Link between prenatal antidepressant exposure, autism risk called into question

The authors note that, while genetic factors are known to play a substantial role in autism, exactly how that risk may be exacerbated by environmental factors is not well understood. While animal studies and investigations based on health records have suggested an increased risk associated with prenatal antidepressant exposure, others found no such association. Credit: © milosducati / Fotolia

Previous studies that have suggested an increased risk of autism among children of women who took antidepressants during pregnancy may actually reflect the known increased risk associated with severe maternal depression. In a study receiving advance online publication in Molecular Psychiatry, investigators from Massachusetts General Hospital (MGH) report that -- while a diagnosis of autism spectrum disorder was more common in the children of mothers prescribed antidepressants during pregnancy than in those with no prenatal exposure -- when the severity of the mother's depression was accounted for, that increased risk was no longer statistically significant. An increased risk for attention-deficit hyperactivity disorder (ADHD), however, persisted even after controlling for factors relating to a mother's mental health.

"We know that untreated depression can pose serious health risks to both a mother and child, so it's important that women being treated with antidepressants who become pregnant, or who are thinking about becoming pregnant, know that these medications will not increase their child's risk of autism," says Roy Perlis, MD, MSc, MGH Department of Psychiatry, senior author of the report.

The authors note that, while genetic factors are known to play a substantial role in autism, exactly how that risk may be exacerbated by environmental factors is not well understood. 

While animal studies and investigations based on health records have suggested an increased risk associated with prenatal antidepressant exposure, others found no such association. And since discontinuing antidepressant treatment significantly increases the risk of relapse -- including an increased risk of postpartum depression -- the current study was designed to clarify whether or not any increased autism risk could actually be attributed to the medication.

To investigate this possibility, the research team analyzed electronic health record data for children born at MGH, Brigham and Women's Hospital, or Newton Wellesley Hospital -- hospitals belonging to Partners HealthCare System -- for whom a diagnostic code for pervasive developmental disorder, a category that includes autism, was entered at least once between 1997 and 2010. They matched data for almost 1,400 such children with that of more than 4,000 controls with no autism diagnoses, born the same years and matched for a variety of demographic factors.

The children's information was paired with that of their mothers, noting any factors related to the diagnosis and treatment of major depression or other mental illness, including prescriptions for antidepressants and other psychotropic drugs. A similar analysis was done for almost 2,250 children with an ADHD diagnosis, compared with more than 5,600 matched controls with no ADHD diagnoses.

While prenatal exposure to antidepressants did increase the risk for either condition, in the autism-focused comparison, adjusting for factors indicating more severe maternal depression reduced the strength of that association to an insignificant level. Taking antidepressants with stronger action in the serotonin pathway, which has been suspected of contributing to a possible autism risk, did not increase the incidence of the disorder. In addition, the children of mothers who took a serotonin-targeting non-antidepressant drug for severe morning sickness had no increased autism incidence. Prescriptions for antipsychotic drugs sometimes used to treat severe, treatment-resistant depression, as well as psychotic disorders, did appear to increase the risk for autism. For ADHD, however, the increased risk associated with prenatal antidepressant exposure remained significant, although reduced, even after adjustment for the severity of maternal depression.

"There are a range of options -- medication and non-medication -- for treating depression and anxiety in pregnancy," says Perlis, an associate professor of Psychiatry at Harvard Medical School. "But if antidepressants are needed, I hope parents can feel reassured about their safety."

Source: Massachusetts General Hospital

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Targeting fatty acids may be treatment strategy for arthritis, leukemia

The bone marrow of mice with normal ether lipid production (top) contains more white blood cells than are found in the bone marrow of mice with ether lipid deficiency (bottom).
Credit: Washington University School of Medicine

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, potentially opening up new avenues for treating these diverse diseases, according to new research at Washington University School of Medicine in St. Louis.

Working with genetically engineered mice, the researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of specialized white blood cells called neutrophils. Neutrophils are the most abundant type of white blood cell and a hallmark of inflammation, which is a key component of rheumatoid arthritis. Abnormally high levels of neutrophils also are common in patients with leukemia.

The study is published Jan. 6 in the journal Cell Metabolism.

"The link between these enzymes and neutrophils was a big surprise," said first author Irfan J. Lodhi, PhD, assistant professor of medicine. "We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking."

In the study, mice that couldn't make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

"This may be a pathway to limit inflammation," said senior investigator Clay F. Semenkovich, MD, the Herbert S. Gasser Professor of Medicine. "If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis."

Semenkovich, also a professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, said the enzymes specifically target neutrophils without affecting other immune cells.

"So ether lipids appear to be a very precise target," he said.

Working with Daniel Link, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, the researchers learned that inactivating the enzymes didn't harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient's neutrophil count gradually would rise, allowing the immune system to return to normal.

Source: Washington University in St. Louis

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High-intensity sound waves may aid regenerative medicine

This is a cross section through a histotripsy lesion created in bovine liver tissue with the liquified cellular contents washed out revealing the remaining extracellular matrix. The scale bar represents 5mm. Credit: T.Khoklova/UW

Researchers at the University of Washington have developed a way to use sound to create cellular scaffolding for tissue engineering, a unique approach that could help overcome one of regenerative medicine's significant obstacles. The researchers will present their technique at the 168th meeting of the Acoustical Society of America (ASA), held October 27-31, 2014, at the Indianapolis Marriott Downtown Hotel.

The development of the new technique started with somewhat of a serendipitous discovery. The University of Washington team had been studying boiling histotripsy -- a technique that uses millisecond-long bursts of high-intensity ultrasound waves to break apart tissue -- as a method to eliminate cancerous tumors by liquefying them with ultrasound waves. After the sound waves destroy the tumors, the body should eliminate them as cellular waste. When the researchers examined these 'decellularized' tissues, however, they were surprised by what the boiling left intact.

"In some of our experiments, we discovered that some of the stromal tissue and vasculature was being left behind," said Yak-Nam Wang, a senior engineer at the University of Washington's Applied Physics Laboratory. "So we had the idea about using this to decellularize tissues for tissue engineering and regenerative medicine."

The structure that remains after decellularizing tissues is known as the extracellular matrix, a fibrous network that provides a scaffold for cells to grow upon. Most other methods for decellularizing tissues and organs involve chemical and enzymatic treatments that can cause damage to the tissues and fibers and takes multiple days. Histrostipsy, on the other hand, offers the possibility of fast decellularization of tissue with minimal damage to the matrix.

"In tissue engineering, one of the holy grails is to develop biomimetic structures so that you can replace tissues with native tissue," Wang said. Stripping away cells from already developed tissue could provide a good candidate for these structures, since the extracellular matrix already acts as the cellular framework for tissue systems, Wang said.

Due to its bare composition, the matrix also induces only a relatively weak immune response from the host. The matrix could then theoretically be fed with stem cells or cells from the same person to effectively re-grow an organ.

"The other thought is that maybe you could just implant the extracellular matrix and then the body itself would self-seed the tissues, if it's just a small patch of tissue that you're replacing," Wang said. "You won't have any immune issues, and because you have this biomimetic scaffold that's closer to the native tissue, healing would be better, and the body would recognize it as normal tissue."

Wang is currently investigating decellularization of kidney and liver tissue from large animals. Future work involves increasing the size of the decellularized tissues and assessing their in-vivo regenerative efficacy.

Source: Acoustical Society of America (ASA)

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Wearable device to track diet under development

A concept of the device with sensor was made through 3-D printing. Credit: The University of Alabama

Sensors and software used to track physical activity are increasingly popular, as smart phones and their apps become more powerful and sophisticated, but, when it comes to food, they all rely on the user to report meals.

Dr. Edward Sazonov, an associate professor of electrical and computer engineering at The University of Alabama, hopes to change that through development of a sensor worn around the ear that would automatically track diet, giving medical professionals and consumers accurate information that can be missed with self-reporting.

"Weight gain comes from an unbalance of the energy we take in versus the energy we expend," Sazonov said. "We can estimate diet and nutrient intake, but the primary method is self-reporting. The sensor could provide objective data, helping us better understand patterns of food intake associated with obesity and eating disorders."

Sazonov is the lead on a $1.8 million, five-year grant from the National Institute of Health to test the practical accuracy of the wearable sensor in tracking diet. Already proven viable, the device will be updated, further miniaturized and validated in a more formal, robust experiment in the community.

Called an Automatic Ingestion Monitor, or AIM, it has potential to monitor eating by automatically detecting and capturing imagery of food intake and to estimate the mass and the energy content of ingested food.

The sensor feels vibrations from movement in the jaw during food intake, and the device is programmed to filter out jaw motions, such as talking, that are not coming from drinking or eating. Estimates of energy intake would be taken from the pictures of food or drink.

More than two-thirds of adults in the United States are clinically overweight or obese, according to estimates from the Center for Disease Control and Prevention.

"Eating may be an unconscious, even automatic behavior for some individuals, and the literature is full of examples of dietary behaviors which increase the risk for overeating," Sazonov said.

In a study, the AIM will be tested against the accuracy of an alternative method, the use of a doubly-labeled water to track energy use by humans. That method measures the body's elimination rate of stable isotopes of hydrogen and oxygen added to the water, a process that can take two weeks. The information can be used to estimate how many calories a person consumes over a period of time.

However, this method is expensive and requires medical specialization, and, unlike the proposed AIM, does not track eating behavior.

The information provided by AIM could be used to improve behavioral weight loss strategies or to develop new kinds of weight-loss interventions. In addition, the AIM could also provide an objective method of assessing the effectiveness of pharmacological and behavioral interventions for eating disorders.

It's likely the technology's first application would be as a medical device, but Sazonov said it's possible it could become a consumer device that would eliminate the need for health-conscious people to keep a record of their diet.

Source: University of Alabama

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Body weight heavily influenced by gut microbes: Genes shape body weight by affecting gut microbes

Body sizes (stock image). New research shows that our genetic makeup influences whether we are fat or thin by shaping which types of microbes thrive in our body. Credit: © olly / Fotolia

Our genetic makeup influences whether we are fat or thin by shaping which types of microbes thrive in our body, according to a study by researchers at King's College London and Cornell University.

By studying pairs of twins at King's Department of Twin Research, researchers identified a specific, little known bacterial family that is highly heritable and more common in individuals with low body weight. This microbe also protected against weight gain when transplanted into mice.

The results, published today in the journal Cell, could pave the way for personalised probiotic therapies that are optimised to reduce the risk of obesity-related diseases based on an individual's genetic make-up.

Previous research has linked both genetic variation and the composition of gut microbes to metabolic disease and obesity. Despite these shared effects, the relationship between human genetic variation and the diversity of gut microbes was presumed to be negligible.

In the study, funded by National Institutes of Health (NIH), researchers sequenced the genes of microbes found in more than 1,000 fecal samples from 416 pairs of twins. The abundances of specific types of microbes were found to be more similar in identical twins, who share 100 per cent of their genes, than in non-identical twins, who share on average only half of the genes that vary between people. These findings demonstrate that genes influence the composition of gut microbes.

The type of bacteria whose abundance was most heavily influenced by host genetics was a recently identified family called 'Christensenellaceae'. Members of this health-promoting bacterial family were more abundant in individuals with a low body weight than in obese individuals. Moreover, mice that were treated with this microbe gained less weight than untreated mice, suggesting that increasing the amounts of this microbe may help to prevent or reduce obesity.

Professor Tim Spector, Head of the Department of Twin Research and Genetic Epidemiology at King's College London, said: 'Our findings show that specific groups of microbes living in our gut could be protective against obesity -- and that their abundance is influenced by our genes. The human microbiome represents an exciting new target for dietary changes and treatments aimed at combating obesity.

'Twins have been incredibly valuable in uncovering these links -- but we now want to promote the use of microbiome testing more widely in the UK through the British Gut Project. This is a crowd-sourcing experiment that allows anyone with an interest in their diet and health to have their personal microbes tested genetically using a simple postal kit and a small donation via our website (www.britishgut.org). We want thousands to join up so we can continue to make major discoveries about the links between our gut and our health.'

Ruth Ley, Associate Professor at Cornell University in the United States, said: 'Up until now, variation in the abundances of gut microbes has been explained by diet, the environment, lifestyle, and health. This is the first study to firmly establish that certain types of gut microbes are heritable -- that their variation across a population is in part due to host genotype variation, not just environmental influences. These results will also help us find new predictors of disease and aid prevention.'

Source: King's College London

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Weigh-in once a week or you'll gain weight

The researchers found that weight loss was related to how often individuals weighed themselves. Credit: Image courtesy of Cornell Food & Brand Lab

Stepping on the scale is common among dieters but how does the frequency of weigh-ins impact weight? A new study in PLOS ONE showed that the more frequently dieters weighed themselves the more weight they lost, and if participants went more than a week without weighing themselves, they gained weight.

The researchers analyzed 2,838 weight measurements (up to a years' worth of weigh-ins) from 40 overweight individuals (with a body mass index of 25 and over) who indicated that weight loss was a personal goal or concern. The researchers found that weight loss was related to how often individuals weighed themselves. "The more often you weigh yourself the more weight you lose," says to lead author Elina Helander from Tempere Univeristy of Technology in Finland. This observational study cannot prove causation -- it may be that less serious dieters weight themselves less or that dieters who stop losing weight stop weighting themselves. The average time that participants could go between weighting without gaining weight was 5.8 days or about a weekly weigh-in.

Previous Findings by the Research Team

Weigh yourself at least once a week if you wish to lose weight, and weighing yourself everyday may help you stay on track. A previous study by the same research team found that your weight naturally fluctuates throughout the week and that most people weigh the least on Wednesday. To summarize both studies Brian Wansink, PhD, Director of the Cornell Food and Brand Lab and author of Slim by Design: Mind Eating Solutions for Everyday Life advises, "The bottom line is: If you want to lose weight, it's best to weigh yourself every day. But if you weigh yourself only once a week, do it on Wednesday because that will give you the most accurate reading."

Source: Cornell Food & Brand Lab

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When you lose weight, where does the fat go? Most of the mass is breathed out as carbon dioxide, study shows

Despite a worldwide obsession with diets and fitness regimes, many health professionals cannot correctly answer the question of where body fat goes when people lose weight.
Credit: © Lovrencg / Fotolia

Despite a worldwide obsession with diets and fitness regimes, many health professionals cannot correctly answer the question of where body fat goes when people lose weight, a UNSW Australia study shows.

The most common misconception among doctors, dieticians and personal trainers is that the missing mass has been converted into energy or heat.

"There is surprising ignorance and confusion about the metabolic process of weight loss," says Professor Andrew Brown, head of the UNSW School of Biotechnology and Biomolecular Sciences.

"The correct answer is that most of the mass is breathed out as carbon dioxide. It goes into thin air," says the study's lead author, Ruben Meerman, a physicist and Australian TV science presenter.

In their paper, published in the British Medical Journal today, the authors show that losing 10 kilograms of fat requires 29 kilograms of oxygen to be inhaled and that this metabolic process produces 28 kilograms of carbon dioxide and 11 kilograms of water.

Mr Meerman became interested in the biochemistry of weight loss through personal experience.

"I lost 15 kilograms in 2013 and simply wanted to know where those kilograms were going. After a self-directed, crash course in biochemistry, I stumbled onto this amazing result," he says.

"With a worldwide obesity crisis occurring, we should all know the answer to the simple question of where the fat goes. The fact that almost nobody could answer it took me by surprise, but it was only when I showed Andrew my calculations that we both realised how poorly this topic is being taught."

The authors met when Mr Meerman interviewed Professor Brown in a story about the science of weight loss for the Catalyst science program on ABC TV in March this year.

"Ruben's novel approach to the biochemistry of weight loss was to trace every atom in the fat being lost and, as far as I am aware, his results are completely new to the field," says Professor Brown.

"He has also exposed a completely unexpected black hole in the understanding of weight loss amongst the general public and health professionals alike."

If you follow the atoms in 10 kilograms of fat as they are 'lost', 8.4 of those kilograms are exhaled as carbon dioxide through the lungs. The remaining 1.6 kilograms becomes water, which may be excreted in urine, faeces, sweat, breath, tears and other bodily fluids, the authors report.

"None of this is obvious to people because the carbon dioxide gas we exhale is invisible," says Mr Meerman.

More than 50 per cent of the 150 doctors, dieticians and personal trainers who were surveyed thought the fat was converted to energy or heat.

"This violates the Law of Conservation of Mass. We suspect this misconception is caused by the energy in/energy out mantra surrounding weight loss," says Mr Meerman.

Some respondents thought the metabolites of fat were excreted in faeces or converted to muscle.

"The misconceptions we have encountered reveal surprising unfamiliarity about basic aspects of how the human body works," the authors say.

One of the most frequently asked questions the authors have encountered is whether simply breathing more can cause weight loss. The answer is no. Breathing more than required by a person's metabolic rate leads to hyperventilation, which can result in dizziness, palpitations and loss of consciousness.

The second most frequently asked question is whether weight loss can cause global warming.

"This reveals troubling misconceptions about global warming which is caused by unlocking the ancient carbon atoms trapped underground in fossilised organisms. The carbon atoms human beings exhale are returning to the atmosphere after just a few months or years trapped in food that was made by a plant," says Mr Meerman, who also presents the science of climate change in high schools around Australia.

Mr Meerman and Professor Brown recommend that these basic concepts be included in secondary school curricula and university biochemistry courses to correct widespread misconceptions about weight loss among lay people and health professionals.

Source: University of New South Wales

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Making lab-grown tissues stronger

Connective tissues like cartilage are made of cross-linked bundles of collagen fibers. UC Davis biomedical engineers have discovered that reducing oxygen or adding an enzyme called LOX can make these bundles stronger. The technique can be used to strengthen both natural cartilage kept in the lab for transplant, and artificial cartilage grown in culture. Credit: Eleftherios Makris and Kyriacos Athanasiou, UC Davis

Lab-grown tissues could one day provide new treatments for injuries and damage to the joints, including articular cartilage, tendons and ligaments.

Cartilage, for example, is a hard material that caps the ends of bones and allows joints to work smoothly. UC Davis biomedical engineers, exploring ways to toughen up engineered cartilage and keep natural tissues strong outside the body, report new developments this week in the journal Proceedings of the National Academy of Sciences.

"The problem with engineered tissue is that the mechanical properties are far from those of native tissue," said Eleftherios Makris, a postdoctoral researcher at the UC Davis Department of Biomedical Engineering and first author on the paper. Makris is working under the supervision of Professor Kyriacos A. Athanasiou, a distinguished professor of biomedical engineering and orthopedic surgery, and chair of the Department of Biomedical Engineering.

While engineered cartilage has yet to be tested or approved for use in humans, a current method for treating serious joint problems is with transplants of native cartilage. But it is well known that this method is not sufficient as a long-term clinical solution, Makris said.
The major component of cartilage is a protein called collagen, which also provides strength and flexibility to the majority of our tissues, including ligaments, tendons, skin and bones. Collagen is produced by the cells and made up of long fibers that can be cross-linked together.

Engineering new cartilage

Researchers in the Athanasiou group have been maintaining native cartilage in the lab and culturing cartilage cells, or chondrocytes, to produce engineered cartilage.

"In engineered tissues the cells produce initially an immature matrix, and the maturation process makes it tougher," Makris said.

Knee joints are normally low in oxygen, so the researchers looked at the effect of depriving native or engineered cartilage of oxygen. In both cases, low oxygen led to more cross-linking and stronger material. They also found that an enzyme called lysyl oxidase, which is triggered by low oxygen levels, promoted cross-linking and made the material stronger.

"The ramifications of the work presented in the PNAS paper are tremendous with respect to tissue grafts used in surgery, as well as new tissues fabricated using the principles of tissue engineering," Athanasiou said. Grafts such as cadaveric cartilage, tendons or ligaments -- notorious for losing their mechanical characteristics in storage -- can now be treated with the processes developed at UC Davis to make them stronger and fully functional, he said.
Athanasiou also envisions that many tissue engineering methods will now be altered to take advantage of this strengthening technique.

Source: University of California - Davis

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Natural substance in red wine has an anti-inflammatory effect in cardiovascular diseases

Researchers see great therapeutic potential in the natural substance resveratrol, particularly in connection with prevention of the synthesis of inflammatory factors in cardiovascular diseases. Credit: photo/©: Peter Pulkowski, Mainz University Medical Center

A natural substance present in red wine, resveratrol, inhibits the formation of inflammatory factors that trigger cardiovascular diseases. This has been established by a research team at the Department of Pharmacology of the University Medical Center of Johannes Gutenberg University of Mainz (JGU) working in collaboration with researchers of the Friedrich Schiller University in Jena and the University of Vienna. Their results have recently been published in the scientific journal Nucleic Acids Research.

Despite the fact that they eat more fatty foods, the French tend to less frequently develop cardiac diseases than Germans. This so-called French Paradox is attributed to the higher consumption of red wine in France and it has already been the subject of various studies in the past. A number of research projects have actually demonstrated that the natural product resveratrol, present in red wine, has a protective effect against cardiovascular diseases. But what exactly is the reason for this? It seems that at least part of the protective effect can be explained by the fact that resveratrol inhibits the formation of inflammatory factors, a conclusion reached by the research team of Junior Professor Andrea Pautz and Professor Hartmut Kleinert of the Mainz University Medical Center following collaboration in a joint project with Professor Oliver Werz of the Friedrich Schiller University in Jena and Professor Verena Dirsch of the University of Vienna. In fact, the researchers discovered that the natural substance binds to the regulator protein KSRP and activates it. KSRP reduces the stability of messenger RNA (mRNA) in connection with a number of inflammatory mediators and thus inhibits their synthesis.

"We now know more precisely how resveratrol inhibits the formation of the inflammatory factors that trigger cardiovascular diseases. This is an important finding in view of the fact that more recent research has shown that cardiovascular diseases are significantly promoted by inflammatory processes in the body," said Pautz. Cardiovascular disorders, such as myocardial infarction and strokes, frequently occur in association with chronic inflammatory diseases, such as arthritis. The natural substance resveratrol thus has major therapeutic potential, particularly when it comes to the treatment of inflammatory diseases that can cause serious damage to the cardiovascular system.

Source: Universität Mainz

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