Right side heart failure. Credit: Scientific Animations CC4.0
There is a natural mechanism that protects the heart from heart failure with preserved ejection fraction (HFpEF), according to findings published in Circulation. An international team of researchers at the University of Manchester, Baylor College of Medicine and collaborating institutions discovered that when the cardioprotective mechanism fails, it promotes the development of HFpEF. Restoring the mechanism prevents progression, and presents a promising therapeutic target to prevent and treat this life-threatening disease.
“HFpEF is a complex, multifactorial disease associated with metabolic stress. One of the factors involved is the toxic accumulation of lipids in heart cells,” said co-author Dr Tamer M. A. Mohamed, associate professor of surgery and director of the Laboratory for Cardiac Regeneration Baylor.
The team began by assessing gene changes in hearts from people diagnosed with metabolic stress along with various cardiovascular complications and found alterations in the expression of 488 genes. “We found particularly relevant the simultaneous reduction of the expression of genes XBP1 and EDEM2 in human HFpEF hearts,” Mohamed said.
The link between EDEM2 and other conditions has been studied, but its role in the heart remains unexplored.
“We discovered that the XBP1 protein regulates the Edem2 gene in animal models and that EDEM2 was downregulated in hearts from individuals with metabolic disorders and in mouse models,” Mohamed said. “Further evidence supported the involvement of EDEM2 and XBP1 in cardiovascular diseases and lipid regulation.”
To investigate whether XBP1 and EDEM2 were directly involved in lipid toxicity and HFpEF, the researchers removed the Xbp1 or the Edem2 gene in mice. Consequently, these mice became more vulnerable to metabolic stress-induced heart lipid toxicity and cardiac dysfunction. “It was exciting to see that restoring Xbp1 or Edem2 alleviated lipid overload in the heart and reversed HFpEF,” Mohamed said.
This comprehensive study uncovered that XBP1 and EDEM2 work together to maintain a healthy lipid balance in heart cells.
“Our findings support further study of the XBP1s and EDEM2 pathway as a promising therapeutic target for mitigating cardiac lipotoxicity and progression of HFpEF,” Mohamed said.
African countries face a major challenge of dealing with high rates of communicable diseases, such as malaria and HIV/Aids, and rising levels of non-communicable diseases. But the continent’s health systems don’t have the resources to provide accessible and affordable healthcare to address these challenges.
Historically, aid has played a critical role in supporting African health systems. It has funded key areas, including medical research, treatment programmes, healthcare infrastructure and workforce salaries. In 2021, half of sub-Saharan Africa’s countries relied on external financing for more than one-third of their health expenditures.
As aid dwindles, a stark reality emerges: many African governments are unable to achieve universal health coverage or address rising healthcare costs.
The reduction in aid restricts healthcare services and threatens to reverse decades of health progress on the continent. A fundamental shift in healthcare strategy is necessary to address this crisis.
The well-known maxim that “prevention is better than cure” holds not just for health outcomes but also for economic efficiency. It’s much more affordable to prevent diseases than it is to treat them.
As an infectious diseases specialist, I have seen how preventable diseases can put a financial burden on health systems and households.
For instance, each year, there are global economic losses of over US$33 billion due to neglected tropical diseases. Many conditions, such as lymphatic filariasis, often require lifelong care. This places a heavy burden on families and stretches national healthcare systems to their limits.
African nations can cut healthcare costs through disease prevention. This often requires fewer specialist health workers and less expensive interventions.
To navigate financial constraints, African nations must rethink and redesign their healthcare systems.
Three key areas where cost-effective, preventive strategies can work are: improving water, sanitation, and hygiene; expanding vaccination programmes; and making non-communicable disease prevention part of community health services.
A shift in healthcare delivery
Improving water, sanitation, and hygiene infrastructure
Many diseases prevalent in Africa are transmitted through contact with contaminated water and soil. Investing in safe water, sanitation, and hygiene (WASH) infrastructure is an opportunity. This alone can prevent a host of illnesses such as parasitic worms and diarrhoeal diseases. It can also improve infection control and strengthen epidemic and pandemic disease control.
Currently, WASH coverage in Africa remains inadequate. Millions are vulnerable to preventable illnesses. According to the World Health Organization (WHO), in 2020 alone, about 510 000 deaths in Africa could have been prevented with improved water and sanitation. Of these, 377 000 deaths were caused by diarrhoeal diseases.
Unsafe WASH conditions also contribute to secondary health issues, such as under-nutrition and parasitic infections. Around 14% of acute respiratory infections and 10% of the undernutrition disease burden – such as stunting – are linked to unsafe WASH conditions.
By investing in functional WASH infrastructure, African governments can significantly reduce the incidence of these diseases. This will lead to lower healthcare costs and improved public health outcomes.
Local production of relevant vaccines
Vaccination is one of the most cost-effective health interventions available for preventing infection. Immunisation efforts save over four million lives every year across the continent.
There is an urgent need for vaccines against diseases prevalent in Africa whose current control is heavily reliant on aid. Neglected tropical diseases are among them.
Vaccines can also prevent some non-communicable diseases. A prime example is the human papillomavirus (HPV) vaccine, which can prevent up to 85% of cervical cancer cases in Africa.
HPV vaccination is also more cost-effective than treating cervical cancer. In some African countries, the cost per vaccine dose averages just under US$20. Treatment costs can reach up to US$2,500 per patient, as seen in Tanzania.
It is vital to invest in a comprehensive vaccine ecosystem. This includes strengthening local research and building innovation hubs. Regulatory bodies across the continent must also be harmonised and markets created to attract vaccine investment.
Integrating disease prevention into community healthcare services
Historically, African healthcare systems were designed to address communicable diseases, such as tuberculosis and HIV. This left them ill-equipped to handle the rising burden of non-communicable diseases, such as type 2 diabetes and cardiovascular diseases. One cost-effective approach is to integrate the prevention and management of these diseases into existing community health programmes.
Community health workers currently provide low-cost interventions for health issues such as pneumonia and malaria. They can be trained to address non-communicable diseases as well.
In some countries, community health workers are already filling the service gap. Getting them more involved in prevention strategies will strengthen primary healthcare services in Africa. This investment will ultimately reduce the long-term financial burden of treating chronic diseases.
A treatment-over-prevention approach will not be affordable
Current estimates suggest that by 2030, an additional US$371 billion per year – roughly US$58 per person – will be required to provide basic primary healthcare services across Africa.
Adding to the challenge is the rising global cost of healthcare, projected to increase by 10.4% this year alone. This marks the third consecutive year of escalating costs. For Africa, costs also come from population growth and the rising burden of non-communicable diseases.
By shifting focus from treatment to prevention, African nations can make healthcare accessible, equitable and financially sustainable despite the decline in foreign aid.
Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash
The concept of using vaccines to treat cancers has been around for several decades. A vaccine was first approved for prostate cancer in 2010, and another was approved in 2015 for melanoma. Since then, many therapeutic – as opposed to preventive – cancer vaccines have been in development, but none approved. One hurdle is the difficulty in finding antigens in tumours that look foreign enough to trigger an immune response.
Researchers at Tufts have now developed a cancer vaccine that makes tumour antigens more visible to the immune system, leading to a potent response and a lasting immunological memory that helps prevent tumour recurrence. Their vaccine avoids the need to hunt down a specific tumour antigen, instead relying on a digested mix of protein fragments called a lysate that can be generated from any solid tumour.
The vaccine they produced worked against multiple solid tumours in animal models, including melanoma, triple-negative breast cancer, Lewis lung carcinoma, and clinically inoperable ovarian cancer.
Developed by a team led by postdoctoral scholar Yu Zhao and Qiaobing Xu, professor of biomedical engineering, the method builds on earlier work expressing specific antigens for an enhanced immune response by making lipid nanoparticles that carry mRNA into the lymphatic system.
“We have significantly improved the cancer vaccine design by making it applicable to any solid tumour from which we can create a lysate, possibly even tumours of unknown origin, without having to select mRNA sequences, and then conjugating another component called AHPC that helps channel the protein fragments from the cancer cells into the immunological response pathway,” said Xu.
Unlike traditional vaccines designed to prevent infectious diseases caused by bacteria or viruses, cancer vaccines work by stimulating the body’s immune system to recognise and attack cancer cells. Unlike most vaccines against pathogens, they are designed to be therapeutic rather than preventive, acting to eliminate an existing disease. Some preventive cancer vaccines do exist, but they are generally targeted to viruses that are linked to cancers, such as HPV.
The key to the increased potency of the new cancer vaccine lies in its ability to direct tumour-derived antigens into a cellular pathway that efficiently presents the antigens to the immune system.
Rounding up the antigens and getting them into an antigen presenting cell like a macrophage or dendritic cell (the police stations, if we continue with the analogy) is generally an inefficient process for tumor antigens. This is where the Tufts research team applied a two-stage method to power up the process.
First, to make sure they round up all tumour proteins-of-interest, they modified the mix of tumour proteins with the AHPC molecule, which in turn recruits an enzyme to put a tag on the protein called a ubiquitin. It allows the cell to identify and process the protein into fragments for presentation to the immune system.
The researchers then packaged the AHPC-modified tumour proteins into tiny lipid nanoparticles, specifically designed to home in on lymph nodes, where most antigen-presenting cells can be found.
Tested in animal models of melanoma, triple-negative breast cancer, Lewis lung carcinoma, and inoperable ovarian cancer, the vaccine elicited a strong response by cytotoxic T cells, which attack the growing tumours, suppressing further growth and metastasis.
“Fighting cancer has always been an arsenal approach,” said Xu. “Adding cancer vaccines to surgical excision, chemotherapy, and other drugs used to enhance cytotoxic T cell activity could lead to improved patient responses and longer-term prevention of cancer recurrence.”
In sports, the connection between head injuries and neurodegenerative diseases such as chronic traumatic encephalopathy, Alzheimer’s disease, and Parkinson’s disease is now well recognised.
Researchers at Tufts University and Oxford University have now uncovered mechanisms that may connect the dots between trauma events and the emergence of disease. They point to latent viruses lurking in most of our brains that may be activated by the jolt, leading to inflammation and accumulating damage that can occur over the ensuing months and years.
The results suggest the use of antiviral drugs as potential early preventive treatments post-head injury. The findings are published in a study in Science Signaling.
The microbiome aids in digestion, immune system development, and protection against harmful pathogens.
But the microbiome also includes dozens of viruses that swarm within our bodies at any given time. Some of these can be potentially harmful, but simply lie dormant within our cells. Herpes simplex virus 1 (HSV-1), found in over 80% of people, and varicella-zoster virus, found in 95% of people, are known to make their way into the brain and sleep within our neurons and glial cells.
Dana Cairns, GBS12, research associate in the Department of Biomedical Engineering and lead author of the study, had found evidence in earlier studies suggesting that activation of HSV-1 from its dormant state triggers the signature symptoms of Alzheimer’s disease in lab models of brain tissue: amyloid plaques, neuronal loss, inflammations, and diminished neural network functionality.
“In that study, another virus – varicella – created the inflammatory conditions that activated HSV-1,” said Cairns. “We thought, what would happen if we subjected the brain tissue model to a physical disruption, something akin to a concussion? Would HSV-1 wake up and start the process of neurodegeneration?”
The link between HSV-1 and Alzheimer’s disease was first suggested by co-author Ruth Itzhaki, visiting professorial fellow at Oxford University, who more than 30 years ago identified the virus in a high proportion of brains from the elderly population. Her subsequent studies suggested that the virus can be reactivated in the brain from a latent state by events such as stress or immunosuppression, ultimately leading to neuronal damage.
Blows to Brain-like Tissue
In the current study, the researchers used a lab model that reconstructs the environment of the brain to better understand how concussions may set off the first stages of virus reactivation and neurodegeneration.
The brain tissue model consists of a 6mm-wide donut-shaped sponge-like material made of silk protein and collagen suffused with neural stem cells, which are then coaxed into mature neurons, growing axons and dendrite extensions and forming a network. Glial cells also emerge from the stem cells to help mimic the brain environment and nurture the neurons.
The neurons communicate with each other through their extensions similarly to how they would communicate in a brain. And just like cells in the brain, they can carry within them the DNA of dormant HSV-1 virus.
After enclosing the brain-like tissue in a cylinder and giving it a sudden jolt atop a piston, mimicking a concussion, Cairns examined the tissue under the microscope over time. Some of the tissue models had neurons with HSV-1, and some were virus-free.
Following the controlled blows, she observed that the infected cells showed re-activation of the virus, and shortly after that the signature markers of Alzheimer’s disease, including amyloid plaques, p-tau (a protein that creates fiber-like “tangles” in the brain), inflammation, dying neurons, and a proliferation of glial cells called gliosis.
More strikes with the pistons on the tissue models mimicking repetitive head injuries led to the same reactions, which were even more severe. Meanwhile, the cells without HSV-1 showed some gliosis, but none of the other markers of Alzheimer’s disease.
The results were a strong indicator that athletes suffering concussions could be triggering reactivation of latent infections in the brain that can lead to Alzheimer’s disease. Epidemiological studies have shown that multiple blows to the head can lead to doubling or even greater chances of having a neurodegenerative condition months or years down the line.
“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks, and lower the risk of Alzheimer’s disease,” said Cairns.
The problem goes far beyond the concerns for athletes. Traumatic brain injury is one of the most common causes of disability and death in adults, affecting about 69 million people worldwide each year, at an economic cost estimated at $400 billion annually.
“The brain tissue model takes us to another level in investigating these connections between injury, infection, and Alzheimer’s disease,” said David Kaplan, Stern Family Endowed Professor of Engineering at Tufts.
“We can re-create normal tissue environments that look like the inside of a brain, track viruses, plaques, proteins, genetic activity, inflammation and even measure the level of signalling between neurons,” he said. “There is a lot of epidemiological evidence about environmental and other links to the risk of Alzheimer’s. The tissue model will help us put that information on a mechanistic footing and provide a starting point for testing new drugs.”
A new study from Mass General Brigham suggests that eating only during the daytime could help people avoid the health risks associated with shift work. Results are published in Nature Communications.
“Our prior research has shown that circadian misalignment – the mistiming of our behavioral cycle relative to our internal body clock – increases cardiovascular risk factors,” said senior author Frank A.J.L. Scheer, PhD, a professor of Medicine at Brigham and Women’s Hospital. “We wanted to understand what can be done to lower this risk, and our new research suggests food timing could be that target.”
Animal studies have shown that aligning food timing with the internal body clock could mitigate the health risks of staying awake during the typical rest time, which prompted Scheer and his colleagues to test this concept in humans.
For the study, researchers enlisted 20 healthy young participants to a two-week in-patient study at the Brigham and Women’s Center for Clinical Investigation. They had no access to windows, watches, or electronics that would clue their body clocks into the time. The effect of circadian misalignment could be determined by comparing how their body functions changed from before to after simulated night work.
Study participants followed a “constant routine protocol,” a controlled laboratory setup that can tease apart the effects of circadian rhythms from those of the environment and behaviours (eg, sleep/wake, light/dark patterns). During this protocol, participants stayed awake for 32 hours in a dimly lit environment, maintaining constant body posture and eating identical snacks every hour. After that, they participated in simulated night work and were assigned to either eating during the nighttime (as most night workers do) or only during the daytime. Finally, participants followed another constant routine protocol to test the aftereffects of the simulated night work. Importantly, both groups had an identical schedule of naps, and, thus, any differences between the groups were not due to differences in sleep schedule.
The investigators examined the aftereffects of the food timing on participants’ cardiovascular risk factors and how these changed after the simulated night work. Researchers measured various cardiovascular risk factors, including autonomic nervous system markers, plasminogen activator inhibitor-1 (which increases the risk of blood clots), and blood pressure.
Remarkably, these cardiovascular risk factors increased after simulated night work compared to the baseline in the participants who were scheduled to eat during the day and night. However, the risk factors stayed the same in the study participants who only ate during the daytime, even though how much and what they ate was not different between the groups—only when they ate.
Limitations of the study include that the sample size was small, although of a typical size for such highly controlled and intensive randomised controlled trials. Moreover, because the study lasted two weeks, it may not reflect the chronic risks of nighttime versus daytime eating.
A strength is that the study participants’ sleep, eating, light exposure, body posture, and activity schedule were so tightly controlled.
“Our study controlled for every factor that you could imagine that could affect the results, so we can say that it’s the food timing effect that is driving these changes in the cardiovascular risk factors,” said Sarah Chellappa, MD, MPH, PhD, an associate professor at the University of Southampton, and lead author for the paper.
While further research is necessary to show the long-term health effects of daytime versus nighttime eating, Scheer and Chellappa said the results are “promising” and suggest that people could improve their health by adjusting food timing. They add that avoiding or limiting eating during nighttime hours may benefit night workers, those who experience insomnia or sleep-wake disorders, individuals with variable sleep/wake cycles, and people who travel frequently across time zones.
An Edith Cowan University (ECU) study has found children born to mothers who experienced gestational diabetes (GDM) during pregnancy are more likely to develop attention-deficient hyperactive disorder (ADHD) and externalising behaviour. The study appears in BMC Paediatrics.
The study used data from 200 000 mother-child pairs across Europe and Australia, and found that in children aged 7 to 10, those born to mothers with gestational diabetes had consistently higher ADHD symptoms.
Children aged 4 to 6 years, born to mothers with gestational diabetes consistently exhibited more externalising problems than those born who didn’t.
“Externalising symptoms are behaviours directed outward. Instead of experiencing depression or anxiety, these children often display hyperactivity, impulsivity, defiance, or aggression,” explained first author Dr Rachelle Pretorius, ECU Honorary researcher.
“Externalising problems frequently coexist with ADHD symptoms and tend to emerge before medical intervention, especially during the early school years,” she added.
“At younger ages, children may exhibit more externalising problems and as the child matures, symptoms or behaviour related to ADHD may become more apparent. ADHD does not have biological markers for diagnosis, making ADHD a disorder that is difficult to detect before symptoms manifest,” said senior author Professor Rae-Chi Huang.
It is still unclear why children exposed to gestational diabetes retained more externalising problems and ADHD symptoms respectively after adjustments.
“However, our findings suggest that these externalising behaviours may decrease over time but could extend into other domains such as neurodevelopment outcomes such as ADHD symptoms.”
Dr Pretorius noted that while the exact mechanics of gestational diabetes influence on child development is still unclear, it is believed that acute and chronic maternal inflammation during pregnancy may influence certain pathways in a child’s brain programming in-utero and contribute to neurodevelopment, cognitive and behaviour outcomes later in life.
“Several studies suggest that the severity of maternal diabetes, associated with maternal obesity, chronic inflammation have a joint impact on the development of autism spectrum disorder and ADHD in children, which is greater than the impact of either condition alone.”
Benzodiazepines like Valium and Xanax are often prescribed to treat anxiety, insomnia and seizures. While these drugs can be effective as a short-term treatment, researchers are trying to better understand the impact of benzodiazepines after extended use. Some experts believe long-term use of the medication may influence inflammation levels in our bodies, as previous research has shown that benzodiazepines may increase the risk of developing or worsening inflammatory conditions, like lung inflammation and inflammatory bowel disease. For years, experts have tried with little success to better understand the molecular mechanisms that may be driving these side effects.
Now, a research team led by Virginia Commonwealth University and Columbia University has gained novel insights into a protein suspected to be involved in benzodiazepine-related inflammation. Their findings, published in PNAS, could inform strategies to improve benzodiazepine drug design as well as open new opportunities for treating inflammation-related conditions, including certain cancers, arthritis, Alzheimer’s disease and multiple sclerosis.
“Numerous attempts have been made to determine the structure and elucidate the function of this mysterious membrane protein family,” said Youzhong Guo, PhD, associate professor in medicinal chemistry and one of the lead researchers of the new study. “Now, after decades of research, we finally have promising evidence that resolves some of the mysteries around this protein and could be crucial for advancing benzodiazepine drug design.”
Benzodiazepines produce their therapeutic effect by binding with GABAA receptors in the brain; however, the drug has an equally strong affinity to human mitochondrial tryptophan-rich sensory proteins (HsTSPO1), located on the outer membrane of mitochondria in cells. This type of protein is linked to several neurodegenerative diseases, including Alzheimer’s, and researchers have suspected that HsTSPO1 may be involved in certain side effects of benzodiazepine drugs.
Both the structure and function of this protein family have been debated within the scientific community, inhibiting efforts to understand its role in disease and develop effective therapeutics. Many scientists have theorised that HsTSPO1’s potential function is transporting cholesterol across membranes to regulate the development of steroid hormones. But Guo and Wayne Hendrickson, PhD, biochemistry professor at Columbia’s Vagelos College of Physicians and Surgeons and co-author of the new study, believed that HsTSPO1 is more likely to have a different function.
“Tryptophan-rich sensory proteins like HsTSPO1 are found in all forms of life, from bacteria and plants to animals and humans,” said Guo, who also serves on research faculty at the VCU Center for Drug Discovery. “We know that this type of protein functions as enzymes in bacteria, and when you consider evolutionary theory, the same type of protein is likely to be an enzyme in humans as well.”
HsTSPO1’s structure has remained unresolved for so long in part because of the methods used to analyze membrane proteins. The membrane of cells and organelles like mitochondria are composed of a lipid bilayer, with proteins either attached to or embedded within the structure. Researchers use detergents to extract and stabilize these proteins. However, the process can interfere with protein-lipid interactions that are often essential for the structural stability and functionality of these proteins.
To overcome this challenge, Guo and his colleagues developed a detergent-free method, named the native cell membrane nanoparticles system, which uses membrane-active polymers to isolate and stabilize membrane proteins while maintaining their interactions with the native lipids. Using this technology, the researchers were able to study HsTSPO1 in a state that more closely reflects its natural cell membrane environment, revealing new insights into the protein’s structure and interactions with other compounds.
“Protein instability caused by detergents had thwarted our previous efforts to fully characterize its structure and function,” Guo said. “However, in our analysis, we found that HsTSPO1 performed its function when cholesterol was present, demonstrating how crucial it is to study this protein in an environment that is similar to its natural habitat. Similar to if you take a fish out of the water, it’s still a fish, but it will behave very differently.”
Through this method, the research team found evidence to suggest that HsTSPO1 functions as an enzyme. They discovered that HsTSPO1 breaks down protoporphyrin IX, a compound found in oxygen-rich red blood cells, to create a novel product that the scientists have named bilindigin. This product helps control the level of “reactive oxygen species” (ROS) in our bodies, a type of compound that can lead to inflammation and kill cells if left unregulated. This finding suggests that, when valium and other benzodiazepines bind to HsTSPO1, they inhibit the protein’s ability to manage ROS levels in our cells. This may help explain why such medications cause side effects over time, though more research is needed to fully understand whether these molecular mechanisms play a part in driving adverse side effects.
“The enzyme activity that we found for HsTSPO1 both reduces the production and the neutralization of ROS,” Hendrickson said. “This discovery then provides a rationale for fresh approaches in drug discovery.”
The new insights into HsTSPO1’s function could help pharmaceutical companies develop improved benzodiazepines. Furthermore, because of its newly discovered role in regulating reactive oxygen species, the researchers say HsTSPO1 might serve as a promising drug target for monitoring and treating neurodegenerative diseases, like Alzheimer’s, as well as other inflammation-related conditions that have connections to HsTSPO1. This includes some cancers, arthritis and MS.
“Benzodiazepines are still widely used to treat anxiety, insomnia, seizures and other conditions. Now that we have an understanding of how HsTSPO1 works, we could potentially create better drugs with less side effects,” Guo said. “But on a larger scale, our insights into this protein could have significant implications for developing new therapeutic options for patients impacted by inflammatory diseases.”
Female hormones can suppress pain by making immune cells near the spinal cord produce opioids, a new study from researchers at UC San Francisco has found. This stops pain signals before they get to the brain.
The discovery could help with developing new treatments for chronic pain. It may explain why some painkillers work better for women than men and why postmenopausal women, whose bodies produce less of the key hormones oestrogen and progesterone, experience more pain.
The work reveals an entirely new role for T regulatory immune cells (T-regs), which are known for their ability to reduce inflammation.
“The fact that there’s a sex-dependent influence on these cells – driven by oestrogen and progesterone – and that it’s not related at all to any immune function is very unusual,” said Elora Midavaine, PhD, a postdoctoral fellow and first author of the study, which appears in Science.
The researchers looked at T-regs in the protective layers that encase the brain and spinal cord in mice. Until now, scientists thought these tissue layers, called the meninges, only served to protect the central nervous system and eliminate waste. T-regs were only discovered there in recent years.
“What we are showing now is that the immune system actually uses the meninges to communicate with distant neurons that detect sensation on the skin,” said Sakeen Kashem, MD, PhD, an assistant professor of dermatology. “This is something we hadn’t known before.”
That communication begins when a neuron, often near the skin, receives a stimulus and sends a signal to the spinal cord.
The team found that the meninges surrounding the lower part of the spinal cord harbour an abundance of T-regs. To learn what their function was, the researchers knocked the cells out with a toxin.
The effect was striking: Without the T-regs, female mice became more sensitive to pain, while male mice did not. This sex-specific difference suggested that female mice rely more on T-regs to manage pain.
“It was both fascinating and puzzling,” said Kashem, who co-led the study with Allan Basbaum, PhD. “It actually made me sceptical initially.”
Further experiments revealed a relationship between T-regs and female hormones that no one had seen before: Estrogen and progesterone were prompting the cells to churn out enkephalin, a naturally occurring opioid.
Exactly how the hormones do this is a question the team hopes to answer in a future study. But even without that understanding, the awareness of this sex-dependent pathway is likely to lead to much-needed new approaches for treating pain.
In the short run, it may help physicians choose medications that could be more effective for a patient, depending on their sex. Certain migraine treatments, for example, are known to work better on women than men.
This could be particularly helpful for women who have gone through menopause and no longer produce oestrogen and progesterone, many of whom experience chronic pain.
The researchers have begun looking into the possibility of engineering T-regs to produce enkephalin on a constant basis in both men and women.
Photo by Mikhail Nilov: https://www.pexels.com/photo/paramedics-using-a-defibrillator-on-a-patient-8942635/
Patients who receive an add-on medication soon after a heart attack have a significantly better prognosis than those who receive it later, or not at all. These are the findings of a new study from researchers at Lund University in Sweden and Imperial College London.
Their analysis suggests that treating patients earlier with a combination of statins and the cholesterol-lowering drug ezetimibe could prevent thousands of new heart attacks in the UK over a decade.
Cardiovascular disease is by far the most common cause of death worldwide, with heart attack (‘myocardial infarction’) being the most common acute event.
For those who survive a heart attack, the risk of a new heart attack is greatest in the first year after the initial event because the blood vessels are more sensitive, making it easier for blood clots to develop.
Our findings suggest that a simple change in treatment guidelines could have a huge impact on patients and reduce the demand on the NHS.
Professor Kausik Ray, School of Public Health
Reducing LDL or “bad” cholesterol in the blood can stabilise changes in the vessels, decreasing the risk for new events.
The current treatment guidelines for patients are high-potency statins immediately after a heart attack, to lower their cholesterol levels.
However, the majority of patients do not reach recommended cholesterol levels using only statins, and so need an add-on treatment, such as ezetimibe.
“Today’s guidelines recommend stepwise addition of lipid-lowering treatment. But it’s often the case that this escalation takes too long, it’s ineffective and patients are lost to follow-up,” says Margrét Leósdóttir, Associate Professor at Lund University and senior cardiology consultant at Skåne University Hospital in Malmö, Sweden. “By giving patients a combination treatment earlier, we could help to prevent many more heart attacks.”
Co-investigator Professor Kausik Ray, from Imperial College London’s School of Public Health, said: “This study shows that we could save lives and reduce further heart attacks by giving patients a combination of two low-cost drugs.
“But at the moment patients across the world aren’t receiving these drugs together. That’s causing unnecessary and avoidable heart attacks and deaths – and also places unnecessary costs on healthcare systems.
“Our study shows the way forward; care pathways must now change for patients after this type of heart event.”
Reducing heart attacks
In the latest study, the international team examined outcomes for heart attack patients if they received a combination of statins with the add-on therapy ezetimibe (within 12 weeks after a heart attack), statins with ezetimibe added later (between 13 weeks and 16 months), or just statins with no ezetimibe at all.
Based on Swedish registry data from 36 000 patients who had a heart attack between 2015 and 2022, the researchers used advanced statistical models to emulate a clinical trial.
The results show that patients who received a combination treatment of statins and ezetimibe within 12 weeks of a heart attack and were able to lower cholesterol to the target level early, had a better prognosis and less risk of new cardiovascular events and death than those who received the add-on treatment later, or not at all.
From the analysis, the researchers believe many new heart attacks, strokes and deaths could be prevented every year internationally if the treatment strategy were to be changed.
Under a scenario in which 100% of patients would receive ezetimibe early, they estimate 133 heart attacks could be avoided in a population of 10 000 patients in 3 years.
The researchers suggest that in the UK, which records an estimated 100 000 hospital admissions from heart attacks a year,[1] this would equate to an estimated 5000 heart attacks being prevented over a ten year period.[2]
Improving guidance
Dr Leósdóttir said: “Combination therapy is not applied up-front for two main reasons. General recommendations are not included in today’s guidelines and a precautionary principle is applied to avoid side effects and overmedication.
However, there are positive effects from applying both medicines as soon after the infarction as possible. Not doing this entails an increased risk. In addition, the drug we have examined in the study causes few side effects and is readily available and inexpensive in many countries.”
Margrét Leósdóttir hopes that the research results will in time provide support for changes in the recommendations. A treatment algorithm has already been introduced at her hospital in Sweden to help doctors to prescribe appropriate lipid-lowering treatment for patients who have had a myocardial infarction.
It has been noted that patients achieve their treatment goals earlier and two months after the infarction twice as many patients have reduced their bad cholesterol to the target level, compared with previously.
“Several other hospitals in Sweden have also adopted the algorithm and there are similar examples from other countries that have produced as good results. My hope is that even more will review their procedures, so that more patients will get the right treatment in time, and we can thereby prevent unnecessary suffering and save lives.”
In a move that will come as a relief for the hundreds of unemployed doctors currently seeking positions within public healthcare, the Department of Health has announced the creation of 1650 new positions for healthcare professionals. The move includes 1200 new positions for doctors – but only 200 for nurses.
Health Minister Dr Aaron Motsoaledi made the announcement at a media briefing on Thursday 10 April.
“We believe we’re in a position to announce today that the council has approved the advertisement of 1200 jobs for doctors, 200 for nurses and 250 for other healthcare professionals,” Motsoaledi stated. This would come with a cost of R1.78 billion – out of a healthcare budget that has not risen in line with inflation.
Jobless doctors picketed earlier this year as more than 1800 were left in limbo without positions – the true number is likely higher. The South African Medical Association (SAMA) had sent an urgent letter to President Cyril Ramaphosa, warning that if the problem was not addressed, doctors would leave for the private sector or emigrate, leading to the collapse of the public healthcare sector.
The road to specialisation had also been made more challenging by the shortage of positions, with junior doctors have been taking unpaid roles. Such unpaid work does not count toward the registrar component of specialisation and largely only serves to bump up the doctor’s CV by, for example, enabling them to apply for diplomas. Hiring freezes also saw GPs unable to move into government positions, and the limited number of registrar positions has also by some accounts become a bottleneck, with no additional registrar positions added for the past 10–15 years.
Regarding the loss of US funding for HIV programmes, he said that there was a buffer of stock for ARVS, and that “no person needing ARVs would lack” those drugs.
But the small number of new nurse positions was not well received. The Democratic Nursing Organisation of South Africa (DENOSA) was particularly unimpressed given the pressure on overburdened nurses.
DENOSA spokesperson Sonia Mabunda-Kaziboni said, “In the face of a nationwide crisis of nurse shortages, this announcement is not only shockingly inadequate but downright insulting to the nursing fraternity.”
Calling it a “slap in the face”, she continued: “The shortage of nurses in South Africa is nothing short of a devastating crisis. The Free State alone faces a 28% vacancy rate, and similar figures are reflected in other provinces such as the Eastern Cape. National projections estimate that South Africa could be short by over 100 000 nurses by 2030 if urgent interventions are not made.”
DENOSA plans to “name and shame” institutions that have become “dangerous to communities” as a result of unresolved poor conditions.
