vegetables do not enhance the taste of tobacco.

"Foods like fruit and vegetables may actually worsen the taste of cigarettes," says Haibach.

While smoking rates in the U.S. continue to decline, Giovino notes, the rate of that decline has slowed during the past decade or so. "Nineteen percent of Americans still smoke cigarettes, but most of them want to quit," he says.

Haibach adds: "It's possible that an improved diet could be an important item to add to the list of measures to help smokers quit. We certainly need to continue efforts to encourage people to quit and help them succeed, including proven approaches like quitlines, policies such as tobacco tax increases and smoke-free laws, and effective media campaigns."

The UB researchers caution that more research is needed to determine if these findings replicate and if they do, to identify the mechanisms that explain how fruit and vegetable consumption may help smokers quit. They also see a need for research on other dietary components and smoking cessation.

Gregory G. Homish, PhD, assistant professor in the UB Department of Community Health and Health Behavior, also is a co-author.

Funding was provided by the Robert Wood Johnson Foundation and LegacyA®.

Source: University at Buffalo [June 06, 2012]

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1 Million Billion Billion Billion Billion Billion Billion: Number of Undiscovered Drugs

A new voyage into "chemical space" -- occupied not by stars and planets but substances that could become useful in everyday life -- has concluded that scientists have synthesized barely one tenth of 1 percent of the potential medicines that could be made. The report, in the journal ACS Chemical Neuroscience, estimates that the actual number of these so-called "small molecules" could be 1 novemdecillion (that's 1 with 60 zeroes), 1 million billion billion billion billion billion billion, which is more than some estimates of the number of stars in the universe.

A new voyage into "chemical space" -- occupied not by stars and planets but substances that could become useful in everyday life -- has concluded that scientists have synthesized barely one tenth of 1 percent of the potential medicines that could be made [Credit: Web]

Jean-Louis Reymond and Mahendra Awale explain that small molecules, which are able to cross cell walls and interact with biological molecules in the body, are prime targets for scientists who develop new medicines. Most existing medications are small molecules. The authors focused on the "chemical space" inhabited by all of the small molecules that could possibly exist according to the laws of physics and chemistry. 

Researchers have identified millions of these compounds -- the ACS' Chemical Abstracts Service database contains almost 67 million substances. Reymond and Awale estimate that the molecules synthesized and tested as potential drugs so far represent less than 0.1 percent of chemical space. To aid researchers looking for new ways to prevent and treat disease, they set out to find the best ways to search for new small molecules.

The authors discuss several ways of getting a handle on chemical space, including by the size, shape and makeup of molecules. They show how computers can help researchers efficiently narrow a search for a new drug candidate. Computer modeling of chemical interactions can help researchers find a handful of promising molecules to synthesize and test in the lab. "Small molecule drugs are essential to the success of modern medicine," the authors note, and suggest that their methods may be particularly useful for finding new pharmaceuticals that target the central nervous system.

Source: American Chemical Society [June 06, 2012]

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Air Pollution Linked to Chronic Heart Disease

Air pollution, a serious danger to the environment, is also a major health risk, associated with respiratory infections, lung cancer and heart disease. Now a Tel Aviv University researcher has concluded that not only does air pollution impact cardiac events such as heart attack and stroke, but it also causes repeated episodes over the long term.

Cardiac patients living in high pollution areas were found to be over 40 percent more likely to have a second heart attack when compared to patients living in low pollution areas, according to Dr. Yariv Gerber of TAU's School of Public Health at the Sackler Faculty of Medicine. "We know that like smoking cigarettes, pollution itself provokes the inflammatory system. If you are talking about long-term exposure and an inflammatory system that is irritated chronically, pollution may well be involved in the progression of atrial sclerosis that manifests in cardiac events," explains Dr. Gerber.

Done in collaboration with Prof. Yaacov Drory and funded by the Environmental and Health Fund in Jerusalem, the research was presented at the San Diego Epidemiological Meeting of the American Heart Association in March and the Annual Meeting of the Israeli Heart Society in April.

Risking recurrence

Air pollution has previously been acknowledged as a factor in heart attack risk, as well as other health risks. The goal of this study, says Dr. Gerber, was to quantify that association and determine the long-term effects of air pollution on myocardial infarction (MI) patients. Their study followed 1,120 first-time MI patients who had been admitted to one of eight hospitals in central Israel between 1992 and 1993, all of whom were under the age of 65 at the time of admittance. The patients were followed up until 2011, a period of 19 years.

Air quality was measured at 21 monitoring stations inareas where the patients lived, and analyzed by a group of researchers at the Technion in Haifa. After adjusting for other factors such as socio-economic status and disease severity, the researchers identified an association between pollution and negative clinical outcomes, including mortality and recurrent vascular events such as heart attack, stroke and heart failure.

Compared to patients who lived in areas with the lowest recorded levels of pollution, those in the most polluted environment were 43 percent more likely to have a second heart attack or suffer congestive heart failure and 46 percent more likely to suffer a stroke. The study also found that patients exposed to air pollution were 35 percent more likely to die in the almost 20 year period following their first heart attack than those who were exposed to lower levels of pollution.

According to Dr. Gerber, the true impact of air pollution might be even stronger than this study shows. "Our method of assessing exposure does have limitations. Because we are using data from monitoring stations, it's a crude estimate of exposure, which most likely leads to an underestimation of the association," he warns. He estimates that air pollution could have double the negative impact with more precise measurement.

Identifying vulnerable groups

The results of the study not only indicate a health benefit for a public policy that curtails air pollution caused by industrial emissions and second hand smoke, but also call for heightened awareness by clinicians. Doctors should be making their patients aware of the risks of remaining in high pollution areas, suggesting that they work to limit their exposure, Dr. Gerber suggests.

Another purpose of this study was to begin identifying populations that are vulnerable to MI and re-occurring MI. Establishing the connection between air pollution and long-term risk for patients with cardiovascular diseases was an important step towards that goal.

Source: American Friends of Tel Aviv University [June 05, 2012]

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