Publisher Health

A WEHI-led study has identified a molecular ‘culprit’ responsible for causing damaging levels of cell death and inflammation in the body. The findings could lead to improved treatment options for a range of conditions driven by inflammatory cell death, including the SARS-CoV-2 virus.
Cell death is an important part of the body’s immune response to infection. When uncontrolled, however, it can cause harmful amounts of inflammation in otherwise healthy organs and tissue. The research team uncovered how an overproduction of the molecule nitric oxide, which the protein caspase-8 helps to produce, caused dangerous levels of cell death. They showed that arresting the function of caspase-8 could prevent unregulated cell death and inflammation.
Published in Immunity, the findings highlight the potential to create drugs that block caspase-8 and nitric oxide to prevent this novel inflammatory cell death process. Manipulating this cell death pathway could lead to new and improved treatments for people living with inflammatory disease.
The study was led by PhD student Daniel Simpson, Associate Professor James Vince and Dr Rebecca Feltham from WEHI, in collaboration with researchers from Monash University, Australian National University, the Hudson Institute of Medical Research and Germany’s Cologne University.
At a glance Nitric oxide and the protein that enables its production, caspase-8, have been shown to cause a unique form of cell death that can drive excessive levels of inflammation in the body. The team showed that blocking the activity of caspase-8 and nitric oxide in a preclinical SARS-CoV-2 model reduced the severity of inflammation and infection. The findings suggest targeting this novel cell death pathway could create new therapeutics for a range of diseases where damaging levels of nitric oxide, cell death and inflammation occur including asthma, inflammatory bowel disease and COVID-19.Killer culprit
While nitric oxide is critical to the body’s circulatory and nervous systems, the recent findings link an overproduction of the molecule with excessive levels of cell death and inflammation. Cell death is critical for a healthy immune response, however, too much of it can send the immune system into overdrive and trigger inflammatory disease.

A study led by A*STAR’s Genome Institute of Singapore (GIS) and Infectious Diseases Labs (ID Labs) has identified a gene, KCNJ15, that is associated with helping our immune system fight tuberculosis (TB), and potentially other infectious diseases. The research was published in Nature Microbiology on 31 January 2022.
The team used high-throughput genomic technologies to learn how the DNA packaging in blood cells changes when a person has active TB, a bacterial disease that killed one and a half million people globally in 2020. They discovered that TB patients had altered acetylation (a type of chemical modification within the cells) levels at thousands of DNA regions. Their goal was to identify which of these alterations will help to fight TB, and which will help the bacteria to grow.
They discovered that a gene, KCNJ15, which regulates intracellular potassium, was one of the weapons employed by the immune system to fight TB. It increases the level of potassium in the cell, which then causes the cell to self-destruct through a process called apoptosis. This reduces the ability of the bacteria to reproduce inside the cell. Further research could potentially lead to drug development targeting these potassium modulators, to add to the antibiotics currently used against infectious diseases, and may help in building the arsenal against antibiotic-resistant bacteria.
Dr Shyam Prabhakar, Associate Director of the Spatial and Single-Cell Systems, and Principal Investigator of the Laboratory of Systems Biology & Data Analytics at GIS, as well as corresponding author of the study, said, “Histone acetylation has been implicated by multiple studies in our immune response to TB and other infectious diseases. However, those studies did not examine the genome in detail to determine which specific parts were affected and to what extent. This is the first study to examine infection-associated histone acetylation changes genome-wide.”
Dr Amit Singhal, Principal Investigator at ID Labs, and co-corresponding author of the study, said, “Our study highlights how respiratory infections can affect the chromatin structure and transcriptional programme of host cells. These epigenetic alterations might play an essential role in the onset of various respiratory diseases including COVID-19 and can be exploited to develop therapeutic and prophylactic interventions.”
Prof Patrick Tan, Executive Director of GIS, said, “Proteins such as KCNJ15 could potentially play a role in protecting us from multiple infectious diseases. The success of this study should encourage researchers to perform similar analyses in other infectious diseases, and expand to inflammatory and autoimmune conditions such as type 1 diabetes and rheumatoid arthritis, among others. In addition, results indicate that the role of potassium channels in modulating infection may have been under-appreciated. This is a promising area for future molecular studies and potential drug development.”
Prof Lisa Ng, Executive Director of ID Labs, said, “TB is a global disease and with growing resistance to available antibiotics, the disease is becoming more deadly and difficult to treat. Since potassium channels are druggable, this study opens up a new avenue for research into host-directed therapies for TB and other respiratory diseases..”
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Developing therapies for genetic forms of blindness is extremely challenging, in part because they vary so widely, but scientists from Trinity College Dublin have highlighted a target with great promise for treating a range of these conditions.
The scientists have highlighted that a specific gene (SARM1) is a key driver in the damage that ultimately leads to impaired vision (and sometimes blindness), and — in a disease model — showed that deleting this gene protects vision after a chemical kick-starts the chain of dysfunction that mimics a host of ocular conditions.
This means that therapies targeting suppression of SARM1 activity may hold the key to effective new options for treating a suite of diseases that can have a devastating impact on quality of life, and for many of which there are no treatment options currently available.
The scientists, led by a team from Trinity’s School of Genetics and Microbiology, have just published their findings in the International Journal of Molecular Sciences.
First author on the paper, Laura Finnegan, a PhD Candidate at Trinity, said:
“In response to injury SARM1 contributes to a process that leads to the degeneration of specialised cells and their axons in the eye. When this happens it essentially means that the optic nerve can no longer deliver signals from the eye to the brain.
“Impaired vision and blindness is extremely debilitating for millions of people across the globe, which is one of the main motivations for us to seek to better understand the genetic causes and, potentially, develop life-changing therapies.”
Jane Farrar, Professor in Trinity’s School of Genetics and Microbiology, senior author on the paper, said:
“Another important finding was that visual function was still preserved when reassessed four months after SARM1 was deleted, indicating that the benefits can remain over time. This raises hopes that a targeted therapy delivered early enough may offer people diagnosed with an ocular neuropathy long-lasting preservation of sight.
“We have a way to go before such a therapy is available but this work represents a significant step, sheds light on the pathway forward and offers hope that a range of diseases involving the optic nerve — from maternally inherited conditions such as Leber Hereditary Optic Neuropathy to the more commonly known glaucoma — will one day be treatable via such therapies.”
The research is the result of collaboration between Professor Farrar’s lab in the School of Genetics and Microbiology and that of Professor Andrew Bowie’s in the School of Biochemistry and Immunology in the Trinity Biomedical Sciences Institute.
It was funded by the Irish Research Council, Science Foundation Ireland, the Health Research Board of Ireland and Fighting Blindness Ireland.
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An international team has discovered a protein that plays a key biological role in a parasite that causes malaria. Deactivating this protein reduces in vitro growth of Plasmodium falciparum, the protozoa behind the most virulent form of the disease, by more than 75%. The team, led by Professor Dave Richard of Université Laval, recently published details of the discovery in the scientific journal mBio.
“This breakthrough could lead to the development of a treatment that targets a function of the parasite that no malaria drug has yet exploited,” said Richard, professor in the Faculty of Medicine at Université Laval and researcher at CHU de Québec-Université Laval Research Centre.
Plasmodium falciparum is transmitted to humans through mosquito bites. After infecting the host’s liver it circulates in the blood, hiding inside red blood cells and thereby avoiding attacks from the immune system. The parasite’s main food source is hemoglobin, the protein that carries oxygen from the red blood cells to the rest of the body. The parasite digests the hemoglobin in structures called digestive vacuoles.
“The protein we discovered, PfPX1, is involved in transporting hemoglobin to these digestive vacuoles,” said Professor Richard. “When we deactivate PfPX1, we deprive the parasite of its main source of amino acids. This has an impact on its growth and survival.”
In light of these findings, Richard sees a potential new way to fight malaria: “We could block the parasite’s PfPX1 protein from performing its functions. Since the protein isn’t present in humans, there would be decreased risk of disrupting any important functions in the human body.”
Malaria continues to plague many parts of the world, including Sub-Saharan Africa. In 2020, 241 million people contracted malaria and 627,000 died from it. The disease mainly affects children under the age of five and pregnant women.
Although the World Health Organization recognized the first malaria vaccine last year, Richard thinks it is essential to continue exploring new therapeutic avenues: “As we have seen with COVID-19, new strains can continue to emerge and threaten the effectiveness of vaccines. What’s more, strains resistant to artemisinin, the main anti-parasite drug used against malaria, have already emerged in Southeast Asia. To maintain treatment efficacy and reduce the risk of new drug-resistant strains, it is important to combine therapeutic approaches, as we do with AIDS. Our discovery may well have a role to play in the fight against malaria.”
The authors of the mBio article are from Université Laval, Purdue University, the University of Alberta, the Biology Centre of the Czech Academy of Sciences, and the University of Notre Dame.
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Sweden is one of the few countries that have removed the dental health recommendation to give prophylactic antibiotics to people at a higher risk of infection of the heart valves, so-called infective endocarditis. Since the recommendation was removed in 2012, there has been no increase in this disease, a registry study from Karolinska Institutet published in the journal Clinical Infectious Diseases shows.
Infective endocarditis is a rare but life-threatening disease caused by bacterial infection of the heart valves that affects some 500 people a year in Sweden. Individuals with congenital heart disease, prosthetic heart valves or previous endocarditis are at higher risk of infection.
People at a higher risk of infective endocarditis in Sweden used to receive the antibiotic amoxicillin as a prophylactic ahead of certain dental procedures, such as tooth extraction, tartar scraping and surgery. This recommendation was lifted in 2012 due to a lack of evidence that the treatment was necessary and to help prevent antibiotic resistance by reducing antibiotic use. A collaborative project involving researchers from Karolinska Institutet has now studied how the decision has affected the incidence of infective endocarditis.
Supports the change in recommendation
“We can only see small, statistically non-significant variations in morbidity, nothing that indicates a rise in this infection in the risk group since 2012,” says the study’s corresponding author Niko Vähäsarja, dentist and doctoral student at the Department of Dental Medicine, Karolinska Institutet. “Our study therefore supports the change in recommendation. This is an internationally debated issue and Sweden and the UK are the only countries in Europe to restrict antibiotic use like this.”
The registry study encompassed 76,762 high-risk individuals and 396,048 individuals at a low risk of infective endocarditis, who were monitored from 2008 to 2018 with the help of the Medical Birth Registry, the National Patient Register and the Swedish Endocarditis Registry.
The recommendation was supplemented in 2016 with an instruction to consider prophylactic antibiotic treatment if prescribed by the patient’s doctor. It is unclear how this addition has influenced the prescription of antibiotics by dentists.
Reduction of amoxicillin prescriptions
After the change in recommendation in 2012, prescriptions of amoxicillin in dentistry declined by approximately 40 per cent. However, the study is unable to demonstrate that this was an effect of the amended recommendation and amoxicillin has other uses in dental medicine.
“The next step is to examine which dental procedures the individuals in the risk group underwent during the 2008-2018 period, since this is information we lack and it could add to our knowledge of what is to date a poorly studied issue,” says Mr Vähäsarja. “This and the study we’ve just published could inform similar recommendation changes in other countries, resulting in a reduction in antibiotic use.”
The study was financed by Karolinska Institutet, the Swedish Public Health Agency, Folktandvården Stockholm AB, the Steering Committee for Dental Research at Karolinska Institutet and Stockholm City and the Swedish Dental Association. There are no reported conflicts of interest.
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Juvenile fibromyalgia is a syndrome characterized by a chronic pain affecting the whole body. It also causes fatigue as well as sleep and mood disorders. It affects children and adolescents — mainly girls — worldwide and it appears during a critical period of the brain development. Analysing the brain changes that occur in the first stages of juvenile fibromyalgia could help to better understand the pathophysiology of this syndrome, which had not been approached from this perspective to date.
A study published in the journal Arthritis and Rheumatology characterizes for the first time the alterations in the grey matter volume in adolescents affected by juvenile fibromyalgia, and it analyses its functional and clinical relevance. The study contributes to identifying potential risk factors that will help testing the efficiency of different treatments to reverse these brain alterations. The new research is led by the postdoctoral researcher Maria Suñol and the lecturer Marina López Solà, from the research group Pain and Emotion Neuroscience Laboratory of the Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBNeuro) of the University of Barcelona.
The study, which applies several neurophysiology study techniques, counted on the participation of 34 adolescent girls affected by the pathology and a control group of 38 healthy adolescents. The new research has been carried out in collaboration with the professors Susmita Kashikar-Zuck and Robert Coghill, members of the Cincinnati Children’s Hospital (United States).
Juvenile fibromyalgia: brain, self-perception and emotions
The study reveals that the adolescents with juvenile fibromyalgia have less grey matter in the anterior-midcingulate cortex (MCC) region, a brain region which is decisive for pain processing. This feature could be related to the excessive engagement of brain circuits that process pain and it points out to the existence of a reorganization with these neuronal circuits.
The most affected patients by the pathology — and with more symptoms — also show an increase of volume in the frontal regions of the brain that is related to the creation of narratives about oneself and the emotional processing and regulation.
This increase in volume could reflect a certain immaturity in the process of the development of frontal circuits involved with emotion and language. “These findings strengthen the need to consider therapeutic strategies aimed at modulating the activity in these circuits in order to reverse the harmful narratives patients might feel about themselves,” notes Maria Suñol, first author of the study.
It also states that some brain alterations associated with related to juvenile fibromyalgia coincide with those identified in adult women with fibromyalgia. “This suggests that both syndromes share part of the pathophysiology,” notes the lecturer López Solà. “Therefore, it is important to promote the early and guided study of the pathology in adolescents in order to prevent the transition from juvenile to adult fibromyalgia.”
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Scientists have discovered that “rogue” antibodies found circulating in the blood of COVID-19 patients have the potential to cause cells to lose their resistance to clotting.
Researchers at Michigan Medicine and the National Heart, Lung, and Blood Institute studied the blood samples of nearly 250 patients hospitalized for COVID-19. They found higher-than-expected levels of antiphospholipid autoantibodies, which can trigger blood clots in the arteries and veins of patients with autoimmune disorders, including lupus and antiphospholipid syndrome.
Antibodies typically help the body neutralize infections. Autoantibodies are antibodies produced by the immune system that mistakenly target and sometimes damage the body’s own systems and organs.
In a 2020 study, the research group found that autoantibodies from patients with active COVID-19 infections caused “a striking amount of clotting” in mice. In the new study they uncover the possible reason: the autoantibodies appear to stress the endothelial cells that make up the inner lining of blood vessels and, in doing so, cause the cells to lose their ability to prevent blood clots from forming. The results are published in Arthritis & Rheumatology.
“This provides an even stronger connection between autoantibody formation and clotting in COVID-19,” said Hui Shi, M.D., Ph.D., lead author of the paper and rheumatology research fellow at Michigan Medicine. “When endothelial cells are activated, they cause healthy blood vessels to become ‘sticky,’ attracting other cells to the vessel walls and becoming more prone to thrombosis. This can affect many of the body’s essential organs.”
The researchers found that when they removed the antiphospholipid autoantibodies from COVID-19 blood samples, the endothelial cell activation that promotes clotting was lost. While the link is strong, future studies must be done to find whether these autoantibodies are the precise cause of thrombosis that contributes to clotting and increased severity of COVID-19, says Jason Knight, M.D., Ph.D., co-author of the study and associate professor of rheumatology at Michigan Medicine.
“We must do more research to decide if it is beneficial to screen patients with severe COVID-19 for these autoantibodies to evaluate their risk of clotting and progressive respiratory failure,” Knight said. “Eventually, we may be able to repurpose treatments used in traditional cases of antiphospholipid syndrome for COVID-19. This is a further step towards a full understanding of the interplay between coronavirus infection, the human immune system and vascular health.”
Additional authors include Yu (Ray) Zuo, M.D., Sherwin Navaz, B.S., Alyssa Harbaugh, B.S., Claire Hoy, B.S., Alex Gandhi, M.S., Gautam Sule, Ph.D., Srilakshmi Yalavarthi, M.S., Kelsey Gockman, Jacqueline Madison, M.D., Melanie Zuo, M.D., Michael Maile, M.D., all of Michigan Medicine, as well as Jinato Wang, NHLBI, Yue Shi, Shanghai University of Sport, Yogendra Kanthi, M.D., NHLBI
This work was supported by a grant from the Rheumatology Research Foundation.

After the first person known to have become infected with the Omicron variant in the United States was revealed to have attended a 53,000-person anime convention in Manhattan, concerns quickly mounted that the event had sown the seeds of a major coronavirus outbreak.But a new study released on Thursday by the Centers for Disease Control and Prevention suggested that a combination of good air filtration, widespread vaccination and indoor masking had in fact helped prevent the anime convention in November from becoming a superspreader event.The share of attendee tests that came back positive was similar to the share of coronavirus tests that were positive across New York City around the same time, the C.D.C. said. What’s more, the few positive samples that were genetically sequenced were largely of the Delta variant, not Omicron.And conventiongoers who became infected were more likely than those who tested negative to have gone to bars, nightclubs or karaoke clubs.Still, the C.D.C. said that the virus’s spread at the convention could have been much worse had it been held after Omicron became dominant in the city, given that the variant is so contagious and capable of spreading among the vaccinated. At the anime convention, the C.D.C. said in a separate report on Thursday, the only documented Omicron infections were in a single cluster of at least 16 positive cases.The first study relied largely on people who came forward for testing after the event, which introduced potential biases: Those people could have been more cautious than the average convention attendee, or more inclined to report cautious behaviors. Health officials had urged attendees to get tested. The C.D.C. could only look for cases among people on a registration list of ticket buyers, which did not account for the full number of attendees.The agency’s findings matched those of New York City contact tracing officials, who said in early December that they had not found signs of widespread transmission at the anime convention.In the aftermath of the event, held at the sprawling Javits Center, the convention organizers came under scrutiny as people reported seeing attendees flouting masking rules and pushing past checkpoints.But among attendees who were tested, the C.D.C. said, “evidence of widespread transmission during the event was not identified.”The study drew on test results identified through health department surveillance systems for 4,560 attendees. Of those, 119 people — 2.6 percent — tested positive. Researchers also sent online surveys to attendees asking about their test results, symptoms and activities during the convention.The anime convention required attendees to have received at least one vaccine dose. The C.D.C. said that among attendees who could be matched with test and vaccination data in health department surveillance systems, 85 percent had completed their primary vaccination series, another 12 percent had received a booster dose and 3 percent were partly vaccinated.The C.D.C. study also credited the convention hall for being outfitted with HEPA filters, which have been shown to efficiently remove coronavirus particles from the air.

Children with insomnia symptoms are likely to persist with them as young adults and are significantly more likely to develop an insomnia disorder in early adulthood compared to children who do not have difficulty sleeping, according to new research led by scientists at Penn State College of Medicine. The study is the first long-term cohort study to describe the developmental trajectories of childhood insomnia symptoms through adolescence and into young adulthood.
“Young adulthood is a stage in life where there is a documented increase in the severity and prevalence of physical and mental health problems, such as cardiovascular disease and suicide rates,” said Julio Fernandez-Mendoza, associate professor of psychiatry and behavioral health. “Sleep disorders — especially sleep apnea and insomnia — are linked with poorer cardiovascular and mental health. Given that up to 25% of children, 35% of adolescents and 45% of young adults suffer from insomnia symptoms, we were interested in learning how these symptoms evolve over time as the child grows into adulthood.”
The team’s longitudinal study, which began in the year 2000, was designed as a random, population-based study of children, ages 5-12 years. Children and their parents provided reports of the children’s insomnia symptoms — defined as moderate-to-severe difficulties initiating and/or maintaining sleep. The children also participated in an objective in-laboratory sleep study using polysomnography, which can identify sleep apnea and other indicators such as the amount and quality of sleep. The team studied 502 children 7.4 years later as adolescents (median 16 years old) and 15 years later as young adults (median 24 years old).
The team found that 43% of children with insomnia symptoms continued to suffer through adolescence into adulthood. Although about 27% of children with insomnia symptoms experienced remission of symptoms by adolescence, close to 19% experienced a waxing and waning pattern into adulthood. Among children without insomnia symptoms, about 15% of them developed insomnia symptoms in the transition to adolescence and persisted with them into adulthood, and another 21% newly developed them in young adulthood. In addition, about 16% of these children without insomnia symptoms experienced a waxing-and-waning pattern.
“We know that not everyone who complains of insomnia symptoms has the same degree of sleep disturbance when sleep is measured objectively in the laboratory, so it was important that our study included these objective in-lab measurements in addition to the self-reports,” said Fernandez-Mendoza. “Indeed, the study found that insomnia symptoms in adolescents who slept short in the lab were 5.5 times more likely to worsen into adult insomnia, while those who reported the same insomnia symptoms and slept normally in the lab were not at increased risk of worsening into adult insomnia.
The results published today (Feb. 16) in the journal Pediatrics.

A new review of COVID-19 hospitalization data by researchers at The University of Toledo has found that taking immune-boosting supplements such as vitamin C , vitamin D and zinc do not lessen your chance of dying from COVID-19.
Early in the pandemic, healthcare providers tried a variety of micronutrients as potential therapies for the new illness. More recently, supplements have been promoted by some as an alternative to the safe and proven vaccines.
However, Dr. Azizullah Beran said there’s been little evidence those strategies work, despite the enduring interest in them.
“A lot of people have this misconception that if you load up on zinc, vitamin D or vitamin C, it can help the clinical outcome of COVID-19,” said Beran, an internal medicine resident at The University of Toledo College of Medicine and Life Sciences. “That hasn’t been shown to be true.”
Beran is the lead author on a new paper that significantly strengthens the emerging medical consensus that micronutrient supplements are not an effective treatment for COVID-19.
He and his collaborators reviewed 26 peer-reviewed studies from around the globe that included more than 5,600 hospitalized COVID-19 patients. Their analysis found no reduction in mortality for those being treated with vitamin D, vitamin C or zinc compared to patients who did not receive one of those three supplements.