Month: November 2023

Categories : Cardiovascular Disease GeneticsTags :

A Single Gene-editing Infusion may Control Inherited High LDL Cholesterol

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

A single infusion of a CRISPR-based gene-editing therapy significantly reduced low-density lipoprotein cholesterol (LDL-C, the ‘bad cholesterol’) in people who carry one gene for the inherited condition that results in very high LDL-C levels and a high risk of heart attack at an early age, according to findings presented at the American Heart Association’s Scientific Sessions 2023.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option – a single-course therapy that may lead to deep LDL-C lowering for decades,” said senior study author Andrew M. Bellinger, M.D., Ph.D., chief scientific officer at Verve Therapeutics in Boston.

The investigational treatment, VERVE-101, uses DNA-editing technology to permanently turn off the PCSK9 gene in the liver. PCSK9 is a gene that plays a critical role in controlling blood LDL-C through its regulation of the LDL receptor. People with heterozygous familial hypercholesterolaemia (ie, one gene for the disorder inherited from one parent) are treated with oral lipid-lowering medications such as statins as well as PCSK9 inhibitors to bring levels under control, though this only occurs in a small percentage of patients. The study presented is the first human trial of VERVE-101.

Earlier this year, the results of the researchers’ one-year animal study were published in Circulation. In that animal study, VERVE-101 lowered PSCK9 levels 67%-83% and LDL-C 49%-69%, depending on the dose. After a single dose, the reductions have now lasted 2.5 years, supporting the idea that VERVE-101 may potentially be an effective long-term or permanent treatment for high LDL-C.

The ongoing, first-in-human study included 7 men and 2 women in New Zealand or the United Kingdom: average age of 54 years; 8 white adults; and 1 Asian adult. Each participant was diagnosed with heterozygous familial hypercholesterolemia and had extremely high bad cholesterol levels (average measure of 201mg/dL) despite taking the maximum-tolerated LDL cholesterol-lowering medication.

“These numbers are consistent with the fact that, despite available treatments, only about 3% of patients living with heterozygous familial hypercholesterolemia globally have reached target treatment goals,” Bellinger said.

The majority of study participants had pre-existing severe coronary artery disease and had already experienced a heart attack, or undergone coronary bypass surgery or stenting to allow adequate blood flow to heart muscle. None were taking PCSK9 inhibitors while enrolled in the study.

Each participant received a single intravenous infusion of VERVE-101, with the first cohort (n=3) receiving a low dose of 0.1 mg/kg and other cohorts receiving escalating doses, after consultation with an independent safety monitoring board. The highest dose received was 0.6 mg/kg.

The study found that the highest-two VERVE-101 doses:

  • reduced LDL-C by 39% and 48% in the two participants receiving 0.45mg/kg of the drug and 55% in the sole participant receiving 0.6mg/kg;
  • reduced blood PCSK9 protein levels by 47%, 59% and 84% in the three participants receiving the 0.45 mg/kg or 0.6 mg/kg doses; and
  • reduced LDL-C at six months in the sole participant receiving 0.6mg/kg, with follow-up ongoing.

“We were thrilled to see that the previous testing we had done of VERVE-101 in animal models translated faithfully to these findings in humans,” Bellinger said.

Most adverse events encountered were mild and unrelated to treatment. Serious adverse cardiovascular events, specifically a cardiac arrest, a myocardial infarction and an arrhythmia, occurred in two patients who had underlying advanced coronary artery disease. “All safety events were reviewed with the independent data safety monitoring board, who recommended continuation of trial enrolment with no protocol changes required,” Bellinger said.

Studies involving a larger number of patients and with a control group will be required to fully document the efficacy and safety of VERVE-101, noted Bellinger.

The study is still enrolling patients to receive the highest-two doses of VERVE-101. After a year’s follow-up, each participant will go into a long-term follow-up study for an additional 14 years, as required by the FDA for all participants in any human genome editing trials.

Among the study’s limitations is that this is an interim report with a few participants who all received the treatment; therefore, no participants receiving an alternate treatment or no treatment were available for direct comparison. Results in the study were measured by reductions in LDL-C, not changes in the occurrence of heart attacks; however, LDL-C reduction is a well-known, validated endpoint among patients with heterozygous familial hypercholesterolaemia and coronary artery disease.

Source: American Heart Assoication

Categories : Cardiovascular Disease Diet and NutritionTags :

Cholesterol Discovery could Lead to New Therapies to Prevent Cardiovascular Disease

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Source: CC0

Researchers at the University of Leicester have discovered the mechanism by which cholesterol in the diet is absorbed into cells. This discovery, which has just been published in the journal Science opens up new opportunities for therapeutic intervention to control cholesterol uptake that could complement other therapies and potentially save lives.

The research, conducted with colleagues from the USA, China and Australia, has shown that two proteins (called Aster B and Aster C) play a key role in transporting cholesterol from the membrane of the cells lining our intestine to the internal compartment where it is modified prior to circulation.

Funding came from the Leducq Foundation which awarded $6 million to eight laboratories across the USA and Europe for collaborative research into how cholesterol is transported in our bodies.

University of Leicester researchers from the Institute of Structural and Chemical Biology, used their expertise to reveal how Ezetimibe, a cholesterol lowering drug, blocks the ability of Aster B and C to transport cholesterol.

Professor John Schwabe, Director of the Institute for Structural and Chemical Biology, said: “This breakthrough is the result of a long-lasting collaboration and forms part of an international effort to identify ways in which we can combat cardiovascular disease and stroke. A better understanding of important areas of cholesterol absorption and metabolism and, particularly, how cholesterol moves within cells and tissues is essential. This knowledge will allow us to design new drugs and therapies that target specific proteins involved in these pathways to combat most pressing public health problems such as heart attacks and stroke.

Professor Schwabe added: “If we can prevent some cholesterol from being absorbed into our cells, we may ultimately be able to prevent individuals from having high cholesterol and cut down their risks of heart attack and stroke and therefore potentially save lives.

“The Leducq team of experts have different expertise that is used to target the problem at different levels and following different approaches. In addition to target cholesterol absorption, we are trying to identify how cholesterol metabolism and transport affect cholesterol levels and atherosclerotic disease. Cholesterol transporters are essential to regulate blood cholesterol levels therefore we are testing small molecules that influence the function of these transporters in order to develop drugs that ultimately lower the risk for heart attack and stroke.”

Postdoctoral Researcher, Dr Beatriz Romartinez-Alonso, added: “This has been a great project to work on – discovering new science highly relevant to human health.”

Source: University of Leicester

Categories : Diseases, Syndromes and ConditionsTags :

Obinutuzumab Reduces Lupus Kidney Flareups and Preserves Function

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Photo by Robina Weermeijer on Unsplash

In a post hoc analysis of the phase 2 NOBILITY trial, researchers found that treatment with obinutuzumab was superior to placebo for preserving kidney function and preventing flares in patients with lupus nephritis, a kidney condition associated with the autoimmune disease lupus.

Obinutuzumab is a recombinant, humanised type II anti-CD20 IgG1 monoclonal antibody glycoengineered to enhance antibody-dependent cell-mediated cytotoxicity and phagocytosis.

In the analysis, which is published in Arthritis & Rheumatology, compared with standard-of-care treatment alone, the addition of obinutuzumab to lupus nephritis treatment reduced the risk of developing a composite outcome of death, fall in kidney function, or treatment failure by 60%. Adding obinutuzumab also reduced the risk of lupus nephritis relapses by 57% and significantly decreased the rate of decline in kidney function over the trial’s two years duration.    

Overall, 38% of obinutuzumab-treated patients compared with 16% of placebo-treated patients achieved a complete remission of lupus nephritis by week 76, with the need for fewer glucocorticoids.   

“These data are really important because the ultimate goal of lupus nephritis therapy is to preserve kidney survival so patients never have to face the need for dialysis or transplantation because their kidneys failed,” said corresponding author Brad Rovin, MD, of Ohio State University Wexner Medical Center. “The addition of obinutuzumab to standard lupus nephritis therapy may increase the likelihood of achieving this goal.”

Source: Wiley

Categories : Cardiovascular DiseaseTags :

Experimental Drug Slashes Levels of Lipoprotein(a) by 94% in Early Trial

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Image by Scientific Animations, CC4.0

Findings from a phase 1 trial reported by a Cleveland Clinic physician show that a single dose of an experimental therapy produced greater than 94% reductions in blood levels of lipoprotein(a), a key cardiovascular risk driver, with the results lasting for nearly a year. 

The findings were presented at the American Heart Association’s Scientific Sessions 2023 and simultaneously published in the Journal of the American Medical Association.  

Lipoprotein(a), or Lp(a), is made in the liver and has similarities to low-density lipoprotein (LDL). Unlike other types of cholesterol particles, Lp(a) levels are 80–90% genetically determined. The structure of the Lp(a) particle causes atherosclerosis, which greatly increases the risk of heart attacks and strokes. 

Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved drug treatments to lower Lp(a). Since Lp(a) levels are genetically determined, lifestyle changes such as diet or exercise have no effect. 

In the trial, participants who received an injection of lepodisiran had lipoprotein(a) levels reduced by the top dose as much as 96% within two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to manufacture a key component of lipoprotein(a) in the liver. 

The findings add lepodisiran to the growing list of therapies that could be promising treatments for atherosclerotic cardiovascular diseases in people with high levels of Lp(a), which is estimated to affect a fifth of the global population.   

“These results showed that this therapy was well tolerated and produced very long-duration reductions in Lp(a), an important risk factor that leads to heart attack, stroke and aortic stenosis,” said lead author Steven Nissen, MD, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic.  

In the trial, researchers enrolled 48 patients in the US and Singapore, average age 47. Investigators studied six different dosages and a placebo, which were all administered as injections. Participants were monitored for up to 48 weeks after administration.   

Maximum Lp(a) plasma concentrations were reduced by 49% from baseline levels for the 4mg dose and up to 96% for the 608mg dose vs a 5% decrease for the placebo. No safety issues were observed, and the only tolerability issue was mild injection site reactions. 

“Despite the strong evidence of the importance of elevated Lp(a) as a risk factor for heart disease, effective treatment has been elusive,” commented Dr Nissen. “This approach to treatment gives hope to the 20% of the world’s population who have elevated Lp(a) levels.” 

A phase 2 trial studying lepodisiran is currently underway. The trial was sponsored by Eli Lilly and Company (Lilly), the company developing lepodisiran. 

Source: Cleveland Clinic

Categories : Diseases, Syndromes and Conditions General InterestTags :

H3D’s Pioneering Research Adds Hope to the Fight against Malaria 

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Members of the University of Cape Town’s Holistic Drug Discovery and Development Centre H3D

A formidable disease that has plagued humanity for centuries, malaria has exacted a heavy toll on human lives, disrupting communities and hindering socio-economic progress across some of the most vulnerable regions of the world, particularly the African continent.  

With its stealthy transmission through the bites of infected mosquitoes, malaria has earned the dubious reputation of being one of the deadliest vector-borne diseases on the planet. So much so that the World Health Organization’s World Malaria Report reveals that malaria cases are on the rise, with instances rising from 245 million cases in 2020 to over 247 million a year later1. 

With an estimated 619,000 people succumbing to the disease in 20211, it remains a defining challenge for global healthcare systems. However, through the unyielding persistence and spirit of medical innovation and scientific ingenuity exemplified by research facilities such as the University of Cape Town’s Holistic Drug Discovery and Development Centre (H3D), solutions to mitigate the severity of malaria are on the horizon.  

“As the first and only integrated drug discovery platform on the African continent, H3D’s mission is to discover and develop innovative life-saving medicines for diseases that predominantly affect African patients,” explains Bada Pharasi, CEO of the Innovative Pharmaceutical Association of South Africa (IPASA).

H3D’s focus on building Africa-specific models aims to improve treatment outcomes in African patients and to educate and train a critical mass of skilled African-based drug discovery scientists. H3D’s scientific output and research model includes attracting international investment in local innovative pharmaceutical research and development (R&D) across the African continent to address the disproportionately high global disease burden. Importantly, H3D targets critical infectious diseases, including tuberculosis, antibiotic-resistant microbial diseases, and malaria. 

“Given the vulnerability of many of the African populations, the continent accounted for 95% of malaria cases and 96% of malaria deaths in 20211. Accordingly, continued antimalarial drug research and development, such as the studies conducted by H3D, is important to prevent and treat the millions of cases that arise each year, all of which have consequences on both the health and socioeconomic development of the continent,” adds Pharasi.

Since the official launch of H3D’s programs in April 2011, there have been notable advances in innovative drug discovery projects. The centre has demonstrated a strong track record with multiple chemical series discovered and being progressed at H3D in each stage of the drug development pipeline.

A significant achievement reached by H3D was the discovery of the malaria clinical candidate, MMV390048, which reached phase II human trials in African patients. This was the first ever small molecule clinical candidate, for any disease, researched on African soil by an African drug discovery research unit. 

According to Dr Candice Soares de Melo, Chief Investigator at H3D, the centre’s current anti-malarial programmes will focus on the identification of quality leads suitable for optimisation and candidate selection as potential agents for the treatment of uncomplicated Plasmodium falciparum malaria, ideally with additional activity against liver-stage parasites to offer protection and prevent relapses (in case of malaria caused by the species Plasmodium vivax), as well as blocking the transmission of the disease. 

“A critical component of the research conducted at H3D is to develop medicines that are safe and sufficiently tolerated to be given to the widest range of recipients, including infants and pregnant women,” says Soares de Melo.

Besides the potential benefits of providing a new cure for malaria, H3D serves as a catalyst for training scientists in infectious disease research and influencing the R&D environment in Africa.  As part of its partnership with the South African Medical Research Council, H3D has worked to mentor and develop scientists at other African universities, including those at Historically Disadvantaged Institutions (HDIs) within South Africa. 

Furthermore, apart from strengthening drug discovery innovation at UCT, the centre has also taken a lead role in partnership with the Bill & Melinda Gates Foundation in catalysing drug discovery across sub-Saharan Africa, with upwards of 16 university research groups working on malaria and tuberculosis drug discovery. 

“An example of this is the Phase 1 clinical trial for the H3D clinical candidate MMV390048, which was carried out at the UCT Division of Clinical Pharmacology,” adds Soares de Melo. 

Another is the MATRIX independent special project, which has the potential to transform local drug manufacturing across the continent. Funded by the United States Agency for International Development (USAID), the project aims to pilot cost-effective local manufacture of antiretroviral Active Pharmaceutical Ingredients using flow reactor technology.

“Should Africa intend on a path to self-sufficiency, it’s important to drive continued investment in health innovations developed for and by Africa.

“We support the research efforts of H3D, and strongly believe that now is the time to take a deliberate and systematic approach to develop new capabilities, transfer technologies, leverage partnerships and networks, and train scientists, all while delivering on drug discovery projects to help address the continent’s, and the world’s, greatest health challenges,” concludes Pharasi.

For more information, visit https://h3d.uct.ac.za/ or contact Candice Soares de Melo at candice.soaresdemelo@uct.ac.za.

Categories : Diseases, Syndromes and ConditionsTags :

Sex-specific DNA Fragment Explains Lupus’s Prevalence in Women

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A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

The autoimmune condition lupus occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease’s high prevalence in women have eluded discovery, but in a new study published in the Journal of Clinical Investigation Insight, Johns Hopkins Medicine researcher investigated the immune system processes in lupus and the X chromosome, and uncovered answers about the disease’s frequency in females.

A number of dysregulated genetic and biological pathways contribute to the development of lupus and its varied symptoms of muscle and joint pain, skin rashes, kidney problems and other complications throughout the body. One such pathway involves a protein in the immune system called toll-like receptor 7 (TLR7), which, in lupus, reacts to the body’s own RNA, molecules that act as messengers of genetic information. TLR7’s reaction to RNA triggers an immune response that damages healthy tissue.

In the full article, researchers honed in on this TLR7 immune response in lupus, looking specifically at how a piece of genetic material only found in women, known as X-inactive specific transcript (XIST), could trigger TLR7’s immune system response. XIST is a type of RNA that plays a crucial role in inactivating one of the two X chromosomes found in female cells so that females do not have imbalanced gene expression.

“XIST has previously been implicated in autoimmunity, but more as something that could prevent autoimmune conditions like lupus, rather than drive the disease’s development,” says study author and lead researcher Erika Darrah, PhD. “Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity – increasing the susceptibility to lupus and its severity in women.”

The research team first tested whether XIST could bind to TLR7 and initiate the receptor’s immune response using cellular experiments. They observed that XIST could strongly bind to TLR7 and trigger the production of molecules called interferons, an immune system protein seen at high levels in lupus that contributes to tissue damage in this disease. Rather than protect from TLR7 and interferon’s negative effects on the body, these tests illustrated that XIST drove the process of an overactive immune response and therefore contributed to lupus development.

“XIST has now taken on a different role, an alarm signal related to autoimmunity,” says study author Brendan Antiochos, MD. “The immune system activation through XIST and TLR7 is female-specific, helping explain the observation that lupus is so much more common in women compared to men.”

To further study XIST’s role in lupus, researchers also examined XIST levels in patients from two lupus cohorts. The team tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels, and also used publicly available data from another study that showed XIST and interferon levels in white blood cells taken from the kidneys of people with lupus. They assessed that not only did the levels of XIST in the kidney correlate with higher interferon levels, but also, those with more XIST in their blood cells experienced greater disease severity and worsened lupus symptoms.

Darrah and Antiochos say these findings may implicate XIST in other autoimmune conditions that are more often seen in women, and that more research should be conducted to investigate this female-specific process.

Researchers also say that understanding XIST’s role in lupus development may lead to creative therapies that target the XIST-TLR7 pathway, as well as offer an additional explanation for patients who may wonder about the origins of their disease.

Source: Johns Hopkins Medicine

Categories : Uncategorized

Paving the Way to Safer Breast Cancer Treatment With C. Diff-derived Substances

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Clostridioides difficile. Credit: CDC

New experimental evidence suggests that substances known as narrow-spectrum Wnt signaling inhibitors can suppressing breast cancer tumour growth in mice. These substances, which are derived from Clostridioides difficile bacteria, could have fewer side effects than existing treatments. Aina He of Shanghai Jiaotong University Affiliated Sixth People’s Hospital, China, and colleagues published these findings in the open access journal PLOS Biology.

While certain subtypes of breast cancer can be targeted with special medications, others can only be treated with standard chemotherapy. For some patients, chemotherapy may lead to the growth of stem cell-like cancer cells that are drug resistant. Previous studies suggest that medications that inhibit a specific biological process called Wnt signaling could potentially combat these cells, but so far, the potential benefits of Wnt signaling inhibitors have been hampered by their damaging side effects, particularly on bone density.

These side effects arise from the fact that humans have ten different versions of the Wnt signaling receptor, Frizzled, with distinct functions. Researchers have therefore recently developed new Wnt signaling inhibitors that could reduce side effects by targeting just three of these receptors. However, it has been unclear how effective these narrow-spectrum Wnt signaling inhibitors might be at treating cancer.

To shed new light, He and colleagues conducted a series of experiments with a specific narrow-spectrum Wnt signaling inhibitor known as TcdBFBD, which was derived from a toxin found naturally in the bacterial species Clostridioides difficile. They tested TcdBFBD in several different mouse models that mimic different types of breast cancer – basal-like and luminal-like – found in humans.

The researchers found evidence suggesting that TcdBFBD suppressed tumour growth and reduced the activity of stem cell-like cancer cells in the mice, without side effects on bone density. They also found evidence that TcdBFBD can synergise with the standard chemotherapy drug cisplatin to inhibit both basal-like and luminal-like breast cancer tumours in mice.

These findings provide preliminary evidence for the potential therapeutic promise of narrow-spectrum Wnt signaling inhibitors like TcdBFBD. However, more research will be needed to investigate their effectiveness in humans, examine how they might synergise with other cancer treatments beyond cisplatin, and explore their effects in additional types of cancer, such as serous ovarian cancer and oral squamous cell carcinoma.

The authors add, “A bacterial toxin fragment targets and suppresses breast cancer tumour-initiating and chemo-resistant cells.”

Source: Medical Xpress

Categories : COVID Mental HealthTags :

Having Pets did not Result in Better Well-being During COVID

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Photo by Pauline Loroy on Unsplash

Although pets are generally perceived as having a positive impact on well-being, a new study has found that there was no association between well-being and owning a pet during the COVID pandemic. This finding, published in the Personality and Social Psychology Bulletin, was in spite of pets owners reporting that pet ownership improved their lives.

There is a general understanding that pets have a positive impact on one’s well-being. A new study by Michigan State University found that although pet owners reported pets improving their lives, there was not a reliable association between pet ownership and well-being during the COVID-19 pandemic.

The study assessed 767 people over three periods in May 2020. The researchers took a mixed-method approach that allowed them to look at several indicators of well-being while also asking people in an open-ended question to reflect on the role of pets from their point of view. Pet owners reported that pets made them happy. They claimed pets helped them feel more positive emotions and provided affection and companionship. They also reported negative aspects of pet ownership like being worried about their pet’s well-being and having their pets interfere with working remotely.

However, when their happiness was compared to nonpet owners, the data showed no difference in the well-being of pet owners and nonpet owners over time. The researchers found that it did not matter what type of pet was owned, how many pets were owned or how close they were with their pet. The personalities of the owners were not a factor.

“People say that pets make them happy, but when we actually measure happiness, that doesn’t appear to be the case,” said William Chopik, an associate professor in MSU’s Department of Psychology and co-author of the study. “People see friends as lonely or wanting companionship, and they recommend getting a pet. But it’s unlikely that it’ll be as transformative as people think.”

The researchers explored several reasons why there is not a difference between the well-being of pet owners and nonpet owners. One of them being that nonpet owners may have filled their lives with a variety of other things that make them happy.

Source: Michigan State University

Categories : Obstetrics & Gynaecology PaediatricsTags :

Umbilical Cord Milking Safer for Preterm Babies Born after 28 Weeks

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Photo by Hush Naidoo on Unsplash

A treatment to move blood from the umbilical cord into an infant’s body may provide a safe option for preterm infants born after 28 weeks who need rapid support, suggests a study supported by the National Institutes of Health. The procedure, called umbilical cord milking, involves gently squeezing the cord between the thumb and forefinger and pushing the blood into the newborn’s abdomen.

The new findings suggest that concerns raised by a 2019 study of infants born before 28 weeks (which concluded that umbilical cord milking might increase the risk of bleeding inside the brain) do not apply to preterm infants born after 28 weeks. The current study appears in Pediatrics.

The standard procedure, delaying cord clamping while blood naturally flows into the infant’s body, takes 30 to 180 seconds. However, cord milking, takes about 20 seconds, reducing delay for infants who need immediate assistance, such as respiratory support. Both procedures allow for umbilical cord blood to reach the infant’s body before clamping, reducing the risk of anaemia and other complications seen among infants receiving immediate cord clamping and cutting.

The study was conducted by Anup Katheria, M.D., of the Sharp Mary Birch Hospital for Women & Newborns in San Diego, and colleagues in the United States, Canada and Europe. It was supported by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

More than 1000 infants were randomly assigned either to umbilical cord milking or delayed cord clamping. Rates of severe intraventricular haemorrhage and/or death did not differ significantly between the two groups (just over 1%). Moreover, the rates of overall intraventricular haemorrhage were also similar between the groups (approximately 12%). The researchers will follow all the infants in the study for two years to observe longer term outcomes.

Source: NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

Categories : Exercise Immune SystemTags :

Firefighter Study Reveals how Extreme Exercise can Suppress the Immune System

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Source: CC0

A study of firefighters on a punishing training course has revealed clues as to why extreme exercise temporarily weakens the immune system – a phenomenon seen in elite athletes. The findings, published in Military Medical Research, may lead to better ways to support the health of people who undergo extreme exertion, such as firefighters tackling wildfires.

Thirteen firefighters volunteered for the study, average age 25 and male. They went through a rigorous training exercise, carrying 9 to 20kg of gear over hilly terrain during a 45-minute training exercise in the California sun. Gloves, helmets, flashlights, goggles, and more weighted them down as they sprinted through the countryside wearing fire-resistant clothing to show they were ready to serve as wildland firefighters.

After the training, they immediately gave samples of their blood, saliva, and urine for analysis. Two were excluded, one being unable to finish the course and the other arriving to late to provide a sample. The 11 participants who completed the course lost an average of 2.2% of their initial weight.

Then, the scientists from the Department of Energy’s Pacific Northwest National Laboratory (PNNL) analysed more than 4700 molecules, consisting of proteins, lipids, and metabolites, from each of the firefighters, looking to understand what happens when the body undergoes intense physical exercise. Measuring and interpreting the data from thousands of such measurements is a specialty of PNNL scientists who explore issues related to climate science and human health by analysing millions of sensitive measurements using mass spectrometry each year.

The researchers’ aim was to increase safety for first responders and others.

“Heat stress can be life threatening,” said Kristin Burnum-Johnson, a corresponding author of the study. “We wanted to take an in-depth look at what’s happening in the body and see if we’re able to detect danger from exhaustion in its earliest stages. Perhaps we can reduce the risk of strenuous exercise for first responders, athletes, and members of the military.”

As expected, the team detected hundreds of molecular changes in the firefighters. The differences before and after exercise underscored the body’s efforts at tissue damage and repair, maintenance of fluid balance, efforts to keep up with increased energy and oxygen demand, and the body’s attempts to repair and regenerate its proteins and other important substances.

But in the saliva, the team found some unexpected results. There was a change in the microbial mix of the mouth – the oral microbiome – showing that the body was increasingly on the lookout for bacterial invaders. Scientists also saw a decrease in signaling molecules important for inflammation and for fighting off viral infections.

A decrease in inflammation makes sense for people exercising vigorously; less inflammation allows people to breathe in air more quickly, meeting the body’s eager demand for more oxygen. Having fewer inflammatory signals in the respiratory system helps the body improve respiration and blood flow.

Less inflammation, more inhalation

But less inflammation leaves the body more vulnerable to viral respiratory infection, which other studies observed in elite athletes and others who exercise vigorously. Some studies have shown that a person is up to twice as likely to come down with a viral respiratory infection in the days after an especially energetic workout.

“People who are very fit might be more prone to viral respiratory infection immediately after vigorous exercise. Having less inflammatory activity to fight off an infection could be one cause,” said Ernesto Nakayasu, a corresponding author of the paper. He notes that the work provides a molecular basis for what clinicians have noticed in their patients who do strenuous workouts.

The team hopes that the findings will help explain why come people are more vulnerable to respiratory infection after a workout.

Source: DOE/Pacific Northwest National Laboratory