Tag: 15/4/25

Categories : Cardiovascular Disease Diet and NutritionTags : Leave a comment

Daytime-only Meals Could Protect People from the Heart Risks of Shift Work

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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.

Source: Mass General Brigham

Categories : Mental Health Obstetrics & GynaecologyTags : Leave a comment

Gestational Diabetes Linked to ADHD in Children

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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.”

Source: Edith Cowan University

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Solving a Decades-old Mystery Behind Side Effects of Benzodiazepines

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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.”

Source: Virginia Commonwealth University

Categories : Obstetrics & Gynaecology Pain ManagementTags : Leave a comment

Oestrogen and Progesterone Stimulate the Body to Make Opioids

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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.

Source: University of California – San Francisco

Categories : Cardiovascular Disease New Compounds and TreatmentsTags : Leave a comment

Add-on for Statins Greatly Reduces Recurrence of Heart Attacks

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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 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.”

Source: Imperial College London