Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
Francisella tularensis is the bacterium that causes tularemia, a life-threatening disease spread to humans via contact with an infected animal or through mosquito, tick or deer fly bites. As few as 10 viable bacteria can cause the disease, which has a death rate of up to 60 percent. Scientists from the National Institute of Allergy and Infectious Diseases — part of the National Institutes of Health — have unraveled the process by which the bacteria cause disease. They found that F. tularensis tricks host cell mitochondria, which produce energy for the cell, in two different phases of infection. In the first eight hours of infection, the bacteria increase mitochondria function, which inhibits cell death and prevents the cell from mounting an inflammatory response to avoid an immune system attack. In the 24 hours after, the bacteria impair mitochondrial function, undergo explosive replication and spread. These basic science findings could play a role in developing effective treatment strategies, according to the researchers.
Previously, researchers discovered that F. tularensis could inhibit inflammation following infection of immune system cells called macrophages, but they did not understand how it occurred. The new study, published in Infection and Immunity, illuminates that process, confirming that the bacterium’s manipulation of the mitochondrial machinery in the host cell is required to block strong inflammatory responses. Also, the researchers show that the timing of the manipulation of the mitochondria machinery during infection is important to how the bacteria control host cell death. The researchers also said this could be the first study to show that a bacterium’s sugar-like protective outer capsule, or polysaccharide, can increase mitochondria function, in this case, during early infection.
Study yields potential clues to understanding eye disease and blindness in people
Loss of eye tissue in blind cavefish (Astyanax mexicanus), which occurs within a few days of their development, happens through epigenetic silencing of eye-related genes, according to a study led by the National Institutes of Health. Epigenetic regulation is a process where genes are turned off or on, typically in a reversible or temporary manner. This mechanism differs from genetic mutations, which are permanent changes in the DNA code. The study appears in Nature Ecology & Evolution.
“Subterranean animals provide a unique opportunity to study how animals thrive in extreme environments, some of which can mimic human disease conditions,” said Brant M. Weinstein, Ph.D., senior investigator at NIH’s Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD) and one of the study authors. “Many of the cavefish genes identified in our study are also linked to human eye disorders, suggesting these genes are conserved across evolution and may be similarly regulated in people.”
Photographs of Astyanax mexicanus, surface form with eyes (top) and cave form without eyes (bottom).
A new study published in the May 2018 issue of Preventive Medicine shows that African Americans and Latinos are significantly more likely to experience serious depression than Whites, but chronic stress does not seem to explain these differences. Dr. Eliseo J. Pérez-Stable, director of the National Institute on Minority Health and Health Disparities (NIMHD) was the senior author of the study, which also found that African Americans and Latinos were more likely to have higher levels of chronic stress and more unhealthy behaviors. NIMHD is part of the National Institutes of Health.
To examine the relationship between unhealthy behaviors, chronic stress, and risk of depression by race and ethnicity, researchers used data collected on 12,272 participants, aged 40 to 70 years, from 2005 to 2012. These data were part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative health interview and examination survey of U.S. adults. This age range population was selected for this study to capture the effects of chronic stress over the lifetime of the participants.
“Understanding the social and behavioral complexities associated with depression and unhealthy behaviors by race/ethnicity can help us understand how to best improve overall health,” said Pérez-Stable.
Researchers have shown that pain-induced changes in the rat brain’s opioid receptor system may explain the limited effectiveness of opioid therapy in chronic pain and may play a role in the depression that often accompanies it. These findings clearly show the impact of chronic pain on the brain and its relation to depression. The study, conducted by scientists at the National Institutes of Health (NIH) and colleagues from McGill University, Montreal, Quebec, Canada, was published in the journal Pain.
“We know that people with chronic pain have reduced availability of opioid receptors — the molecules opioid drugs bind to — in the brain,” said Mark Pitcher, Ph.D., visiting fellow in the Division of Intramural Research at the National Center for Complementary and Integrative Health (NCCIH) and one of the authors of the study. “What we haven’t known ― until now ― is why. Are there preexisting brain differences that might predispose some people to develop chronic pain? Or might chronic pain cause these differences? Our findings suggest that chronic pain itself is responsible.”
In the study, cross-sectional positron emission tomography (PET) imaging was performed on the brains of 17 rats that had undergone surgery to produce a nerve injury that causes chronic pain and on 17 rats that had undergone sham surgery (a similar procedure that does not cause chronic pain). Three months later, the availability of opioid receptors had decreased in multiple regions of the brain in the nerve-injured rats, but no changes had occurred in the sham-surgery rats.
Scientists have found a connection between bacteria in the gut and antitumor immune responses in the liver. Their study, published online May 24 in Science, was led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI). It showed that bacteria found in the gut of mice affect the liver’s antitumor immune function. The findings have implications for understanding the mechanisms that lead to liver cancer and for therapeutic approaches to treat them. NCI is part of the National Institutes of Health.
“What we found using different tumor models is that if you treat mice with antibiotics and thereby deplete certain bacteria, you can change the composition of immune cells of the liver, affecting tumor growth in the liver,” said Tim Greten, M.D., of NCI’s CCR, who led the study. “This is a great example of how what we learn from basic research can give us insight into cancer and possible treatments.”
The microbiome is the collection of bacteria and other microorganisms that live in or on the body. In humans, the greatest proportion of the body’s total microbiome is in the gut. Despite extensive research into the relationship between the gut microbiome and cancer, the role of gut bacteria in the formation of liver cancer has remained poorly understood.
Scientists developed monoclonal antibody from Ebola survivor
A first-in-human trial evaluating an experimental treatment for Ebola virus disease has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland. The Phase 1 clinical trial is examining the safety and tolerability of a single monoclonal antibody called mAb114, which was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and their collaborators. Investigators aim to enroll between 18 and 30 healthy volunteers aged 18 to 60. The trial will not expose participants to Ebola virus.
Ebola virus disease is a serious and often fatal illness that can cause fever, headache, muscle pain, weakness, fatigue, diarrhea, vomiting, stomach pain and hemorrhage (severe bleeding). It was first discovered in humans in 1976 in the Democratic Republic of the Congo (DRC) and has caused periodic cases and outbreaks in several African countries since then. The largest outbreak, which occurred in West Africa from 2014 to 2016, caused more than 28,600 infections and more than 11,300 deaths, according to the World Health Organization. In May 2018, the DRC reported an Ebola outbreak, located in Équateur Province in the northwest of the country. As of May 20, health officials have reported 51 probable or confirmed cases and 27 deaths. There are currently no licensed treatments available for Ebola virus disease, although multiple experimental therapies are being developed.
“We hope this trial will establish the safety of this experimental treatment for Ebola virus disease — an important first step in a larger evaluation process,” said NIAID Director Anthony S. Fauci, M.D. “Ebola is highly lethal, and reports of another outbreak in the DRC remind us that we urgently need Ebola treatments.”
NIH-funded study suggests need for more research into contributing factors; targeted interventions for children
New research suggests the suicide rate is roughly two times higher for black children ages 5-12 compared with white children of the same age group. The study, funded by the National Institute of Mental Health (NIMH), appears online May 21 in JAMA Pediatrics.
Suicide is a major public health problem and a leading cause of death in the United States. While suicide among young children is quite rare, it can be devastating to families, friends, and communities. Past patterns of national youth suicide rates revealed higher rates for white compared to black youth.
Jeffrey Bridge, Ph.D., of the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, Lisa Horowitz, Ph.D., of the NIMH Intramural Research Program, and coauthors set out to investigate race-related differences in suicide rates in youth overall. Using data from the Centers for Disease Control and Prevention’s Web-based Injury Statistics Query and Reporting System (WISQARS), which provides fatal and nonfatal injury, violent death, and cost-of-injury data, the team of researchers analyzed the data from 2001-2015 separately for children ages 5-12 and adolescents ages 13-17.
Squares indicate the estimated natural logarithm of the age-specific incidence rate ratio (IRR): Vertical lines, 94% CI. The reference group is white youth. The 95% CIs that do not include zero are considered to be statistically significant.
Gestational diabetes may predispose women to early-stage kidney damage, a precursor to chronic kidney disease, according to a study by researchers at the National Institutes of Health and other institutions. The study appears in Diabetes Care.
Gestational diabetes occurs only in pregnancy and results when the level of blood sugar is too high. The condition increases the risk for preterm birth and cesarean delivery, among other complications. Other forms of diabetes that occur outside of pregnancy are known to increase the risk for chronic kidney disease, in which the kidneys have difficulty filtering wastes from the blood. Few studies have investigated the potential link between gestational diabetes and chronic kidney disease.
“Our findings suggest that women who have had gestational diabetes may benefit from periodic checkups to detect early-stage kidney damage and receive subsequent treatment,” said the study’s senior author, Cuilin Zhang, M.D., M.P.H., Ph.D., of the Epidemiology Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Prion diseases are slow degenerative brain diseases that occur in people and various other mammals. No vaccines or treatments are available, and these diseases are almost always fatal. Scientists have found little evidence of a protective immune response to prion infections. Further, microglia — brain cells usually involved in the first level of host defense against infections of the brain — have been thought to worsen these diseases by secreting toxic molecules that can damage nerve cells.
Now, scientists have used an experimental drug, PLX5622, to test the role of microglia against scrapie, a prion disease of sheep. PLX5622 rapidly kills most of the microglia in the brain. When researchers gave the drug to mice infected with scrapie, microglia were eliminated and the mice died one month faster than did untreated mice. The results, published in the Journal of Virology by researchers from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, suggest that microglia can defend against a prion infection and thus slow the course of disease. The scientists hypothesize that microglia trap and destroy the aggregated prion proteins that cause brain damage.
The findings suggest that drugs that increase the helpful activity of microglia may have a role in slowing the progression of prion diseases. Researchers are now studying the details of how microglia may be able to destroy prions in the brain. The scientists note that microglia could have a similar beneficial effect on other neurodegenerative diseases associated with protein aggregation, such as Alzheimer’s disease and Parkinson’s disease.
Microglia, shown in green, are part of the immune response that protects the brain. They could play a role in slowing the progress of prion and other neurodegenerative diseases.
Researchers have identified a compound that blocks the spread of pancreatic and other cancers in various animal models. When cancer spreads from one part of the body to another in a process called metastasis, it can eventually grow beyond the reach of effective therapies. Now, there is a new plan of attack against this deadly process, thanks to scientists at the National Institutes of Health, Northwestern University and their collaborative research partners.
The team collaborated to identify a compound, which they named metarrestin, that stopped tumor metastasis in multiple animal models. Mice treated with metarrestin also had fewer tumors and lived longer than mice that did not receive treatment. These results were published May 16, 2018 in Science Translational Medicine.
“Many drugs are aimed at stopping cancer growth and killing cancer cells,” said co-author Juan Marugan, Ph.D., group leader of the NIH’s National Center for Advancing Translational Sciences (NCATS) Chemical Genomics Center. “However, there is no single approved drug specifically aimed at treating metastasis. Our results show metarrestin is a very promising agent that we should continue to investigate against metastasis.”
The compound metarrestin breaks down a component of cancer cells called the perinucleolar compartment (PNC). PNCs are found only in cancer cells, and in a greater number of cells in advanced cancer. In the four panels on the left, the green dots indicate the presence of PNCs in untreated pancreatic and metastatic liver tumors. On the right, treatment with metarrestin reduced the prevalence of PNCs.
