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.
Investigators at the National Institutes of Health have found that sesame allergy is common among children with other food allergies, occurring in an estimated 17% of this population. In addition, the scientists have found that sesame antibody testing — whose utility has been controversial — accurately predicts whether a child with food allergy is allergic to sesame. The research was published on Oct. 28 in the journal Pediatric Allergy and Immunology.
“It has been a challenge for clinicians and parents to determine if a child is truly allergic to sesame,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “Given how frequently sesame allergy occurs among children who are allergic to other foods, it is important to use caution to the extent possible when exposing these children to sesame.”
Sesame is among the 10 most common childhood food allergies. Only an estimated 20% to 30% of children with sesame allergy outgrow it. Severe reactions to sesame are common among sesame-allergic children. About 1.1 million people in the United States, or an estimated 0.23% of the U.S. population, have sesame allergy, according to a recently published study funded by NIAID. These factors underscore the need to optimize recognition and diagnosis of this allergy. The Food and Drug Administration is currently considering whether to include sesame in the list of allergens that must be disclosed on food labels.
Scientists hope findings mean vaccine supplies could stretch farther
A single dose of a highly diluted VSV-Ebola virus (EBOV) vaccine — approximately one-millionth of what is in the vaccine being used to help control the ongoing Ebola outbreak in the Democratic Republic of the Congo (DRC) — remains fully protective against disease in experimentally infected monkeys, according to National Institutes of Health scientists. The NIH investigators completed the vaccine dosage study using cynomolgus macaques and an updated vaccine component to match the EBOV Makona strain that circulated in West Africa from 2014-16. The study appears in Lancet’s EBioMedicine.
Nearly 250,000 people have received the investigational VSV-EBOV vaccine since August 2018 as part of a “ring vaccination” program to help stem the outbreak. The vaccine appears to be safe and highly effective. The manufacturer has announced that it has submitted a biologics license application to the U.S. Food and Drug Administration. VSV-EBOV is based on a live-attenuated vesicular stomatitis virus and delivers an EBOV protein to elicit protective immune responses. With the continued need to vaccinate individuals in the DRC and surrounding countries, a potential shortage of VSV-EBOV vaccine is a concern and further dose adjustment is a possible solution.
Scientists from NIH’s Rocky Mountain Laboratories (RML), part of the National Institute of Allergy and Infectious Diseases, tested several dosage strengths, including one with 10 million plaque-forming units (PFU). They determined that a vaccine with 10 PFUs was just as effective as the highest dose tested (a dose which was still lower than the one currently in use in the DRC). They vaccinated macaques 28 days prior to infecting them with a lethal dose of EBOV and then monitored the animals for 42 days after infection. Even the macaques given the lowest dose appeared completely protected from disease due to EBOV.
Samples of cerebrospinal fluid used to detect tauopathies
National Institutes of Health scientists have developed an ultrasensitive new test to detect abnormal forms of the protein tau associated with uncommon types of neurodegenerative diseases called tauopathies. As they describe in Acta Neuropathologica, this advance gives them hope of using cerebrospinal fluid, or CSF — an accessible patient sample — to diagnose these and perhaps other, more common neurological diseases, such as Alzheimer’s disease.
Scientists have linked the abnormal deposition of tau in the brain to at least 25 different neurodegenerative diseases. However, to accurately diagnose these diseases, brain tissue often must be analyzed after the patient has died.
For their study, the researchers used the same test concept they developed when using post-mortem brain tissue samples to detect the abnormal tau types associated with Pick disease, Alzheimer’s disease and chronic traumatic encephalopathy (CTE). They adapted the test to use CSF for the detection of abnormal tau of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other less common tauopathies.
Representative negative-stained transmission electron microscopy images of 4R RT-QuIC products seeded with brain homogenates from individuals with the designated diseases –frontotemporal dementia and Parkinsonism linked to chromosome 17; corticobasal degeneration; and progressive supranuclear palsy.
Tesamorelin prevented progression to liver fibrosis in NIH study
Researchers at the National Institutes of Health and their colleagues at Massachusetts General Hospital (MGH) in Boston report that the injectable hormone tesamorelin reduces liver fat and prevents liver fibrosis (scarring) in people living with HIV. The study was conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute, both parts of NIH. The findings were published online today in The Lancet HIV.
“Many people living with HIV have overcome significant obstacles to live longer, healthier lives, though many still experience liver disease,” said NIAID Director Anthony S. Fauci, M.D. “It is encouraging that tesamorelin, a drug already approved to treat other complications of HIV, may be effective in addressing non-alcoholic fatty liver disease.”
Non-alcoholic fatty liver disease, or NAFLD, frequently occurs alongside HIV, affecting as many as 25% of people living with HIV in the developed world. However, no effective treatments currently exist to treat the condition, which is a risk factor for progressive liver disease and liver cancer. Investigators led by Colleen M. Hadigan, M.D., senior research physician in NIAID’s Laboratory of Immunoregulation, and Steven K. Grinspoon, M.D., Chief of the Metabolism Unit at MGH, tested whether tesamorelin could decrease liver fat in men and women living with both HIV and NAFLD. Among the participants enrolled, 43% had at least mild fibrosis, and 33% met the diagnostic criteria for a more severe subset of NAFLD called nonalcoholic steatohepatitis (NASH). Thirty-one participants were randomized to receive daily 2-mg injections of tesamorelin, and 30 were randomized to receive identical-looking injections containing a placebo. Researchers provided nutritional counseling to all participants, as well as training in self-administering the daily injections. Researchers then compared measures of liver health in both groups at baseline and 12 months.
A microscopic image of liver tissue affected by non-alcoholic fatty liver disease (NAFLD). The large and small white spots are excess fat droplets filling liver cells (hepatocytes).
Research explores dual role of amygdala in regulating pain
A new study in mice uncovered a previously unknown role that the central amygdala can play in upgrading or downgrading pain signals in the brain’s circuitry. The study, published in Cell Reports, was conducted by researchers at the Division of Intramural Research at the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health.
"We know that pain is not static and that it can be modulated by several factors. Early research showed that the central amygdala, long known for its role in processing fear, can dial up pain signals. Yet, other studies have pointed to the central amygdala’s role in suppressing pain, or prompting an analgesic response,” said Yarimar Carrasquillo, Ph.D., senior author of the study and lead scientist for the Behavioral Neurocircuitry and Cellular Plasticity Section in the NCCIH Intramural Division. “This study unravels what seemed to be a contradiction in early research and reveals a previously hidden ‘switch’ in the central amygdala that can turn up or turn down pain signals.”
The “switch” acts more like a “pain rheostat,” similar to a home thermostat that modulates temperature — the pain rheostat reacts to pain signals to modulate pain sensations. In the mice, researchers found that activity in neurons that express protein kinase C-delta (CeA-PKCδ) turned up the pain rheostat and demonstrated an increase in pain-related responses. Conversely, researchers found that activity in neurons that express somatostatin (CeA-Som) turned down the pain rheostat, inhibiting nociception or the chain of activity in the nerves required to communicate pain.
Nerve-Injury-Induced ERK Activation and c-Fos Expression Is Preferentially Localized to CeA-PKCδ Neurons.
NIH study examines effects of blood vessel damage following brain injury
Using advanced imaging, researchers have uncovered new information regarding traumatic microbleeds, which appear as small, dark lesions on MRI scans after head injury but are typically too small to be detected on CT scans. The findings published in Brain suggest that traumatic microbleeds are a form of injury to brain blood vessels and may predict worse outcomes. The study was conducted in part by scientists at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
“Traumatic microbleeds may represent injury to blood vessels that occur following even minor head injury,” said Lawrence Latour, Ph.D., NINDS researcher and senior author of the study. “While we know that damage to brain cells can be devastating, the exact impact of this vascular injury following head trauma is uncertain and requires further study.”
This study, which involved researchers from Cold Spring Harbor Laboratory in New York and the Uniformed Services University of the Health Sciences in Bethesda, Maryland, included 439 adults who experienced head injury and were treated in the emergency department. The subjects underwent MRI scans within 48 hours of injury, and again during four subsequent visits. Participants also completed behavioral and outcome questionnaires.
The results showed that 31% of all study participants had evidence of microbleeds on their brain scans. More than half (58%) of participants with severe head injury showed microbleeds as did 27% of mild cases. The microbleeds appeared as either linear streaks or dotted, also referred to as punctate, lesions. The majority of patients who exhibited microbleeds had both types. The findings also revealed that the frontal lobes were the brain region most likely to show microbleeds.
Traumatic microbleeds appear as dark lesions on MRI scans and suggest damage to brain blood vessels after head injury.
IRP mouse study could prompt scientists to rethink how benzodiazepines work
Between 1999 and 2017, the United States experienced a 10-fold increase in the number of people who died from overdoses of Valium and other benzodiazepines. For years, scientists thought that these powerful sedatives, which are used to treat anxiety, muscle spasms, and sleeping disorders, worked alone to calm nerves. Now, in an article published in Science, researchers from the National Institutes of Health show that this view of the drugs and the neural circuits they affect may have to change. In a study of mice, scientists discovered that both may need the assistance of a ‘sticky’ gene, named after a mythological figure, called Shisa7.
“We found that Shisa7 plays a critical role in the regulation of inhibitory neural circuits and the sedative effects some benzodiazepines have on circuit activity,” said Wei Lu, Ph.D., a Stadtman Investigator at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We hope the results will help researchers design more effective treatments for a variety of neurological and neuropsychiatric disorders that are caused by problems with these circuits.”
Dr. Lu’s lab studies the genes and molecules used to control synapses; the trillions of communications points made between neurons throughout the nervous system. In this study, his team worked with researchers led by Chris J. McBain, Ph.D., senior investigator at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), to look at synapses that rely on the neurotransmitter gamma-aminobutyric acid (GABA) to calm nerves. Communication at these synapses happens when one neuron fires off packets of GABA molecules that are then quickly detected by proteins called GABA type A (GABAA) receptors on neighboring neurons.
In a study of mice, NIH researchers showed that a protein encoded by a gene called Shisa7 (green) may boost the nerve calming effects of valium and other benzodiazepines by sticking to GABA type A neurotransmitter receptors (red).
Strategy appears feasible for decontaminating hunting, meat processing equipment
A 5-minute soak in a 40% solution of household bleach decontaminated stainless steel wires coated with chronic wasting disease (CWD) prions, according to a new study by National Institutes of Health scientists. The scientists used the wires to model knives and saws that hunters and meat processors use when handling deer, elk and moose — all of which are susceptible to CWD. The research was conducted at Rocky Mountain Laboratories (RML) in Hamilton, Montana. RML is a component of the NIH’s National Institute of Allergy and Infectious Diseases. The findings are published in the open-access journal PLOS One.
CWD is a brain-damaging and fatal prion disease in cervids, members of the deer family. To date CWD has never been found in people. However, other prion diseases can affect people, therefore scientists, wildlife managers and public health agencies have suggested handling CWD cervid tissues with caution. CWD is spreading in North America, increasing the potential for human exposure. The disease has been found in cervids in 26 states and three Canadian provinces, as well as in Norway, Finland and South Korea. Not all animals infected with CWD will show signs of disease, but those that do appear weak and thin.
Infectious prions — types of proteins found in mammals that when misfolded can cause disease — are extremely difficult to inactivate, which led the scientists to seek a practical, low-cost CWD decontamination method. Bleach has been proven as a decontaminant against other types of prions but had never been tested against CWD.
‘Forward-oriented’ design might boost treatment effectiveness and broaden use
Researchers at the National Institutes of Health have developed a new and improved viral vector — a virus-based vehicle that delivers therapeutic genes — for use in gene therapy for sickle cell disease. In advanced lab tests using animal models, the new vector was up to 10 times more efficient at incorporating corrective genes into bone marrow stem cells than the conventional vectors currently used, and it had a carrying capacity of up to six times higher, the researchers report.
The development of the vector could make gene therapy for sickle cell disease much more effective and pave the way for wider use of it as a curative approach for the painful, life-threatening blood disorder. Sickle cell disease affects about 100,000 people in the United States and millions worldwide.
“Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease,” said study senior author John Tisdale, M.D., chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI). “It’s the new kid on the block and represents a substantial improvement in our ability to produce high capacity, high efficiency vectors for treating this devastating disorder.”
Diagram shows steps involved in conducting gene therapy for sickle cell disease.
A new study published this week online in Emerging Infectious Diseases suggests that transmission of a protozoan parasite from insects may also cause leishmaniasis-like symptoms in people. The parasite, however, does not respond to treatment with standard leishmaniasis drugs. The research was conducted by scientists at the Federal Universities of Sergipe and São Carlos, the University of São Paulo, and the Oswaldo Cruz Foundation, all in Brazil, along with investigators at the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health.
Leishmaniasis is a parasitic disease found in parts of the tropics, subtropics, and southern Europe. It is classified as a neglected tropical disease and is often transmitted by the bite of some sand flies. The most common forms of leishmaniasis are cutaneous, which causes skin sores, and visceral, which affects several internal organs (usually spleen, liver, and bone marrow). According to the World Health Organization, each year between 50,000 and 90,000 people become sick with visceral leishmaniasis (kala-azar), a form of the disease that attacks the internal organs and is fatal in more than 95 percent of cases left untreated. During the last several decades, researchers have described rare cases of patients co-infected with both Leishmania and other groups of protozoan parasites that usually infect insects, including Crithidia. The current study of parasites isolated from a Brazilian patient confirms that Crithidia parasites also can infect people.
A female Anopheles albimanus mosquito taking a blood meal. Some Crithidia parasites are known to parasitize anopheline mosquitoes. Photo credit: CDC/James Gathany.
