Tag: 10/1/24

Categories : Ageing Regenerative MedicineTags :

Restoring Muscle Strength Lost to Aging or Injury

On By ModernMedia
Photo by Barbara Olsen on Pexels

A small molecule previously shown to enhance strength in injured or old laboratory mice does so by restoring lost connections between nerves and muscle fibres, Stanford Medicine researchers have found.

The molecule blocks the activity of an aging-associated enzyme, or gerozyme, called 15-PGDH that naturally increases in muscles as they age. The study, which was published in Science Translational Medicine, showed that levels of the gerozyme increase in muscles after nerve damage and that it is prevalent in muscle fibres of people with neuromuscular diseases.

The research is the first to show that damaged motor neurons can be induced to regenerate in response to a drug treatment and that lost strength and muscle mass can be at least partially regained. It suggests that, if similar results are seen in humans, the drug may one day be used to prevent muscle loss of muscle strength due to aging or disease or to hasten recovery from injury.

It’s estimated that sarcopenia, or debilitating muscle frailty, affects about 30% of people over 80 and costs the United States around $380 billion each year.

“There is an urgent, unmet need for drug treatments that can increase muscle strength due to aging, injury or disease,” said Helen Blau, PhD, professor of microbiology and immunology. “This is the first time a drug treatment has been shown to affect both muscle fibres and the motor neurons that stimulate them to contract in order to speed healing and restore strength and muscle mass. It’s unique.”

Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study. Postdoctoral scholar Mohsen Bakooshli, PhD, and former postdoctoral scholar Yu Xin Wang, PhD, are the lead authors of the study. Wang is now an assistant professor at the Sanford Burnham Prebys Medical Discovery Institute in San Diego.

Addressing loss of strength

The finding is the latest from the Blau laboratory focused on understanding how muscles weaken from aging or disease, and whether it’s possible to combat this decline. In 2021, the group showed that blocking the activity of 15-PGDH in 24-month-old laboratory mice significantly enhances the animals’ leg strength and endurance when running on a treadmill. (Laboratory mice typically live about 26 to 30 months.) But it wasn’t clear exactly how.

The new research shows that the effect is due to the restoration of lost connections between the nerves and the muscle. These connections, called neuromuscular junctions, are how the brain signals muscles to contract. In aging, some of these connections are lost, causing muscle contractions to become less powerful and muscles to atrophy. People typically lose muscle mass and strength, up to 10% per decade, after the age of 50.

Conditions other than aging can also destabilise these connections, including the disuse of muscles due to bedrest after illness or injury, or muscle-wasting diseases like spinal muscular atrophy or amyotrophic lateral sclerosis (also known as ALS).

Blau’s previous research showed that a molecule called PGE2 is critical to the function of stem cells in muscle fibres that repair damage – including the microtears from exercise that lead to an increase in muscle mass and strength. They subsequently showed that levels of 15-PGDH, which breaks down PGE2, increase in the muscles with age and that the loss of strength with aging could be overcome by inhibiting the activity of this PGE2-degrading enzyme.

“PGE2 is part of the body’s natural healing mechanism, and its levels increase in muscle after injury,” Blau said. “We wanted to learn how age triggers an increase in 15-PGDH, and therefore the degradation and loss of PGE2.”

A lack of nerves

The researchers knew that muscles become less innervated, or infiltrated with nerves, as people and animals age. They wondered if that loss could be what triggers the rising levels of 15-PGDH.

“We found that when you cut the nerve that innervates the leg muscles of mice, the amount of 15-PGDH in the muscle increases rapidly and dramatically,” Blau said. “This was an exciting new insight. But what surprised us most was that when these mice are treated with a drug that inhibits 15-PGDH activity, the nerve grows back and makes contact with the muscle more quickly than in control animals, and that this leads to a faster recovery of strength and function.”

Additional experiments showed that treatment with the drug restored neuromuscular junctions lost during aging and increased muscle strength and function in old laboratory mice. The researchers also identified discrete clumps of 15-PGDH in the muscle fibres of people with several types of neuromuscular disorders suggesting that the gerozyme may have a role in causing these human disorders.

Blau and her colleagues plan to investigate at a molecular level how neural growth is stimulated by blocking 15-PGDH activity. Blau has also co-founded a company, Epirium Bio, to develop similar drugs for use in humans. Although her lab is still conducting animal studies, the company hopes to launch a clinical trial within the next year or so.

“Our next steps will be to examine whether blocking 15-PGDH function in people with spinal muscular atrophy can increase lost muscle strength in combination with gene therapy or other treatments,” Blau said. “We are also looking at ALS to see if something like this might help these patients. It’s really exciting that we are able to affect both muscle function and motor neuron growth.”

Source: Stanford Medicine

Categories : NeurologyTags :

Oestrogen Receptor Involved in Social Anxiety Suppression in Male Mice

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Source: CC0

Researchers at the University of Tsukuba in Japan have discovered that oestrogen receptor (ER) β, expressed in the lateral septum of the limbic system, plays a crucial role in suppressing anxiety-like behaviour by male mice in social situations. Publishing their findings in Neuroscience, they also reported that the distribution and expression region of ERβ differs from that of ERα.

Oestradiol, a sex steroid hormone, plays an essential role in social behaviour, including regulating social anxiety, which is anxiety experienced when unknown individuals are encountered.

In males, testosterone secreted by the testes is converted to oestradiol in the brain, and the oestradiol binds to two types of oestrogen receptors (ERs), ERα and ERβ, to regulate social behaviour. However, its neuroendocrine basis has not been understood. In this study, the role of ERα and ERβ expressed in the lateral septum (LS), which regulates social anxiety, was investigated using male mice.

The researchers first investigated the expression of ERα and ERβ in the LS using genetically modified male mice. ERβ-expressing cells in the mice were labelled with red fluorescent protein, which revealed that the distributions of ERα and ERβ are different.

Furthermore, the researchers investigated the knockdown effects of ERα or ERβ gene expression in the LS of male mice during situations of social and nonsocial anxiety. The results show that social anxiety increases with the inhibition of ERβ expression.

Additionally, ERα- and ERβ-positive cells in the LS projected into different regions of the hypothalamus.

Thus, the researchers concluded that ERα- and ERβ-expressing cells in LS are distinct cell populations with different localisations and neuronal projections, and the ERβ population plays a crucial role in neural circuitry that regulates anxiety-like behaviour in social situations.

Source: University of Tsukuba

Categories : COVIDTags :

Paxlovid does not Reduce Risk of Long COVID, Study Finds

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Image by Fusion Medical on Unsplash

A recent has study found that Paxlovid (Nirmatrelvir-ritonavir) did not reduce the risk of developing long COVID for vaccinated, non-hospitalised individuals during their first COVID infection. The study also revealed a higher proportion of individuals with acute symptoms rebound and test-positivity than previously reported.

The study, by a team of researchers from UC San Francisco, is published in the Journal of Medical Virology.

Paxlovid treatment for acute COVID has been shown to be effective for high-risk unvaccinated individuals. But the effect of the treatment on long COVID risk, including whether it protects vaccinated people from getting long COVID, has been less clear.

The research team selected a group of vaccinated people from the UCSF Covid-19 Citizen Science study who had reported their first positive test for COVID-19 between March and August of 2022 and who were not hospitalised.

Some of these participants reported taking oral Paxlovid treatment during the acute phase of their COVID infection, while others did not.

In December of 2022, they were invited to answer a follow-up survey with questions about long COVID, COVID rebound symptoms and how long they continued to test positive.

Researchers found the two groups were similar. About 16% of those treated with Paxlovid had long COVID symptoms compared to 14% of those who were not treated with the medication.

Commonly reported symptoms included fatigue, shortness of breath, confusion, headache, and altered taste and smell.

Those who took Paxlovid and then went on to develop long COVID reported as many long COVID symptoms as those who were not treated with Paxlovid.

A small percentage of people developed severe long COVID, and those who had received Paxlovid were just as likely to have severe Long COVID symptoms as those who did not.

Among individuals who experienced symptomatic improvement during Paxlovid treatment, 21% reported rebound symptoms.

And among those with rebound symptoms, 10.8% reported one or more Long COVID symptom compared to 8.3% without rebound symptoms.

For participants who repeated antigen testing after testing negative and completing treatment, 25.7% reported rebound test positivity.

In total, 26.1% reported rebound symptoms or test positivity.

“We found a higher proportion with clinical rebound than previously reported but did not identify an effect of post-treatment rebound on long COVID symptoms,” said study first author Matthew Durstenfeld, MD, MAS, a cardiologist and UCSF assistant professor of Medicine.

“Our finding that Paxlovid treatment during acute infection is not associated with lower odds of long COVID surprised us, but it is consistent with two other rigorously conducted studies finding no difference in post-COVID conditions between 4 and 6 months after infection.”

The authors note that the study may have been impacted by limitations arising from its observational nature with researchers relying on patient self-reporting of treatment and Long COVID symptoms.

Source: University of California San Francisco Medical Center

Categories : Mental Health Obstetrics & GynaecologyTags :

Perinatal Depression Triples the Risk of Suicidal Behaviour

On By ModernMedia
Photo by Sydney Sims on Unsplash

Maternal suicide is an alarming public health issue and the second most common cause of death during the postnatal period. New research from Karolinka Institutet in Sweden shows that mothers with clinically diagnosed perinatal depression had a three times higher risk of suicidal behaviour compared to mothers without perinatal depression. The findings were published in JAMA Network Open.

Some 13–36% of maternal deaths are attributable to suicide, and the consequences are devastating to the newborn and the family. Maternal suicide is linked to a complex interplay of risk factors, including history of psychiatric disorders, socioeconomic disparities, and inadequate access to healthcare service. It is of paramount importance to identify high-risk populations for preventing maternal suicide and suicidal attempt.

Our findings suggest that women with clinically diagnosed PND are at an increased risk of suicidal behavior, particularly within one year after PND yet throughout 18 years of follow-up. This highlights the pressing need for vigilant clinically monitoring and prompt intervention for this vulnerable population to prevent such devastating outcomes, regardless of pre-pregnancy history of psychiatric disorders.

Hang Yu, PhD student

In this nationwide population-matched cohort study with a maximal follow-up of 18 years, 86 551 women with PND from 2001 to 2017 and 865 510 unaffected women individually matched on age and calendar year at delivery. Sibling comparison was employed to account for familial confounding. It was found that women with a clinical diagnosis of PND have an elevated risk of suicidal behaviour compared to population-matched women or their full sisters without PND. Attenuated yet still substantially elevated risks were observed when comparing with full sisters without PND who share partial genetic and familial environmental factors with affected women. Importantly, such excess risk was apparent among women regardless of their history of psychiatric disorders, suggesting that PND is linked to an added risk of suicidal behaviour beyond that the risk associated with psychiatric disorders occurring before the perinatal period. Moreover, the risk elevations were particularly high shortly after the PND diagnosis, and despite of the rapid decline over time, remained throughout 18 years of follow-up.

Source: Karolinska Institutet

Categories : Dentistry Expert OpinionTags :

Opinion: We can’t Simply Close Dental Facilities during the Festive Period

On By ModernMedia
Photo by Tima Miroshnichenko on Pexels

By Bulela Vava for Spotlight

On the 2nd of January 2024, Simphiwe*, needing emergency oral healthcare, turned to the Cala District Hospital in the Eastern Cape. However, she was confronted with a note on the door that read, “Dear Community Members, starting from the 18th of December 2023 to the 12th of January 2024 there is no dentist. The dentist will start working on the 15th of January 2024.”

Many such notices hang in front of oral health clinic doors, mostly where dentists work alone to respond to the myriad of emergency oral health needs within their catchment area. Having previously worked alone at a provincial government funded hospital in the rural Eastern Cape, similar notices would be placed on the door to the oral health clinic I operated, until such time as a colleague joined me at the facility.

Oral diseases affect more than 3 billion people globally, while in Africa, it affects an estimated 400 million people.

Oral diseases and conditions that affect people include trauma-related oral injuries, oral cancers, dental decay, and periodontal disease amongst others.

While dental decay remains the most common form of oral disease, untreated, it can lead to life-threatening complications. The closure of dental services at any oral health clinic may subject people to the risk of developing conditions such as Ludwig’s angina, a life-threatening condition that is linked to delayed access to care.

Fewer than 200 dentists

The Eastern Cape is predominantly a rural province, with most of the province’s 7.2 million people largely depending on public healthcare services for the majority, if not all their healthcare needs. The province employs fewer than 200 dentists, a majority of whom are concentrated in the more urban/peri-urban centres.

Cala, a rural town in the province’s Sakhisizwe Local Municipality, is home to an estimated 63 000 people and Cala District Hospital provides access to oral health services to this population. The hospital’s closed dental clinic over the festive period deprived the people of Cala of much-needed care.

It is well known that the festive period results in an increased need for emergency healthcare, including oral healthcare services. People often present with jaw fractures, tooth fractures -often a result of violence or accidents associated with an increase in alcohol consumption -, oral pain and sepsis. While the festive period may result in the increased need for managing these conditions, these are the usual conditions, amongst others, that are managed in many public oral health clinics in most provinces.

Oral health professionals, in particular dentists, are trained to manage the complete spectrum of general oral diseases and often refer to dental specialists for complex and specialised management. In a province like the Eastern Cape, characterised by a dire shortage of dental specialists, dentists are the last defence for many of the people in the province.

A significant portion of dentists in the province work alone, with limited options to manage their leave, often leaving clinics closed in their absence.

However, the closure of dental clinics without a detailed and well-communicated plan is unacceptable and places the lives of populations in danger. At times, people have been known to resort to harmful and dangerous home practices to relieve themselves of their anguish.

We need a plan

A comprehensive plan must be put in place for efficient management and referral of emergency oral healthcare cases during the festive period so that we avoid a repeat of this year’s unacceptable situation at Cala District Hospital 12 months down the line. People in need of oral health services must be made aware of where they can access such services without any delay.

Beyond this, there is a need to invest in building adequate human resource capacity for oral health in the province, to ensure that services are readily available. A mix of oral health professionals and the prioritisation of “lone dentist” clinics for community service placements should help alleviate some of the problems in the system.

It is concerning that the challenges faced in the Eastern Cape is very similar to those in other parts of the country. Fewer than 3000 dentists are working in the public healthcare sector nationwide. With such numbers it is unlikely that what happened to Simphiwe was an isolated incident. Her experience should serve as an important case study, highlighting the significant problems faced by communities and oral health professionals.

Those responsible for managing oral healthcare services in South Africa must take note and recognise that the continued deprioritisation and neglect of the population’s oral health cannot be allowed to continue.  We must work together to ensure that oral health is given the attention it deserves as a critical aspect of general health and well-being.

*Dr Vava is the President of the Public Oral Health Forum, a network of public oral health professionals striving for oral health equity, dignity and well-being for all.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight