Estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote survival, resulting in reduced osteoclastic bone resorption and enhanced osteoblastic bone formation. Sema3A-activated sGC-cGMP signaling through Nrp1 protected osteocytes from apoptosis. Credit: Department of Cell Signaling,TMDU
Osteoporosis is a condition in which bones become weak and prone to fractures. Fractures typically occur in the wrist, spine or hip, and can often lead to permanently impaired mobility. Women over 50 are at a high risk of developing osteoporosis, which may be due to the loss of estrogen that occurs after menopause. While studies have linked estrogen levels to bone health, the exact details of this connection are not entirely clear. Researchers at Tokyo Medical and Dental University (TMDU) have described a new molecular link between estrogen and bone aging, which may eventually lead to new strategies to treat postmenopausal osteoporosis.
Bone is a complex tissue, consisting of a matrix of proteins and minerals that give it the flexibility and strength to support body movement. Bone also contains several types of specialized cells, including osteocytes, that help to maintain this matrix. Over a person’s lifetime, many factors can affect how healthy bone structure is maintained. One of these factors is the female sex hormone, estrogen.
“Over the last few decades, we’ve learned that estrogen plays an important role in maintaining a functional bone matrix,” corresponding authors Tomoki Nakashima and Hiroshi Takayanagi explain. “Exactly how estrogen does this, though, is not fully understood. Our laboratory recently discovered that bone matrix is maintained by a protein called Sema3A, which is secreted by osteocytes. This led us to suspect that there might be a mechanistic relationship between estrogen and Sema3A.”
Sema3A does, indeed, appear to be linked to estrogen. The researchers found that blood serum levels of the protein decrease in premenopausal women as they get older, and drop even further once women reach menopause. But how, at the biological level, are estrogen and Sema3A related? And what is Sema3A doing in bone tissue?
To answer these questions, the researchers turned to mice. Scientists know that after removing the ovaries of mice, subsequent estrogen loss causes their bone mass to decrease. This can be prevented, however, by giving the mice an extra supply of the hormone. The team took advantage of this to explore the function of Sema3A.
“When we genetically removed Sema3A from the osteoblast lineage cells (including osteocytes) of mice, we found that intravenous estrogen no longer prevented bones from deteriorating after an ovariectomy,” lead author Mikihito Hayashi says. “In addition, we found that Sema3A sets off a chain of signaling events that promote the survival of osteocytes in these mice. This suggests that Sema3A serves as a key mechanistic link between estrogen and bone maintenance. We believe that as women lose estrogen with age and Sema3A levels drop off, osteocytes begin to die and bone loses the ability to maintain its supportive structure.”
The researchers hope that the discovery of Sema3A as a major player in bone health and the signaling molecules it controls in bone may offer new therapeutic approaches to treating osteoporosis.
(HealthDay)—Of patients diagnosed with osteoporosis who have a history of hip fracture, only 14 percent are receiving appropriate calcium and vitamin D supplementation, according to a study presented at the annual meeting of the American Academy of Orthopaedic Surgeons, held from March 12 to 16 in Las Vegas.
Evan D. Nigh, of the University of Miami/Jackson Memorial Medical Center, and colleagues analyzed six years of data from the National Health and Nutrition Examination Survey (NHANES) to identify 1,065 patients who self-reported an osteoporosis diagnosis (87 percent female; mean age, 67 years). The authors evaluated dietary questionnaire and examination data for adequate calcium and vitamin D supplement intake, femoral neck bone mineral density, and a history of hip fracture.
The researchers found that 861 patients (80.8 percent) with osteoporosis were not receiving enough calcium and vitamin D supplementation (at least 1,000 mg of calcium and 600 international units of vitamin D). No significant link was seen between a history of hip fracture and appropriate treatment (OR, 0.685). In a subset analysis, 14 percent of patients were receiving enough calcium and vitamin D supplementation; only 26 percent of patients were taking adequate calcium and 32 percent were getting enough vitamin D. Factors linked to an increased likelihood of appropriate supplementation were female sex (OR, 2.354), older age (OR, 1.019), Caucasian race (OR, 1.456), and an osteoporosis diagnosis (OR, 1.651).
“While osteoporotic individuals are receiving calcium and vitamin D supplements at a higher rate than individuals without osteoporosis, our analysis of the NHANES database indicates that the majority of patients with osteoporosis are not receiving adequate therapeutic supplementation,” the authors write.
Wilson disease (copper storage disease) is a rare genetic disorder in which one or more genetic mutations disrupt copper metabolism in the liver. At some point, the liver becomes incapable of eliminating copper with bile, and copper accumulates in the liver, eyes and central nervous system. This results in serious liver damage and neurological problems inter alia. MedUni Vienna researchers led by hepatologist Peter Ferenci have now discovered that a recently described genetic mutation protects against fatty liver – apparently via vitamin A metabolism –and also ensures a better outcome for Wilson disease patients. In future, this finding could prove very useful in the personalised treatment of such patients.
The gene that has been identified is “HSD17B13,” which, according to Ferenci, plays an important role in vitamin A metabolism. Follow-up studies are planned to establish whether Wilson disease patients could benefit from this knowledge and potential treatment through the administration of vitamin A. Overall, this genetic mutation was found in every fourth person (around 26 percent). “We can assume that the HSD17B13 gene plays a critical role in the progression of Wilson disease,” explains Ferenci. “If patients do not have this mutation, their prognosis is poorer. So, in the spirit of precision medicine, we are able to predict much more accurately how the disease will progress.
In a highly regarded study published in Hepatology in 2018, the researchers showed that the protein ATP7B, known as the Wilson disease gene, and of which there are hundreds of mutations, did not provide any definitive information regarding prognosis.
Wilson disease can go undetected for years, and is usually discovered by accident. The age range is huge: The youngest known case in Vienna is a two-year-old child and the oldest patient was 74 years old. Even the symptoms are diverse: The disease can be symptomless for a long time or manifest in the form of severe liver damage, Kayser-Fleischer rings in the eyes (corneal changes) and neurological problems including movement disorders such as twitching or tremor in the limbs or even slurred speech and difficulty in swallowing. “In addition to that, there are often psychiatric disorders such as compulsive behaviours through to psychosis,” adds Ferenci.
Researchers of the University of Barcelona (UB) have used massive sequencing techniques with samples from patients to determine the evolution of the hepatitis A virus. The results, published in the journal EBioMedicine, show the presence of variants of the virus that could escape the effects of the vaccine. The study, led by the Research Group on Enteric Viruses of the UB, in collaboration with Vall d”Hebron Research Institute (VHIR) and the Public Health Agency of Barcelona (ASPB), has implications for vaccination policies.
Hepatitis A virus antigenic variants
Hepatitis A is a liver inflammation caused by a virus. Its symptomatology is minimal and can disappear after the first few weeks, but in some cases, the disease can last for months. Among the most affected groups are men who have sex with other men (MSM).
This study analysed samples from MSM patients, both vaccinated and non-vaccinated, who contracted the virus during an outbreak of hepatitis A in Barcelona (2016-2018). The objective was to study the evolution of the virus and check whether there are emerging variants that can escape the effects of the vaccine. “We identified antigenic variants in vaccinated and non-vaccinated patients, but only the former increase in number, which suggests the positive selection,” says Rosa Maria Pintó.
The appearance of hepatitis A virus antigenic variants could become a threat to public health and the use of available vaccines. “If we select a variant that escapes the vaccine, it could stop being effective. The study shows that, in cases such as the one that occurred due the lack of vaccines, this can happen,” says the researcher.
Reviewing vaccination practice
In some countries, controlling recent outbreaks of hepatitis A has been inhibited by the low coverage of vaccination and lack of vaccines, which made health administrations apply restrictions in the doses.
During the outbreak, these restrictions particularly affected people in the MSM group. “If a few doses of vaccination are given, or if the common doses were given long ago, or the vaccine is given to patients who caught the virus weeks ago, those variants of the virus that avoid the effects of the vaccine can be selected. This is especially relevant in the MSM group, since the virus dose through risky sexual practises is very high, and circulating antibodies are not enough to neutralize the inoculum or the first produced viruses,” says Rosa Maria Pintó.
Researchers therefore recommend giving two doses of the vaccine, and in some situations, suggest giving additional booster doses. Apart from specifying the vaccination protocol, the expert states they should “work in order to have easier-to-get vaccines so there are no vaccine shortages and doses do not have to be reduced.”
Dr. Michael Rieder, professor at Western University and scientist at Robarts Research Institute with his new rapid test kit for E. coli. Credit: University of Western Ontario
A new E.coli rapid testing kit developed by researchers at Western University is revolutionizing food safety testing by producing results within hours, not days – and ensuring contaminated food doesn’t make it to the produce aisle of your neighbourhood grocery store.
The kit detects E. coli 0157, the same food-borne bacteria causing the current outbreak in the US and Canada linked to romaine lettuce. The kit has been approved by Health Canada and translated for commercial use. The first production lot of this assay was last summer and this kit is now making its way to food processing plants in North America.
“Our goal is to get the testing to occur as close as possible to the source,” said Dr. Michael Rieder, professor at Western’s Schulich School of Medicine & Dentistry and scientist at Robarts Research Institute. “This technology is not only faster, but it’s less expensive, it’s easy to use, and it can occur right in the processing plant.”
Current food testing methods typically rely on culture, which requires samples to be sent away for testing, with results taking up to two weeks to come back. By that time, the food has often been shipped to market and large recalls have to occur.
The Western-developed kit detects a protein unique to the pathogenic E. coli bacteria, and using flow through technology is able show results in hours rather than days. The process works in much the same way as a pregnancy test – showing one line for negative and two lines for positive.
“We are looking at this specific biomarker because it is unique to this pathogenic bacteria. The presence of bacteria itself isn’t bad, but we want to be able to identify specific bacteria that will cause people to get sick,” Rieder said. “The goal is a safer food chain for everyone so that public safety can be assured.”
The system was developed as a result of collaborations between Dr. Rieder, a team at International Point of Care (IPOC), and London entrepreneurs, Craig Combe and the late Michael Brock. The commercialization and sale of the kits has been accomplished with industrial partners both in Canada and the United States. Much of the work was funded through grant from Mitacs, a federal non-profit that encourages academic and industrial collaboration.
Health officials say they’ve identified two new cases of children infected with adenovirus at a New Jersey pediatric health care facility.
The Voorhees Pediatric Facility near Philadelphia tells WPVI-TV Friday that brings the total number of infected patients to 12. Facility officials say there have been no related deaths and none of the patients are in critical condition.
At least 10 people died earlier this year after an outbreak of a different strain of adenovirus at Wanaque Center for Nursing and Rehabilitation in New Jersey in Haskell, about 100 miles(161 kilometers) away. There have been 28 cases associated with the respiratory virus at the center, where the affected children had severely compromised immune systems. One death was a young adult.
Officials have said there is no wider public health concern.
Ebola virus particles (red) on a larger cell. Credit: NIAID
The World Health Organization says a worrying number of the newest Ebola cases amid Congo’s ongoing outbreak are in patients not usually known to catch the disease: babies.
In an update published this week, the U.N. health agency reported 36 new confirmed cases of Ebola, including seven in newborn babies and infants younger than 2 years old. Six cases were reported in children aged between 2 and 17 and one case was in a pregnant woman.
While Ebola typically infects adults, as they are most likely to be exposed to the lethal virus, children have been known in some instances to catch the disease when they act as caregivers.
Few cases of Ebola in babies have been reported, but experts suspect transmission might happen via breast milk or close contact with infected parents. Ebola is typically spread by infected bodily fluids. WHO noted that health centers have been identified as a source of Ebola transmission, with injections of medications “a notable cause.”
WHO called Congo’s current epidemic “complex and challenging.” Congo’s health ministry says there are 346 confirmed cases, including 175 deaths, in what has become the worst Ebola outbreak in the country’s recorded history.
The outbreak has been plagued by security problems, with health workers attacked by rebels in districts where the virus has been spreading. Earlier this month, Ebola containment operations were paused after seven U.N. peacekeepers and 12 Congolese soldiers were killed, but all activities have resumed.
The increasing number of cases in children and health workers —39 health workers have been infected to date—suggests outbreak responders are having major problems stopping the virus in health clinics and convincing people to seek help when they develop symptoms. This is the first time this part of Congo has faced an Ebola outbreak.
WHO said the risk of the outbreak spreading to neighboring countries remains “very high” but it does not recommend travel restrictions. Uganda this month started vaccinating health workers against Ebola in a heavily traveled border district near the outbreak.
Gut-directed hypnotherapy delivered by psychologists appears as effective in group or individual sessions, potentially offering a new treatment option for irritable bowel syndrome in primary and secondary care.
Hypnotherapy might help relieve irritable bowel syndrome (IBS) complaints for some patients for as long as 9 months after the end of treatment, according to a randomised controlled trial of 354 adults with IBS in primary and secondary care published in The Lancet Gastroenterology & Hepatology journal.
After 3 months of treatment, adequate relief of IBS symptoms was reported by more patients who received individual (40%; 41/102 for whom data were available) and group hypnotherapy (33%; 31/91) than those given education and supportive care (17%; 6/35), and these benefits persisted at 9 months follow-up (42% [38/91], 50% [40/80], and 22% [7/31]).
Importantly, the findings suggest that group hypnotherapy is as effective as individual sessions, which could enable many more patients with IBS to be treated at reduced cost.
The study is the largest randomised trial of hypnotherapy for IBS to date, and one of the first conducted in primary care, where the vast majority of IBS patients are treated.
The study found that IBS patients undergoing hypnotherapy reported a greater overall improvement in their condition and were more able to cope with, and were less troubled by, their symptoms compared with those who received educational supportive therapy. However, hypnotherapy did not appear to reduce the severity of symptoms.
While the findings are promising, the authors conclude that more research will be needed to test the optimum number of hypnotherapy sessions, the effect that patient expectations may have on treatment outcome, and the extent to which hypnotherapy outcomes are influenced by the magnitude of the psychological complaints of the patient.
“Our study indicates that hypnotherapy could be considered as a treatment option for patients with IBS, irrespective of symptom severity and IBS subtype,” says Dr. Carla Flik from the University Medical Center Utrecht, Netherlands, who led the research. “It is also promising to see that group hypnotherapy is as effective as individual sessions, which may mean that more people could be treated with it at lower cost, should it be confirmed in further studies.”
“What’s striking about these findings is the extent to which patient’s perception of their illness has an effect on their suffering, and that their perception of symptoms appears to be as important as actual symptom severity.”
IBS affects around 1 in 5 people worldwide and is a persistent and difficult-to-treat condition, with symptoms that can seriously affect quality of life including abdominal pain, bloating, diarrhoea, and constipation. For many sufferers, drug and dietary treatments are not successful.
Psychological interventions have proven effective, but their use is limited by a shortage of trained therapists. Hypnotherapy has previously shown promising results for IBS, but the majority of studies have been done in highly specialised centres, and more research is needed into whether hypnotherapy is beneficial in primary and secondary care where most patients are treated.
The IMAGINE study recruited 354 adults (aged 18-65 years) with IBS who were referred by primary care physicians and hospital specialists to 11 hospitals across the Netherlands between May 2011 and April 2016. Participants were randomly assigned to receive either 45-minute individual sessions (150 patients) or group sessions (150) of hypnotherapy twice weekly for 6 weeks, or education and supportive care (54).
Hypnotherapy treatment was provided by psychologists who were trained as hypnotherapists and involved a technique of positive visualisation during which patients were given suggestions about how they could gain control over their digestive system to reduce feelings of pain and discomfort. Patients were also given a CD so they could practice self-hypnosis exercises at home for 15-20 minutes every day.
Participants completed assessments on their level of symptom severity, quality of life, psychological symptoms, health-care costs, and work absence at the start of the trial and immediately after treatment (3 months) and again 9 months later, as well as symptom relief immediately after treatment and 9 months later.
Results showed that immediately after treatment, participants in the two hypnotherapy groups reported satisfactory relief at substantially higher rates than those who received educational supportive care, and these benefits persisted for 9 months after the treatment ended (table 2).
Nevertheless, satisfactory relief of symptoms was not accompanied by a significant improvement in symptom severity.
As Dr. Flik explains: “We do not know exactly how gut-directed hypnotherapy works, but it may change patients’ mindset and internal coping mechanisms, enabling them to increase their control over autonomic body processes, such as how they process pain and modulate gut activity.”
Improvements in quality of life, psychological complaints, cognitions and reductions in medical costs and IBS-related work absence were similar between groups.
Overall, hypnotherapy was well tolerated. Eight serious unexpected adverse reactions (six in the individual hypnotherapy group and two in the group hypnotherapy group) were reported, mostly cancer and inflammatory bowel disease, but were not related to hypnotherapy.
The authors note some limitations—for instance, that 22 (15%) patients in the individual hypnotherapy group, 22 (15%) in the group hypnotherapy group, and 11 (20%) in the control group dropped out before or during therapy, and a substantial number of participants did not complete questionnaires at 3 months and 9 months after treatment, which might have biased the results (figure 1). They also point out that the inexperience of therapists in dealing with IBS, and the low number (six) of hypnotherapy sessions provided (half the usual number), might have led to underestimations of the effects of hypnotherapy.
Writing in a linked Comment, Professor Olafur Palsson, University of North Carolina at Chapel Hill, USA discusses factors that may have contributed to the “modest” therapeutic impact of hypnosis in the study.
He writes: “The hypnotherapy tested in this study might have been suboptimal in amount or implementation. However, as the authors note, the smaller therapeutic effect in this trial compared with most hypnotherapy trials in tertiary care might have been because IBS in primary and secondary care is different to that in tertiary care—perhaps simpler in nature and with less involvement of psychological factors. Therefore, despite this impressive investigative effort by Flik and colleagues, it remains unclear whether gut-directed hypnotherapy is well suited for the treatment of patients with IBS in primary and secondary care, and future trials are needed to provide definitive answers.”
An international study lead by University of Manchester scientists has discovered the identity of genes that predispose people to chronic kidney disease.
The discovery is a major advance in understanding of the significantly under-diagnosed disorder which, if left undetected, can lead to failing kidneys that need dialysis or kidney transplantation.
The discovery of 35 kidney genes is an important step forward to the future development of new diagnostic tests and treatments for the disease that affects around one in ten adults.
The team, based in Poland, Australia and the UK publish the Kidney Research UK funded study in Nature Communications today.
Lead researcher Professor Maciej Tomaszewski from The University of Manchester said: “Chronic kidney disease is known for its strong genetic component.
“Our limited knowledge of its exact genetic mechanisms partly explains why progress in the development of new diagnostic tests and treatments of chronic kidney disease has been so slow.
“The findings were made possible by using a state-of-the art technology known as “next-generation RNA sequencing” applied to one of the largest ever collections of human kidneys.
“We hope that some of the kidney genes we discovered may become attractive targets for the development of future diagnostics and treatment for patients with chronic kidney disease.”
Co-author Professor Adrian Woolf from Manchester Children’s Hospital and The Universality of Manchester said: “One of the genes—mucin-1- is especially interesting.
“It makes a sticky protein called mucin that coats urinary tubes inside the kidney. Mutations of this gene have already been found in rare families with inherited kidney failure”
Professor Fadi Charchar from Federation University Australia said: “We hope that early prediction by genetic testing even before the development of symptoms will in the future be the first line of defence against one of the world’s top killers.”
“Early detection followed by treatment using kidney-protective medication or avoidance of drugs which can damage the kidneys is the key to healthier kidneys later in life.”
Director of research operations at Kidney Research UK, Elaine Davies said: “Nearly 2 million people in the UK have been diagnosed with moderate-severe CKD by their GP but it is estimated that a further one million people remain undiagnosed. We refer to CKD as a silent killer because it is common for it to have little or no symptoms until the consequences of the disease have taken hold.
“The findings of this research are hugely important as they bring us a step closer to being able to understand, diagnose earlier and prevent kidney disease.”
Mosquitoes of the genus Anopheles are well known as primary vectors of malaria. But a new study suggests that Anopheles species, including some found in the United States, also are capable of carrying and transmitting an emerging pathogen, Mayaro virus, which has caused outbreaks of disease in South America and the Caribbean.
Mayaro virus—which can cause fever, joint aches, muscle pains, headache, eye pain, rash, nausea, vomiting and diarrhea—first was isolated from the blood of five symptomatic workers in Mayaro County, Trinidad, in 1954. Since then, it has caused sporadic outbreaks and small epidemics in several South and Central American countries.
In addition, imported cases may be on the rise, with several reported recently in the Netherlands, Germany, France and Switzerland, according to researchers.
“Because the symptoms of Mayaro infection are similar to those caused by other arboviruses [arthropod-borne virus] such as dengue and chikungunya, its prevalence in areas where these other viruses circulate may be higher than reported,” said the study’s senior author, Jason Rasgon, professor of entomology and disease epidemiology, College of Agricultural Sciences, Penn State.
Rasgon explained that Mayaro virus is thought to be transmitted primarily by canopy-dwelling mosquitoes of the genus Haemagogus. Human infections are sporadic, he said, because Haemagogus species tend to live in rural areas in proximity to forests—where they cycle the virus among nonhuman primates and birds—and do not typically prefer to feed on people. However, when the virus is introduced into urban areas, other mosquito species potentially could trigger epidemics in human populations.
“With the recent increase in imported cases, there are invasion concerns similar to those associated with Zika and chikungunya viruses,” Rasgon said. “But little is known about the range of mosquito species that are capable vectors of Mayaro, so our aim was to address that knowledge gap.”
In this study, the researchers tested six mosquito species—Aedes aegypti, Anopheles freeborni, An. gambiae, An. quadrimaculatus, An. stephensi and Culex quinquefasciatus—for their ability to transmit two strains of the Mayaro virus. The four Anopheles species were selected to cover different geographical regions: North America (An. freeborni and An. quadrimaculatus), Africa (An. gambiae) and Southeast Asia (An. stephensi).
Mosquitoes were allowed to feed on human blood spiked with the virus via a glass feeder. Researchers then assessed each species at seven and 14 days after infection to determine infection rate (rate of mosquitoes with infected bodies among those analyzed), dissemination rate (rate of mosquitoes with infected legs among those with positive bodies), transmission rate (rate of mosquitoes with infectious saliva among those with positive legs), and transmission efficiency (rate of mosquitoes with infectious saliva among the total number analyzed).
They found that Aedes aegypti and Culex quinquefasciatus were poor vectors of Mayaro virus, with either poor or null infection and transmission rates. However, the results, reported today (Nov. 7) in PLoS Neglected Tropical Diseases, demonstrated that all four Anopheles species were competent laboratory vectors of the virus.
“The capacity of the two North American species of Anopheles to transmit Mayaro is particularly relevant to the United States, because the estimated geographic distribution of these species covers the entire country,” Rasgon said.
“The transmission cycle of Mayaro involves mostly nonhuman primates and birds, although there is some evidence of circulation in rodents and marsupials,” he said. “We don’t know about the capacity of North American mammal species to act as vertebrate reservoirs, but it’s possible that Mayaro virus could be maintained in a human-mosquito-human urban cycle similar to what we’ve seen with chikungunya.”
In addition, the researchers noted, Anopheles mosquitoes tend to take multiple blood meals between egg-laying events, and this bite frequency increases their capacity to transmit viruses.
“Despite the fact that Anopheles mosquitoes are widely dispersed worldwide, they currently are neglected as potential vectors of arboviruses,” Rasgon said. “Our results suggest that Anophelesspecies may be important vectors driving the emergence and invasion of Mayaro virus across geographically diverse regions of the world, and more research is needed on their epidemiological role in virus invasions.”
Colorized scanning electron micrograph of Neisseria gonorrhoeae bacteria, which causes gonorrhea. Credit: NIAID
An investigational oral antibiotic called zoliflodacin was well-tolerated and successfully cured most cases of uncomplicated gonorrhea when tested in a Phase 2 multicenter clinical trial, according to findings published today in the New England Journal of Medicine. The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, sponsored the clinical study.
Gonorrhea is a common sexually transmitted disease (STD) that affects both men and women, particularly young people ages 15 to 24 years. Gonorrhea is the second most commonly reported notifiable disease in the United States. In 2017, more than 550,000 cases of gonorrhea were reported in the United States. If untreated, gonorrhea infection can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and an increased risk of HIV infection. Pregnant women can pass the infection to their babies, who can become blind or develop life-threatening infections as a result.
Gonorrhea is caused by the bacterium Nesseria gonorrhoeae, which has progressively developed resistance to each of the antimicrobials used to treat it. As a result, in 2015, the U.S. Centers for Disease Control and Prevention revised gonorrhea treatment guidelines to recommend dual therapy with injectable ceftriaxone and oral azithromycin to reduce the emergence of resistance to ceftriaxone.
Zoliflodacin (formerly known as ETX0914 and AZD0914), developed by Entasis Therapeutics based in Waltham, Mass., represents a new type of oral antibiotic that inhibits DNA synthesis in a different way than currently approved antibiotics.
“The rate of reported gonorrhea cases in the United States has increased 75 percent since the historic low in 2009, and antibiotic resistance has considerably reduced the number of treatment options for this disease,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging research findings published today suggest that zoliflodacin has the potential to be a useful and easy-to-administer oral antibiotic for treating gonorrhea.”
The study took place from November 2014 through December 2015 and was led by Stephanie N. Taylor, M.D., of Louisiana State University Health Sciences Center in New Orleans. Study investigators recruited patients from sexual health clinics there and in Seattle; Indianapolis, Indiana; Birmingham, Alabama; and Durham, N.C. The trial enrolled 179 participants (167 men and12 non-pregnant women) ages 18 to 55 years with either symptoms of uncomplicated urogenital gonorrhea, untreated urogenital gonorrhea or sexual contact with someone with gonorrhea within 14 days before enrollment. Participants were randomly selected to receive either a single 2 or 3-gram dose of oral zoliflodacin or a 500-milligram (mg) dose of injectable ceftriaxone. Among the 117 per-protocol participants who were evaluated six days after treatment, 98 percent (48 of 49 participants) of those who received the 2-gram zoliflodacin dose, 100 percent (47 of 47 participants) of those who received the 3-gram dose, and all (21 of 21) of the participants in the ceftriaxone group were considered cured of their urogenital gonorrhea based on culture results.
Zoliflodacin cured all rectal gonorrheal infections (4 of 4 participants who received the 2-gram dose and 6 of 6 participants who received the 3-gram dose) as did ceftriaxone (3 of 3 participants). However, the investigational drug did not fare as well in treating patients with gonorrhea infections of the throat (pharyngeal): 67 percent of volunteers who received the 2- gram dose (4 of 6 participants) and 78 percent of those who received the 3-gram dose (7 of 9 participants) were cured. All of the participants (4 of 4) in the ceftriaxone group achieved a cure.
The investigational antibiotic was well tolerated with transient gastrointestinal upset the most commonly reported adverse effect. Microbiological evaluation of post-treatment clinical isolates did not demonstrate resistance to zoliflodacin.
In March 2018, NIAID completed a study to evaluate zoliflodacin’s pharmacokinetics, safety and tolerability as a single oral dose to serve as a bridge from the Phase 2 clinical trial formulation to the final formulation for Phase 3 testing. Results from that study have not yet been made public. Additionally, in September 2018 NIAID launched a Phase 1 study to evaluate the investigational drug’s cardiac effects, a standard safety test for new drugs such as this.
Zoliflodacin has been awarded fast track status by the U.S. Food and Drug Administration for development as oral treatment for gonococcal infections. It is expected to begin Phase 3 testing in the Netherlands, South Africa, Thailand and the United States next year.
If you’ve ever visited the emergency department with appendicitis, or you’re one of the 100 million U.S. adults who suffer from chronic pain, you’re familiar with a row of numbered faces, with expressions from smiling to grimacing, used to indicate pain levels.
Despite that tool’s widespread use, some researchers say a more empirical approach would better serve both patients and the physicians who provide care.
“Sadly, this scale of smiley faces, called the visual analogue scale, is the gold-standard pain-assessment tool,” said Carl Saab, an associate professor of neuroscience and neurosurgery (research) at Brown University and Rhode Island Hospital. “Our goal is to associate specific brain activity with various scores on the numerical scale to make pain assessment more objective. We want to help patients with chronic pain and their physicians get into agreement about pain level so it is better managed and diagnosed, which may reduce the over-prescription of opioids.”
Saab and his colleagues have developed an electroencephalography-based test to objectively measure pain. Electroencephalography (EEG) is a method that measures brain activity using electrodes placed on the scalp. The brain activity is measured in the form of oscillations or “waves” of a certain frequency, somewhat like the specific frequency that dictates a radio station.
A frequency that correlates with pain in animals is called the “theta band,” Saab said. Computational analysis of theta brain waves to determine their power can be used to objectively measure pain in rodents and humans in a non-invasive manner, he added.
In a Nov. 6 paper published in Scientific Reports, Saab’s team reported that measuring the power of theta waves using EEG is an effective and direct test of pain and potential pain medication efficacy in pre-clinical animal models.
Testing new pain medications
The current method to measure pain, and the effectiveness of potential pain medications, in a pre-clinical animal model is to poke the animal’s paw and see how quickly it moves its paw away. Slow paw withdrawal is linked to less pain and better pain medication. Faster paw withdrawal is linked to more pain and less effective pain medication.
“When I was a graduate student, I hated this test because it had nothing to do with clinical pain,” said Saab, who is affiliated with Brown’s Carney Institute for Brain Science. “Nobody pokes a patient with back pain. I’m just so happy that I beat this test, now we’re working with something better.”
Since the EEG-based test is a more direct measure of ongoing, spontaneous pain than the current approach, it could help researchers develop more effective medications for chronic back pain or sciatica, which don’t have many effective treatments, Saab said.
In the paper, his team looked at three pain medications and compared their effectiveness in an animal model of sciatica. The researchers used the traditional behavior test, the EEG test and an analysis to determine blood concentration of the medications, which was compared with the clinical blood concentration of the medications in human patients.
The first medication they tested was a proven treatment for some forms of chronic pain, which is sold under the brand name Lyrica. The second was a promising pain medication in phase two clinical trials, and the third was a medication with inconclusive effectiveness in earlier studies.
Overall, the theta wave measurement and behavior test gave similar results, said Saab.
However, for a few of the experiments, such as a dose below the effective level of the first medication, the EEG test provided results that were more accurate—more similar to the results found in patients than the behavior test—said Saab. Specifically, the EEG test showed a decrease in theta power measurement at the clinical dose but not the low dose, while the behavior test showed slower paw withdrawal at the low dose and the clinical dose. By indicating pain relief at a dose lower than the effective dose, the behavior test gave a false positive.
“The ability to detect false positive or false negative outcomes is crucial to the drug development process,” the authors wrote. Saab believes that the EEG test can aid researchers in identifying false positives in pre-clinical trials of new pain medications, improving the development process.
Future impact of pain test
The ultimate goal of the research is an objective tool to measure pain for clinics and emergency departments. Toward this end, Saab is working to translate his findings to patients by calibrating the EGG signatures of pain with the traditional smiley-face-based pain assessment tool.
In addition to aiding the development of more effective pain medications and improving the diagnosis and management of chronic pain, both of which address contributing factors to the opioid epidemic, an objective measure of pain could improve health disparities, Saab said. These range from women whose pain is dismissed by medical practitioners to patients with difficulty communicating, including young children.
Three years ago, Saab launched a start-up company to develop the next generation of pain sensors, which he hopes can become the new gold standard for pain measurement. Saab added there’s considerable interest in a pain measurement tool for veterinary medicine.
Saab and Brown collaborators David Borton, an assistant professor of engineering, and Stephanie Jones, an associate professor of neuroscience, are working to understand the fundamental neuroscience of chronic pain and what kind of activity in the neurons produces the brain waves that constitute “signatures” of pain. In September, the team received a BRAIN grant from the National Institutes of Health to support this work.
Saab presented his findings on the EGG test to determine the effectiveness of new pain medications on Monday, Nov. 5, at the annual convention of the Society for Neuroscience in San Diego.
