Friday, October 28, 2016

Natural product darwinolide may help combat fatal MRSA infection

A serious and sometimes fatal bacterial infection, known as methicillin-resistantStaphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica. The sponge extract, known as Dendrilla membranosa, yields a new, natural product chemical which has shown in laboratory tests that it can eliminate more than 98 percent of MRSA cells. The research team has named the new chemical "darwinolide."

Image result for darwinolide

The study describing their methods and results was published this week in the American Chemical Society's journal Organic Letters.
While years ago the highly-resistant MRSA infection was particularly problematic in places such as hospitals and nursing homes, it has developed into an infection that can be found in commonly-used places such as gyms, locker rooms and schools.
"In recent years, MRSA has become resistant to vancomycin and threatens to take away our most valuable treatment option against staph infections," said study co-author and USF microbiologist Dr. Lindsey N. Shaw.
MRSA is unique in that it can cause infections in almost every niche of the human host, from skin infections, to pneumonia, to endocarditis, a serious infection of tissues lining the heart. Unfortunately, the pace of the pharmaceutical industry's efforts to find new antibiotics to replace those no longer effective has slowed in recent years, said Shaw.
Like many other bacterium, the MRSA bacteria forms a biofilm.
"Biofilms, formed by many pathogenic bacteria during infection, are a collection of cells coated in a variety of carbohydrates, proteins and DNA," said Shaw. "Up to 80 percent of all infections are caused by biofilms and are resistant to therapy. We desperately need new anti-biofilm agents to treat drug resistant bacterial infections like MRSA."
USF chemistry professor Dr. Bill Baker and colleagues have literally gone to the 'ends of the Earth' to help in the fight against MRSA. Baker, who also serves as director of the USF Center for Drug Discovery and Innovation (CDDI), studies the chemical ecology of Antarctica and dives in the frigid waters near Palmer Station to retrieve marine invertebrates, such as sponges, to carry out "natural product isolation," which means drawing out, modifying and testing natural substances that may have pharmaceutical potential.
His group led the effort to extract and characterize chemical structures to create darwinolide from the freeze-dried Antarctic sponges and then test in Shaw's lab to determine its effectiveness against the MRSA bacteria.

"When we screened darwinolide against MRSA we found that only 1.6 percent of the bacterium survived and grew. This suggests that darwinolide may be a good foundation for an urgently needed antibiotic effective against biofilms," said Baker, whose research team "rearranged" the chemical composition of the extracted sponge.

In the last 70 years, despite the discovery and use of antibiotics to treat infections, bacterial disease remains the second-leading cause of death globally, especially among children and the elderly, noted the researchers. In the U.S. alone there are two million hospital acquired infections annually with at least 100,000 deaths, many resulting from bacteria resistant to current antibiotics.
"We suggest that darwinolide may present a highly suitable scaffold for the development of urgently needed, novel, anti-biofilm-specific antibiotics," concluded the researchers.

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Natural product darwinolide may help combat fatal MRSA infection: A serious and sometimes fatal bacterial infection, known as methicillin-resistant Staphylococcus aureus (MRSA), may soon be beatable thanks to the efforts of University of South Florida scientists who have isolated and tested an extract from a sponge found in Antarctica.

Thursday, October 27, 2016

Ramizol drug shows promise in treatment of Clostridium difficile infections


A scientific paper released today in the Journal of Antibiotics presents the pre-clinical development of Ramizol, a first generation drug belonging to a new class of styrylbenzene antibiotics with a novel mechanism of action.

The research was undertaken by Australian company Boulos & Cooper Pharmaceuticals in partnership with the University of South Australia, Flinders University, Eurofins Panlabs and Micromyx LLC. The study found that over 99.9% of the drug, administered orally, stays in the gastrointestinal tract where it can reach the bacteria in the colon at high enough concentrations to yield a therapeutic effect.

Chief Executive Officer of Boulos & Cooper Pharmaceuticals, Dr Ramiz Boulos, said "this new class of antibiotics has antioxidant properties and can be manufactured for a low cost; benefits that will be felt by the end-user".

The new antibiotic has low frequency of resistance and shows promise as a monotherapy for the treatment of Clostridium difficile associated disease. Dr Boulos stated "we are very excited about these results given the unforgiving nature of Clostridium difficile infections". He added "In a world where there are few treatment options, we are desperate for new antibiotics to fight intractable infections".

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Wednesday, October 26, 2016

Magic mushroom compound psilocybin could provide new avenue for antidepressant research

In continuation of my update on psilocybin

Kekulé, skeletal formula of canonical psilocybin

The small feasibility trial, which involved 12 people with treatment-resistant depression, found that psilocybin was safe and well-tolerated and that, when given alongside supportive therapy, helped reduce symptoms of depression in about half of the participants at 3 months post-treatment. The authors warn that strong conclusions cannot be made about the therapeutic benefits of psilocybin but the findings show that more research in this field is now needed.
"This is the first time that psilocybin has been investigated as a potential treatment for major depression," says lead author Dr Robin Carhart-Harris, Imperial College London, London, UK. "Treatment-resistant depression is common, disabling and extremely difficult to treat. New treatments are urgently needed, and our study shows that psilocybin is a promising area of future research. The results are encouraging and we now need larger trials to understand whether the effects we saw in this study translate into long-term benefits, and to study how psilocybin compares to other current treatments."
Depression is a major public health burden, affecting millions of people worldwide and costing the US alone over $200 billion per year. The most common treatments for depression are cognitive behaviour therapy (CBT) and antidepressants. However, 1 in 5 patients with depression do not respond to any intervention, and many relapse.
"Previous animal and human brain imaging studies have suggested that psilocybin may have effects similar to other antidepressant treatments," says Professor David Nutt, senior author from Imperial College London "Psilocybin targets the serotonin receptors in the brain, just as most antidepressants do, but it has a very different chemical structure to currently available antidepressants and acts faster than traditional antidepressants."
The trial involved 12 patients (6 women, 6 men) with moderate to severe depression (average length of illness was 17.8 years). The patients were classified as having treatment-resistant depression, having previously had two unsuccessful courses of antidepressants (lasting at least 6 weeks). Most (11) had also received some form of psychotherapy. Patients were not included if they had a current or previous psychotic disorder, an immediate family member with a psychotic disorder, history of suicide or mania or current drug or alcohol dependence.
Patients attended two treatment days -- a low (test) dose of psilocybin 10mg oral capsules, and a higher (therapeutic) dose of 25mg a week later. Patients took the capsules while lying down on a ward bed, in a special room with low lighting and music, and two psychiatrists sat either side of the bed. The psychiatrists were present to provide support and check in on patients throughout the process by asking how they were feeling. Patients had an MRI scan the day after the therapeutic dose. They were followed up one day after the first dose, and then at 1, 2, 3, and 5 weeks and 3 months after the second dose.
The psychedelic effects of psilocybin were detectable 30 to 60 minutes after taking the capsules. The psychedelic effect peaked at 2-3 hours, and patients were discharged 6 hours later. No serious side effects were reported, and expected side effects included transient anxiety before or as the psilocybin effects began (all patients), some experienced confusion (9), transient nausea (4) and transient headache (4). Two patients reported mild and transient paranoia.
At 1 week post-treatment, all patients showed some improvement in their symptoms of depression. 8 of the 12 patients (67%) achieved temporary remission. By 3 months, 7 patients (58%) continued to show an improvement in symptoms and 5 of these were still in remission. Five patients showed some degree of relapse.
The patients knew they were receiving psilocybin (an 'open-label' trial) and the effect of psilocybin was not compared with a placebo. The authors also stress that most of the study participants were self-referred meaning they actively sought treatment, and may have expected some effect (5 had previously tried psilocybin before). All patients had agreement from their GP to take part in the trial. They add that patients were carefully screened and given psychological support before, during and after the intervention, and that the study took place in a positive environment. Further research is now needed to tease out the relative influence of these factors on symptoms of depression, and look at how psilocybin compares to placebo and other current treatments.
Writing in a linked Comment, Professor Philip Cowen, MRC Clinical Scientist, University of Oxford, Oxford, UK, says: "The key observation that might eventually justify the use of a drug like psilocybin in treatment-resistant depression is demonstration of sustained benefit in patients who previously have experienced years of symptoms despite conventional treatments, which makes longer-term outcomes particularly important. The data at 3 month follow-up (a comparatively short time in patients with extensive illness duration) are promising but not completely compelling, with about half the group showing significant depressive symptoms. Further follow-ups using detailed qualitative interviews with patients and family could be very helpful in enriching the assessment."
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Tuesday, October 25, 2016

Cancer-fighting properties of horseradish revealed

Horseradish contains cancer-fighting compounds known as glucosinolates. Glucosinolate type and quantity vary depending on size and quality of the horseradish root. For the first time, the activation of cancer-fighting enzymes by glucosinolate products in horseradish has been documented.

 Armoracia rusticana.jpg

The humble horseradish may not be much to look at, but a recent University of Illinois study shows that it contains compounds that could help detoxify and eliminate cancer-causing free-radicals in the body.
"We knew horseradish had health benefits, but in this study, we were able to link it to the activation of certain detoxifying enzymes for the first time," says U of I crop scientist Mosbah Kushad.
Kushad's research team had previously identified and quantified the compounds responsible for the cancer-fighting compounds, known as glucosinolates, in horseradish, noting that horseradish contains approximately 10 times more glucosinolates than its superfood cousin, broccoli.
"No one is going to eat a pound of horseradish," Kushad points out. Luckily, a teaspoon of the pungent condiment is sufficient to get the benefit.
In the new study, Kushad and his team looked for the products of glucosinolate hydrolysis, which activate enzymes involved in detoxification of cancer-causing molecules. They compared the quantity and activity of these products in 11 horseradish strains rated U.S. Fancy, U.S. No. 1, or U.S. No. 2. The USDA puts fresh-market horseradish in these categories based on diameter and length of the root.
"There was no information on whether the USDA grade of the horseradish root is associated with cancer preventive activity, so we wanted to test that," Kushad explains.
The group found that the higher-grade U.S. Fancy accessions had significantly more glucosinolates than U.S. No. 1. Concentrations of various glucosinolate hydrolysis products differed according to USDA grade, with U.S. Fancy having greater allyl isothiocyanate (AITC) and U.S. No. 1 having greater 1-cyano 2,3-epithiopropane (CETP).
The two compounds differ, with CETP being a comparatively weaker cancer-fighter than AITC. Still, the detection of CETP in horseradish is noteworthy, according to Kushad. "To our knowledge, this is the first detection and measurement of CETP from horseradish," he says.
The team suggests that AITC is a good dietary anti-carcinogen, not only because it activates the enzyme responsible for detoxifying cancer-causing molecules, but also because a large proportion of it, 90 percent, is absorbed when ingested.
Bottom line? Next time horseradish is on the menu, pick up a spoon.
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Monday, October 24, 2016

Statins may shield unborn babies from mother's stress, study suggests

In continuation of my update on statins
Scientists have discovered that the widely-prescribed drugs help to counteract the negative impact of stress hormones on fetal growth and heart development in mice.
The therapy could lower the chances of babies being born underweight and reduce their risk of health problems in later life, including heart disease, researchers say.
Further studies are needed to assess the long-term effects of statins in pregnancy, but the drugs are already used occasionally in pregnant women and should be suitable for clinical trials, the team says.
Babies that are exposed to excessive stress hormones in the womb are often born underweight and have a greater risk of heart disease in later life.
Normally, the unborn baby is protected by a key enzyme produced by the placenta that breaks down stress hormones and greatly limits the amount of active hormones that reach the baby's blood supply.
When the expectant mother is stressed, they produce less of this enzyme and the baby is less well protected.
Scientists at the University of Edinburgh studied mice that cannot produce the enzyme as a model of maternal stress.
They found that stress hormones stop the placenta from developing normal blood vessels, which cuts back the blood supply to the growing fetus.
The developing fetus does not grow to full size as a result, and its heart function does not develop normally.
Treating the mother with a type of statin triggers production of a molecule called VEGF, which stimulates the development of blood vessels in the placenta.
By re-establishing the blood supply, the treatment promotes normal development of the heart and helps the baby to grow to a healthy birthweight, the team showed.
Around 2.5 million people in the UK take statins to lower high cholesterol.
The study is published in the journal Proceedings of the National Academy of Sciences and was funded by the Wellcome Trust. The research also received funding from the Raine Medical Research Foundation, University of Western Australia.
Professor Megan Holmes, of the University of Edinburgh's British Heart Foundation Centre for Cardiovascular Sciences, said: "These are very exciting results suggesting that there may finally be a potential therapy for women whose placenta is unable to maintain the normal growth of her baby.
"At present there is no treatment and babies may be born prematurely or small, and will be at greater risk of developing cardiovascular disease, diabetes and even psychiatric disorders later in life. Although more work needs to be done to show statins are safe in human pregnancy, these results show a new way forward for the major unmet need of fetal growth retardation."
Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "Low birthweight has been associated with maternal stress, and babies with low birthweights may be more prone to cardiovascular complications later in life.
"In this study the researchers have discovered that a drug called Pravastatin may counteract the consequences of increased levels of the stress hormone corticosterone within the placentas of mice. How Pravastatin counteracts the stress hormone is not yet understood, therefore more research is needed to see whether the drug will have the same effect in humans."
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Friday, October 21, 2016

Surprising mechanism of acid reflux damage identified by researchers

For more than 80 years, it has been assumed that stomach acid backing up through the esophagus damaged the lining of the esophagus by causing chemical burns, but their research suggests that the damage in patients with gastroesophageal reflux disease (GERD) actually occurs through an inflammatory response prompted by the secretion of proteins called cytokines.
"Although this radical change in the concept of how acid reflux damages the esophagus of GERD patients will not change our approach to its treatment with acid-suppressing medications in the near future, it could have substantial long-term implications," said senior author Dr. Stuart Spechler, Professor of Internal Medicine at UT Southwestern and Chief of the Department of Gastroenterology at the Dallas VA Medical Center.
"Someday we might treat GERD with medications that target the cytokines or inflammatory cells that really cause the damage to the esophagus," said co-senior author Dr. Rhonda Souza, Professor of Internal Medicine at UT Southwestern and staff physician with the Department of Gastroenterology at the Dallas VA Medical Center.
Dr. Spechler and Dr. Souza co-direct the Esophageal Diseases Center at the Dallas VA Medical Center, which conducted the research. The research appears online in the Journal of the American Medical Association.
The research builds on previous work in mice demonstrating that it takes several weeks from the time stomach acid is introduced into the esophagus before damage occurs.
"A chemical burn should develop immediately, as it does if you spill battery acid on your hand," said Dr. Spechler, who holds the Berta M. & Cecil O. Patterson Chair in Gastroenterology.
In the current study, the researchers looked at patients at the VA North Texas Health Care System's Dallas VA Medical Center who had reflux esophagitis that had been successfully treated by medicines called proton pump inhibitors (PPIs). The researchers thought that GERD might redevelop if PPIs were stopped, providing an opportunity to observe the early changes of GERD. In 11 of 12 patients with reflux esophagitis, an injury to the lining of the esophagus, changes to the esophagus reoccurred after the PPIs were stopped. Importantly, the changes that re-occurred were not consistent with chemical burns. Rather, the findings supported the new idea that refluxed stomach acid stimulates the esophagus to make small proteins called cytokines, which then sets up the process of inflammation.
"This study challenges some of the long-held beliefs about how gastroesophageal reflux damages the esophageal mucosa in patients with gastroesophageal reflux disease," said first author Dr. Kerry Dunbar, Associate Professor of Internal Medicine and staff physician with the Department of Gastroenterology at the Dallas VA Medical Center.
GERD is an extremely common disorder of the esophagus that affects 20 percent of adult Americans. In severe cases, it can lead to bleeding ulcers in the esophagus and it can be associated with a dangerous condition called Barrett's esophagus, which can lead to esophageal cancer.
"We think that it is important for physicians to have an accurate understanding of the mechanisms underlying the diseases that we treat, especially one as common as GERD," Dr. Spechler said. "Furthermore, our study should open up new avenues for novel GERD treatments."
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Thursday, October 20, 2016

Combination of COX-2-selective NSAID with PPI can reduce risk of stomach, intestinal ulcers

Non-steroidal anti-inflammatory drugs (NSAIDs)—including ibuprofen, diclofenac, naproxen and others—are commonly used pain medications that are generally safe but may increase the risk of developing stomach and intestinal ulcers.

After researchers analyzed a large number of clinical trials that compared different ways of reducing these risks of NSAIDs, they found that the best strategy with the lowest overall risk was to combine a certain type of NSAID, known as a COX-2-selective NSAID, with a proton pump inhibitor (PPI). PPIs are most often used to treat heartburn and gastro-oesophageal reflux disease.

"The combination of a COX-2-selective NSAID with a PPI will be expensive and is not recommended for all patients who need to be on a NSAID; however, it is the safest and most effective treatment strategy for those at high risk of ulcer bleeding from NSAID treatment," said Prof. Jin Ling Tang, co-author of the Alimentary Pharmacology and Therapeutics study.

Wednesday, October 19, 2016

Multiple sclerosis drug mitoxantrone may be linked to increased risk of colorectal cancer

In continuation of my update on Mitoxantrone

Mitoxantrone is used for aggressive types of relapsing-remitting or progressive MS that do not respond to other MS drugs. But its use is limited because previous studies have shown an increased risk of leukemia and heart damage.
Mitoxantrone skeletal.svg Mitoxantrone
The current study examined whether the drug increases the risk of other types of cancer. For the study, German researchers looked at all people with MS who were treated with mitoxantrone from 1994 to 2007 and followed them until 2010.
Of the 676 people, 37 people, or 5.5 percent, were diagnosed with cancer after taking the drug, including nine people with breast cancer, seven with colorectal cancer and four with acute myeloid leukemia, which has been associated with mitoxantrone.
The rate of leukemia was 10 times higher in the people treated with mitoxantrone than in the general population in Germany. The rate of colorectal cancer, which is cancer of the colon and rectum, was three times higher than that of the general population. For breast cancer and all other types of cancer, people who had taken mitoxantrone were no more likely to develop the diseases than those in the general population.
Of the seven people with colorectal cancer, three died from the cancer during the study. The four people with leukemia all went into remission after treatment and were alive at the end of the study.
The researchers also looked at whether factors such as how much of the drug people had received cumulatively and whether they also received other immunosuppressant drugs affected their risk of developing cancer. The only factor related to a higher risk of cancer was being older when starting to take the drug.
"Despite an increased risk of acute myeloid leukemia and colorectal cancer, the overall rate of cancer was low enough to justify still using this drug for people severely affected by MS if no better treatment is available," said study author Mathias Buttmann, MD, of the University of Würzburg in Würzburg, Germany. "Mitoxantrone is the only approved treatment for people with secondary progressive MS without relapses and should be considered in people where the disease is evolving quickly. Also, many of the new and highly effective MS drugs are not available to people in a number of countries for economic reasons, so mitoxantrone is being used for people with very active relapsing forms of the disease."
Buttmann noted that the study was relatively small and needs to be confirmed. If the results are confirmed, he said that colonoscopies should be given after treatment with the drug to screen for colorectal cancer, which can be treated more effectively when diagnosed earlier.
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Tuesday, October 18, 2016

Eating oat fibre can reduce three markers linked to cardiovascular risk

Researchers have known for more than 50 years that eating oats can lower cholesterol levels and thus reduce a person's risk of developing cardiovascular disease.

Studies during that time have focused on the impact of oats on levels of LDL (or "lousy") cholesterol, which collects in the walls of blood vessels where it can cause blockages or blood clots.

But there is growing evidence that two other markers provide an even more accurate assessment of cardiovascular risk -- non-HDL cholesterol (total cholesterol minus the "H" or "healthy cholesterol") and apolipoprotein B, or apoB, a lipoprotein that carries bad cholesterol through the blood. This is especially true for people with metabolic syndrome and Type 2 diabetes, since they typically do not have elevated LDL cholesterol levels.

A new systematic review and meta-analysis of randomized controlled trials has concluded that eating oat fibre can reduce all three markers. The study, led by Dr. Vladimir Vuksan, a research scientist and associate director of the Risk Factor Modification Centre of St. Michael's Hospital, was published online today in the British Journal of Nutrition.

Dr. Vuksan said oats are a rich source of beta-glucan, a viscous soluble fibre, which seems to be responsible for the beneficial effects. The first study of its kind, published in 1963, found that substituting white bread with oat bread containing 140g of rolled oats lowered LDL cholesterol.

Dr. Vuksan's group looked at 58 clinical trials involving almost 4,000 people from around the world that assessed the effect of diets enriched with oat beta-glucan compared with controlled diets on LDL cholesterol, and, for the first time, on non-HDL cholesterol and apoB as well.

"Diets enriched with about 3.5 grams a day of beta-glucan fiber from oats were found to modestly improve LDL cholesterol, but also non-HDC and apoB compared to control diets," Dr. Vuksan said.

The review found that overall, LDL cholesterol was reduced by 4.2 per cent, non-HDL cholesterol by 4.8 per cent and apoB by 2.3 per cent.

Dr. Vuksan said it could be difficult for people to consume the recommended amount of oat fiber by eating oat meal alone so he recommends people increase their consumption of oat bran. For example, one cup of cooked oat bran (88 calories) contains the same quantity of beta-glucan as double the amount of cooked oat meal (166 calories). Oat bran can also be eaten as a cereal, used in some baked goods (although since it is low in gluten, the texture may be tough) or sprinkled on other foods.

Canada is the third largest producer of oats in the world, so increasing consumption is good for health and the economy as well, Dr. Vuksan said. Consumption of oats has been declining considerably for many years.

High fruit intake during adolescence linked with lower breast cancer risk: But increasing alcohol intake in later life associated with higher risk

The first study reports that high fruit consumption during adolescence may be associated with lower breast cancer risk, while the second study finds that increasing alcohol intake in later life is associated with an increased risk of breast cancer.
Fruit and vegetables are thought to protect against breast cancer, but the evidence is conflicting. Most studies have assessed intakes during midlife and later, which may be after the period when breast tissue is most vulnerable to carcinogenic influences.
So a team of US researchers wanted to see whether fruit and vegetable consumption might affect subsequent breast cancer risk. They followed 90,000 nurses for over 20 years who reported their diet in early adulthood, of whom half also recalled their usual diet during adolescence.
They found that high fruit consumption during adolescence (2.9 v 0.5 servings per day) was associated with a roughly 25% lower risk of breast cancer diagnosed in middle age.
In particular, greater consumption of apple, banana and grapes during adolescence, as well as oranges and kale during early adulthood was significantly associated with a reduced breast cancer risk. But there was no link between intake of fruit juice in either adolescence or early adulthood and risk.
The authors say their findings are in line with cancer prevention advice to eat more fruits and vegetables, and suggest that food choices during adolescence may be particularly important.
In a linked editorial, University of Oxford researchers say "much more evidence is needed before we can draw conclusions on the reported protective association between adolescent fruit intake and breast cancer risk." But that these foods "have well known beneficial effects on health, and efforts should continue to increase intake of both fruit and vegetables at all ages."
In the second study, a team of Danish researchers wanted to test the effect of a change in alcohol intake on the risk of breast cancer and heart disease. Alcohol is responsible for about 11% of female breast cancers in the UK.
They followed the health of nearly 22,000 post-menopausal women in Denmark and found that women who increased their alcohol intake by two drinks per day over five years had around a 30% increased risk of breast cancer but around a 20% decreased risk of coronary heart disease, compared with women with a stable alcohol intake.
However, results for women who decreased their alcohol intake over the five year period were not significantly associated with risk of breast cancer or coronary heart disease.
Altogether, the authors say their findings support the hypothesis that alcohol is associated with breast cancer and coronary heart disease in opposite directions.
The results for breast cancer are in line with previous research, but the true effect of alcohol on risk of ischaemic heart disease remains uncertain, say the editorial authors.
"There may be some benefit with low to moderate intakes of alcohol, but this could be outweighed by an increased risk of breast cancer and other morbidities," they explain. "Furthermore, risk of ischaemic heart disease can be reduced substantially by other lifestyle changes, as well as by drugs such as statins shown to be effective in primary prevention."
Both studies are observational, so their interpretation needs to consider the potential impact of other factors before any firm conclusions can be drawn about cause and effect, they add.