Day: February 7, 2025

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Why do Some People with Obesity Remain Healthy?

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Although obese individuals are at greater risk of diabetes, high blood pressure or high cholesterol, not all obese people develop metabolic diseases of this kind. With around a quarter of all obese individuals are healthy, scientists are trying to work out why some obese people become unhealthy while others do not.

Now, a comprehensive study by researchers from Zurich and Leipzig has provided a vital basis for this work. Specifically, the researchers have produced a detailed atlas with data from healthy and unhealthy overweight people, on their fat (adipose) tissue, and on the gene activity in this tissue’s cells. “Our results can be used to look for cellular markers that provide information on the risk of developing metabolic diseases,” explains Adhideb Ghosh, a researcher in ETH Professor Christian Wolfrum’s group and one of the two lead authors of the study. “The data is also of great interest for basic research. It could help us develop new therapies for metabolic diseases.”

The study appears in Cell Metabolism.

Investigating a large biobank

For this study, Ghosh and his colleagues used the Leipzig Obesity Biobank, an extensive collection of biopsies taken from obese individuals. Compiled by scientists from the University of Leipzig, these samples originate from obese patients who underwent elective surgery and consented to the collection of adipose tissue samples for research purposes. The collection also includes extensive medical information on the patients’ health.

Since the tissue samples were all taken from obese individuals with or without metabolic diseases, they allow comparison between individuals with healthy and unhealthy obesity. In samples from 70 volunteers, the researchers at ETH Zurich examined which genes were active, and to what extent, on a cell-by-cell basis for two types of adipose tissue: subcutaneous and visceral.

Scientists and medical experts assume that visceral fat, which lies deep in the abdominal cavity and surrounds the internal organs, is primarily responsible for metabolic diseases. By contrast, experts generally believe that fat located directly beneath the skin is less problematic.

For the study, it was vital that the adipose tissue cells were not all simply lumped together, as this tissue comprises not only fat cells (adipocytes) but also cells of other types. “In fact, the adipocytes are in the minority,” explains lead author Isabel Reinisch, a postdoc in Wolfrum’s group. A large part of adipose tissue is made up of immune cells, cells that form blood vessels, and immature precursor cells of adipocytes. Another cell type, known as mesothelial cells, are found only in visceral adipose tissue and mark its outer boundary.

Abdominal fat remodelled – and gender differences

As the researchers were able to show, there are significant functional changes in cells in the visceral adipose tissue of people with metabolic diseases. This remodelling affects almost every cell type in this form of tissue. For example, the genetic analyses showed that the adipocytes of unhealthy individuals could no longer burn fats as effectively and instead produced greater quantities of immunologic messenger molecules. “These substances trigger an immune response in the visceral fat of obese people,” explains Reinisch. “It’s conceivable that this response promotes the development of metabolic diseases.”

The researchers also found very clear differences in the number and function of mesothelial cells: in healthy obese individuals, there is a far greater proportion of mesothelial cells in the visceral fat and these cells exhibit greater functional flexibility. Specifically, the cells can switch into a sort of stem cell mode and therefore convert into different cell types, such as adipocytes, in healthy individuals. “The ability of fully differentiated cells to convert into stem cells is otherwise primarily associated with cancer,” says Reinisch. She was surprised, therefore, to find this ability in adipose tissue as well. “We suspect that the flexible cells at the edge of the adipose tissue in healthy obese individuals facilitate smooth tissue expansion.”

Finally, the researchers also found differences between men and women: a certain type of progenitor cell is present only in the visceral fat of women. “This could explain differences in the development of metabolic diseases between men and women,” says Reinisch.

Finding new biomarkers

The new atlas of gene activity in overweight people describes the composition of cell types in adipose tissue and their function. “However, we cannot say whether the differences are the reason why someone is metabolically healthy or whether, conversely, metabolic diseases cause these differences,” says Ghosh. Instead, the scientists view their work as providing the basis for further research. They have published all the data in a publicly accessible web app so that it is available for other researchers to work with.

In particular, this atlas now makes it possible to find new markers that provide information on the risk of developing a metabolic disease. At present, the ETH researchers are also looking for these kinds of markers, which could help to improve the treatment of such diseases. For example, there is a new class of drugs that suppress the appetite and promote insulin release in the pancreas – but these medications are in short supply. “Biomarkers that can be derived from our data could help to identify those patients who are most in need of this treatment,” says Reinisch.

Source: ETH Zurich

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New Study Identifies a Key Protein’s Role in Psoriasis

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A new study on psoriasis has determined that a protein called NF-kB c-Rel can intensify the condition’s symptoms when activated by signals from the body’s immune system. Understanding how “c-Rel” affects skin inflammation could lead to new treatments, said the researchers at Case Western Reserve University School of Medicine.

The study, published recently in eBioMedicine, examined how c-Rel contributes to the function of dendritic cells (DCs), a type of immune cell. The study examined how c-Rel responds to specific immunological signals through Toll Like Receptor 7 (TLR7), which regulates innate immunity and inflammation, exacerbating psoriasis.

The researchers also found the absence of c-Rel alleviates inflammation that causes red, scaly patches on the skin. TLR7 meanwhile is known to be activated by diseases such as HIV and HPV, which are also linked to the development psoriasis.

“We believe that by focusing on c-Rel and TLR7, scientists might be able to create more targeted treatments that reduce inflammation and help psoriasis symptoms,” said Parameswaran Ramakrishnan, associate professor of pathology, member of the Case Comprehensive Cancer Center and researcher at Louis Stokes Cleveland VA Medical Center, the study’s principal investigator.

“This may help relieve the discomfort millions of people live with skin inflammation.”

The researchers examined skin samples from psoriasis patients and a mouse model with similar skin changes.

They analysed c-Rel levels and its behaviour in specially engineered cells lacking the protein; they also examined the mouse model lacking c-Rel.

Their goal: to better understand how c-Rel impacts the immune response in psoriasis.

“Our research shows that c-Rel plays a major role in psoriasis inflammation,” said Angela Liu, lead author and a recent graduate of the School of Medicine’s pathology department.

“We saw higher levels of c-Rel in psoriasis; mice lacking c-Rel were significantly protected from developing psoriasis and showed less inflammation.”

Ramakrishnan said their study revealed the potential role for TLR7 and c-Rel signalling in human psoriasis. A range of viruses that activates TLR7, including human immunodeficiency virus (HIV), human papilloma virus (HPV) and hepatitis C virus (HCV), are linked to the development of psoriasis.

“The research warrants future studies on TLR7-c-Rel-dependent molecular mechanism regulating DC function as a potential link for how viral TLR7 activation is involved in worsening psoriatic disease,” Ramakrishnan said. “From a broad perspective, it would be interesting to further explore the role of c-Rel and TLR7 in other biologically relevant diseases involving these proteins, such as systemic lupus erythematosus and wound-healing in diabetes.”

Source: Case Western Reserve University

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Study Identifies Risk Factors in Heavy Drinkers for Advanced Liver Disease

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A new study finds that heavy drinkers with either diabetes, high blood pressure or a high waist circumference are as much as twice as likely to develop advanced liver disease.

The answer may lie in three common underlying medical conditions, according to a new study published in Clinical Gastroenterology and Hepatology from Keck Medicine of USC. The research found that heavy drinkers with either diabetes, high blood pressure or a high waist circumference are as much as 2.4 times more likely to develop advanced liver disease.  

“The results identify a very high-risk segment of the population prone to liver disease and suggest that preexisting health issues may have a large impact on how alcohol affects the liver,” said Brian P. Lee, MD, MAS, a hepatologist and liver transplant specialist with Keck Medicine and principal investigator of the study. 

Diabetes, high blood pressure and a high waist circumference (89cm for women; 101cm for men), which is associated with obesity, belong to a cluster of five health conditions that influence an individual’s risk for heart attack and stroke known as cardiometabolic risk factors.  

Cardiometabolic risk factors have been linked to the buildup of fat in the liver (also known as metabolic dysfunction-associated steatotic liver disease), which can lead to fibrosis, or scarring of the liver. These risk factors affect more than one in three Americans, and cardiometabolic health has been worsening among the population, especially among those under 35, according to Lee.  

Alcohol also causes fat buildup in the liver, and alcohol consumption has been on the rise since the COVID-19 pandemic, said Lee. Due to the prevalence of both cardiometabolic risk factors and drinking in the United States, Lee and his fellow researchers undertook the study to investigate which cardiometabolic risk factors predisposed the liver to damage from alcohol. 

They analysed data from the National Health and Nutrition Examination Survey, a large national survey of more than 40 000 participants, looking at the intersection of heavy drinking, individual cardiometabolic risk factors and the incidences of significant liver fibrosis. Significant liver fibrosis refers to liver scarring that can lead to liver failure.  

For the study, heavy drinking was characterised as 1.5 drinks a day for women (20 grams) and two drinks a day for men (30 grams). 

Researchers discovered that heavy drinkers with either diabetes or a high waist circumference were 2.4 times more likely to develop advanced liver disease and those with high blood pressure 1.8 times more likely. They found that the other two cardiometabolic risk factors – high triglycerides and low HDL (high-density lipoprotein) had less significant correlations to liver disease.  

While the study did not analyse why these three cardiometabolic risk factors are more dangerous for the liver, Lee speculates that these conditions share a common pathway to fat buildup in the liver that when combined with extra fat deposits in the liver from excessive alcohol, can cause significant damage.  

Lee stresses that the study does not imply it is safe for those without these three cardiometabolic risks to consume large amounts of alcohol. “We know that alcohol is toxic to the liver and all heavy drinkers are at risk for advanced liver disease,” he said.  

Lee hopes that the study results will encourage people to consider their individual health and risk profile when making decisions about alcohol consumption. He would also like to see practitioners offer more personalized health screenings and interventions for those who drink with cardiometabolic risk factors so that liver damage among this high-risk group can be caught early and treated.  

Source: University of Southern California – Health Sciences

Categories : Implants and Prostheses NeurologyTags : Leave a comment

Progress and Challenges in the Development of Brain Implants

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In a paper recently published in The Lancet Digital Health, a scientific team led by Stanisa Raspopovic from MedUni Vienna looks at the progress and challenges in the research and development of brain implants. New achievements in the field of this technology are seen as a source of hope for many patients with neurological disorders and have been making headlines recently. As neural implants have an effect not only on a physical but also on a psychological level, researchers are calling for particular ethical and scientific care when conducting clinical trials.

The research and development of neuroprostheses has entered a phase in which experiments on animal models are being followed by tests on humans. Only recently, reports of a paraplegic patient in the USA who was implanted with a brain chip as part of a clinical trial caused a stir. With the help of the implant, the man can control his wheelchair, operate the keyboard on his computer and use the cursor in such a way that he can even play chess. About a month after the implantation, however, the patient realised that the precision of the cursor control was decreasing and the time between his thoughts and the computer actions was delayed.

“The problem could be partially, but not completely, resolved – and illustrates just one of the potential challenges for research into this technology,” explains study author Stanisa Raspopovic from MedUni Vienna’s Center for Medical Physics and Biomedical Engineering, who published the paper together with Marcello Ienca (Technical University of Munich) and Giacomo Valle (ETH Zurich). “The questions of who will take care of the technical maintenance after the end of the study and whether the device will still be available to the patient at all after the study has been cancelled or completed are among the many aspects that need to be clarified in advance in neuroprosthesis research and development, which is predominantly industry-led.”

Protection of highly sensitive data

Neuroprostheses establish a direct connection between the nervous system and external devices and are considered a promising approach in the treatment of neurological impairments such as paraplegia, chronic pain, Parkinson’s disease and epilepsy. The implants can restore mobility, alleviate pain or improve sensory functions. However, as they form an interface to the human nervous system, they also have an effect on a psychological level: “They can influence consciousness, cognition and affective states and even free will. This means that conventional approaches to safety and efficacy assessment, such as those used in clinical drug trials, are not suitable for researching these complex systems. New models are needed to comprehensively evaluate the subjective patient experience and protect the psychological privacy of the test subjects,” Raspopovic points out.

The special technological features of neuroimplants, in particular the ability to collect and process neuronal data, pose further challenges for clinical validation and ethical oversight. Neural data is considered particularly sensitive and requires an even higher level of protection than other health information. Unsecured data transmission, inadequate data protection guidelines and the risk of hacker attacks are just some of the potential vulnerabilities that require special precautions in this context. “The use of neural implants cannot be reduced to medical risks,” summarises Stanisa Raspopovic. “We are only in the initial phase of clinical studies on these technological innovations. But questions of ethical and scientific diligence in dealing with this highly sensitive topic should be clarified now and not only after problems have arisen in test subjects or patients.”

Source: Medical University of Vienna

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Link between Early and Long-term Side Effects from Prostate Cancer Radiotherapy

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

Men undergoing radiation therapy for prostate cancer who experience side effects early in treatment may face a higher risk of developing more serious long-term urinary and bowel health issues, according to a new study led by investigators from the UCLA Health Jonsson Comprehensive Cancer Center.

The study found that patients who experienced moderate acute urinary side effects in the first three months after radiation were nearly twice as likely to develop late urinary complications years later compared to those without early symptoms. Similarly, patients with early bowel side effects had nearly double the risk of chronic bowel issues.

The findings, published in The Lancet Oncology, highlight the importance of developing strategies to better manage acute toxicities to help improve long-term outcomes and quality of life for patients.

“Men with prostate cancer are living longer than ever, and our goal is to reduce the risk of late toxicities, such as difficulty urinating or rectal bleeding, that can impact a patient’s quality of life for years,” said Dr Amar Kishan, executive vice chair of radiation oncology and senior author of the study. “This study highlights innovations we’re developing, such as using smaller treatment margins in prostate radiation to minimize early side effects, that can lead to lasting benefits by also reducing the risk of long-term complications for patients.”

Radiation therapy is often a key treatment for localised prostate cancer, often involving higher doses to better control the disease. While this approach effectively controls cancer, it can also harm nearby healthy tissues, causing acute and late-term side effects.

Acute toxicity refers to side effects that occur during treatment or within the first three months after it ends, and they are typically temporary. Common urinary side effects include increased frequency of urination, difficulty urinating and discomfort during urination. Bowel-related side effects may include softer stools or diarrhea, as well as rectal discomfort during bowel movements.

Late toxicity, on the other hand, can appear months or even years later and can last for years. Late urinary toxicities include narrowing of the urethra and having blood in the urine. Late bowel toxicities include having blood in the stool or having an ulcer in the wall of the rectum. These issues often can have a bigger impact on a person’s quality of life compared to acute side effects.

While both acute and late toxicities are caused by radiation’s effect on healthy tissues, the connection between the two hasn’t been well-studied, particularly using large-scale data. 

To better understand this relationship, the researchers analysed data from over 6500 patients from six randomised phase 3 clinical trials that shared detailed, individual-level data on short-term and long-term side effects affecting the urinary and bowel systems.

The researchers found patients with moderate or worse early side effects were more likely to experience severe late effects, even years after treatment. Men with early urinary or bowel issues were also more likely to report significant drops in their ability to manage daily activities and overall quality of life.

For urinary toxicity, experiencing acute toxicity increased the rate of late toxicity from 7.5% to 12.5%, and for bowel toxicity, experiencing acute toxicity increased the rate of late toxicity from 12.7% to 22.5%.

The odds of having a clinically-significant decline in urinary quality of life were 1.4 times as high for men who had moderate acute urinary toxicity. The odds of having a clinically-significant decline in bowel quality of life were 1.5 times as high for men who had moderate acute bowel toxicity.

“These results show that acute toxicities following prostate radiotherapy are associated with late toxicities months and years later,” said first author Dr John Nikitas, oncology resident at UCLA Health. “This underscores the importance of measures that reduce the risk of acute toxicities because they may also potentially improve long-term outcomes and quality of life for patients.”

Kishan emphasised the potential impact of newer techniques to reduce both acute and late toxicities:

“Reducing early side effects through advanced techniques like MRI-guided radiation, which allows for more precise targeting of tumours, and urethral-sparing methods, which uses spacers between the prostate to protect surrounding tissues and rectum could potentially help lower the risk of lasting side effects.”

However, more studies are needed to determine if specific strategies to reduce early side effects will improve long-term outcomes and whether treating short-term side effects early can help prevent long-term complications.

Source: University of California – Los Angeles Health Sciences

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UTI Pain Stems from Hypersensitivity in Nerves for Bladder Fullness

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New insights into what causes the painful and disruptive symptoms of urinary tract infections (UTIs) could offer hope for improved treatment. Nearly one in three women will experience UTIs before the age of 24, and many elderly people and those with bladder issues from spinal cord injuries can experience multiple UTI’s in a single year.

Findings from a new study led by Flinders University’s Dr Luke Grundy and SAHMRI’s Dr Steven Taylor show that UTIs cause the nerves in the bladder to become hypersensitive resulting in the extremely painful and frequent urge to urinate, pelvic pain, and burning pain while urinating.

“We found that UTIs, caused by bacterial infections such as E. coli, can significantly alter the function and sensitivity of the nerves that usually detect bladder fulness, a phenomenon known as ‘bladder afferent hypersensitivity’, says Dr Grundy, from the College of Medicine and Public Health.

“The study was the first of its kind to explore the impact of UTIs on the sensory signals that travel from the bladder to the brain, and the direct link this response has to causing bladder pain and dysfunction.”

A normal bladder will expand to store urine and can store up to two cups of urine for several hours.  Once full, the bladders nervous system will signal that it is time to urinate, or empty the bladder.

Described in Brain, Behavior, & Immunity – Health, researchers analysed how UTIs cause sensory nerves that respond to bladder distension to become hypersensitive, so that they send signals of bladder fulness, even when the bladder is not yet full.

“Our findings show that UTIs cause the nerves in the bladder to become overly sensitive, which means that even when the bladder is only partly filled, it can trigger painful bladder sensations that would signal for the need to urinate,” he says.

“We think that these heightened sensory responses may serve as a protective mechanism, alerting the body to the infection and prompting more frequent urination to expel the bacteria.”

Building on previous research, the new study reveals a deeper understanding of how UTIs affect bladder function and the nervous system, and raises important questions about the role of bladder hypersensitivity in the development of UTI-related symptoms.

“Our findings go further in identifying the significant changes that occur during UTIs and provide a clearer picture of the mechanisms behind the painful and disruptive bladder sensations often associated with these infections,” says Dr Grundy.

The study also suggests that better understanding and targeting of bladder afferent hypersensitivity could improve treatment options for patients suffering from recurrent UTIs or other bladder conditions where sensory dysfunction plays a role.

“Theoretically we should be able to find a way to address hypersensitive nerves in the bladder and reduce or eliminate the painful and debilitating symptoms of a UTI,” he adds. This would improve quality of life whilst antibiotics are taking care of the infection.

Researchers are striving to address the limited treatments available for bladder pain by exploring how the findings may translate into clinical practice and improve the management of UTIs in patients.

Source: Flinders University