Interdisciplinary project explores the phenomenon of so-called “superspreaders”

Scientists from the Departments of Physics, Biomedical Sciences and Process Engineering at Otto von Guericke University Magdeburg are in the process of analyzing the emergence and spread of infectious air bubbles in our breath, known as aerosols, using tissue cultivations and artificially-produced, virus-filled suspended particles.

The aim of the interdisciplinary project, which is funded by the German Research Foundation (DFG) to the tune of almost €900,000, is to find out why the phenomenon of so-called "superspreaders" exists.

The team of researchers is looking into the question of how the virus particles in the human body are packed into the tiny aerosols and which mechanisms lead to these aerosol particles adhering to the airways of other people, where they burst and leading to further infection. Process engineers are then developing simulation models to assist in making reliable predictions about the distribution and spread of the aerosols.

"The background to these scientific questions is that there is a considerable amount of knowledge already available about the biological processes involved in the actual infection process, so we already have an exact idea of how the virus reaches human cells and multiplies," explains biomedical scientist Professor Dr. rer. biol. hum.

Heike Walles from the Core Facility Tissue Engineering at Magdeburg University, where researchers are cultivating human cells on scaffolds to produce 3-dimensional biological models of human tissues.

However, what we do not know is how the viruses are then repackaged in the aerosols and how they exit our bodies in order to infect other people."

Heike Walles, Professor and Biomedical Scientist, Core Facility Tissue Engineering, Otto von Guericke University Magdeburg

Answering these questions requires the involvement of a wide variety of scientific disciplines within the university. "The great challenge in this exciting, interdisciplinary project lies in bringing together all of these individually extremely complicated technologies under sterile working conditions."

To this end, the team around physicist Professor Claus-Dieter Ohl from the Faculty of Natural Sciences will produce aerosols based on those found in nature and experimentally pack them with fluorescent proteins, and subsequently virus particles. Like the particles found in human lungs, a range of different sizes of particles are being produced.

The team around biomedical scientist Professor Heike Walles is cultivating artificial tissue models from the different regions of our airways in the laboratory and also tubular networks constructed from polymers, i.e. chemical molecules, in the geometries of our airways. These artificial respiratory tract models are coated with protein solutions to replicate mucus, in order to simulate the physical conditions in the airways.

Next, the way in which the aerosols are disseminated in the tubular networks after high-pressure application and the way that they adhere to biological surfaces and ultimately burst is also being tested. The movements of the aerosols is documented using high-speed cameras.

The team around Junior Professor Dr. Ing. Fabian Denner from the Chair for Mechanical Process Engineering in the Faculty of Process and Systems Engineering will populate simulation models with the multitude of data obtained from the experiments and so provide a basis of decision-making concerning which adjustments and changes are needed to the experimental approach.

"When we understand how the aerosols are produced, how they are disseminated and when and under what conditions they burst, it may, for example, be possible to to think about medications that affects and reduces the formation of aerosols in the airways or that fewer viruses end up in the aerosols," explains Professor Ohl. "This would make it possible to limit the spread of highly infectious viruses very effectively."

Biomedical scientist Professor Heike Walles adds: "If, as planned, we are able, to clarify the fundamental mechanisms of action, this established process could be transferred to the world-wide spread of a great number of infectious diseases, from Covid-19 to swine flu."

Source:

Otto-von-Guericke-Universität Magdeburg

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Flu, Infectious Diseases, Laboratory, Lungs, Microscope, Polymers, Protein, Research, Respiratory, Swine Flu, Tissue Engineering, Virus

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Weather forecasts can be a potential tool to help combat meningitis

Scientists are using weather-based surveillance to predict impending meningitis outbreaks in Sub-Saharan Africa, making weather forecasts a possible tool to help health services combat the disease.

Meningitis affects more than five million people globally each year, with one in ten dying and two in ten left with an impairment such as brain injury or amputation, according to Meningitis Research Foundation.

The early-warning system being piloted across Africa uses weather data to give up to two weeks' advanced warning of conditions that are likely to trigger a meningitis outbreak, project leaders say.

The technology is being tested by the African Centre of Meteorological Applications for Development (ACMAD) in Niger, and the African SWIFT initiative led by the University of Leeds and the National Centre for Atmospheric Science, both based in the UK.

Meningitis is affecting more than 30,000 people over Africa each year with several thousand deaths. Our key findings are to operationalise the production of an early-warning system on meningitis outbreaks over the African meningitis belt."

Cheikh Dione, research scientist at ACMAD and member of the African SWIFT project

The project, run jointly with the World Health Organization's regional office for Africa, is helping health staff understand how climate change is linked to meningitis outbreaks, according to Dione.

It also enables climate scientists to evaluate their forecasts and understand the response of health services to stop meningitis outbreaks.

"This collaboration between climate scientists and health services is allowing [us] to save lives," he explains, adding that the lead time allows health services to better plan in locations with limited resources and enables country-level health services to be aware of potential outbreaks.

Scientists involved in the project say that during the dry season, which occurs from January to June, episodic dust outbreaks develop over the Sahel and Sahara and are linked to meningitis epidemics.

Forecasts are being generated in the African meningitis belt, which covers 26 African countries including Senegal in West Africa and Ethiopia in East Africa, Dione explains.

Scientists are using forecast data from the European Centre for Medium-Range Weather Forecasts made available by the World Meteorological Organization.

"Based on weekly mean forecast of temperature, wind, relative humidity and surface dust concentrations, we are able to map areas where meningitis cases or outbreaks are expected to occur in the coming two weeks," he says.

The forecast is generated every Monday and sent to the WHO's regional office for Africa, which then shares the bulletin with the weekly reported meningitis cases to the health services in each country in the meningitis belt.

"Every two weeks, we have a meeting to discuss the forecasts, present the meningitis reported cases and make some recommendations based on the observed meningitis cases and the forecasts," Dione says.

Justin Bienvenu Eyong, an epidemiologist with Epicentre Africa, a research arm of Doctors Without Borders, tells SciDev.Net that monitoring climatic factors in regions at high risk can effectively predict meningitis outbreaks.

Eyong, says: "Being able to predict an epidemic outbreak implies that we have the possibility of better anticipating the response [that includes] vaccination, strengthening of diagnostic and management capacities."

In the context of global warming, considering the relationship between climate and meningitis can help anticipate any future additional burden to already fragile health systems on the continent, Eyong explains.

Source:

SciDev.Net

Posted in: Disease/Infection News | Healthcare News

Tags: Brain, Climate Change, Diagnostic, Health Systems, Meningitis, Research

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Inhibition of Meprin Β enzyme can trigger the development of Alzheimer's disease, cancer

Researchers at Johannes Gutenberg University Mainz (JGU) in Germany and the Institute of Molecular Biology of Barcelona in Spain have discovered how the blood plasma protein fetuin-B binds to the enzyme meprin β and used a computer model to visualize their findings.

These results could lead to the development of new drugs to treat serious diseases such as Alzheimer's and cancer. Meprin β releases proteins from cell membranes, thus controlling important physiological functions in the human body.

However, a dysregulation of this process can trigger the development of Alzheimer's and cancer. Meprin β is regulated by fetuin-B binding to the enzyme when required, thereby preventing the release of other proteins. Presenting their findings in the journal Proceedings of the National Academy of Sciences, the researchers are now the first to describe this binding in detail.

The team at Mainz University produced both meprin β and fetuin-B in insect cells and then allowed them to react with one other in a test tube. By means of measurement of enzyme kinetics and biophysical analyses, the researchers determined that this reaction resulted in an exceptionally stable, high-molecular-mass complex.

Their colleagues in Barcelona subsequently managed to crystallize the complex and determine its three-dimensional structure using X-ray crystallography. This involved X-rays being fired at the protein crystals, which allowed the atomic structure of the crystals to be calculated from the diffraction of the X-rays. A computer model of the structure was then generated.

"Thanks to the model, we can now see exactly how meprin β and fetuin-B bind together," said Professor Walter Stöcker, who conducted the research at JGU together with Dr. Hagen Körschgen and Nele von Wiegen. "This research represents an excellent starting point for gaining a better understanding of diseases such as Alzheimer's and for developing the drugs to combat them."

Meprin β is already known to be involved in the formation of so-called beta-amyloid plaques, which are a characteristic feature of the condition. Moreover, people with Alzheimer's disease have relatively little fetuin-B in their blood, which in turn may lead to a lack of regulation of meprin β.

If it is possible to develop a drug that binds to the enzyme and inhibits it in a similar way to fetuin-B, this could be a new way of treating Alzheimer's."

Walter Stöcker, Professor, Johannes Gutenberg University Mainz (JGU), Germany

Source:

Johannes Gutenberg University Mainz

Journal reference:

Eckhard, U., et al. (2021) The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2023839118.

Posted in: Medical Research News | Medical Condition News

Tags: Alzheimer's Disease, Blood, Cancer, Cell, Crystallography, Diffraction, Drugs, Enzyme, Molecular Biology, Protein, Research, X-Ray

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Novel PET tracer is safe and can clearly identify early stages of rheumatoid arthritis

New research shows that a novel positron emission tomography (PET) tracer that targets inflammation is safe and can clearly identify early stages of rheumatoid arthritis. The promising PET tracer, 68Ga-DOTA-Siglec-9, rapidly clears from blood circulation, has a low radiation dose, and can be easily produced. This first-in-human study was published in the April issue of the Journal of Nuclear Medicine.

Inflammation is a significant part of several chronic diseases, including rheumatoid arthritis and its related issues. While PET imaging with 18F-FDG is a valuable tool for the diagnosis and monitoring of the effects of treatments, it is not specific enough to assess inflammation.

It's important to detect inflammation early so that patients can receive the best treatment. Our institution has worked for several years to develop an imaging agent that targets areas of inflammation, and in this study, tested its effectiveness in humans for the first time."

Anne Roivainen, PhD, Professor of Preclinical Imaging and Drug Research, Turku PET Centre, University of Turku and Turku University Hospital in Finland

To evaluate the radiotracer's safety and biodistribution characteristics, six healthy study participants underwent whole body 68Ga-DOTA-Siglec-9 PET/computed tomography scans. 68Ga-DOTA-Siglec-9 was well-tolerated and cleared quickly from the blood, and its radiation dose was similar to other 68Ga tracers. In one additional study participant with rheumatoid arthritis, the tracer was able to clearly detect joints with arthritis.

"We have proven that the characteristics of 68Ga-DOTA-Siglec-9 are favorable for use in patient imaging studies," remarked Roivainen. "Future studies will clarify whether 68Ga-DOTA-Siglec-9 PET imaging has the potential to detect other inflammatory diseases early. It could also help to evaluate the effectiveness of treatments and promptly identify patients who are unlikely respond to therapy."

Source:

Society of Nuclear Medicine and Molecular Imaging

Journal reference:

Viitanen, R., et al. (2021) First-in-Humans Study of 68Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1. Journal of Nuclear Medicine. doi.org/10.2967/jnumed.120.250696.

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Arthritis, Blood, Chronic, Computed Tomography, CT, Heart, Hospital, Imaging, Immunology, Inflammation, Laboratory, Ligand, Medicine, Molecular Imaging, Nuclear Medicine, Oncology, Positron Emission Tomography, Preclinical, Preclinical Imaging, Protein, Radiology, Radiotherapy, Research, Rheumatoid Arthritis, Rheumatology, Theranostics, Tomography, Vascular

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Recovered COVID-19 patients may develop blood clots due to overactive immune response

People who have recovered from COVID-19, especially those with pre-existing cardiovascular conditions, may be at risk of developing blood clots due to a lingering and overactive immune response, according to a study led by Nanyang Technological University, Singapore (NTU) scientists.

The team of researchers, led by NTU Assistant Professor Christine Cheung, investigated the possible link between COVID-19 and an increased risk of blood clot formation, shedding new light on "long-haul COVID" – the name given to the medium- and long-term health consequences of COVID-19.

The findings may help to explain why some people who have recovered from COVID-19 exhibit symptoms of blood clotting complications after their initial recovery. In some cases, they are at increased risk of heart attack, stroke or organ failure when blood clots block major arteries to vital organs.

The team, comprising researchers from NTU, Agency for Science, Technology and Research's (A*STAR) Singapore Immunology Network (SIgN), and the National Centre of Infectious Diseases, Singapore (NCID), collected and analysed blood samples from 30 COVID-19 patients a month after they had recovered from the infection and were discharged from hospital.

They found that all recovered COVID-19 patients had signs of blood vessel damage, possibly from a lingering immune response, which may trigger the formation of blood clots.

Their findings were published on 23 March in the peer-reviewed scientific journal eLife.

"With more people recovering from COVID-19, we started hearing from clinicians about patients returning with blood clotting issues after they had been discharged and cleared of the virus," said Asst Prof Christine Cheung from NTU's Lee Kong Chian School of Medicine. "This makes a strong case for the close monitoring of recovered COVID-19 patients, especially those with pre-existing cardiovascular conditions like hypertension and diabetes who have weakened blood vessels."

Blood vessel damage due to post-recovery overactive immune system

The team found that recovered COVID-19 patients had twice the normal number of circulating endothelial cells (CECs) that had been shed from damaged blood vessel walls. The elevated levels of CECs indicate that blood vessel injury is still apparent after recovering from viral infection.

The researchers also found that recovered COVID-19 patients continued to produce high levels of cytokines – proteins produced by immune cells that activate the immune response against pathogens – even in the absence of the virus.

Unusually high numbers of immune cells, known as T cells, that attack and destroy viruses were also present in the blood of recovered COVID-19 patients.

The presence of both cytokines and higher levels of immune cells suggest that the immune systems of recovered COVID-19 patients remained activated even once the virus was gone.

The researchers hypothesise that these persistently activated immune responses may attack the blood vessels of recovered COVID-19 patients, causing even more damage and increasing the risk of blood clot formation further.

While COVID-19 is mainly a respiratory infection, the virus may also attack the linings of blood vessels, causing inflammation and damage. Leakage from these damaged vessels triggers the formation of blood clots that may result in the sort of complications seen in the patients during hospitalisation."

Florence Chioh, Study First Author and Research Assistant, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

One of the co-authors of the paper, Professor Lisa Ng, Executive Director of A*STAR Infectious Diseases Labs and previously Senior Principal Investigator at SIgN, said: “We assessed the levels of immune mediators in these patients, which revealed several proinflammatory and activated T lymphocyte-associated cytokines sustained from infection to recovery phase. This correlated positively with CEC measure, implying cytokine-driven vessel damage. We found that COVID-19 patients with vascular complications have a higher frequency of T cells, which may in turn attack the blood vessels. Preventive therapy may be needed for these patients.”

Emphasising post- hospitalisation care for at-risk COVID-19 patients

The study's key findings can help inform guidelines for post-hospitalisation care of COVID-19 patients who might be susceptible to 'long-haul COVID' symptoms, said the research team.

In January this year, the World Health Organisation (WHO) released a recommendation in their revised clinical management guidelines, targeted at the risk of blood clot formation. For hospitalised patients, WHO recommended the use of low dose anticoagulants for preventing the blood clots forming in blood vessels.

Asst Prof Cheung added: "Those with cardiovascular conditions need to be more cautious since their underlying conditions already weaken their vascular systems. It's a double blow with COVID-19. As we gain greater understanding of complications COVID 'long-haulers' face, there is hope to encourage vaccine take-up rate to protect oneself from both the virus and its long-term complications."

Moving forward, the team is investigating the longer-term effects of COVID-19 in patients who have recovered from the infection for at least six months or longer.

Source:

Nanyang Technological University

Journal reference:

Chioh, F. W., et al. (2021) Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. eLife. doi.org/10.7554/eLife.64909.

Posted in: Medical Research News | Disease/Infection News

Tags: Blood, Blood Clot, Blood Vessel, Blood Vessels, Cytokine, Cytokines, Diabetes, Frequency, Heart, Heart Attack, Hospital, Immune Response, Immune System, Immunology, Infectious Diseases, Inflammation, Lymphocyte, Medicine, Research, Respiratory, Stroke, Vaccine, Vascular, Virus

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Study reveals molecular mechanisms of drug resistance in Mycobacterium tuberculosis

A consortium of researchers from Russia, Belarus, Japan, Germany and France led by a Skoltech scientist have uncovered the way in which Mycobacterium tuberculosis survives in iron-deficient conditions by utilizing rubredoxin B, a protein from a rubredoxin family that play an important role in adaptation to changing environmental conditions.

The new study is part of an effort to study the role of M. tuberculosis enzymes in developing resistance to the human immune system and medication. The paper was published in the journal Bioorganic Chemistry.

According to the World Health Organization, every year 10 million people fall ill with tuberculosis and about 1.5 million die from it, making it the world's top infectious killer. The bacterium that causes TB, Mycobacterium tuberculosis, is notorious for its ability to survive within macrophages, cells of the immune system that destroy harmful bacteria.

Continuing spread of drug resistance of M. tuberculosis to widely used therapeutics over recent decades became a substantial clinical problem. In this regard, the identification of novel molecular drug targets and deciphering the molecular mechanisms of drug resistance are of pivotal importance.

Natallia Strushkevich, Assistant Professor at the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE), and her colleagues studied the crystal structure and function of rubredoxin B (RubB), a metalloprotein that ensures the proper functioning of cytochrome P450 (CYP) proteins essential to bacterial survival and pathogenicity.

The team hypothesizes that M. tuberculosis switched over to more iron-efficient RubB to survive iron starvation when granulomas are formed (these are largely unsuccessful attempts at defense against TB by the immune system).

During the long-term co-evolution with mammals, M. tuberculosis developed a variety of strategies to subvert or evade the host innate immune response, from recognition of the bacterium and phagosomal defenses within infected macrophages, to adaptive immune responses by antigen presenting cells. Iron assimilation, storage and utilization is essential for M. tuberculosis pathogenesis and also involved in emergence of multi- and extensively-drug resistant strains. Heme is the preferable iron source for M. tuberculosis and serves as a cofactor for various metabolic enzymes."

Natallia Strushkevich, Assistant Professor, Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE)

Based on our finding, we linked rubredoxin B to heme monoooxygenases important for metabolism of host immune oxysterols and anti tubercular drugs. Our findings indicate that M. tuberculosis has its own xenobiotics transformation system resembling human drug metabolizing system," explains Natallia Strushkevich.

According to Natallia: New targets for drug design efforts are in great demand and the cytochrome P450 enzymes have emerged as novel targets for the development of tuberculosis therapeutic agents.

The classic approaches to block these enzymes are not straightforward. Finding the alternative redox partner, such as RubB, enables further understanding of their function in different host microenvironments. This knowledge could be exploited to identify new ways to block their function in M. tuberculosis.

Earlier research by the consortium showed that one of the CYPs enabled by RubB can act against SQ109, a promising drug candidate against multidrug-resistant tuberculosis. Another study focused on how Mycobacterium tuberculosis protects itself by intercepting human immune signaling molecules — a hurdle that limits drug discovery.

Source:

Skolkovo Institute of Science and Technology (Skoltech)

Journal reference:

Sushko, T., et al. (2021) A new twist of rubredoxin function in M. tuberculosis. Bioorganic Chemistry. doi.org/10.1016/j.bioorg.2021.104721.

Posted in: Molecular & Structural Biology | Microbiology | Biochemistry

Tags: Aging, Antigen, Artificial Intelligence, Bacteria, Biochemistry, Cytochrome P450, Drug Discovery, Drugs, Evolution, Immune Response, Immune System, Metabolism, Photonics, Protein, Research, Structural Biology, Therapeutics, Tuberculosis

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Surgery to correct congenital heart disease linked to increased risk of adult hypertension

In a medical records study covering thousands of children, a U.S.-Canadian team led by researchers at Johns Hopkins Medicine concludes that while surgery to correct congenital heart disease (CHD) within 10 years after birth may restore young hearts to healthy function, it also may be associated with an increased risk of hypertension — high blood pressure — within a few months or years after surgery.

Reporting their findings in the April 8, 2021, issue of JAMA Network Open, the researchers showed that children who had cardiac repair surgeries were 13 times more likely to develop hypertension as adults when compared with the general population.

"Congenital heart disease is among the most common forms of birth defects, and successful surgical interventions are usually performed before the age of 2; however, the specific risks of long-term, negative outcomes — including hypertension — are basically unknown for this population," says Chirag Parikh, M.D., Ph.D., director of the Division of Nephrology at the Johns Hopkins University School of Medicine and lead author of the new paper.

"So, we conducted what is believed to be the largest study with the longest follow-up ever of these children to better understand these risks and guide the development of methods to help them lessen the chance of hypertension-related cardiac disease or death," he says.

The hypertension study used the same data registry from a 2019 investigation of CHD repair and long-term risk of end-stage kidney disease.

Parikh says that clinical outcome studies in recent years provide evidence that surgical repair of heart problems during the first decade of life leaves behind some pathological changes that can continue in the cardiovascular system.

In an attempt to more precisely measure the problem of hypertension after childhood heart surgery, Parikh and his colleagues looked at medical records from seven linked Canadian patient databases. Since Canadians have universal access to health care services, the study population was less likely to have disparities and differences in the treatment and follow-up care they received.

From the list of all babies born in Ontario, Canada, between April 1, 2012, and March 31, 2015, the researchers selected 3,600 children who had surgeries to repair CHD within 10 years of birth, and matched them with 36,000 others who did not have the congenital condition nor any procedures performed on their hearts. The majority of the patients who had repair surgery were prematurely born males with low birth weights and around 150 days old at the time of their first surgery.

Cardiac repair surgeries performed on the patients were ranked from 1 to 4 in increasing complexity, with 43% being listed at categories 3 or 4 (the most complex), and including some even more complex than category 4. The two most commonly seen procedures (64%) were closure of a hole between the atria (upper chambers of the heart) or between the ventricles (lower chambers of the heart).

Both the cardiac repair surgery and the nonsurgery subjects were followed medically for up to 13 years, with data collected until death, diagnosis of hypertension or the end of the study (March 31, 2015). Of the 3,600 subjects who had surgery, 445 — or 12.4% — developed hypertension, compared with 398 out of 36,000 people — or 1.1% — who did not have the procedure. This means the children who had CHD repair surgery were 12 times more likely to become hypertensive.

The hypertension incidence rate — the total number of high blood pressure cases identified during the study period divided by the cumulative time in years for all of the patients participating (known as person-years) — also showed significantly higher risk of developing hypertension as an outcome of early age CHD repair surgery. For the surgery patients, the incident rate was 141.3 cases per 10,000 person-years compared with 11.1 cases per 10,000 person-years for those who did not have the surgery — a difference of nearly 13 to 1.

"We also saw that the more complex the cardiac surgery performed, the higher the risk for developing hypertension," Parikh says. "In the most extreme case, patients who had surgery to correct a hypoplastic left heart — a severe defect where the left side of the heart is underdeveloped — were three times more likely to develop hypertension than the congenital heart condition next in severity."

Other factors raising the risk of future hypertension were CHD repair surgery at age 3 months or younger, needing kidney dialysis during recovery from CHD repair surgery, and one or more cardiac surgeries after the initial repair.

Parikh cautions that medical records studies that "look back" at patient histories have limitations, but says that the research team's findings should be useful in guiding better long-term care for those at highest risk for hypertension, and subsequently, heart disease, stroke or kidney disease.

"For now, we recommend that children who have cardiac repair as infants be monitored more closely for hypertension throughout their lives," he says. "Future research will need to explore if early treatment of hypertension in these patients can prevent cardiovascular or renal problems later on."

Source:

Johns Hopkins Medicine

Journal reference:

Greenberg, J.H., et al. (2021) Long-term Risk of Hypertension After Surgical Repair of Congenital Heart Disease in Children. JAMA Network Open. doi.org/10.1001/jamanetworkopen.2021.5237.

Posted in: Child Health News | Medical Procedure News | Medical Research News | Medical Condition News

Tags: Biopharmaceutical, Birth Defects, Blood, Blood Pressure, Cardiac Surgery, Children, Congenital Heart Defect, Congenital Heart Disease, Dialysis, Health Care, Heart, Heart Defect, Heart Disease, Heart Surgery, High Blood Pressure, Hospital, Hypoplastic, Kidney, Kidney Disease, Medicine, Nephrology, pH, Research, Stroke, Surgery

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'Brain glue' may aid in functional neural repair after severe TBI

At a cost of $38 billion a year, an estimated 5.3 million people are living with a permanent disability related to traumatic brain injury in the United States today, according to the Centers for Disease Control and Prevention. The physical, mental and financial toll of a TBI can be enormous, but new research from the University of Georgia provides promise.

In a new study, researchers at UGA's Regenerative Biosciences Center have demonstrated the long-term benefits of a hydrogel, which they call "brain glue," for the treatment of traumatic brain injury. The new study provides evidence that not only does the gel protect against loss of brain tissue after a severe injury, but it also might aid in functional neural repair.

Brain damage following significant TBI commonly results in extensive tissue loss and long-term disability. There currently are no clinical treatments to prevent the resulting cognitive impairments or tissue loss.

Reported on March 5 in Sciences Advances, the new finding is the first to provide visual and functional evidence of the repair of brain neural circuits involved in reach-to-grasp movement in brain glue-implanted animals following severe TBI.

Our work provides a holistic view of what's going on in the recovery of the damaged region while the animal is accomplishing a specific reach-and-grasp task."

Lohitash Karumbaiah, Lead Investigator, Associate Professor, University of Georgia's College of Agricultural and Environmental Sciences

Created by Karumbaiah in 2017, brain glue was designed to mimic the structure and function of the meshwork of sugars that support brain cells. The gel contains key structures that bind to basic fibroblast growth factor and brain-derived neurotrophic factor, two protective protein factors that can enhance the survival and regrowth of brain cells after severe TBI.

In a prior short-term study, Karumbaiah and his team showed that brain glue significantly protected brain tissue from severe TBI damage. In this new research, to harness the neuroprotective capacity of the original, they further engineered the delivery surface of protective factors to help accelerate the regeneration and functional activity of brain cells. After 10 weeks, the results were apparent.

"Animal subjects that were implanted with the brain glue actually showed repair of severely damaged tissue of the brain," said Karumbaiah. "The animals also elicited a quicker recovery time compared to subjects without these materials."

To measure the glue's effectiveness, the team used a tissue-clearing method to make brain tissue optically transparent, which allowed them to visually capture the immediate response of cells in the reach-to-grasp circuit using a 3D imaging technique.

"Because of the tissue-clearing method, we were able to obtain a deeper view of the complex circuitry and recovery supported by brain glue," said Karumbaiah. "Using these methods along with conventional electrophysiological recordings, we were able to validate that brain glue supported the regeneration of functional neurons in the lesion cavity."

Karumbaiah pointed out that the RTG circuit is evolutionarily similar in rats and humans. "The modulation of this circuit in the rat could help speed up clinical translation of brain glue for humans," he said.

With support from UGA's Innovation Gateway, Karumbaiah has filed for a patent on the brain glue. He is also partnering with Parastoo Azadi, technical director of analytical services at the UGA Complex Carbohydrate Research Center, and GlycoMIP, a $23 million, National Science Foundation-funded Materials Innovation Platform, created to advance the field of glycomaterials through research and education.

"Doing the behavioral studies, the animal work and the molecular work sometimes takes a village," said Karumbaiah. "This research involved a whole cross-section of RBC undergraduate and graduate students, as well as faculty members from both UGA and Duke University."

The collaborative research effort provided five UGA RBC fellow undergraduates with an experiential learning opportunity and to publish their first paper. This is the first publication for Rameen Forghani, an aspiring M.D.-Ph.D. undergraduate working in the Karumbaiah lab.

Forghani said the undergraduate team "learned how to collaborate on this project" and about the impact of moving lab research to patients who need treatment.

"My fellow undergraduates and I were empowered to take ownership of a piece of the project and see it through from the planning stages of data analysis to writing and being published," said Forghani. "As an aspiring, early-career physician-scientist, working on a project that has translational impact and directly addresses a very relevant clinical problem is very exciting to me."

Charles Latchoumane, research scientist in the Karumbaiah lab and first author on the study, divides his time between UGA and Lausanne, Switzerland, where he works at NeurRestore, a research center aimed at restoring lost neurological function for people suffering from Parkinson's disease or from neurological disorders following a head injury or stroke.

"This study has been four to five years in the making," said Latchoumane. "Our collaborative research is so painstakingly documented that, after you read about it, you have to believe there is new hope for severe victims of brain injury."

Source:

University of Georgia

Journal reference:

Latchoumane, C.V., et al. (2021) Engineered glycomaterial implants orchestrate large-scale functional repair of brain tissue chronically after severe traumatic brain injury. Science Advances. doi.org/10.1126/sciadv.abe0207.

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: 3D Imaging, Brain, Carbohydrate, Disability, Education, Fibroblast, Growth Factor, Head Injury, Hydrogel, Imaging, Medicine, Neurons, Parkinson's Disease, pH, Protein, Research, Stroke, students, Translation, Traumatic Brain Injury

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New biomarker of glucocorticoid action could help clinicians to tailor treatments

Researchers have uncovered pathways involved in the body's response to glucocorticoid treatments and identified a novel biomarker that could be used to monitor how these drugs work in patients, according to a clinical study published today in eLife.

A more reliable indicator of an individual's response to glucocorticoid drugs could be used to develop a clinically applicable test that could help tailor treatments and potentially minimize side-effects.

Glucocorticoids, such as cortisol, are a type of hormone with key roles in the body's response to stress. Glucocorticoid drugs are one of the most commonly prescribed treatments for a range of conditions, including for patients whose adrenal glands are unable to produce enough cortisol. The effects of glucocorticoids are complex, meaning the level of cortisol in the blood does not reliably reflect what is happening in the tissues. This makes it hard for medical professionals to know how to tailor treatments.

Side effects of glucocorticoid treatments are common in patients, indicating that current methods to monitor their action, which typically focus on clinical response or disease activity, are inadequate. We wanted to find some kind of biomarker that could be measured to monitor the action of glucocorticoids in individuals, with the hopes this will help clinicians understand how best to treat patients."

Dimitrios Chantzichristos, First Author, Head Physician, Section for Endocrinology-Diabetes-Metabolism, Sahlgrenska University Hospital, Sweden

The team studied patients with Addison's disease who lack the ability to produce their own cortisol. This allowed them to compare the activity in the tissues of the same patient both when their cortisol levels were low and when they were being restored by glucocorticoid treatments, helping account for variations between individuals.

Rather than focusing only on the metabolic products associated with glucocorticoid exposure, they also looked at gene expression and microRNAs in the patients using new computational approaches developed in collaboration with Dr Adam Stevens at the University of Manchester, UK. MicroRNAs are short strands of ribonucleic acid (RNA) that can regulate the expression of genes by interfering with protein production. The team analyzed these different factors in blood cells and body fat, an important metabolic tissue, as the patients' cortisol levels were changed, revealing close relationships between different elements involved in glucocorticoid action.

Among the elements they identified, a microRNA called miR-122-5p closely correlated with genes and metabolites that are regulated by the glucocorticoid treatments. To test this correlation, the team looked at miR-122-5p levels in blood from patients exposed to different levels of glucocorticoids from three independent studies and found the same pattern, supporting the idea that this microRNA could be a useful biomarker of glucocorticoid action.

"This potential biomarker can now be investigated in larger groups of patients with the aim to develop a clinically applicable test," concludes senior author Gudmundur Johannsson, Professor at the Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sweden. "Our work has also increased our understanding of the action of glucocorticoids, which may help uncover their role in many common diseases such as diabetes, obesity and cardiovascular diseases."

This study was a collaborative effort between researchers at the Universities of Manchester (UK), Edinburgh (UK), Copenhagen (Denmark) and Gothenburg (Sweden), as well as Newcastle University (UK) and Sahlgrenska University Hospital (Sweden).

Source:

eLife

Journal reference:

Chantzichristos, D., et al. (2021) Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial. eLife. doi.org/10.7554/eLife.62236.

Posted in: Molecular & Structural Biology | Biochemistry

Tags: Addison's Disease, Biomarker, Blood, Cortisol, Diabetes, Drugs, Endocrinology, Gene, Gene Expression, Genes, Glucocorticoid, Hormone, Hospital, Medical Research, Medicine, Metabolism, Metabolites, MicroRNA, Nutrition, Obesity, Protein, Research, Rheumatism, Ribonucleic Acid, RNA, Stress

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Women experienced high rates of mental health problems early in COVID-19 pandemic

A study at the University of Chicago Medicine found U.S. women experienced increased incidence of health-related socioeconomic risks (HRSRs), such as food insecurity and interpersonal violence, early in the COVID-19 pandemic. This was associated with "alarmingly high rates" of mental health problems, including depression and anxiety. The research was published April 5 in the Journal of Women's Health.

Other studies have found evidence for higher rates of anxiety and depression and related issues, such as alcohol overuse, connected to the pandemic — but this study is the first to link early pandemic-related changes in HRSRs to mental health effects in women.

Most national surveys tend to report aggregated findings rather than stratifying by gender. Those early studies gave us snapshots of the health and behaviors of the whole population, but gave us limited insight on women. Yet, women constitute the majority of the essential workforce, including healthcare workers, and we wanted to make sure that women's experiences were being documented."

Stacy Lindau, MD, Professor of Obstetrics and Gynecology and Medicine-Geriatrics, UChicago Medicine

The researchers conducted a survey of 3,200 U.S. women over the age of 18 between April 10 and 24, 2020. More than 40% of participants reported experiencing at least one HRSR during the prior year, which included issues such as food insecurity, housing instability, difficulties with their utilities, transportation challenges and interpersonal violence; 22% reported experiencing two or more HRSRs during the year before the pandemic.

But by the first spring of the pandemic, nearly half of all women — including 29% of those who did not experience pre-pandemic HRSRs — reported new (incident) or worsening HRSRs. The greatest challenge was an increase in food insecurity. Nearly 80% of those without pre-pandemic HRSRs who reported a new HRSR became food insecure. Almost a quarter experienced interpersonal violence.

"It's incredible and concerning that nearly half of women — including more than a quarter of those who had no health-related socioeconomic risks — had experienced incident or worsening conditions," said Lindau. "It's even more striking that more than a quarter of the women who had none of these risks in January or February 2020 now had at least one by April.

That points to the likelihood that a large portion of women were already near the edge of vulnerability. When the world shut down, transportation became more difficult, food access became harder, and very soon after the crisis began, many women found themselves struggling to meet basic needs."

Those who experienced socioeconomic risks prior to the pandemic also experienced the greatest increase in insecurity. Three-quarters of women with pre-pandemic HRSRs experienced new or worsening risks during the early pandemic; 38% experienced two or more, with more than half experiencing increased food insecurity.

Significantly, the survey also found that 29% of women reported symptoms of depression and anxiety — nearly twice the estimated pre-pandemic rates. One in six women screened positive for symptoms of post-traumatic stress, a rate similar to that seen after other significant disasters, such as the SARS and Ebola epidemics. Those who experienced at least one new or worsening HRSR were at significantly higher risk of experiencing anxiety and post-traumatic stress.

"Given very high rates of these problems, we're really concerned about the current capacity of our mental health system," said co-author Marie Tobin, MD, Professor of Psychiatry at UChicago Medicine. "Women are principally responsible for parenting, family caregiving and other essential work — they are key to managing and recovering from this pandemic, and now are afflicted by very significant socioeconomic risk levels that appear to be drivers of anxiety, depression and traumatic stress. We should be especially concerned that socioeconomically vulnerable women are at high risk for developing pandemic-related psychiatric morbidity."

These results, the investigators say, should help spur healthcare providers and policy makers to address the underlying and modifiable health-related socioeconomic risk factors in order to prevent these negative outcomes.

"We can't change a person's gender, but we can act to ensure that all people have the basic nutrition and shelter they need to survive," said Lindau. "We can intervene on transportation barriers, we can pass policies to delay or offset rent or utilities payments. These are modifiable factors that can be addressed by leveraging the humanitarian resources of our communities and implementing policies that ensure everyone can live independently with their basic needs met. Ensuring equitable access to the basics would be a powerful buffer against mental illness in general and could help mitigate costly and painful mental health crisis among women and everyone who depends on us in the context of this and other public health emergencies."

Source:

University of Chicago Medical Center

Journal reference:

Lindau, S. T., et al. (2021) Change in Health-Related Socioeconomic Risk Factors and Mental Health During the Early Phase of the COVID-19 Pandemic: A National Survey of U.S. Women. Journal of Women's Health. https://doi.org/10.1089/jwh.2020.8879.

Posted in: Medical Condition News | Women's Health News | Disease/Infection News

Tags: Alcohol, Anxiety, Cancer, Children, Depression, Geriatrics, Gynecology, Health Systems, Healthcare, Hospital, Medicine, Mental Health, Nutrition, Obstetrics, Pandemic, Parenting, Physiology, Psychiatry, Public Health, Research, SARS, Stress

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