Tag: 17/1/24

Categories : Cardiovascular Disease Environmental EffectsTags :

Reduced Blood Lead Levels Tied to Lower Blood Pressure

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Researchers found that small declines in blood lead levels were associated with long-term cardiovascular health improvements in American Indian adults. Participants who had the greatest reductions in blood lead levels saw their systolic blood pressure fall by about 7mmHg, comparable to the effects of antihypertensives.

The findings as reported from researchers at Columbia University Mailman School of Public Health and NIEHS and NHLBI are published in the Journal of the American Heart Association.

“This is a huge win for public health,” said senior author Anne E. Nigra, PhD, assistant professor of environmental health sciences at Columbia Mailman School of Public Health.

“We saw that even small decreases in a person’s blood lead levels can have meaningful health outcomes.”

Nigra and her co- authors, including Wil Lieberman-Cribbin, MPH, also at Columbia Mailman School, credit these improvements in large part to public health and policy changes that have occurred over the last few decades.

In addition to seeing improvements in systolic blood pressure, the investigators found that reductions in blood lead levels were associated with reductions in a marker associated with hypertrophic cardiomyopathy and heart failure.

To conduct this research, investigators partnered with 285 American Indian adults through an extension of the Strong Heart Study, the largest study following cardiovascular health outcomes and risk factors among American Indian adults.

The researchers looked at blood lead levels and blood pressure readings over time in participants living in one of four tribal communities. Lead was first measured in blood collected during the 1997–1999 study visit and again in blood collected during a follow-up visit between 2006–2009.

During this time, participants’ blood pressure was taken and they participated in medical exams, including echocardiographs to assess their heart’s structure and function. Multiple factors were controlled for, including social variables, cardiovascular disease risks, and medical history.

At the start of the study, the average blood lead level was 2.04µg/dL. Throughout the study, the average blood lead level fell by 0.67µg/dL, or 33%.

The most significant changes, categorized by participants with average starting blood lead levels of 3.21 µg/dL and who experienced reductions of about 1.78 µg/dL, or 55%, were linked to a 7mmHg reduction in systolic blood pressure.

“This is a sign that whatever is happening in these communities to reduce blood lead levels is working,” said Mona Puggal, MPH, an epidemiologist in the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI). “The reductions in blood pressure are also comparable to improvements you would see with lifestyle changes, such as getting 30 minutes of daily exercise, reducing salt intake, or losing weight.”

The reductions in blood lead levels observed in the study are similar to those seen in the general US population following policies and efforts implemented within the past 50 years to reduce lead exposure through paint, gasoline, water, plumbing, and canned items.

Source: Columbia University’s Mailman School of Public Health

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Categories : NeurologyTags :

Amnesia from Head Injury Reversed in Early Mouse Study

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A mouse-based study to investigate memory loss in people who experience repeated head impacts, such as athletes, suggests the condition could potentially be reversed. The research in mice finds that amnesia and poor memory following head injury is due to inadequate reactivation of neurons involved in forming memories.

The study, conducted by researchers at Georgetown University Medical Center in collaboration with Trinity College Dublin, Ireland, is reported in the Journal of Neuroscience.

Importantly for diagnostic and treatment purposes, the researchers found that the memory loss attributed to head injury was not a permanent pathological event driven by a neurodegenerative disease.

Indeed, the researchers could reverse the amnesia to allow the mice to recall the lost memory, potentially allowing cognitive impairment caused by head impact to be clinically reversed.

The Georgetown investigators had previously found that the brain adapts to repeated head impacts by changing the way the synapses in the brain operate, which can cause trouble in memory storage and retrieval.

In their new study, investigators were able to trigger mice to remember memories that had been forgotten due to head impacts.

“Our research gives us hope that we can design treatments to return the head-impact brain to its normal condition and recover cognitive function in humans that have poor memory caused by repeated head impacts,” says the study’s senior investigator, Mark Burns, PhD, a professor and Vice-Chair in Georgetown’s Department of Neuroscience and director of the Laboratory for Brain Injury and Dementia.

In the new study, the scientists gave two groups of mice a new memory by training them in a test they had never seen before. One group was exposed to a high frequency of mild head impacts for one week (similar to contact sport exposure in people) and one group were controls that didn’t receive the impacts. The impacted mice were unable to recall the new memory a week later.

“Most research in this area has been in human brains with chronic traumatic encephalopathy (CTE), which is a degenerative brain disease found in people with a history of repetitive head impact,” said Burns.

“By contrast, our goal was to understand how the brain changes in response to the low-level head impacts that many young football players regularly experience.”

Researchers have found that, on average, college football players receive 21 head impacts per week with defensive ends receiving 41 head impacts per week.

The number of head impacts to mice in this study were designed to mimic a week of exposure for a college football player, and each single head impact by itself was extraordinarily mild.

Using genetically modified mice allowed the researchers to see the neurons involved in learning new memories, and they found that these memory neurons (the “memory engram”) were equally present in both the control mice and the experimental mice.

To understand the physiology underlying these memory changes, study first author Daniel P. Chapman, PhD, said, “We are good at associating memories with places, and that’s because being in a place, or seeing a photo of a place, causes a reactivation of our memory engrams. This is why we examined the engram neurons to look for the specific signature of an activated neuron. When the mice see the room where they first learned the memory, the control mice are able to activate their memory engram, but the head impact mice were not. This is what was causing the amnesia.”

The researchers were able to reverse the amnesia to allow the mice to remember the lost memory using lasers to activate the engram cells.

“We used an invasive technique to reverse memory loss in our mice, and unfortunately this is not translatable to humans,” Burns adds.

“We are currently studying a number of non-invasive techniques to try to communicate to the brain that it is no longer in danger, and to open a window of plasticity that can reset the brain to its former state.”

Source: Georgetown University Medical Center

  1. Daniel P. Chapman, Sarah D. Power, Stefano Vicini, Tomás J. Ryan, Mark P. Burns. Amnesia after repeated head impact is caused by impaired synaptic plasticity in the memory engram. The Journal of Neuroscience, 2024; e1560232024 DOI: 10.1523/JNEUROSCI.1560-23.2024
Categories : Mental Health NeurologyTags :

Scientists may have Found out How Rapid-acting Antidepressants Work

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Photo by Marek Piwnicki

Rapid-acting antidepressants, including ketamine, scopolamine and psilocybin, have been found to have immediate and lasting positive effects on mood in patients with major depressive disorder but how these effects arise is unknown. New research led by the University of Bristol and published in Science Translational Medicine explored their neuropsychological effects and found that all three of these drugs can modulate affective biases associated with learning and memory.

Negative affective biases are a core feature of major depressive disorder. Affective biases occur when emotions alter how the brain processes information and negative affective biases are thought to contribute to the development and continuation of depressed mood.

The research team used an affective bias test, based on an associative learning task, to investigate the effects of rapid-acting antidepressants (RAADs) in rats.

They found that all the treatments were able to reduce negative affective biases associated with past experiences but there were additional characteristics of the dissociative anaesthetic, ketamine, and the serotonergic psychedelic, investigational COMP360 psilocybin (Compass Pathways’ proprietary formulation of synthetic psilocybin), which could explain why the effects of a single treatment can be long-lasting.

The findings suggest that these sustained effects are due to adaptive changes in the brain circuits which control affective biases, and these can influence how past experiences are remembered.

The effects at low doses were very specific to affective bias modulation and were localised to the prefrontal cortex of the brain, a region known to play an important role in mood.

Emma Robinson, Professor of Psychopharmacology in the School of Physiology, Pharmacology & Neuroscience at Bristol, and lead author, said: “Using a behavioural task we showed that drugs that are believed to have rapid and sustained benefits in depressed patients, specifically modulate affective biases associated with past experiences, something which we think is really important for understanding why they can improve a patient’s mood so quickly.

“We also found differences in how ketamine, scopolamine and COMP360 psilocybin interact with these neuropsychological mechanisms which may explain why the effects of a single treatment in human patients can be long-lasting, days (ketamine) to months (psilocybin).

“By using an animal model, we have been able to investigate these important interactions with learning and memory processes and neural plasticity and propose a two-stage model that may explain the effects we observe.”

In the task, each animal learnt to associate a specific digging material with a food reward under either treatment or control conditions.

The treatment condition is designed to generate a change in the animal’s affective state and a choice test is used to quantify the affective bias this generates.

Acute treatment with the RAADs ketamine, scopolamine, or psilocybin prevented the retrieval of the negative affective bias induced in this model.

However, the most exciting finding was at 24 hours after treatment when low, but not high, doses of ketamine and psilocybin led to a re-learning effect where the negatively biased memory was retrieved with a more positive affective valence.

Only psilocybin, but not ketamine or scopolamine treatment also positively biased new experiences.

Exploring in more detail the re-learning effects of ketamine in the studies, the researchers found they were protein synthesis-dependent, localised to the medial prefrontal cortex and could be modulated by cue-reactivation, consistent with their predictions of experience-dependent neural plasticity.

The study’s findings propose a neuropsychological mechanism that may explain both the immediate and sustained effects of RAADs, potentially linking their effects on neural plasticity with mood.

Source: University of Bristol

Categories : Ageing Diet and NutritionTags :

How Calorie Restriction Slows Aging in the Brain

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Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially in regard to how it protects the brain. Now, scientists from the Buck Institute for Research on Aging have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging.

“When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain,” said Kenneth Wilson, PhD, Buck postdoc and first author of the study, published in Nature Communications. “As it turns out, this is a gene that is important in the brain.”

The team additionally demonstrated a detailed cellular mechanism of how dietary restriction can delay aging and slow the progression of neurodegenerative diseases. The work, done in fruit flies and human cells, also identifies potential therapeutic targets to slow aging and age-related neurodegenerative diseases.

“We found a neuron-specific response that mediates the neuroprotection of dietary restriction,” said Buck Professor Pankaj Kapahi , PhD, co-senior author of the study. “Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects.”

“The gene is an important brain resilience factor protecting against aging and neurological diseases,” said Buck Professor Lisa Ellerby, PhD, co-senior author of the study.

Understanding variability in response to dietary restriction

Members of the team have previously shown mechanisms that improve lifespan and healthspan with dietary restriction, but it was not clear why there is so much variability in response to reduced calories across individuals and different tissues. This project was started to understand why different people respond to diets in different ways.

The team began by scanning about 200 strains of flies with different genetic backgrounds. The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10% of normal nutrition. Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts in human genetics.

The team chose one gene to explore thoroughly, called “mustard” (mtd) in fruit flies and “Oxidation Resistance 1” (OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism for how this gene functions was unclear. The loss of OXR1 in humans results in severe neurological defects and premature death. In mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).

The link between brain aging, neurodegeneration and lifespan

To figure out how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids. “The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” said Wilson. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Alzheimer’s and Parkinson’s diseases.

Overall, their results told the story of how dietary restriction slows brain aging by the action of mtd/OXR1 in maintaining the retromer. “This work shows that the retromer pathway, which is involved in reusing cellular proteins, has a key role in protecting neurons when nutrients are limited,” said Kapahi. The team found that mtd/OXR1 preserves retromer function and is necessary for neuronal function, healthy brain aging, and lifespan extension seen with dietary restriction.

“Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1,” said Wilson.

The team also found that boosting mtd in flies caused them to live longer, leading researchers to speculate that in humans excess expression of OXR1 might help extend lifespan. “Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging,” said Ellerby.

“Hopefully from this we can get more of an idea of why our brains degenerate in the first place,” said Wilson.

“Diet impacts all the processes in your body,” he said. “I think this work supports efforts to follow a healthy diet, because what you eat is going to affect more than you know.”

Source: Buck Institute for Research on Aging

Categories : Cardiovascular DiseaseTags :

Researchers Urge Caution in Co-prescribing Potency Drugs and Nitrates

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Co-prescribing potency drugs such as Viagra and organic nitrates for angina is associated with a 35–40% increased mortality risk and about 70% higher risk of heart attack and heart failure. This is according to a Swedish registry study published in the Journal of the American College of Cardiology. The Swedish researchers are now urging caution.

Drugs for erectile dysfunction or impotence containing phosphodiesterase inhibitors type 5 are contraindicated in the treatment of angina with organic nitrates. Because the two types of drugs enhance each other’s antihypertensive effect, they can cause serious side effects, including death, if taken together.

But many people who treat angina with organic nitrates use the medication as emergency relief for a sudden onset of angina. The medication is quickly absorbed by the body, exerts its effect, and then breaks down quickly again. It is not usually a permanent treatment, although maintenance treatment is possible. 

Does not necessarily indicate an increased risk

Potency drugs are also taken as needed, which theoretically makes it possible to separate the two treatments in time to avoid side effects. If patients are aware of these factors, co-prescribing does not necessarily mean an increased risk.

Previous studies have shown that an increasing number of men who treat their angina with organic nitrates are also prescribed potency drugs. However, there is no evidence that side effects have increased. 

The picture is not entirely clear, as it has also been shown that type 5 phosphodiesterase inhibitors for men with cardiovascular disease without angina reduce the risk of death and heart failure.

“There is an increasing demand for medication for erectile dysfunction from men with cardiovascular disease. And even if these drugs are beneficial for most men with cardiovascular disease, those who are also treated with nitrates need to consider the benefits of the drug against the cardiovascular risks,” says first author Ylva Trolle Lagerros, Associate Professor at the Department of Medicine at Karolinska Institutet.

To find out what the actual risk of concurrent prescribing is, the researchers used Swedish health registers between 2005 and 2013. They found nearly 61 500 men who had been prescribed organic nitrates, of which just over 5700 had also been prescribed one of the potency drugs in question. A clear majority of those who had a prescription for both medications used nitrates as an emergency treatment only.

Adjusted for differences

The men who received the drugs were on average nine years younger and significantly healthier than those who did not receive them. The researchers therefore had to adjust for these and other differences.

The adjusted results show that co-prescribing potency drugs with type 5 phosphodiesterase inhibitors and organic nitrates is associated with a 35–40% increased risk of death. In addition, the researchers show an approximately 70% increased risk of heart attack and heart failure. This suggests that the theoretical separation in time of the treatments does not seem to work fully.

“We want to point out the importance of careful and patient-centered consideration before prescribing this type of potency medication to men treated with nitrates,” says Ylva Trolle Lagerros.

Source: Karolinska Institutet