Tag: 12/11/21

Nicotine Linked to Sleep Apnoea Risk

Source: Pawel Czerwinski on Unsplash

In a first-of-its-kind, scientists from the Heart Research Institute (HRI) have made the link between amounts of nicotine in the blood and their sleep apnoea risk.

Sleep apnoea occurs when a person’s throat and upper airway become partly or totally blocked during sleep, causing short periods where breathing ceases.

In a new paper published in ESC Heart Failure, Heart Research Institute (HRI) scientists found increases in nicotine levels were associated with a 2.3 minute increase in the time spent with oxygen saturations below 90%.

One of the markers of severity of sleep apnoea is time spent with an oxygen saturation less than 90%.

Lead researcher Dr John O’Sullivan, said this meant that for every cigarette a person smoked, the more they increased the risk of “dangerously low” oxygen levels.

“People who spend more time with an oxygen saturation less than 90 percent end up with more cardiovascular death than people who don’t,” Dr O’Sullivan said.

“We know smoking is bad for the heart – it’s one of the major risks for heart attacks – and although smoking is known to reduce oxygen concentration in the blood, the interaction of smoking with sleep apnoea has not been quantified. Using blood concentrations of the major nicotine metabolite, we were able for the first time to quantify the effect of smoking on oxygen concentrations at night in people with sleep apnoea.

“A standardised increase in levels of this metabolite was associated with 2.3 more minutes with an oxygen concentration less than 90 percent in people with sleep apnea. Time with an oxygen concentration less than 90% is a proven indicator of bad cardiovascular outcome.”

Sleep apnoea and congestive heart failure comorbidities are common, but their interaction is unclear. To find out more, Dr O’Sullivan’s team used hundreds metabolites to understand this interaction.

“Believe it or not, stiff heart failure – when the heart muscle can still pump blood but is stiff and cannot relax properly – is the most common form of heart failure today and we have almost no treatment options,” Dr O’Sullivan said.

“We measured molecules in the blood called metabolites and looked at the changes in these metabolites and related these to the severity of sleep apnoea.”

Metabolomics is a relatively new field of study that investigates metabolites, which are the components of your metabolism and play key roles in disease. They can provide insight into how one disease is linked to another, like in this case the consequences of sleep apnea and heart failure. Several metabolites are also key fuels for the working heart, and others form the units of energy by which the heart works.

The team studied metabolites and lipids in 3443 people from two US studies, including the landmark Framingham study.

Dr O’Sullivan said Framingham was known as the “town that changed America” because of the multi-generational study started in 1948 that subsequently identified the cardiovascular risk factors we still use today. Much research using this study is openly available internationally, enabling researchers around the world.

“Accurate measurement of disease combined with blood metabolite levels is far more accurate than self-reported questionnaires – that’s one of the strengths of this study,” he said.

While sleep apnoea is very common (up to one in four adults), its consequences and interactions with other diseases remain poorly understood. Almost no studies  have sleep study data, heart failure data, and metabolomic data in the same individuals, which is a major new feature of this study.

Source: Heart Research Institute

An Inspiration Led to Understanding Metformin’s Anti-tumour Effect

Scientists report that metformin, used to treat type 2 diabetes mellitus, induces activation and proliferation of tumor-targeting CD8+ T-lymphocytes (CD8TIL), via mechanisms that involve the generation of reactive oxygen species in mitochondria of CD8TIL and an increase in glycolysis. Credit: Heiichiro Udono from Okayama University

Researchers in Japan have elucidated how the antidiabetic drug metformin exerts an anti-tumour effect as well.

Certain drugs like metformin have recently been found to have anti-cancer properties. Metformin appears to bolster anti-tumour immunity but the underlying immunological mechanisms were a mystery. With all the permutations and combinations of cancer, a blanket, yet targeted therapy would be ideal. 

Japanese scientists led by Professor Heiichiro Udono from Okayama University thus decided to address this oncological research question. In their recent study, they looked at how a specific subset of immune cells, called CD8+ infiltrating T-lymphocytes (CD8TIL), which specifically attack tumor cells, behaved in response to metformin. Their findings have been published as a research article in Journal for ImmunoTherapy of Cancer.

Interestingly, Prof. Udono almost gave up on his anti-cancer pursuits, when he lost his own father to cancer. However, a bolt of inspiration came at a conference: “Nearly 10 years ago, a switch turned on in my head when I attended a Keystone Symposia discussing cancer, and hypoxia, held in Banff, Alberta. I realised that we had missed addressing Warburg effect, an effect which bolsters the growth of cancer, in our previous research. So, reverting Warburg effect to normal metabolic profile in cancers became a topic that got me thinking. Surprisingly, I got a hint from the same conference that metformin may aid cancer immunity. So, we got to work!”

Prof Udono and his team got to work, meticulously conducting a series of experiments on cancer cell lines, and ‘knockout gene’ mice, searching for possible biomolecules that result in metformin-dependent anti-tumour immunity. They probed the intracellular mechanisms in CD8TIL, when exposed to metformin, and assessed different biomarkers for growth. Given that CD8TIL produces proteins called interferons to attack cancer cells, they also assessed corresponding levels.

Accordingly, the scientists found that metformin causes the generation of reactive oxygen species in the mitochondria of CD8TIL (mtROS) and increases glycolysis. They also found that mtROS activated growth pathways in CD8TIL, allowing these cells to proliferate. Notably, this is achieved through a transcription factor involved in anti-oxidative stress response, called Nrf. Though metformin did not directly cause apoptosis, ‘cell suicide’ in tumours, it did cause CD8TIL to secrete interferon-ɣ to alter the tumour microenvironment in favour death of tumour cells.

Summing up the findings, Prof. Udono said: “More than anything else, our study provides the knowledge that we can ourselves protect our body from cancer. We hope that this understanding will result in not only the reduction of cancer incidence and improve treatment, but also will help prolong our life.”

The researchers also added that these findings strongly suggest the possibility of using metformin as a drug to strengthen anti-tumour immunity in patients with cancer. The findings appear in the Journal for ImmunoTherapy of Cancer.

Source: EurekAlert!

HIV-infected Cells Use Sugars to Avoid Immune Destruction

HIV invading a human cell
HIV invading a human cell: Credit NIH

A new study shows how key features on the surface of HIV-infected cells such as certain sugar molecules help the disease evade detection by the immune system, and how they can be disabled. The findings, published in PLOS Pathogens, represent a first step to eradicating this persistent virus in patients.

“We identified a glyco-immune checkpoint interaction as a novel mechanism that allows HIV-infected cells to evade immune surveillance,” said Mohamed Abdel-Mohsen, PhD, assistant professor in the Vaccine & Immunotherapy Center at The Wistar Institute and coauthor on the paper. “And we developed a novel approach that selectively targets these interactions on the surface of these infected cells.”

Existing treatments can reduce HIV to undetectable levels, but eradication remains elusive, with the disease typically returning quickly when treatment stops. And even when controlled, HIV increases risk for other health problems, including neurological disorders, cardiovascular disease, and cancer.

For the new study, researchers looked at a type of sugar molecule called sialic acid on the surface of HIV-infected cells. These sugars bind with receptors called siglecs on the surface of disease-fighting ‘natural killer’ immune cells. When activated, these receptors act as inhibitors, restraining the killer cells and causing them to stop killing. “We thought, ‘is it possible that these HIV-infected cells are using this interaction – covering themselves with these sugars to evade the natural killer immune surveillance?’” said Prof Abdel-Mohsen.

The researchers found that these infected cells can actually exploit this inhibitory connection to evade immune surveillance. They then investigated whether they could manipulate this connection to make the killer cells more effective at killing HIV-infected cells. Disabling the inhibitors from the killer cells was found to cause the immune cells to attack indiscriminately. The researchers turned to the HIV cells, using the enzyme sialidase to remove the sialic acid sugars that were activating the immune inhibitors but this affected all cells, again causing the killer cells to attack indiscriminately. Finally, they developed a sialidase conjugate linked to HIV antibodies, which only targeted sialic acid on HIV cells. With the sialic acid removed from these cells, the killer immune cells attacked and killed the HIV-infected cells, leaving healthy cells alone.

“The killer cells become a super killer for the HIV-infected cells and they now attack them in a selective manner,” said Prof Abdel-Mohsen. “The discovery could be a missing link in the “shock and kill” approach to HIV treatment that has been a focus of research for the past several years,” he added. This two-step process involves first “shocking” the HIV out of latency so it can be detected, and then stimulating the immune system to “kill” the virus once and for all. However, while effective methods have been discovered to reverse latency, scientists haven’t yet found a way to make HIV-infected cells more killable once reactivated. “We may have the shock, but we don’t yet have the kill,” Prof Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”

First author Samson Adeniji, Ph.D., a postdoctoral fellow at Wistar, noted that the team’s approach could be tested in combination with broadly neutralizing antibody therapies currently being studied in clinical trials. “By combining approaches, we could turn these immune cells from a cop into a kind of Robocop,” he said.

The researchers also noted that, besides  HIV, the approach could be applied in infectious diseases that may evade the immune system, including hepatitis and COVID. In vivo tests with animals are the next step. They’re also investigating other sugar molecules on HIV that may play a similar role as sialic acid. “HIV-infected cells are likely evading immune surveillance through many potential glyco-immune checkpoints,” Abdel-Mohsen said. “We are investigating other mechanisms and how to break them.”

Source: Wistar Institute

Moderate Caffeine Intake May Reduce Gestational Diabetes Risk

Photo by Mike Kenneally on Unsplash

Pregnant coffee lovers can breathe a sigh of relief, as consuming a low amount of caffeine during pregnancy could help to reduce gestational diabetes risk, according to a new study published in JAMA Network Open.

“While we were not able to study the association of consumption above the recommended limit, we now know that low-to-moderate caffeine is not associated with an increased risk of gestational diabetes, preeclampsia, or hypertension for expecting mothers,” said the study’s lead author Stefanie Hinkle, PhD, an assistant professor of Epidemiology at the University of Pennsylvania.

The current recommendation from the American College of Obstetricians and Gynecologists (ACOG) is that pregnant women limit their caffeine consumption to less than 200 mg (about two cups) per day. The recommendations are based on studies that suggest potential associations with pregnancy loss and foetal growth at higher caffeine levels. However, there remains limited data on the link between caffeine and maternal health outcomes.

To better understand this association, researchers studied prospective data from 2529 pregnant participants from 2009 to 2013.

At enrollment and at each visit thereafter, women reported their weekly intake of caffeinated coffee, caffeinated tea, fizzy drinks, and energy drinks. Concentrations of caffeine were also measured in the participants’ plasma at 10 to 13 weeks into their pregnancies. The researchers then matched their caffeine consumption with primary outcomes: clinical diagnoses of gestational diabetes, gestational hypertension, and preeclampsia.

The research team found that caffeine at 10 to 13 weeks gestation was not related to gestational diabetes risk. During the second trimester, drinking up to 100 mg of caffeine per day was associated with 47% less diabetes risk. No statistically significant differences in blood pressure, preeclampsia, or hypertension between those who did and did not consume caffeine during pregnancy.

The findings are in line with research that found an association between and improved energy balance and decreased fat mass, the researchers noted. However, other constituents of coffee and tea such as phytochemicals could be the cause.

The group’s previous work has however shown that caffeine consumption during pregnancy, even in amounts less than the recommended 200 mg per day, was associated with smaller neonatal anthropometric measurements, according to Prof Hinkle.

“It would not be advised for women who are non-drinkers to initiate caffeinated beverage consumption for the purpose of lowering gestational diabetes risk,” she said. One meta-analysis found that any amount of caffeine was a risk to the foetus. “But our findings may provide some reassurance to women who already are consuming low to moderate levels of caffeine that such consumption likely will not increase their maternal health risks.”

Source: Penn Medicine

NHI Implementation on the Financial Rocks – For Now

Photo by Michael Longmire on Unsplash

South Africa’s National Health Insurance (NHI) implementation continues to flounder, as the National Treasury notes its expenditure will not be a significant cost in the medium term. This scheme, which seeks to address the country’s huge gulf in healthcare inequality, has still made barely any progress since its inception over a decade ago.

In its Medium Term Budget Policy Statement published on Thursday (MTBPS), the Treasury said that the national health insurance policy was estimated to cost R40 billion per year in additional funding in the first five years, and perhaps considerably more over time. Therefore, it dismissed the possibility of any substantial work on it, saying that presently, “there is insufficient capacity in the health sector to work substantively on national health insurance. The national health insurance indirect grant has been underspent, the National Health Insurance Fund has not yet been established, and the National Health Insurance Bill still needs to be passed by Parliament.

“It is therefore unlikely that national health insurance will be a significant cost pressure in the medium term,” it said.

While the Department of Health has time and again reiterated its commitment to the NHI system, several studies highlight the system’s deep unpopularity among healthcare professionals. 

“To fund this, we need taxpayers,” said senior researcher Morné Malan at Solidarity Research Institute, when former Health Minister Dr Zweli Mkhize tabled the NHI Bill in Parliament in August 2019.

“To be a taxpayer you must be employed… only 12% of South Africans pay tax.”

In August 2021, trade union Solidarity published a report drawing on three surveys from 2018 to 2021, with 20.8% of respondents already preparing to leave.

Across the studies, the overarching response from healthcare professionals is one of uncertainty and mistrust around the NHI, with general sentiment towards the system being overwhelmingly negative.

“Almost all the respondents have serious concerns regarding the state’s ability to manage and administer the NHI,” Solidarity said. “The total administration and management of funds and decision-making will be in the hands of the state.

“Most are seriously concerned about the fact that the state can determine and enforce tariffs, place of work, type of diagnostic tests and type of medication and treatment.”

The opinions of those surveyed are likely shaped by the observed mismanagement and maladministration at state institutions such as Eskom, Solidarity noted. The NHI will be considerably larger and more complicated, and will have to manage and execute many contracts, it said.

Source: Businesstech

New Study Reveals T-Cell Role in Periodontitis and Bone Loss

There are mechanisms involved in diseases of bone loss, such as periodontitis that are still not well understood, but an unexpected behaviour of a type of T-cell may shed new light on the matter.

Looking at periodontal disease in mice, scientists found that regulatory T (Treg) cells start behaving unexpectedly. They lose their ability to regulate bone loss and begin to promote inflammation instead.

“That is important because, in many therapies analyzed in in-vivo models, researchers usually check if the number of regulatory T cells has increased. But they should check if these cells are indeed functioning,” said lead author Dr Carla Alvarez, a postdoctoral researcher at the Forsyth Institute.

In periodontal disease, bone loss occurs because the immune system responds disproportionately, destroying tissue through inflammation. The Treg cells normally suppress the immune system but lose the ability to do so during periodontal disease.

Understanding this falls into the field of osteoimmunology, which is about understanding the interaction of bone metabolism and the immune system. “This is an interesting mechanism highlighting how the bone loss is taking place in periodontal disease,” said Dr Alpdogan Kantarci, at Forsyth and co-author of the paper.

A potential treatment for periodontal disease would involve reactivating the Treg cell’s immunosuppression function, but this is a complex, nonlinear task complicated by the fact that periodontal disease is initiated by oral microbes.

“The relationship between immune response and bone is not so straightforward,” said Alvarez. “There are multiple components. You have to imagine a complex network of signaling and cells that participate.”
The researchers’ next step is to examine the process in humans.

Source:Medical Xpress

Journal information: Alvarez, C., Suliman, S., Almarhoumi, R. et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep 10, 19018 (2020). doi.org/10.1038/s41598-020-76038-w