Tag: 20/7/23

Categories : Metabolic DisordersTags :

T Cell Monitoring may Help Prevent Type 1 Diabetes

On By ModernMedia
A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0

Scripps Research scientists have shown that people at risk of developing type 1 diabetes could be identified by analysis of the T cells which drive the disease. The new approach, if validated in further studies, could be used to select suitable patients for a newly FDA-approved treatment that stops the autoimmune process, thereby making type 1 diabetes a preventable condition.

In the study, which appears in Science Translational Medicine, the researchers isolated T cells from mouse and human blood samples. By analysing the T cells that can cause type 1 diabetes, they were able to distinguish the at-risk patients who had active autoimmunity from those who had no significant autoimmunity – with 100% accuracy in a small sample.

“These findings represent a big step forward because they offer the possibility of catching this autoimmune process while there is still time to prevent or greatly delay diabetes,” says study senior author Luc Teyton, MD, PhD, professor in the Department of Immunology and Microbiology at Scripps Research.

The study’s first authors were graduate student Siddhartha Sharma and research assistants Josh Boyer and Xuqian Tan, all of the Teyton lab at the time of the study.

Type 1 diabetes usually occurs in childhood or early adulthood, in an autoimmune process that destroys the pancreas’s insulin-producing islet cells. The process can last years, with multiple starts and stops. Exactly how the process begins is not well understood, though it is known to involve genetic factors and may be triggered by routine viral infections.

In 2022, the US Food & Drug Administration approved an immune-suppressing therapy that can protect islet cells and at least delay diabetes onset by months to years if given in the early stages of autoimmunity. However, doctors have not had a good method for identifying people who could benefit from such treatment. They have traditionally examined levels of anti-islet antibodies in patient blood samples, but this antibody response has not been a very accurate measure of autoimmune progression.

“Anti-islet antibody levels are poorly predictive at the individual level, and type 1 diabetes is fundamentally a T cell-driven disease,” Teyton says.

In the study, Teyton and his team constructed protein complexes to mimic the mix of immune proteins and insulin fragments that CD4 T cells normally would recognise to initiate the autoimmune reaction. They used these constructs as bait to capture anti-insulin CD4 T cells in blood samples. They then analysed the gene activity within the captured T cells, and expression of proteins on the cells, to gauge their state of activation.

In this way, they were able to develop a classification algorithm that correctly identified which at-risk patients, in a set of nine, had ongoing anti-islet autoimmunity.

Teyton now hopes to validate the CD4 T cell-based approach with a long-term study in a larger cohort of participants, comparing this approach to the traditional approach of quantifying anti-islet antibodies.

Teyton and his colleagues also are working to make the process of isolating and analysing anti-islet T cells in blood samples more affordable and convenient, so that it can be used more easily in a clinical setting.

“If we can develop this into a useful method for identifying at-risk patients and tracking their autoimmunity status, we not only would have a way of getting the right people into treatment, but also would be able to monitor their disease progress and evaluate potential new preventive therapies,” Teyton says.

Source: Scripps Research Institute

Categories : Hospitals Medical IndustryTags :

Review Links Private Equity Takeovers of Healthcare Services to Patient Harm

On By ModernMedia
Photo by Hush Naidoo Jade Photography on Unsplash

Private equity ownership of healthcare services such as nursing homes and hospitals is associated with harmful impacts on costs and quality of care, suggests a review of the latest evidence published by The BMJ. No consistently beneficial impacts of private equity ownership were identified, and the researchers say these results confirm the need for more research on private equity ownership in healthcare and possibly increased regulation.

Private equity firms use capital from wealthy individuals and large institutional investors to buy companies, and, after a relatively brief period of ownership, sell them for substantial returns. Over the past decade, private equity firms have increasingly invested in, acquired, and consolidated healthcare facilities, with global healthcare buyouts exceeding $200bn since 2021 alone. But despite much speculation, it’s still not clear what impact private equity ownership of healthcare operators has on costs, quality of care, and health outcomes.

To address this uncertainty, researchers analysed the results of 55 studies (47 focused exclusively on the US) published in peer reviewed journals in the past two decades.

Nursing homes were the most commonly studied settings, followed by hospitals and dermatology facilities. The studies were designed differently, and were of varying quality, but the researchers were able to allow for that in their analysis.

Nine of 12 studies showed higher costs to patients or payers at health facilities owned by private equity firms (harmful impact), three found no differences, and none showed lower costs (beneficial impact).

Private equity ownership was also associated with mixed to harmful impacts on quality. Of 27 studies that assessed healthcare quality, 12 found harmful impacts, three found beneficial impacts, nine found mixed impacts (some quality measures declined, some improved), and in three the results were neutral.

Health outcomes showed both beneficial and harmful results, as did costs to operators, but the volume of studies for these outcomes was too low for any definitive conclusions to be drawn.

When nursing homes were analysed separately, private equity ownership often had mixed impacts on quality, but the researchers point out that more evidence suggests a degradation rather than an improvement in quality, such as a decrease in nurse staffing or a shift to lower nursing skill mix.

The researchers acknowledge that they did not differentiate between different types of private equity investment and ownership, and were unable to assess larger possible impacts of private equity on access to care. And because most of the included studies occurred in the US, the impacts identified may not apply to all global settings.

Nevertheless, they say this study fills a gap in the current literature on private equity ownership in healthcare, and presents emergent patterns related to private equity ownership that other studies have been unable to synthesise.

As such, they say: “The results of this study confirm the need for increased rigorous research on private equity ownership in healthcare, particularly its impacts on health outcomes and system costs and in other non-US settings, such as Europe.”

“This said, the current body of evidence is robust enough to confirm that private equity ownership is a consequential and increasingly prominent element in healthcare, warranting surveillance, reporting, and possibly increased regulation.”

Source: EurekAlert!

Categories : Diseases, Syndromes and ConditionsTags :

Scientists Unravel The Reason Why NSAIDs Exacerbate C. Diff Infections

On By ModernMedia
Clostridioides difficile. Credit: CDC

Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate gastrointestinal infections by Clostridioides difficile, the leading cause of antibiotic-associated diarrhoea worldwide – but the reason why has long eluded medical science. In a new paper published in Science Advances, researchers have begun to answer that question, showing that NSAIDs disrupt the mitochondria of cells lining the colon, sensitising them to damage by pathogenic toxins.

C. difficile is a bacterium that leads to a wide range of symptoms, from mild diarrhoea to complex infection and death. The factors that influence this wide spectrum of clinical outcomes remain largely unclear, but emerging evidence suggests that factors like diet and pharmaceutical drugs influence both susceptibility to infection and disease progression. However, little is known about how these factors impact the course of C. difficile infection.

Prior studies have shown that NSAIDs like indomethacin, aspirin, and naproxen negatively affect the gut, both in patients with C. difficile infection and other conditions like inflammatory bowel disease (IBD). Long-term NSAID use can lead to stomach ulcers and intestinal injuries. One hypothesis that this is due to the effects of NSAIDs on cyclooxygenase (COX) enzymes; a process that helps reduce inflammation and pain but also impairs mucosal function in the upper gastrointestinal tract. NSAIDs also have off-target effects and have been shown to affect cellular mitochondria by uncoupling cellular mitochondrial functions, but these had not been studied in C. difficile infections.

To define these effects, Children’s Hospital of Philadelphia (CHOP) researchers, led by graduate student Joshua Soto Ocaña, used in vitro and mouse models of C. difficile infection to test how permeable colonic epithelial cells are in the presence of the NSAID indomethacin. The researchers observed that both indomethacin and C. difficile toxins increased epithelial cell barrier permeability and inflammatory cell death. They also found that the effect was additive: the combined effect on cell permeability of both toxins and indomethacin was increased compared to each independently, suggesting a synergistic effect of NSAIDs and C. difficile in increasing this pathogen’s virulence.

Surprisingly, the researchers found that NSAIDs exacerbate C. difficile infection independent of COX inhibition and instead through off-target effects on mitochondria. They did so by treating colonic epithelial cells with a precursor molecule that is similar in structure to indomethacin but lacks the ability to inhibit the COX enzyme. Not only did they find that this NSAID-like molecule induced cell death, but they also found that adding selective COX inhibitors did not increase cell death, demonstrating that COX enzyme inhibition is not required to induce epithelial cell damage during C. difficile infection and that, instead, this damage occurs through off-target effects of NSAIDs.

To test the role of off-target effects during C. difficile infection, the researchers used mice pretreated either with indomethacin or the NSAID-precursor molecule. When exposed to C. difficile, both groups of mice showed equal enhancement in disease severity and mortality compared to untreated control mice infected with C. difficile only. The researchers also observed a similar effect in mice who were pretreated with the NSAID aspirin. To further define the specific mechanisms driving these off-target effects of NSAIDs, researchers looked at mitochondrial functions in colonic epithelial cells in vitro and in mice. They observed that the combination of NSAIDs and C. difficile toxins increased damage to colonic epithelial cell mitochondria and disrupted several important mitochondrial functions.

“Our work further demonstrates the clinical importance of NSAIDs in patients with C. diff infection and sheds light on why the combination of these two may be so detrimental,” said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at CHOP. “Our mechanistic findings are a starting point for further research that aims to understand the impact of mitochondrial functions during C. diff infection. These data could also inform how NSAID-mediated mitochondrial uncoupling affects other diseases, such as small intestinal injury, IBD, and colorectal cancer.”

Source: Children’s Hospital of Philadelphia

Categories : AgeingTags :

Scientists Discover That a Key Protein Boosts Cell Repair and Healthy Ageing

On By ModernMedia
Photo by Ravi Patel on Unsplash

Researchers have found an anti-ageing function in a protein deep within human cells. They discovered that a protein called ATSF-1 controls a fine balance between the creation of new mitochondria and the repair of damaged mitochondria. Their findings were published in Nature Cell Biology.

Mitochondria create toxic by-products during their energy production process, which contributes to the rate at which the cell ages.

Associate Professor Steven Zuryn and Dr Michael Dai at the Queensland Brain Institute made the discovery of a key repair protein. “In conditions of stress, when mitochondrial DNA has been damaged, the ATSF-1 protein prioritises repair which promotes cellular health and longevity,” Dr Zuryn said.

As an analogy, Dr Zuryn likened the relationship to a race car needing a pitstop.

“ATSF-1 makes the call that a pitstop is needed for the cell when mitochondria need repairs,” he said.

“We studied ATFS-1 in C. elegans, or round worms and saw that enhancing its function promoted cellular health, meaning the worms became more agile for longer. They didn’t live longer, but they were healthier as they aged.”

“Mitochondrial dysfunction lies at the core of many human diseases, including common age-related diseases such as dementias and Parkinson’s. Our finding could have exciting implications for healthy ageing and for people with inherited mitochondrial diseases.”

Understanding how cells promote repair is an important step towards identifying possible interventions to prevent mitochondrial damage.

“Our goal is to prolong the tissue and organ functions that typically decline during ageing by understanding how deteriorating mitochondria contribute to this process,” Dr Dai said. “We may ultimately design interventions that keep mitochondrial DNA healthier for longer, improving our quality of life.”

Source: University of Queensland

Categories : Cancer Obstetrics & GynaecologyTags :

Green Tea Extract may Reduce Uterine Fibroids

On By ModernMedia
Photo by Andrea Piacquadio on Pexels

In a pre-clinical, proof-of-concept study from Johns Hopkins Medicine, researchers found that epigallocatechin gallate (EGCG), a green tea compound with powerful antioxidant properties, could be promising for both treating and preventing uterine fibroids. Results of the study, appearing in Scientific Reports, add to growing evidence that EGCG may reduce fibroid cell growth, though the study is still at an early stage. The study was specifically designed to identify the biochemical mechanisms responsible for EGCG action in fibroid cells.

The investigators emphasise that their study involves in vitro human fibroid cells treated with EGCG extract to explore the possibility of oral EGCG supplementation as a therapy, rather than just drinking cups of green tea as a preventative measure for uterine fibroids.

“The purpose of this study was to examine how EGCG works to treat and prevent uterine fibroids,” says James Segars Jr., MD, professor of gynaecology and obstetrics. “There is no standard protocol for uterine fibroid disease management or prevention, no tools to prevent their growth, so finding a safe nonsurgical therapy is important.”

Uterine fibroids are the most common benign tumours of the uterus. Made up of smooth muscle cells and a large matrix of connective tissue, the fibroids range in size from nearly microscopic to bulky masses that can enlarge and distort the uterus.

An estimated 77% of women will develop fibroids in their lifetime, most of them by age 50. Black and Hispanic women develop them at 1.5 to two times the rate of white women.

While many people with uterine fibroids are symptom-free, about 25% experience significant symptoms including heavy uterine bleeding, pelvic pain and infertility. In addition to complete removal of the uterus, surgical treatment may include various means of removing fibroid tumours from the uterine wall.

For the new study, researchers used laboratory cultures of uterine fibroids collected from living patients. Because uterine fibroid cells have a large extracellular matrix compared to normal cells, researchers designed their experiments to see if treatment of cells with EGCG affects protein expression associated with this matrix. Specifically, they studied fibronectin, a matrix protein; cyclin D1, a protein involved with cell division; and connective tissue growth factor (CTGF) protein.

Cells were dosed with 100mmol/L of EGCG in growth media for 24 hours, and then a Western blot was performed. In this study, researchers looked for levels of cyclin D1 and CTGF proteins in EGCG-treated fibroid cells compared to untreated cell.

They found that EGCG reduced protein levels of fibronectin by 46% to 52%, compared with an untreated controls. They also found that EGCG disrupted pathways involved in fibroid tumour cell growth, movement, signalling and metabolism, and they saw up to an 86% decrease in CTGF proteins compared with the control group.

“The results from this study show that EGCG targets many signalling pathways involved in fibroid growth, particularly the extracellular matrix,” says study lead author Md Soriful Islam, PhD, MSc. “EGCG supplements could be an easily accessible and natural way to relieve symptoms and slow fibroid growth.”

These results lend support to the FRIEND study, an ongoing clinical trial of EGCG in women with fibroids who are seeking pregnancy. While results from this study show promise, researchers caution that more studies need to be done, and consumers should not try to self-dose with green tea supplements. Future research on EGCG will include clinical trials with large and diverse patient groups to determine optimal doses as well as possible side effects of EGCG supplementation.

Source: John Hopkins Medicine