Day: October 21, 2021

Glutamate and Dopamine Interact in Addiction

Image source: Pixabay

Drug addiction is a psychiatric disorder for which no pharmacological treatment with long-term efficacy currently exists: all addictive substances have in common the fact that they raise concentrations of the neurotransmitter dopamine within brain regions forming the neural reward circuit.

This increase in dopamine levels results in long-lasting alteration of signal transmission that is dependent on another neurotransmitter, glutamate, which causes addictive behaviours. Through a new study in mice and humans, an international team including scientists from the CNRS, INRAE, the CEA, Sorbonne University, Paris-Saclay University, the University of Bordeaux, and Université Côte d’Azur has uncovered, the molecular bases of this deleterious interplay between dopamine and glutamate.

The researchers’ findings demonstrate that the inhibition of interactions between dopamine and glutamate receptors prevents pathological behaviours provoked by cocaine in mice, without altering natural reward processing. Their findings, published in Science Advances, will help pave the way for the development of new therapeutic strategies to treat addiction, and a wider spectrum of psychiatric disorders.

Source: CNRS (Délégation Paris Michel-Ange)

No Overall Link of Concussions to Cognitive Decline in Older Ex-rugby Players

Photo by Olga Guryanova on Unsplash

Elite ex-rugby players aged 50+ who suffered three or more rugby-related concussions in their career have similar cognitive function to those who had experienced fewer concussions, according to a new study in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

The BRAIN study worked with nearly 150 retired elite male players now aged 50+ who played for either England, Oxford University or Cambridge University in the pre-professional era.

While no worsening of cognitive function was seen in the group overall and in the under 75s, the study did find that over 75s with three or more rugby-related concussions during their career (14/48) had significantly worse cognitive function on average than those who had experienced fewer concussions, and may be at risk of future cognitive problems.

The findings have implications for the clinical management of older ex-rugby players, and possibly ex-players of other contact sports who may be at risk of impaired cognition, the team noted.

Given the age of the 75+ participants, these findings therefore primarily relate to the pre-professional era in rugby. Additional work is needed for younger players, particularly when reaching older ages when more cognitive problems manifest.

This study marks the first to attempt to measure cognitive function in a large number of former players and to link this to their concussion and playing history. Previous studies which have focussed on younger players have found little or no association between concussions and reduced cognitive function.

The study’s last author, Professor Neil Pearce from the London School of Hygiene & Tropical Medicine, said: “Evidence is accumulating on the possible long-term health risks in former contact sport athletes. However, each sport is different and there is currently little evidence from rugby players. This study adds to this knowledge gap, and shows that playing elite rugby may affect cognitive function in older age. It’s important more research is conducted to confirm this, and on those who played in the early years of professional rugby.”

One partial explanation for the reduced cognition in the 75+ groups could be that the former elite rugby players in this study were mostly highly educated, therefore having a higher average cognitive function at the start of their playing careers.

Dr Valentina Gallo, from the University of Groningen in the Netherlands (formerly at Queen Mary University of London), another of the Principal Investigators of the BRAIN study, and study first author, said: “Our findings are in line with those of previous studies, and perhaps highlight that the high cognitive reserve in this study group may have masked the initial phases of any cognitive problems they experience. We’ll be following up on this group of players to shed further light on our findings.”

Participants took part in an extensive set of tests capturing physical and cognitive capabilities. with cognitive function measured using the Pre-clinical Alzheimer Cognitive Composite (PACC) score, which combines tests that assess episodic memory, timed executive function, and global cognition.

After adjusting for possible confounding factors including age, smoking and player playing position, participants over 75 with three or more concussions scored about two points lower on the PACC score. This indicates a difference in cognitive function that can only be detectable with this sort of detailed testing, but which may indicate an increased risk of developing neuro-degenerative conditions.

A total of 116 (80%) respondents reported at least one rugby-related concussion. Among the concussed, the number of rugby-related concussion ranged between one and 25, with a median of two. The number of rugby-related concussions was not associated with the position they played or with length of rugby career.

Dr Simon Kemp, RFU Medical Services Director, said: “This study, that started in 2017, adds to our developing understanding of the potential long term consequences of head impacts and concussions.  The agreed group of participants were aged 50+ principally because of the greater likelihood that we might detect any neurocognitive decline if present.  It is important to also conduct research with younger retired players.

Source: London School of Hygiene & Tropical Medicine

A New Wound Dressing With Built-in Sensors

Image by Dian Polekhina on Unsplash

A research team has developed a smart wearable sensor that can conduct real-time, point-of-care assessment of chronic wounds wirelessly via an app. The world-first sensor technology can detect temperature, pH, bacteria type and inflammatory factors specific to chronic wounds within 15 minutes, enabling fast and accurate wound assessment.

More patients are suffering from non-healing wounds such as diabetic foot and chronic venous leg ulcers due to ageing and diabets, with an estimated 2% of the world’s population suffering from chronic wounds. Pain, stress and even amputation can result. Timely care and proper treatment of chronic wounds are needed to speed up wound recovery, but requires multiple clinical visits for lengthy wound assessment and treatment. This new technology can alleviate these problems.

The development of the technology was outlined in the journal Science Advances.

Currently, clinical assessments of wounds rely on visual inspection, or collecting and sending wound fluid for lab tests for biomarkers. This process usually takes about one to two days and may impede  medical interventions. Though flexible sensors designed for wound care have been developed, they can only probe a limited set of markers such as acidity, temperature, oxygen, uric acid, and impedance to diagnose wound inflammation.

VeCare is a response to these problems, a point-of-care wound assessment platform consisting of an innovative wound sensing bandage, an electronic chip and a mobile app. The bandage consists of a wound contact layer, a breathable outer barrier, a microfluidic wound fluid collector and a flexible immunosensor. VeCare is the first wound assessment platform that can detect bacteria type and probe inflammatory factors, in addition to measuring acidity and temperature, within a single 15-minute test. The microfluidic wound collector boosts delivery to the immunosensor for analysis.

In addition, the reusable integrated chip transmits data to an app for convenient, real-time wound assessment and analysis onsite.

The VeCare platform and mobile app enable doctors to monitor the condition of patients’ chronic wounds remotely, and complements the patient’s existing medical treatment while facilitating timely medical intervention for wound healing processes.

“Point-of-care devices coupled with telehealth or digital health capability can play a significant role in transforming the healthcare industry and our society, which is catalysed by the COVID-19 pandemic requirements for safe distancing. Our smart bandage technology is the first of its kind designed for chronic wound management to give patients the freedom to perform the test and monitor their wound conditions at home,” said research leader Professor Lim Chwee Teck from the National University of Singapore’s (NUS) Department of Biomedical Engineering.

A small clinical test of VeCare was conducted on patients with chronic venous leg ulcers, successfully demonstrating the platform’s effectiveness.
“The VeCare platform is easily scalable and customisable to accommodate different panels of biomarkers to monitor various types of wounds. The aim is to have an effective and easy to use diagnostic and prognostic tool for precise and data-driven clinical management of patients,” commented Prof Lim.

Next steps include a larger randomised trial and scaling up production to bring the device to market.

Source: National University of Singapore

A Key Immune Function in Red Blood Cells Has Been Discovered

Source: Wikimedia CC0

Red blood cells have been discovered to have a critical function as immune sensors by binding cell-free DNA (nucleic acid) present in the body’s circulation during sepsis and COVID. 

This DNA-binding capability triggers their removal from circulation, driving inflammation and anaemia during severe illness and playing a much larger role in the immune system than previously thought. Scientists have long known that red blood cells also interacted with the immune system, but not whether they directly altered inflammation, until now. The study appears in Science Translational Medicine.

“Anaemia is common, affecting about a quarter of the world’s population. Acute inflammatory anaemia is often seen early after an infection such as parasitic infections that cause malaria,” said senior author Nilam Mangalmurti, MD, an assistant professor of Medicine at Penn. “For a long time we haven’t known why people, when they are critically ill from sepsis, trauma, COVID, a bacterial infection, or parasite infection, develop an acute anaemia. These findings explain one of the mechanisms for the development of acute inflammatory anaemia for the first time.”

Toll-like receptors (TLRs) play a key role in the immune system by activating immune responses like cytokine production. Analysing the red blood cells of about 50 sepsis patients and 100 COVID patients the study found that, during these illnesses, red blood cells express more TLR9 on their surface.

When the red blood cells bind too much inflammation-causing nucleic acid, they lose their normal structure, causing the body to no longer recognise them, prompting macrophages to engulf them. When this happens, it causes the immune system to become activated in otherwise unaffected organs, creating inflammation. The discovery of this mechanism will allow research on blocking this specific receptor and creating targeted therapies for autoimmune diseases, infectious diseases, and various inflammatory illnesses associated with acute anaemia.

“Right now when patients in the ICU become anaemic, which is almost all of our critically ill patients, the standard is to give them blood transfusions, which has long been known to be accompanied by a host of issues including acute lung injury and increased risk of death,” Prof Mangalmurti said. “Now that we know more about the mechanism of anaemia, it allows us to look at new therapies for treating acute inflammatory anaemia without transfusions, such as blocking TLR9 on the red blood cells. Targeting this TLR9 may also be a way to dampen some of the innate immune activation without blocking this receptor in immune cells, which are very important for the host when fighting a pathogen or injury.”

This DNA-binding discovery could also have implications for research into using red blood cells in diagnostics, Prof Mangalmurti said. For example, a physician might be able to take red blood cells from a patient with pneumonia, sequence the nucleic acid absorbed from the infection, and identify the specific kind of pathogen to better determine what kind of antibiotic to prescribe.

Prof Mangalmurti and colleagues are looking at whether this is a valid option in diagnosing infection in critically ill patients and if this DNA-binding mechanism by red blood cells is a universal mechanism of anaemia in parasitic infections.

Source: Perelman School of Medicine at the University of Pennsylvania

Creating a Cross-protective Coronavirus Vaccine

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Researchers have found that by targeting the core region of the spike protein receptor-binding domain, which remains structurally similar among SARS-related viruses, they can create a vaccine that offers cross-protection against SARS coronaviruses.

The COVID pandemic, caused by the β-coronavirus SARS-CoV-2, alerted the world to the seriousness of the threat posed by novel viruses. To protect against similar future outbreaks, there is an urgent need for broadly protective vaccines against SARS-related coronaviruses. In a recent study published in Journal of Experimental Medicine, a team of researchers led by Osaka University generated an immune antigen that was based on a conserved protein on the surface of SARS-related viruses. In mice immunised with this antigen, cross-neutralising antibodies against SARS-related viruses were elicited.

The coronavirus spike protein, specifically the receptor-binding domain (RBD) of spike protein that enables the virus to attach to host cells is a target for the development of neutralising antibodies, and a promising vaccine candidate. The RBD is made of two regions: the head, which is more immune-reactive and so has the most antibodies created for it, and the core. The head however changes more rapidly, while the core region is more stable amongst SARS-related viruses. Antibodies raised against this conserved core region of the RBD can therefore generate cross-protection against multiple SARS-related viruses.

As lead authors Ryo Shinnakasu and Shuhei Sakakibara explained, “The key to generating a vaccine that offers broad cross-protection among related viruses is to target a structure on the viral surface that is highly conserved. Our approach was to generate a vaccine in which the non-conserved region was masked from the immune system by the introduction of a carbohydrate molecule (or glycan) by a method known as glycan engineering. This would in turn expose the conserved core region of the RBD of spike protein.” When used to immunise mice, protective antibodies were induced that recognised the RBD core region not only of SARS-CoV-2 but also of other SARS-related viruses, such as bat SARS-like coronavirus, WIV1-CoV.

This finding is particularly promising because it demonstrates the potential for highly protective vaccines against various SARS-related viruses. As senior author Tomohiro Kurosaki warned, “Despite the existence of effective vaccines against current viruses, there is potential for the emergence of similar viruses in the future. This highlights the real need for broadly protective vaccines against SARS-related coronaviruses.”

The novel approach of vaccine design that they describe may help protect against a future global health crisis such as that experienced during the COVID pandemic.

Source: Osaka University

A New Biomarker for Chronic Lung Diseases

Photo by Robina Weermeijer on Unsplash

Scientists have discovered that people with asthma and chronic obstructive pulmonary disease (COPD) have a protein in their lungs that leaks a molecule into their bloodstream that leads to restricted breathing instead of relaxing their airways.

The findings of their study, appearing in the American Journal of Respiratory Cell and Molecular Biology, will help clinicians diagnose and determine the severity of chronic lung diseases and make bronchodilators more effective.

“This protein has been recognised as important in some diseases, but it has never been defined before in airway diseases, such as asthma and COPD, until now,” explained co-author Reynold Panettieri, vice chancellor of translational medicine at Rutgers. “In addition to identifying this protein, we demonstrated that if you decrease the leakage, the smooth muscles in the airways relax, which could be potentially very important in improving asthma and COPD management. In addition, the presence of too much cAMP in a patient’s blood is a new biomarker that can help characterize specific types of asthma and COPD.”

The researchers found that a protein in smooth muscle cell membranes in the lungs of patients with chronic airway disease can leak cyclic adenosine monophosphate (cAMP), which signals to help relax muscles in the lungs and widen the airways. The leakage causes the airways to become constricted and cAMP can be found in the bloodstream, which can improve diagnosis of chronic airway diseases.

Researchers working together discovered the leak of cAMP from human airway smooth muscle cells from patients with and without asthma.  These cells control airway constriction in asthma, and by losing cAMP, the cells are more apt to constrict and worsen asthma. By analysing blood samples from a well-defined cohort of asthma patients, they defined cAMP in the bloodstream as a biomarker.

“We determined that cAMP blood levels are higher in asthma patients,” Panettieri said. “This knowledge allows for better diagnostics of the illness and forms the basis for new therapeutics that will plug the leak of cAMP in the protein.”

Source: Rutgers University