Tag: 23/9/24

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Fever Drives Enhanced Activity and Mitochondrial Damage in Immune Cells

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Photo by Kelly Sikkema on Unsplash

Fever temperatures accelerate immune cell metabolism, proliferation and activity, but in a particular subset of T cells, it also causes mitochondrial stress, DNA damage and cell death, Vanderbilt University Medical Center researchers have discovered. 

The findings, published in the journal Science Immunology, offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer. 

The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, Professor of Immunobiology and corresponding author of the new study. Most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37°C. 

“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology. 

Graduate student Darren Heintzman was interested in the impact of fevers for personal reasons: Before he joined the Rathmell lab, his father developed an autoimmune disease and had a constant fever for months on end. 

“I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said. 

Heintzman cultured immune system T cells at 39°C. He found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity. 

“If you think about a normal response to infection, it makes a lot of sense: You want effector (helper) T cells to be better at responding to the pathogen, and you want suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said. 

But the researchers also made an unexpected discovery: that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die? 

The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress. 

“There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better – they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.

Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signalling mechanisms that led to DNA damage and activation of the tumour suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.

 The researchers found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined. 

“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what it does. If temperature changes shift the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. This is fundamental textbook kind of stuff.” 

The findings suggest that heat can be mutagenic, when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die. 

“Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation. 

“People ask me, ‘Is fever good or bad?’” Rathmell added. “The short answer is: A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.” 

Source: Vanderbilt University Medical Center

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Transperineal Prostate Biopsy is Safer than the Standard Technique

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

A multi-institutional clinical trial led by Weill Cornell Medicine and NewYork-Presbyterian investigators showed that a newer technique for collecting prostate biopsy samples reduced the risk of infection compared with traditional biopsy approaches and removed the need for prophylactic antibiotics. The results of the study appear in JAMA Oncology.

The technique, called transperineal prostate biopsy, collects prostate tissue via a needle through the skin of the perineum, the area between the rectum and the scrotum. The procedure, which uses local anesthesia to numb the area, allows physicians to bypass the traditional and more infection-prone route of collecting prostate biopsy tissue with a needle through the rectum.

The PReclude infection EVEnts with No prophylaxis Transperineal (PREVENT) trial, funded by the National Cancer Institute, part of the National Institutes of Health, was conducted at multiple sites, including NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. The study found no infections among 382 men randomised to undergo the transperineal procedure compared with six infections affecting 1.6% of the 370 men randomised to undergo the traditional transrectal biopsy procedure. The lower infection rate is particularly remarkable because the men in the transrectal biopsy group received a targeted course of antibiotics designed to help reduce their infection risk, and the men in the transperineal group received no antibiotics.

“Transperineal biopsy should be the new standard of care for prostate biopsy,” said Dr Jim Hu, Professor of Urologic Oncology at Weill Cornell Medicine. “It was as effective as the traditional transrectal biopsy approach at detecting cancer, but without the risk of infection or the need for antibiotics.”

Prostate biopsies are an essential tool for detecting prostate cancer, and about 3 million people worldwide undergo the procedure each year. Dr Hu noted that physicians collect about 90% of these biopsies in the United States via a transrectal procedure. Yet studies have found that 5% to 7% of patients develop infections after biopsy, and 1% to 3% require hospitalisation for these complications, he said. To help prevent infections, physicians typically prescribe a prophylactic course of antibiotics before the procedure.

Dr. Hu noted that the investigators used a personalised approach to prophylactic antibiotics in the patients undergoing the transrectal biopsy procedure. Rather than giving the men a broad-spectrum antibiotic or multiple antibiotics, they matched the antibiotics to cultures obtained from the patient’s rectum during prostate exams before the procedure. This targeted antibiotic approach reduced the infection rate in those undergoing the traditional transrectal procedure substantially compared with the national infection rate for the procedure. Yet, they achieved a statistically significant reduction in infections in the transperineal group by eliminating infections altogether.

 “Transperineal prostate biopsy makes a common diagnostic procedure safer for men,” said Dr Hu, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It also eliminates the use of antibiotics, helping to reduce the emergence of antibiotic-resistant infections, a growing public health concern.”

Despite the promise of the new procedure, Dr. Hu acknowledged a few hurdles to making it more widely available to men in the United States. He explained that few physicians in the country have been trained in the perineal procedure. Additionally, he noted that US insurers pay the same amount for either procedure but the transperineal biopsy costs more and takes longer to perform, creating a financial disincentive for physicians to make the switch.

However, there is reason to think the status quo will change, Dr Hu said, noting the switch to transperineal prostate biopsies in Norway after a man died after a routine transrectal prostate biopsy. The change virtually eliminated biopsy-related infections and deaths in that country with the nationwide switch to transperineal biopsy, he said.

“There is a strong case to make the switch,” he said. “It will take time. But as more patients request the new procedure, we think it will become more widely available.”

Source: Weill Cornell Medicine

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Immune Cell Specialises its Roles in Different Tissues

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Source: CC0

A newly published study in the scientific journal Science Immunology has investigating how MAIT cells (mucosa-associated invariant T cells) behave in different tissues. The Karolinska Institutet study shows that these immune cells, which play an important role in the body’s defence against microbes, exhibit different properties depending on the tissue they are in.

MAIT cells are a type of T cell that recognise by-products formed when microbes synthesise riboflavin. This makes them unique in the way they detect and fight infections. The researchers examined MAIT cells from blood, barrier tissues and lymphoid tissue samples from organ donors to understand how these cells function in different tissues.

Different MAIT cells in intestines and liver

“We found that MAIT cells in the intestines have a specialised immunoregulatory profile with high expression of the regulatory enzyme CD39, suggesting that they play a role in protecting the intestinal barrier,” says Johan Sandberg, Professor at the Center for Infectious Medicine (CIM), at the Department of Medicine, Huddinge, Karolinska Institutet.

“In the liver, on the other hand, MAIT cells predominantly exhibit high expression of the marker CD56 and an increased ability to fight microbes.”

The study also shows that the number of MAIT cells in the blood decreases with age but is preserved in the tissues. At the same time, tissue-adapted functions in the intestines and liver become increasingly evident with age.

“Our results highlight the functional heterogeneity of MAIT cells and their adaptation to different tissues.”

The results of the study add a new dimension to the understanding of the immune system and how different types of immune cells specialise to protect different tissues against infections.

“This gives us a better understanding of how this arm of the immune system works and can help us develop new treatments for infectious diseases,” says Johan Sandberg.

Source: Karolinska Institutet

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SA Has the Third Highest Suicide Rate in Africa – There are Steps We can Take to Tackle it

On By ModernMedia
Photo by Alex Green on Pexels

By Vincenzo Sinisi

South Africa has the third highest suicide rate in Africa and Africa has higher rates of suicide than any other continent. In the wake of World Suicide Prevention Day on September 10th, clinical psychologist Vincenzo Sinisi asks what can be done to bring down suicide rates.

Africa is currently the region with the highest suicide rate worldwide, according to the World Health Organization (WHO). This is driven by a combination of factors, including poverty, unemployment, and untreated mental health issues.

South Africa, with a suicide rate of 23.5 per 100 000 people, ranks third worst on the continent. South Africa is closely followed by Lesotho and Eswatini – countries where limited access to mental health services exacerbates the issue.

Age and gender impact suicide risk. In South Africa, for instance, suicide has been rated as the fourth leading cause of death among people aged 15 to 24, reflecting the devastating mental health toll on young people. The gender disparity is stark – men are four to five times more likely to die by suicide than women. However, women tend to report twice as many suicide attempts as men, indicating a significant gap in prevention efforts targeting both genders

Why is it happening?

While suicide is a global challenge, it manifests differently across Africa due to a variety of factors – these include economic hardship, mental health stigma, and the scarcity of healthcare resources.

Mental healthcare in Africa is severely underfunded. Many African countries have an insufficient number of mental health professionals – sometimes as few as one psychiatrist per 500 000 people. This is compounded by widespread mental health stigma, which prevents many people, particularly men, from seeking help. In some African cultures, suicide is stigmatised to the extent that it is linked to supernatural beliefs, such as curses or sorcery. These deep-seated cultural beliefs often lead to underreporting of suicide cases and contribute to delayed intervention.

In addition to cultural taboos, socioeconomic stressors like unemployment, poverty, and housing insecurity further drive suicide rates across the continent. In South Africa’s townships, the levels of indebtedness and joblessness create a cycle of despair that feeds into psychological distress, ultimately increasing the risk of suicide.

In South Africa, the impact of socioeconomic instability on mental health is evident, particularly in rural and impoverished urban areas. The link between unemployment and mental health distress is well-documented, and for many, this distress leads to thoughts of suicide. In economically deprived areas, suicide prevention efforts are often undermined by poor access to healthcare and low mental health literacy. As economic hardship worsens, so does the mental health of affected populations.

What to do?

Preventing suicide in South Africa and on the African continent more broadly requires a multi-level strategy, combining grassroots initiatives with government support. Many successful interventions have originated from community-based programmes tailored to local needs and cultural contexts – there are after all large differences between countries and, for example, between urban and rural areas.

As a starting point, community involvement is crucial in creating a supportive environment for those at risk. By training community leaders, including traditional healers and faith-based leaders, to recognise signs of mental health struggles, these communities can provide immediate support. Peer support networks have also proven effective, especially in areas with limited access to formal healthcare services. Such networks empower individuals to check in on one another and provide emotional support in times of crisis.

For example, the South African Depression and Anxiety Group (SADAG) runs mental health education programmes across rural South Africa, equipping local leaders and volunteers with tools to recognise and respond to signs of suicide. These efforts are helping to reduce stigma and encourage early intervention in communities often overlooked by national healthcare systems.

While community-led efforts are invaluable, government policy is essential for creating systemic change. South Africa’s National Mental Health Policy Framework (2023-2030) aimed to integrate mental health care into the primary healthcare system. Still, its implementation has been slow, particularly in rural areas. Expanding this framework and ensuring proper funding for mental health initiatives must be a priority. (Spotlight previously reported on expert responses to the new mental health policy.)

Governments can also collaborate with NGOs and the private sector to expand mental health services.

Telehealth and digital solutions have for example emerged as potential tools for addressing mental health challenges, particularly in areas where access to mental health professionals is limited. Telehealth services enable patients in remote and underserved areas to consult with mental health experts without travelling long distances. This is especially helpful for individuals who might otherwise be unable to access support due to geographic or financial barriers. One such initiative I am involved with is TherapyRoute.com, a platform that connects people with therapists and psychologists across Africa and  that maintains a database of South African community health clinics.

Such a digital approach, though promising, still faces challenges. Internet access remains inconsistent in many parts of Africa, and telehealth services must continue to evolve to ensure they are accessible to most of the population. Increasing investment in digital infrastructure will be a critical part of expanding access to mental health services.

Practical strategies

Meanwhile, there are practical things we can do now. Suicide prevention is after all not the responsibility of healthcare professionals alone – everyone can contribute.

We can all be on the lookout for the warning signs. Sudden withdrawal from social activities, mood changes, declining self-care and hygiene, and expressions of hopelessness or helplessness (e.g., “I can’t go on” or “Everyone would be better off without me”) should never be ignored.

If someone you know appears to be at risk, ask direct questions about their mental health. Don’t be afraid to ask if they are considering suicide. Studies show that directly asking about suicide can reduce the risk of an attempt by giving the person a chance to talk about their feelings.

We can also respond as a community. We can organise peer support groups where people can check in on one another. Training community leaders, traditional healers, or local volunteers to recognise suicide risk and provide mental health first aid is another effective way to support those at risk. Running community-wide campaigns to raise awareness about mental health issues and reduce stigma can help normalize seeking professional help.

Governments also have a critical role to play. They must prioritise mental health by increasing funding for prevention and treatment programmes, particularly in rural and underserved areas. The success of such programmes depends heavily on their accessibility to people from all economic backgrounds.

In South Africa, government should focus on implementing the National Mental Health Policy Framework, ensuring it reaches the rural areas that are most in need. By integrating mental healthcare into primary healthcare services, as envisaged in the policy framework, more people will have the chance to receive timely care.

Ultimately, suicide prevention requires a multi-level approach, with involvement from individuals, communities, governments, and the private sector. By recognising warning signs, reducing mental health stigma, and expanding access to care through both in-person and telehealth services, we can make meaningful strides in reducing the suicide rate across Africa.

*Sinisi is a clinical psychologist and psychoanalyst in private practice in Cape Town. He is also a faculty member of the South African Psychoanalysis Association, The South African Psychoanalytical Initiative, and the Centre for Group Analytic Studies.

People in need of help can contact SADAG on the following helplines:

  • 0800 21 22 23 (8am to 8pm)
  • 0800 12 13 14 (8pm to 8am)
  • SMS: 31393

Also see this webpage for a longer list of helplines.

Note: Spotlight aims to deepen public understanding of important health issues by publishing a variety of views on its opinion pages. The views expressed in this article are not necessarily shared by the Spotlight editors.

Republished from Spotlight under a Creative Commons licence.

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