Probiotics affect brain activity

A new study provides the first evidence in humans that probiotics in the diet can modulate brain activity.

In a proof-of-concept study using functional MRI (fMRI), researchers found that women who regularly consumed probiotic-containing yogurt showed altered activity of brain regions that control central processing of emotion and sensation. The study was funded by Danone Research.

"This study is unique because it is the first to show an interaction between a probiotic and the brain in humans," lead author Kirsten Tillisch, MD, associate professor, Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, toldMedscape Medical News.

"We can't say whether the effects are beneficial; that will take larger studies with more complex designs. One of the areas this will move to is study of disease groups like irritable bowel syndrome and anxiety," she added.

The results appear in the June issue of Gastroenterology.

Modulating brain function
"This is a very important study as up to now most of the evidence that the gut microbiota can influence brain and behavior have emerged from studies in mouse models including our own work," said John Cryan, PhD, professor and head of the Department of Anatomy and Neuroscience, University College Cork, Ireland, who was not involved in the study.

"Tillisch and colleagues now have neatly shown that probiotics can also affect resting brain activity in human subjects using neuroimaging techniques. This gives credence to the idea that we may eventually modulate brain function in disease states using probiotics. That said, it is a small study, only in women, and the mechanism as to how the bacteria are inducing their effects remains unclear," Dr. Cryan said.

The study involved 36 healthy women with no gastrointestinal or psychiatric symptoms. Twice daily for 4 weeks, 12 women ate a fermented yogurt product containing the probiotics Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis; 11 women ate a nonfermented milk product (controls), and 13 received no intervention.

The women underwent fMRI before and after the intervention to measure resting brain activity and brain responses to an emotion-recognition task in which they viewed a series of pictures of people with angry or scared faces and matched them to other faces showing the same emotions. The researchers say they chose this task because studies in animals have linked changes in gut flora to changes in affective behaviors.

During the emotional reactivity task, the probiotic group showed significantly reduced activity in a widely distributed functional network containing affective, viscerosensory, and somatosensory cortices.

During resting fMRI, the probiotic group showed greater connectivity between the periaqueductal grey matter of the midbrain and cognition-associated areas of the prefrontal cortex.

These changes were not observed in the group that consumed the nonfermented milk product; "thus the findings appear to be related to the ingested bacteria strains and their effects on the host," the authors say.

Gut-brain interactions
This study, they say, "clearly demonstrates" an effect of probiotic ingestion on evoked brain responses and resting-state networks in women. However, it was not designed to address the mechanisms mediating this effect.

Going forward, they say, "identification of the signaling pathways between the microbiota and the brain in humans is needed to solidify our understanding of microbiota gut-brain interactions. If confirmed, modulation of the gut flora can provide novel targets for the treatment of patients with abnormal pain and stress responses associated with gut dysbiosis."

"The knowledge that signals are sent from the intestine to the brain and that they can be modulated by a dietary change is likely to lead to an expansion of research aimed at finding new strategies to prevent or treat digestive, mental and neurological disorders," Emeran Mayer, MD, professor of medicine, physiology, and psychiatry at the David Geffen School of Medicine at UCLA and the study's senior author, told Medscape Medical News.

Hepatitis B viral levels soar when vitamin D drops

Insufficient serum levels of vitamin D, which ebb and flow with sun exposure, are associated with high levels of hepatitis B virus (HBV) replication in treatment-naive people who suffer from chronic infection.

Harald Farnik, from the Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Germany, and colleagues report the results of their study in an article published online May 22 in Hepatology.

HBV infection remains one of the most significant infectious diseases worldwide. According to the World Health Organization, 2 billion people worldwide have been infected with HBV, and roughly 600,000 die each year. Without antiviral therapy, the virus can attack the liver, and chronic infections progress to liver disease and cirrhosis. An emerging body of evidence has shown that vitamin D plays a role in inflammatory and metabolic liver diseases and that vitamin D can have a therapeutic effect for patients with tuberculosis. Although previous research has failed to demonstrate a correlation between hepatitis C viral load and circulating vitamin D levels, Dr. Farnik and colleagues sought to characterize the relationship between vitamin D metabolism and chronic hepatitis B.

They analyzed serum samples from treatment-naive patients with chronic hepatitis who visited the outpatient liver clinic of the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany from January 2009 to December 2012. Two hundred and three patients were enrolled in the study. Every 3 HBV-infected patients enrolled in the study were randomly matched, according to age and sex, with 2 HCV-infected patients. Sixty-nine of the patients had severe vitamin D deficiency (25(OH)D3 levels < 10 ng/mL), 95 had vitamin D insufficiency (25(OH)D3 ≥ 10 ng/mL and < 20 ng/mL), and 39 had normal vitamin D levels (25(OH)D3 ≥ 20 ng/mL), Dr. Farnik and colleagues write.

"25(OH)D3 and HBV DNA serum levels showed a significant, inverse correlation (P=0.0003)," the authors write. "In both uni- and multivariate analyses, HBV DNA was the strongest determinant of low 25(OH)D3 serum concentration in our cohort (P=0.0007 and P=0.000048), respectively.

Additional studies will be needed to establish a causal relationship between vitamin D metabolism and HBV replication, the researchers write, as well as to explore the effect of adding supplemental vitamin D to existing therapies to improve the durability of treatment.

"In conclusion, we demonstrate a significant association between low 25(OH)D3 serum levels and high levels of HBV replication in chronically infected patients," they authors write. "Future studies to evaluate a therapeutic value of vitamin D and its analogs in HBV infection may be justified."


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Food supplement linked to lower PSA in prostate cancer

A commercially available food supplement that contains pomegranate, broccoli, green tea, and turmeric significantly lowers prostate-specific antigen (PSA) levels, compared with placebo, in patients with prostate cancer, a double-blind placebo-controlled randomized trial has shown.

The study results, presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology, made headlines around the world and caused the polyphenol-rich supplement, known as Pomi-T (nature Medical Products), to sell out within hours.

This is a "promising new therapy," said Tomasz Beer, MD, professor of medicine and director of the prostate cancer research program at the Oregon Health and Science University in Portland, during a "highlights of the day" session.

"We have been staggered by the level of interest...from medical professionals and the public," Marcus Williams, owner and director of natureMedical Products, told Medscape Medical News. As soon as the results of this study were released, the company, based in Porthcawl, South Wales, United Kingdom, received a rush of orders from customers in Australia, Canada, the United Kingdom, and the United States.

"It's awesome," the study's lead investigator, Robert Thomas, MD, a consultant oncologist at Bedford Hospital and Addenbrooke's Hospital, in the United Kingdom, told Medscape Medical News.

"We didn't expect such a big response. People are seeing that this can change practice...because men and their doctors do look at their PSA as a deciding factor in whether to stop active management," he explained.

Significantly different than placebo
The study involved 203 men (average age, 74 years) with a PSA relapse after radiotherapy or surgery for localized prostate cancer. The men, who were being managed with active surveillance, were randomized to receive the supplement 3 times a day for 6 months or placebo.

At 6-month follow-up, the median increase in PSA was 63.8% lower in the supplement groups than in the placebo group (14.7% vs 78.5; P =.0008). In addition, PSA levels were stable or lower than baseline more often in the supplement group (46% vs 14%;P = .00001).

Fewer men in the supplement group than in the placebo group went on to receive brachytherapy, radiotherapy, surgery, or androgen-deprivation therapy (7.4% vs 26.0%; P = 0.01).

At the end of the study, more men in the supplement group than in the placebo group continued on active surveillance (92.6% vs 74.0%). "This is an end point we feel is important: more men were choosing to stay on treatments with less toxicity," Dr. Thomas noted.

There were no differences between the supplement and placebo groups for baseline and serial measurements of cholesterol, blood pressure, serum glucose, C-reactive protein, or adverse events.

"Pomi-T was well tolerated," he said. "More men experienced nonsignificant bloating or diarrhea, but 15% of men reported beneficial effects, including better digestion and improvement of urinary symptoms."

Previous research has shown that the polyphenols and antioxidants in pomegranate, broccoli, green tea, and turmeric have individual anticancer properties, but "we believe there's a synergistic effect in the supplement," said Dr. Thomas.

In addition, the fact that each ingredient originates from a separate food category (fruit, vegetable, herb, and spice) might prevent potential adverse effects from the overconsumption of one particular type of polyphenol, he noted.

In the lab, polyphenols have been shown to have antiproliferative, antiangiogenic, proadhesion, antimetastatic, and proapoptotic properties, and notably, they have no phytoestrogenic or hormonal effects. "We specifically chose to steer away from anything that might have a hormonal effect."

Because of the supplement's effect is likely not hormonal, future trials will involve men with different stages of prostate cancer and those receiving androgen-deprivation therapy, he said. In addition, the researchers hope to look at the impact of the supplement on other slow-growing cancers and even on cancer prevention.

The study received no funding from the manufacturer of the supplement; however, the company worked very closely with the research team to develop the product, said Williams. "Unlike other nutritional supplement products, the manufacture of this supplement was significantly more time-consuming because Dr. Thomas and colleagues, for whom this was initially made, insisted on a great deal of quality assurance, over and above that normally required by the US Food and Drug Administration or European Commission, particularly in terms of purity and authenticity."

He said the study signals "a new era for the nutritional supplement industry, which has previously relied on advertising and marketing rather than evidence of benefit. Clearly, it's the latter that the public wants."

Dr. Beer noted that the product's significant effect on adherence to active surveillance is "potentially clinically meaningful... If this can be confirmed, this is really interesting," he said, although he added that "these patients were more severe than the sort of patients that we would follow [with active surveillance] here in the United States."

Prostate Cancer UK reacted more cautiously to the news, releasing a statment saying that "there is not yet enough evidence that Pomi-T food supplements have a significant impact."

Kate Holmes, MD, head of research at Prostate Cancer UK, said in a statement that "there is increasing evidence showing that men who have a healthy lifestyle, including a balanced diet and regular exercise, have better prostate cancer outcomes than those who do not. At this stage, however, we simply do not have enough evidence to suggest that any particular foods or supplements have a significant impact and these should certainly not be substituted for conventional treatments."


Source: http://www.medscape.com/viewarticle/805549?nlid=31706_1301&src=wnl_edit_dail&uac=129655SZ

Tea and coffee lower blood pressure

A large French retrospective analysis provides good news for caffeine lovers: investigators showed that drinking tea or coffee was associated with a small but statistically significant reduction in systolic and diastolic blood pressure. In addition, drinking tea and coffee was also associated with a significant reduction in pulse pressure and heart rate, although the heart-rate reductions were greater with tea.

Presenting the results at the European Society of Hypertension (ESH) 2013 Scientific Sessions, Dr Bruno Pannier (Centre d'Investigations Préventives et Cliniques, Paris, France) said that other studies have suggested a relationship between coffee and tea consumption and blood pressure, but these analyses haven't been conclusive. Some have suggested a benefit, while others found no relationship between tea/coffee consumption and blood pressure.

Presenting the data on 176 437 subjects aged 16 to 95 years of age who had a checkup at their center between 2001 and 2011, Pannier explained that the analysis was simply based on a questionnaire asking participants how much coffee or tea they drank per day. Individuals were classified into three groups: those who drank no coffee/tea, those who drank one to four cups, and those who drank more than four cups.

Overall, coffee is consumed more frequently than tea, although there were differences between the sexes, said Pannier. Men were more likely to drink coffee, while women were more commonly tea drinkers. Coffee consumption was also significantly associated with tobacco consumption, higher cholesterol levels, and higher scores on stress and depression indexes. Tea consumption, on the other hand, was associated with lower cholesterol levels but similarly high scores on the stress and depression measurements.

After adjustments that included these and other potential confounding variables, both coffee and tea consumption was associated with a significant reduction in systolic and diastolic blood pressure, as well as other variables.

Blood Pressure Among Coffee Drinkers

Variable	None	1 to 4 cups	>4 cups	p (for trend)
Systolic blood pressure (mm Hg)	127.9	126.7	125.5	<0.0001
Diastolic blood pressure (mm Hg)	76.0	76.0	75.7	0.02
Pulse pressure (mm Hg)	51.9	50.7	49.8	<0.0001
Heart rate (beats/min)	63.2	62.9	63.2	0.001

Blood Pressure Among Tea Drinkers

Variable	None	1 to 4 cups	>4 cups	p (for trend)
Systolic blood pressure (mm Hg)	127.3	126.3	125.3	<0.0001
Diastolic blood pressure (mm Hg)	76.2	75.6	75.0	<0.0001
Pulse pressure (mmHg)	51.1	50.7	50.3	<0.0001
Heart rate (beats/min)	63.5	62.7	62.0	<0.0001

Speaking during the session, Pannier explained that the group did not differentiate between green, black, or herbal tea consumption, which is one of the limitations of the analysis. In addition, the questionnaire is not sophisticated enough to address estimates in the caffeine content of the coffee consumed in France.

That said, Pannier believes that tea is a major source of flavonoids in the diet, and these compounds can improve vasodilation. "The vasorelaxing compounds included in these beverages might be involved in these results, something that has been suggested by the experimental data," he said.


Source: http://www.medscape.com/viewarticle/806516?nlid=31779_1301&src=wnl_edit_dail&uac=129655SZ

Mindful meditation has antianxiety effects

Individuals with no experience in meditation who participate in mindful meditation training sessions for as little as 4 days show changes in specific brain mechanisms that correlate with a reduction in anxiety, a new imaging study shows.

"There is plenty of evidence that meditation can improve a host of issues, such as pain and cognitive function, and anxiety is perhaps at the top of the list," explained lead author Fadel Zeidan, PhD, a postdoctoral research fellow in neurobiology and anatomy at Wake Forest School of Medicine, in Winston-Salem, North Carolina.

"But what we've been able to do is to correlate, through imaging, changes in specific brain regions that are related to anxiety, even in a cohort of people with no anxiety or depression."

The findings were published online April 24 in Social Cognitive and Affective Neuroscience.

Buffer to anxiety
For the study, Dr. Zeidan and his colleagues recruited 15 healthy volunteers with normal levels of anxiety and no experience in meditation to participate in four 20-minute training sessions to learn the technique for mindful meditation.

This involves a focus on breathing and a conscious acknowledging of distracting thoughts and emotions, combined with a decision not to react to them.

"You're trained to focus on keeping a very straight posture and the sensations of the rise and fall of your chest and abdomen as you breathe," Dr. Zeidan explained.

"If your mind becomes distracted, you acknowledge the distraction, let it go, and focus back on the breathing. You are regulating your emotional responses."

Before and after each meditation training session, the participants, who included graduate students and faculty, received brain activity imaging with pulsed arterial spin labeling magnetic resonance imaging (MRI).

The participants also were administered the State Anxiety Inventory, a 20-item subscale of the State Trait Anxiety Inventory, before and after the brain imaging.

While the participants reported meditation-related reductions in anxiety ratings by as much as 22%, the MRIs showed anxiety relief to be associated with activation of the anterior cingulate cortex and ventromedial prefrontal cortex (vmPFC), which show decreases in activity when anxiety is present.

The vmPFC is also implicated in the alteration of contextual evaluation of affective processes, the authors write.

"Activation in the vmPFC is associated with modulating higher-order affective appraisals, including cognitive regulation of negative emotions."

In addition, reports of greater anxiety correlated with greater default-related activity (ie, posterior cingulate cortex) on MRI, "possibly reflecting an inability to control self-referential thoughts," the authors write.

The brain mechanisms related to the reduction of anxiety through mindful meditation in healthy people have never been identified, so the findings help confirm that the changes do occur, said Dr. Zeidan.

"It shows that mindful meditation can be sort of this buffer to anxiety. After just a brief training, you can reduce this ruminative thought process, change your attention, and change the context in how you respond to things," he said.

Potential payoff
Amit Sood, MD, director of research and practice in the Mayo Complementary and Integrative Medicine Program at Mayo Clinic, in Rochester, Minnesota, said that such changes are not unexpected over such a short period.

"I'm not surprised to see the correlations with reductions of anxiety in 4 days — other studies looking at brain structure have reported seeing these changes after just 4 to 6 hours of training," said Dr. Sood.

"What I would be surprised to see, however, is if they were still doing it on their own after 6 months," he noted.

"People can learn it quickly, but then they forget. A change in habit requires a lot of effort. People have to carve out the time in their busy days, and what tends to happen is will power depletion."

The study demonstrates, however, the potential payoff, he added.

"I wouldn't call this a landmark study, but it does validate the overall theme we're seeing in this field," Dr. Sood said.

"It adds another bullet point of how we can understand emotional and brain states, and eventually this may help us better classify people based on what is actually happening in the brain, beyond their displayed symptoms."

Source: http://www.medscape.com/viewarticle/806288?nlid=31771_1301&src=wnl_edit_dail&uac=129655SZ

Diclofenac poses similar risks as COX-2 Inhibitors

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has completed its review of diclofenac and concluded that the drug poses similar risks as selective COX-2 inhibitors, particularly when used in high doses (150 mg) or when used long term [1].

Still, committee says the benefits of diclofenac exceed the risks and that physicians should take the same precautions to minimize thromboembolic events as they do with patients treated with selective COX-2 inhibitors.

"Patients who have serious underlying heart or circulatory conditions, such as heart failure, heart disease, circulatory problems, or a previous heart attack or stroke, should not use diclofenac," according to PRAC. "Patients with certain cardiovascular risk factors (such as high blood pressure, raised blood cholesterol, diabetes, or smoking) should only use diclofenac after careful consideration. Healthcare professionals will also be advised to periodically reassess the need for patients to continue taking the medicine."

The review conducted by PRAC was launched in October 2012 after the EMA completed a report on published information assessing the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs). Like PRAC, the EMA concluded that there was a consistent but small increase in the risk of cardiovascular side effects with diclofenac compared with other NSAIDs and that this risk was on par with that observed with COX-2 inhibitors.

The current PRAC conclusions are based on all published and unpublished data. Its recommendations will now be forwarded to the Coordination Group for Mutual Recognition and Decentralized Procedures--Human (CMDh), a regulatory body representing member European Union states, which will adopt a final position.

Source: http://www.medscape.com/viewarticle/806308?nlid=31771_1301&src=wnl_edit_dail&uac=129655SZ

Silver enhances antibiotic activity against gram-negative bacteria in mice

The use of silver in medicine is as old as western medicine itself. Hippocrates is known to have used it to treat ulcers and wounds, the Romans almost certainly knew of its healing properties, its use continued through the middle ages and up to the present day. In the antibiotic age, interest in silver may have waned a little. But with urgent need to fight antibiotic-resistant bacteria, there is resurgence in its uses.

The reason is that silver can kill bacteria selectively and, more importantly, bacteria are unable to develop resistance against it. Despite silver’s long medical history, we do not know how it operates. A paper published last Thursday in the journal Science Translational Medicine sheds some light on silver’s success against bacteria. The most important find is that silver – unlike most antibiotics – works in more than one way. This is perhaps why bacteria are not able to build resistance to silver.

Here is silver’s multi-pronged approach: first, silver sticks very strongly to sulfur, found in parts of proteins. These sulfur groups normally bond to each other in proteins, holding them together and keeping the protein folded up in its correct shape. But if silver interacts with sulfur then the protein cannot fold correctly, and thus it cannot do its job. Next silver interferes with how bacteria use iron. Iron is often held in the places it is needed by binding to sulfur. And since silver also interacts with sulfur it stops the iron doing so. Finally, silver causes bacteria to produce extremely toxic substances called reactive oxygen species. These go on to cause damage inside the cell, harming the DNA, proteins and even the membranes that surround cells.

The net result of this silver onslaught is bacteria with severely damaged defences. Most importantly the membranes and walls that surround it are leakier after the silver treatment. Once weakened, they are much more susceptible to conventional antibiotics. James Collins, at Boston University, who led the research showed that with added silver, less antibiotic drug is needed to kill the bugs. A great result in itself, but it gets better. Silver also reverses antibiotic resistance of E. coli bacteria making them, once more, susceptible to tetracycline.

These experiments not only worked in a Petri dish. When silver was added to standard antibiotics such as gentamicin and vancomycin, Collins could treat E. coli infections in the bladder and abdomens of mice. Normally these drugs have little effect on E. coli infections because they are designed to attack a completely separate class of bacteria.

Bacteria are broadly classified into two groups called Gram-negative or Gram-positive. Gram-negatives have an extra cell membrane that protects the bacteria, which means that it is much more difficult for some antibiotics, such as gentamicin and vancomycin, to penetrate the cell. It seems that silver negates this advantage and allows even weaker drugs to do their jobs. Finally, Collins showed that the mice themselves remain unharmed by silver. If he is able to repeat this work in humans, then he may actually have a “silver bullet” for antibiotic resistance.