Body

Modern neuroscience, for all its complexity, can trace its roots directly to a series of pen-and-paper sketches rendered by Nobel laureate Santiago Ramón y Cajal in the late 19th and early 20th centuries.

His observations and drawings exposed the previously hidden composition of the brain, revealing neuronal cell bodies and delicate projections that connect individual neurons together into intricate networks.

As he explored the nervous systems of various organisms under his microscope, a natural question arose: What makes a human brain different from the brain of any other species?

At least part of the answer, Ramón y Cajal hypothesized, lay in a specific class of neuron--one found in a dazzling variety of shapes and patterns of connectivity, and present in higher proportions in the human brain than in the brains of other species. He dubbed them the "butterflies of the soul."

Known as interneurons, these cells play critical roles in transmitting information between sensory and motor neurons, and, when defective, have been linked to diseases such as schizophrenia, autism and intellectual disability. Despite more than a century of study, however, it remains unclear why interneurons are so diverse and what specific functions the different subtypes carry out.

Now, in a study published in the March 22 issue of Nature, researchers from Harvard Medical School, New York Genome Center, New York University and the Broad Institute of MIT and Harvard have detailed for the first time how interneurons emerge and diversify in the brain.

Using single-cell analysis--a technology that allows scientists to track cellular behavior one cell at a time--the team traced the lineage of interneurons from their earliest precursor states to their mature forms in mice. The researchers identified key genetic programs that determine the fate of developing interneurons, as well as when these programs are switched on or off.

The findings serve as a guide for efforts to shed light on interneuron function and may help inform new treatment strategies for disorders involving their dysfunction, the authors said.

"We knew more than 100 years ago that this huge diversity of morphologically interesting cells existed in the brain, but their specific individual roles in brain function are still largely unclear," said co-senior author Gordon Fishell, HMS professor of neurobiology and a faculty member at the Stanley Center for Psychiatric Research at the Broad.

"Our study provides a road map for understanding how and when distinct interneuron subtypes develop, giving us unprecedented insight into the biology of these cells," he said. "We can now investigate interneuron properties as they emerge, unlock how these important cells function and perhaps even intervene when they fail to develop correctly in neuropsychiatric disease."

Origin to Fate

In collaboration with co-senior author Rahul Satija, core faculty member of the New York Genome Center, Fishell and colleagues analyzed brain regions in developing mice known to contain precursor cells that give rise to interneurons.

Using Drop-seq, a single-cell sequencing technique created by researchers at HMS and the Broad, the team profiled gene expression in thousands of individual cells at multiple time points. This approach overcomes a major limitation in past research, which could analyze only the average activity of mixtures of many different cells.

In the current study, the team found that the precursor state of all interneurons had similar gene expression patterns despite originating in three separate brain regions and giving rise to 14 or more interneuron subtypes alone--a number still under debate as researchers learn more about these cells.

"Mature interneurons exhibit incredible diversity. Their morphology and patterns of connectivity and activity are so different from each other, but our results show that the first steps in their maturation are remarkably similar," said Satija, who is also an assistant professor of biology at New York University.

"They share a common developmental trajectory at the earliest stages, but the seeds of what will cause them to diverge later--a handful of genes--are present from the beginning," Satija said.

As they profiled cells at later stages in development, the team observed the initial emergence of four interneuron "cardinal" classes, which give rise to distinct fates. Cells were committed to these fates even in the early embryo. By developing a novel computational strategy to link precursors with adult subtypes, the researchers identified individual genes that were switched on and off when cells began to diversify.

For example, they found that the gene Mef2c--mutations of which are linked to Alzheimer's disease, schizophrenia and neurodevelopmental disorders in humans--is an early embryonic marker for a specific interneuron subtype known as Pvalb neurons. When they deleted Mef2c in animal models, Pvalb neurons failed to develop.

These early genes likely orchestrate the execution of subsequent genetic subroutines, such as ones that guide interneuron subtypes as they migrate to different locations in the brain and ones that help form unique connection patterns with other neural cell types, the authors said.

The identification of these genes and their temporal activity now provide researchers with specific targets to investigate the precise functions of interneurons, as well as how neurons diversify in general, according to the authors.

"One of the goals of this project was to address an incredibly fascinating developmental biology question, which is how individual progenitor cells decide between different neuronal fates," Satija said. "In addition to these early markers of interneuron divergence, we found numerous additional genes that increase in expression, many dramatically, at later time points."

The association of some of these genes with neuropsychiatric diseases promises to provide a better understanding of these disorders and the development of therapeutic strategies to treat them, a particularly important notion given the paucity of new neuropsychiatric treatments, the authors said.

Over the past 50 years, there have been no fundamentally new classes of neuropsychiatric drugs, only newer versions of old drugs, the researchers pointed out.

"Our repertoire is no better than it was in the 1970s," Fishell said.

"Neuropsychiatric diseases likely reflect the dysfunction of very specific cell types. Our study puts forward a clear picture of what cells to look at as we work to shed light on the mechanisms that underlie these disorders," Fishell said. "What we will find remains to be seen, but we have new, strong hypotheses that we can now test."

As a resource for the research community, the study data and software are open-source and freely accessible online.

A gallery of the drawings of Santiago Ramón y Cajal is currently on display in New York City, and will open at the MIT Museum in Boston in May 2018.

March 29, 2018 - Breast augmentation with implants does not interfere with the ability to detect later breast cancers--in fact, cancers may be detected at a smaller size in breasts with implants, according to a study in the April issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

But mammography may be less likely to detect cancers in breasts with implants, according to the research by Michael Sosin, MD, of MedStar Georgetown University Hospital, Washington, DC, and colleagues. The study also shows some differences in breast cancer diagnosis and treatment in women who have had breast augmentation, including a higher rate of mastectomy.

Palpable Cancers Detected at Smaller Size in Breasts with Implants

The researchers studied 48 patients with breast cancer developing after breast augmentation, along with a group of 302 women with breast cancer who did not have breast implants. Average time from breast augmentation to cancer diagnosis was 14 years. Data on the two groups of patients were analyzed to determine whether and how breast augmentation and the presence of implants affected the detection, staging, and treatment of breast cancer.

At diagnosis, the cancers were significantly smaller in women with breast implants: average size 1.4 centimeter, compared to 1.9 centimeter in women without implants. In patients whose cancers were detected by the finding of a palpable mass--by either breast self-exam or clinical exam--the average tumor size was 1.6 cm in the breast augmentation group versus 2.33 cm in the comparison group.

However, the rate of cancer detection by screening mammograms was lower for women with implants: 77.8 percent, compared to 90.7 percent in breasts without implants. Cancers tended to be diagnosed at an earlier stage in the breast augmentation group, although the difference was not statistically significant.

The study also found some differences in subsequent breast cancer diagnosis and treatment. Women with implants were more likely to undergo excisional biopsy and less likely to undergo imaging-guided core needle biopsy. Women in the breast augmentation group were more likely to be treated with mastectomy, 73 versus 57 percent; and less likely to undergo breast-conserving treatment, 27 versus 43 percent.

Breast cancer detection was unaffected by the type of breast implant (silicone- versus saline-filled), or whether the implant was placed over or under the pectoral muscle. There was some evidence to suggest that mammographic detection was more likely in breasts with saline-filled versus silicone-filled implants.

It's estimated that 1 in 8 women will develop breast cancer during their lives, while almost 300,000 women undergo breast augmentation each year. Studies have clearly shown that breast implants do not increase the risk of breast cancer. But there are continued concerns that implants might lead to delayed diagnosis of breast cancer.

The new findings suggest that breast cancers are likely to be detected at smaller sizes in women who have undergone breast augmentation--especially for palpable masses detected by self-exam or clinical examination.

In contrast, screening mammography may be more likely to miss cancers in women with implants, despite the use of modern mammographic techniques designed to increase detection.

While women with implants may be more likely to undergo mastectomy, the authors note that breast-conserving treatment remains an option for such patients. Dr. Sosin comments, "Our findings may have important implications for patient counseling regarding breast augmentation and breast cancer detection."

ORLANDO, Fla. (March 29, 2018) - A new cancer drug has proven safe and effective for pediatric patients with a rare tumor gene mutation, according to a study published today in The Lancet. The study tested the safety and dose of larotrectinib (LOXO-101) in pediatric patients with a mutation known as tropomyosin receptor kinases (TRK) that can occur in a variety of tumor types.

"This research highlights a paradigm shift in cancer care where we are identifying and treating tumors based on their genetic mutations, rather than just where they exist in the body, said Ramamoorthy Nagasubramanian, MD, an author of the study and division chief of pediatric hematology-oncology at Nemours Children's Hospital. "Additionally, this study represents a win for the field of pediatric research because the drug is being tested in children almost simultaneously with adults, when typically, pediatric research is years behind."

The multicenter, open-label, phase 1/2 study was conducted at eight sites in the U.S. and enrolled infants, children, and adolescents between the ages of 1 month and 21 years, with an average age of 4-5 years. The drug was administered orally among 24 patients with varying increasing dose concentrations adjusted for age and bodyweight. Of the patients enrolled, 17 had tumors with TRK fusions, while 7 of the patients did not have a documented TRK fusion.

Pediatric patients with TRK fusions had primary diagnoses of infantile fibrosarcoma, other soft tissue sarcoma, and papillary thyroid cancer. Previously, the only treatments for many such patients has been chemotherapy, radiation, and, in some cases, surgery, all of which can have serious adverse effects.

The study found that LOXO-101 was well tolerated in patients and showed encouraging anti-tumor activity in all patients with TRK fusion-positive tumors. More than 90 percent of the patients with solid TRK fusion-positive tumors achieved "sustained tumor regressions." However, none of the patients with TRK fusion-negative cancers had an objective response. The recommended phase 2 dose was defined as 100mg/m2 for pediatric patients, regardless of age. The most common adverse events were mild elevations in liver enzyme concentrations, reduction in the number of mature blood cells, and vomiting.

With a median follow-up of eight months, all patients with TRK fusions, except for one, remained
on treatment or underwent potentially curative surgery.

"The TRK gene mutation can be common in pediatric cancers, especially those that are treatment resistant. When we saw this drug was showing promise of anti-tumor activity in adults with TRK fusion tumors, we were hopeful for a similar result for children. Both primary objectives of this study--safety and identifying dosing--were successfully met," said Nagasubramanian.

Clinical trials of LOXO-101 in adults, infants, children, and adolescents with acquired resistance to TRK inhibition are ongoing.

requiring extensive and costly treatment after they return to the United States, reports a study in the April issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

The costs of treating complications due to medical tourism often fall on the patient's public health insurance coverage, according to the report by ASPS Member Surgeon Dennis Orgill, MD, PhD, and colleagues of Brigham and Women's Hospital-Harvard Medical School. Added to previous reports, their experience suggests that complications resulting from plastic surgery procedures performed in other countries poses "a substantial public health problem in the US."

Complications from Medical Tourism - Plastic Surgeons Share Their Experience

The researchers analyzed their department's experience in treating patients with complications related to plastic surgery in a developing country. From 2010 to 2017, the department treated a total of 78 such patients. Almost all were women; the average age was 53 years. The most common plastic surgery procedures were abdominoplasty ("tummy tuck") and breast augmentation.

The most common complications were pain, surgical site infections, and wound healing problems. Twelve patients required hospitalization. Others required long-term wound care or repeated visits to treat infections or wound-related issues.

Three patients still had surgical drains in place, which they were instructed to remove themselves when ready. Three patients had hernias following abdominoplasty. Four patients had received breast implants that they did not consent to, including one patient who was unaware that she had breast implants. Other patients had more typical complications, such as contracture (hardening) of the tissues around breast implants, implant rupture, scarring problems, and dissatisfaction with cosmetic results.

Fifty-nine percent of the patients traveled to the Dominican Republic to have their plastic surgery. That reflects the high Dominican population of Boston; most patients who traveled to the Dominican Republic reported their ethnicity as Dominican. The researchers write: "Many think of medical tourism as wealthy patients traveling to receive care at higher quality medical institutions abroad, whereas we see a group who return to their home countries to undergo elective plastic surgery procedures at a lower price."

On assessment of financial coverage, 62 percent of patients were insured under the Massachusetts Medicaid program and another 10 percent by Medicare. Dr. Orgill comments, "Cosmetic surgery done in developing countries can carry substantial risks of complications, causing a burden on patients, surgeons, and the US healthcare system."

The authors point out some limitations of their relatively small single-center study, including the fact that it included only patients who saw a doctor in the plastic surgery department.

"We hope that this study will bring attention to this emerging issue and encourage others to report any results related to medical tourism treatment and patterns," Dr. Orgill and coauthors conclude. "We hope that the global plastic surgery community will promote better solutions to these complex issues."

RENO, Nev. - The search for answers to protect Central American frogs from extinction is also giving scientists clues on how to predict and respond to emerging diseases and epidemics in humans, plants and other wildlife.

In their paper published in the magazine Science, March 30, University of Nevada, Reno's Jamie Voyles and her colleagues document the recovery of some tropical amphibians following continued exposure to a lethal pathogen.

"Diseases often shift to be less deadly over time," Voyles, assistant professor in the Department of Biology and lead author on the study, said. "But we don't fully understand why. In our study, we found that the pathogen, in this case a lethal fungus, remains just as deadly to hosts a decade after it first appeared."

For amphibians, scientists have known about a highly lethal disease called "chytridiomycosis" since the 1990s. This disease was especially devastating to frogs in Central America, where it may have wiped out entire species. The study shows that nine species that reached critically low numbers are showing evidence of recovery. In addition, some species have defenses against infection that are more effective now than they were prior to the epidemic.

"In this study, we made the exciting discovery that a handful of amphibian species - some of which were thought to have been completely wiped out - are persisting, and may even be recovering, after lethal disease outbreaks," Voyles a disease ecologist in the Department of Biology, said. "We wanted to understand how it was happening. Was it a change in the pathogen, the frogs, or both?"

The fungal pathogen that causes chytridiomycosis, Batrachochytrium dendrobatidis, has been linked to population declines in amphibian species around the world. The team investigated the chytridiomycosis outbreak and its transition away from epidemic by tracking shifts in species detection, community composition, infection patterns, as well as host resistance and pathogen virulence over time.

"Because we have pathogen and host samples from before, during and after the epidemic, we can ask whether some frogs survived because the pathogen grew weaker through time, or because the frogs' immune systems or resistance increased through time," Voyles said.

"The evidence suggests that the pathogen has not changed. It's possible that the hosts have evolved better defenses over a relatively short period of time" she said. "We found that nearly a decade after the outbreak, the fungal pathogen is still equally deadly, but the frogs in Panama are surviving and may have better defenses against it. This suggests that some of Panama's frogs may be fighting back."

"This pathogen infects many different amphibian species -- sometimes without causing disease -- and can survive in the environment outside of its host, so it's not going away anytime soon," said study co-author Allison Byrne, a doctoral student at the University of California, Berkeley. "This study provides hope that some species can recover despite being constantly exposed to a deadly pathogen."

Understanding how amphibian communities are recovering after this disease outbreak is important for multiple reasons. This work suggests that recovery after the epidemics is possible, but likely a slow and gradual process, which underscores the importance of continuing to monitor amphibian populations.

"The study sounds a hopeful note," said Louise A. Rollins-Smith, a co-author of the study from Vanderbilt University School of Medicine, said. "Initially it looked bleak for many frog species, but some of them are certainly recovering."

Detecting species that exist in small, remnant populations means many hours of searching across many sites and habitats. Distinguishing between populations that are lost for good and populations that are limping along, perhaps in need of conservation support, requires a prolonged and extensive monitoring effort.

"Clarifying how disease outbreaks subside will help us predict, and respond to, other emerging pathogens in plants, wildlife - and in humans, Voyles said. "These are increasingly important goals in a time when rapid globalization has increased the rate of introduction of pathogens to new host populations."

Scientists have long known that restricting calories can fend off physiological signs of aging, with studies in fruit flies, roundworms, rodents and even people showing that chronically slashing intake by about a third can reap myriad health benefits and, in some cases, extend lifespan.

From a public health perspective, that advice would be impractical for many and dangerous for some.

But a new University of Colorado Boulder study published today indicates that when people consume a natural dietary supplement called nicotinomide riboside (NR) daily, it mimics caloric restriction, aka "CR," kick-starting the same key chemical pathways responsible for its health benefits.

Supplementation also tends to improve blood pressure and arterial health, particularly in those with mild hypertension, the study found.

"This was the first ever study to give this novel compound to humans over a period of time," said senior author Doug Seals, a professor and researcher in the Department of Integrative Physiology. "We found that it is well tolerated and appears to activate some of the same key biological pathways that calorie restriction does."

For the study, published in the journal Nature Communications, Seals and lead author Chris Martens, then a postdoctoral fellow at CU Boulder, included 24 lean and healthy men and women ages 55 to 79 from the Boulder area.

Half were given a placebo for six weeks, then took a 500 mg twice-daily dose of nicotinamide riboside (NR) chloride (NIAGEN). The other half took NR for the first six weeks, followed by placebo.

The researchers took blood samples and other physiological measurements at the end of each treatment period.

Participants reported no serious adverse effects.

The researchers found that 1,000 mg daily of NR boosted levels of another compound called nicotinamide adenine dinucleotide (NAD+) by 60 percent. NAD+ is required for activation of enzymes called sirtuins, which are largely credited with the beneficial effects of calorie restriction. It's involved in a host of metabolic actions throughout the body, but it tends to decline with age.

Research suggests that as an evolutionary survival mechanism, the body conserves NAD+ when subjected to calorie restriction. But only recently have scientists begun to explore the idea of supplementing with so-called "NAD+-precursors" like NR to promote healthy aging.

"The idea is that by supplementing older adults with NR, we are not only restoring something that is lost with aging (NAD+), but we could potentially be ramping up the activity of enzymes responsible for helping protect our bodies from stress," Martens said.

The new study also found that in 13 participants with elevated blood pressure or stage 1 hypertension (120-139/80-89 mmHg), systolic blood pressure was about 10 points lower after supplementation. A drop of that magnitude could translate to a 25 percent reduction in heart attack risk.

"If this magnitude of systolic blood pressure reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications," the authors note.

Ultimately, the authors say, such CR-mimicking compounds could provide an additional option--alongside the dietary changes and exercise currently recommended--for people whose blood pressure is not yet high enough to warrant medication but who are still at risk for a heart attack.

They stress that the study was small and "pilot in nature."

"We are not able to make any definitive claims that this compound is safe or going to be effective for specific segments of the population," said Martens, now an assistant professor at the University of Delaware. "What this paper provides us with is a really good stepping stone for future work."

Martens and Seals have applied for a grant to conduct a larger clinical trial looking specifically at the impact of NR supplementation on blood pressure and arterial health. Martens is also launching a separate trial looking at the impact NR has on older adults with mild cognitive impairment, a precursor to Alzheimer's disease.

By taking a high-cost drug with a low-fat meal--instead of on an empty stomach, as prescribed--prostate cancer patients could decrease their daily dose, prevent digestive issues and cut costs by 75 percent, according to a new study in the March 28, 2018, issue of the Journal of Clinical Oncology (JCO).

Abiraterone acetate, marketed as Zytiga®, is the standard medicine used to treat metastatic castration-resistant prostate cancer. Patients taking Zytiga are told to take four of the 250 milligram pills first thing in the morning. Then, having gone without food overnight, they must wait at least one more hour before eating breakfast.

"This schedule is not only inconvenient for patients, it's also wasteful, in several ways," said the study's lead author, Russell Szmulewitz, MD, associate professor of medicine at the University of Chicago and a prostate cancer specialist.

A one-month supply of the recommended dose of abiraterone costs $8,000 to $11,000 when purchased wholesale. That adds up to a little more than $100,000 each year. Many patients take the drug for two to three years.

So Szmulewitz and colleague Mark Ratain, MD, the Leon O. Jacobson professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago Medicine, designed a randomized clinical trial to see if the drug could be used more efficiently and at less expense.

Abiraterone, approved in 2011 for the treatment of metastatic prostate cancer, has a "food effect" that is greater than any other marketed drug. The amount of abiraterone that gets absorbed and enters the blood stream can be multiplied four or five times if the drug is swallowed with a low-fat meal (7 percent fat, about 300 calories). That can increase to 10 times with a high-fat meal (57 percent fat, 825 calories).

Working with colleagues at the University of Chicago as well as researchers at the National Cancer Institute, Emory University, Illinois Cancer Care in Peoria, Illinois, and the National University Cancer Institute, Singapore, the team designed a clinical trial that could compare the cost, risks and benefits of taking this drug with or without breakfast.

The study launched in 2012. The team enrolled 72 patients with advanced prostate cancer. Half of those patients agreed to take the recommended dose of 1,000 milligrams: four pills each morning with water on an empty stomach. They had to wait an hour afterwards before they could eat breakfast.

The other half were told to take one-fourth of the standard dose, a single 250-milligram pill, with a low-fat breakfast such as cereal with skim milk. Patients were advised to avoid high-fat items such as bacon or sausage.

Four patients, two from each group, dropped out before the study began.

The researchers found that the lower dose with breakfast kept the disease under control as well as the recommended dose. Abiraterone's ability to lower levels of prostate-specific antigen, a surrogate marker for prostate cancer, was slightly greater for patients in the low-dose with food group when measured at 12 weeks.

Progression-free survival for patients in both the low- and high-dose groups was identical, about 8.6 months. Despite the small size of the study, the authors were confident that the low-dose arm was comparable to the standard dose. It was also slightly more convenient and much less expensive, cutting costs by as much as $300,000 per patient.

"The patient gets a simplified schedule, slightly more control over his daily life, the convenience of eating whenever he chooses and the opportunity to share the cost-savings with his insurance company," Szmulewitz said. "Taking this medicine while fasting is wasteful."

"Although it should be validated with a larger trial with more robust clinical endpoints," he added, "given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers and patients."

"If this study were enlarged and repeated successfully, the resulting cost saving would be in the billions of dollars," according to Allen Lichter, MD, author of a related commentary in the JCO, former CEO of the American Society of Clinical Oncology and board chair of the Value in Cancer Care Consortium (Vi3C).

Abiraterone, taken with prednisone to prevent side effects, "represents a new standard of care for metastatic disease," according to a recent review article in the New England Journal of Medicine. The authors were concerned, however, that the "duration and cost of treatment may influence clinical decision making."

At a per-patient cost of about $10,000 a month, "this is a textbook example of what we now call 'financial toxicity'," Ratain said, referring to the economic burden placed on patients by the high cost of care. "At least three-quarters of this expensive drug is wasted," he added. "It's excreted and flushed away."

Belmont, MA - McLean Hospital neuroscientists have found that immune system activation during pregnancy and right at birth can cause alterations in the brain's neural circuits during young adulthood that are consistent with behavioral symptoms common in autism spectrum disorder (ASD) and other developmental conditions. The detailed findings are available in the March 28, 2018, issue of the Journal of Neuroscience.

"Mounting evidence suggests that immune activation, such as prenatal viral infections and postnatal bacterial infections, can impact later-life brain development in humans," said Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean Hospital and co-senior author of the paper. "While previous studies at McLean and elsewhere have focused on the behavioral symptoms produced by such immune activation, this study goes deeper, going to the cellular level to show how the brain's neural circuits are affected."

"Previous studies have helped demonstrate the types of things that can happen behaviorally as a result of immune system activation," added Bill Carlezon, PhD, chief of the Division of Basic Neuroscience at McLean Hospital, and co-senior author of the paper. "This research, however, is distinguishable in that it is an important step in telling us the biological basis of how these symptoms develop."

To explore the impact of immune activation on the developing brain, the researchers induced either maternal or postnatal immune activation, or gave both treatments, in groups of pregnant mice and their offspring. Pregnant mothers were treated with polycytidylic acid, a chemical that simulates the effects of a viral infection, at a time point that approximates the third trimester of pregnancy in humans. The offspring were treated with a lipopolysaccharide (LPS), a chemical that simulates a bacterial infection and causes a temporary (1-3 day) activation of the immune system. The LPS was given at a time point that approximates the stage of brain development in humans right at the time of birth, thus mimicking the development of a bacterial infection during delivery.

Long after the treatments were applied, during a time point in mice that approximates young adulthood in humans, the investigators examined the impact of the simulated infections on the brain, comparing their results to those from mice that had received inactive injections. Focusing on the neural pathway from the brain's prefrontal cortex to the amygdala, they combined optogenetics--a technique that uses light to control the activity of neurons in living tissue--with behavioral testing, a methodology that allows researchers to study functional connections between different regions of the brain. Behaviorally, the researchers found a strong connection between immune activation and symptoms of enhanced anxiety-like behavior and decreased social interactions. Correspondingly, they found that neural circuits in the brain that contribute significantly to the control of anxiety and social interactions were significantly affected in the immune-activated mice.

While the group that received the combined maternal and postnatal treatment showed the largest behavioral effects, electrophysiology tests easily distinguished the pathway effects in each of the four treatment groups. According to Bolshakov, Carlezon, and fellow study researcher Yan Li, PhD, this ability to definitively detect and distinguish electrophysiological changes suggests that this study's methodology provides a stronger link between immune activation and brain disorders versus studying behavioral effects alone.

"The results are novel, as this sensitive and comprehensive testing has revealed how prenatal and early postnatal immune activation may regulate core behavioral signs associated with ASD and certain other developmental disorders through changes in signal flow between different structural components of behavior-driving neural circuits," said Bolshakov. "These findings may be of a significant translational value, as they provide important clues to understanding the mechanisms of these disorders and potentially their treatment."

CLEVELAND, Ohio -- Today, most people in the United States rarely think of rheumatic heart disease (RHD)-or the rheumatic fever that causes it-as more than a historical footnote.

Rheumatic fever, which usually starts as strep throat, was essentially eliminated as a life-threatening disease with the use of penicillin in the early 20th century.

But for much of the developing world, RHD still kills. Estimates range that between a quarter-million to 330,000 people a year die from what has been called the "disease of poverty" across Africa, the Middle East, Central and South Asia and the South Pacific.

Worse, women of childbearing age who suffer from RHD face a double danger: They face increased risk of complications during pregnancy-including death-while also bearing a cultural burden and expectation that they'll become mothers.

That was among the findings in a recent study in Uganda led by researcher Allison Webel, an assistant professor at the Frances Payne Bolton School of Nursing at Case Western Reserve University.

The survey of 75 women last year is among the first qualitative studies of female RHD patients and their attitudes toward cardiovascular disease and reproduction.

The study has its origins in clinical observations at the Ugandan Heart Institute. A health-care provider there was hearing from women who were cautioned by their doctors about the dangers of bearing and delivering children-but who were also being told by their families and community that they must get pregnant.

Webel said that "tension between maintaining one's own health and the social expectation of becoming pregnant" was clearly illustrated in the Ugandan study.

"Our findings suggest that health programs targeting RHD in low- to moderate-income countries have to pay special attention to female patients of childbearing age," she said.

Webel and six co-authors discuss their findings in a paper published this month in the journal PLOS ONE.

After years of public health efforts, health care at the Los Angeles County Jail has significantly improved, and the facility now typically provides full access to treatment for inmates who have HIV -- including medications that keep their disease in check.

When they are released, however, many former inmates stop making regular visits to a doctor and taking the medication they need, which puts their own health at risk and increases the chance they will transmit the virus to others.

A new UCLA study has found that a new program to help those people to continue getting good treatment after they get out of jail -- and making sure they're able to find the medical care they need -- can help them stay on their anti-HIV medications.

In a paper published in JAMA Internal Medicine, UCLA researchers describe an experimental program they developed and tested to help people maintain their health care regimens after their release from jail. They found that the program was more effective in helping inmates stay on their medications, and in keeping the virus controlled, than the approach that is most commonly used today for former inmates.

Various studies have estimated that inmates have three to five times the rate of HIV infection of people in the U.S. who are not in jail.

For people with HIV, staying on anti-HIV medications is crucial to controlling the virus and staying healthy. Daily use can reduce the amount of HIV in the bloodstream, which is known as viral load, to levels that are undetectable with standard tests, or viral load suppression. But failing to continue taking their medication after being released from jail can cause the level of HIV in their blood to spike.

"Incarceration is more prevalent among people at high risk for substance abuse, mental illness and infectious diseases such as HIV, and adversely affects employment, housing, and access to care for ex-offenders," said Dr. William Cunningham, professor of medicine at the David Geffen School of Medicine at UCLA and the study's principal investigator. "Upon their release, many fail to link to care soon enough or long enough to keep the virus under control."

The researchers recruited 356 HIV-positive men and transgender women from Los Angeles County Jail, 42 percent of whom were black and 31 percent of whom were Latino. Of them, 180 were assigned to "peer navigation treatment." For up to 12 sessions over 24 weeks -- starting while the participants were still in jail -- they received advice from trained staff on how to make their way through the health care system. Following the inmates' release, navigators helped their clients understand how to overcome barriers that could make it difficult for them to continue getting their treatment for HIV or to take their medicine regularly; they also provided counseling and accompanied the subjects to doctors' visits.

The other 176 people received referrals to housing assistance, doctor's appointments and other needs referrals to housing assistance, doctor's appointments and other needs -- but not the additional counseling and support.

The researchers found that 49 percent of the participants assigned to the peer navigation group had viral suppression 12 months after their release -- the same percentage as at the start of the trial. In contrast, just 30 percent of those in the traditional program had maintained their viral suppression by the end of the year, down from 52 percent at the beginning.

"No prior interventions tested in randomized controlled trials, to our knowledge, have resulted in a sustained level of viral suppression after jail release among people living with HIV re-entering the community," said Cunningham, who is also a professor of public health at the UCLA Fielding School of Public Health.

Those in the peer navigation group also were more likely than their counterparts in the other cohort to receive regular medical care, and visit their mental health and case management workers -- and less likely to seek care in an emergency room over the 12-month period.

The study has some limitations. For instance, some data was collected by jail staff, rather than the researchers, which limited some of the information collected. Viral loads were often reported only as detectable or undetectable and not by amounts in the blood, so changes in the amount of virus in the blood were not tracked.

Bottom Line: Despite the steady increase of liver cancer incidence in the United States in recent decades, data from 2015 indicates that less than 13 percent of individuals born between 1945 and 1965 are estimated to have undergone screening for hepatitis C virus (HCV).

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Authors: Susan Vadaparampil, PhD, MPH, senior author, senior member and professor, Health Outcomes and Behavior Program, Moffitt Cancer Center, Tampa, Florida; Monica Kasting, PhD, lead author, postdoctoral fellow, Division of Population Science, Moffitt Cancer Center; Anna Giuliano, PhD, founding director of the Center for Infection Research in Cancer, Moffitt Cancer Center.

Background: "In the United States, approximately one in 30 baby boomers are chronically infected with HCV," said Vadaparampil. "Almost half of all cases of liver cancer in the United States are caused by HCV. Therefore, it is important to identify and treat people who have the virus in order to prevent cancer."

"Hepatitis C is an interesting virus because people who develop a chronic infection remain asymptomatic for decades and don't know they're infected," explained Kasting. "Most of the baby boomers who screen positive for HCV infection were infected over 30 years ago, before the virus was identified."

Because over 75 percent of HCV-positive individuals were born between 1945 and 1965, both the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force (USPSTF) now recommend that baby boomers get screened for the virus. However, data from the 2013 National Health Interview Survey (NHIS) indicated that only 12 percent of baby boomers had been screened for HCV, Kasting explained. The researchers wanted to study if HCV screening rates had increased following the FDA approval of several well-tolerated and effective treatments for HCV infection.

How the Study Was Conducted: Using NHIS data from 2013-2015, Kasting and colleagues analyzed HCV screening prevalence among four different age cohorts (born before 1945, born 1945-1965, born 1966-1985, and born after 1985). Participants were asked if they had ever had a blood test for hepatitis C. As the researchers were interested in assessing HCV screening in the general population, they excluded certain populations who were more likely to be screened for the virus, resulting in a total sample size of 85,210 participants.

Results: After multivariable analysis, Kasting and colleagues found that females were screened less often than males in every age cohort. Additionally, among baby boomers and those born between 1966-1985, HCV screening rates were lower among Hispanics and non-Hispanic Blacks. "This is concerning because these groups have higher rates of HCV infection and higher rates of advanced liver disease," noted Kasting. "This may reflect a potential health disparity in access to screening, and therefore treatment, for a highly curable infection."

Among baby boomers, HCV screening rates ranged from 11.9 percent in 2013 to 12.8 percent in 2015. Regardless of the federal screening recommendations, less than 20 percent of baby boomers reported that the reason for their screening was due to their age.

Author's Comments: "Our most important finding is that the HCV screening rate isn't increasing in a meaningful way," said Giuliano. "Between 2013 and 2015, HCV screening only increased by 0.9 percent in the baby boomer population. Given rising rates of liver cancer and high HCV infection rates in this population, this is a critically important finding. It shows that we have substantial room for improvement and we need additional efforts to get this population screened and treated as a strategy to reduce rising rates of liver cancer in the United States."

Study Limitations: Limitations of the study include a reliance on self-reported data. "Another limitation is that this is secondary data and we didn't collect it ourselves," noted Kasting. "There are several questions we would have liked to ask about behavioral risk factors, such as drug use, that weren't utilized on this survey."

Funding & Disclosures: This study was supported by the Biostatistics Core and the H. Lee Moffitt Cancer Center & Research Institute. Kasting is supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

As a member of Merck Scientific Advisory Boards, Giuliano and her institution have received funds from Merck. An additional author on the study, David Nelson, MD, has received grant support from Abbvie, Gilead, and Merck. All other authors declare no conflicts of interest.

EAST LANSING, Mich. - Michigan State University scientists are testing a promising drug that may stop a gene associated with obesity from triggering breast and lung cancer, as well as prevent these cancers from growing.

These findings are based on two studies featured in the latest issue of Cancer Prevention Research.

The first was a preclinical study, led by Karen Liby, an associate professor in the Department of Pharmacology and Toxicology. Results showed that the drug, I-BET-762, is showing signs of significantly delaying the development of existing breast and lung cancers by zeroing in on how a cancerous gene, called c-Myc, acts.

"I-BET-762 works by targeting DNA so that this gene can't be expressed," Liby said. "It does this by inhibiting a number of important proteins - both in cancer and immune cells - ultimately reducing the amount of cancer cells in mice by 80 percent."

These proteins are important because they play a critical role in what occurs between cells. For example, a particular protein, known as pSTAT3, can become activated in immune cells and stop them from doing their job, such as fighting off an invading cancer. The offending protein also can become overproduced in cancer cells and act as a shield - ultimately protecting the tumor.

"In our study, the drug decreased pSTAT3 levels by 50 percent in both types of cells," Liby said.

The second study, led by Jamie Bernard, an assistant professor of pharmacology and toxicology, applied Liby's findings to precancerous cells.

"We looked directly at the effect I-BET-762 had on human cells that could become tumorigenic, but weren't quite yet," Bernard said. "We found that the drug prevented more than 50 percent of these cells from becoming cancerous."

The c-Myc gene is induced by visceral fat, which is found around the inner organs of the body as opposed to subcutaneous fat, which is located under the skin. This visceral fat is more dangerous to your health.

"Almost half a million of all new cancers have been linked to obesity," Bernard said. "There is evidence that visceral fat and high-fat diets can increase cancer risk; and while current cancer treatments have helped to lower cancer mortality, the number of obesity-associated cancers continues to climb."

Due to the limited success in reducing high mortality rates of breast and lung cancer, new approaches for prevention are desperately needed, Bernard said.

Drugs that act similarly to I-BET-762 also are being tested in clinical trials for the treatment of a variety of other cancers including leukemia, lymphoma, brain tumors and myeloma. Liby and Bernard hope I-BET-762 will increase breast and lung cancer patients' chances of survival.

"The goal is our findings will clarify what needs to be targeted and therefore, can be used to prevent cancer in high-risk patient populations," Bernard said.

New research does not support the previously observed negative impacts of antidepressant use on breastfeeding. In the British Journal of Clinical Pharmacology study, use of serotonin reuptake inhibitors in late pregnancy was not linked with an increased risk of women experiencing low milk supply.

The study found that women with an underlying psychiatric illness appeared at greatest risk of experiencing low milk supply, however.

The findings highlight the importance of providing women with mental health problems with additional breastfeeding education and support. The retrospective study included 3024 women delivering liveborn preterm infants between 2004 and 2008.

"Decisions around the use of antidepressants and breastfeeding can be challenging, but these findings support continued use of antidepressants in this critical time period of mother-infant bonding," said lead author Dr. Luke Grzeskowiak, of the University of Adelaide, in Australia.

In patients who have had a heart attack, the drug varenicline significantly reduced smoking during the following year, found a randomized controlled trial published in CMAJ (Canadian Medical Association Journal) .

Patients who smoke after an acute coronary syndrome, including a heart attack (myocardial infarction) or unstable angina (reduced blood flow to the heart) are at increased risk of another attack and death if they do not quit.

Researchers from Canada looked at the efficacy of varenicline in patients with acute coronary syndrome to determine whether it would increase smoking abstinence. The randomized controlled trial included 302 patients at centres in Canada and the US who had been admitted to hospital for acute coronary syndrome, were motivated to quit smoking and who smoked at least 10 cigarettes a day for the previous year. Patients received smoking cessation counselling as well as either varenicline or a placebo control for 12 weeks. Most participants had moderate to severe nicotine dependency.

Varenicline has been shown to be efficacious in stopping smoking in patients with heart attack within the first 6 months, but its longer term efficacy was not previously known.

About 40% of participants who received varenicline were not smoking at one year, compared with 29% in the placebo group. Reductions in daily cigarette smoking of at least 50% were also higher in the varenicline group (57.8%) compared with the placebo group (49.7%). Rates of adverse events were similar in both groups.

"This suggests that varenicline is safe for use in these patients," writes Dr. Mark Eisenberg, Jewish General Hospital and McGill University, Montreal, Quebec, with coauthors. "However, new strategies for smoking cessation are still needed, given that 60% of smokers who received treatment with varenicline returned to smoking by one year after their acute coronary syndrome."

The authors note that if varenicline was used as routine treatment in smokers after heart attack, it would reduce smoking in this group by about 10%.

In a related commentary http://www.cmaj.ca/lookup/doi/10.1503/cmaj.180125 , Dr. Robert Reid, University of Ottawa Heart Institute and coauthors write, "Given the powerful effect of smoking cessation on subsequent cardiovascular morbidity and mortality, smoking cessation interventions including counselling and medications [such as varenicline], initiated in the hospital and integrated into post-discharge support, should be standard practice for patients with acute coronary syndrome receiving treatment at hospitals in Canada. Anything less reflects substandard care."

"Smoking abstinence 1 year after acute coronary syndrome: follow-up from a randomized controlled trial of varenicline in patients admitted to hospital" is published March 26, 2018.

Alexandria, VA, USA - At the 47th Annual Meeting of the American Association for Dental Research (AADR), held in conjunction with the 42nd Annual Meeting of the Canadian Association for Dental Research (CADR), Teresa A. Marshall, University of Iowa College of Dentistry, Iowa City, presented an oral session titled "Associations Between Longitudinal Beverage Intakes and Adolescent Caries." The AADR/CADR Annual Meeting is in Fort Lauderdale, Fla., USA from March 21-24, 2018.

"Sugar-sweetened beverages (SSB) are the most relevant dietary risk factor for caries in young children, but there has not been as much research done on adolescent caries. Our objective was to assess associations between longitudinal beverage intakes and adolescent caries experience, adjusting for known caries-preventive factors," said Marshall.

Area-under-the-curve daily beverage and fluoride intakes of Iowa Fluoride Study participants were calculated for ages 0.5-17 years from questionnaire-reported intakes of milk, 100% juice, sugar-sweetened beverages (SSB) and water-based sugar-free beverages. Dental exams were completed when the participant reached 17 years old.

The results show that higher SSB intake and lower brushing frequency were significant predictors of the caries. In multivariable models including all beverages, higher SSB and lower juice intakes were also significant predictors of caries.

"The observed associations of sugar-sweetened beverages and juice with caries are consistent with previous studies. The relationship between SSB and caries was reduced by tooth brushing and fluoride intake, and suggests an association between beverage intakes and oral health behaviors. To accurately estimate the effect of SSB on caries, future studies should adjust for preventive factors including brushing frequency and fluoride intake," said Marshall.