Day: December 4, 2024

Categories : Diseases, Syndromes and ConditionsTags :

T Cells Become Exhausted in Chronic Fatigue Syndrome Patients

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Debilitating chronic fatigue syndrome creates conditions T cells becomes exhausted, according to a new study published in Proceedings of the National Academy of Sciences. The findings point the way for important new lines of investigation. 

The study’s authors knew the immune system was dysregulated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), so they began by asking, which parts shift with the condition? A systematic exploration revealed that key CD8+ T cells displayed one of the most pronounced signatures of dysregulation, with signs of constant stimulation that lead to an exhausted state, a condition that is well-studied in cancer.

ME/CFS affects an estimated 3 million people in the United States and some 65 million worldwide, leaving some patients ill for decades and unable to work. Symptoms include overwhelming fatigue that is not helped by rest, and can also include brain fog, body pains, headaches, difficulty sleeping and prolonged increases in symptoms after mild physical exertion or exercise. Causes are unknown and there is no treatment for the disease.

“This is an important finding for ME/CFS because now we can examine the T cells more carefully, and hopefully by looking in the exhausted cells we can start to get hints as to what they are responding to,” said Andrew Grimson, professor of molecular biology and genetics in the College of Arts and Sciences.

Grimson is co-corresponding author of the study. Maureen Hanson, Professor in the Department of Molecular Biology and Genetics, is the other corresponding author.

“Therapies have been developed to reverse T cell exhaustion as treatments for cancer,” Hanson said. “Our findings raise the question of whether such anti-exhaustion drugs might also be helpful in ME/CFS.”

Strong evidence for the phenomenon of T cell exhaustion in ME/CFS has also been reported in long COVID, Hanson added.

The study was led by co-first authors David Iu, a doctoral student in Grimson’s lab, and Jessica Maya, PhD ‘24, formerly in Hanson’s lab and currently a researcher at the Centers for Disease Control and Prevention. 

In a paper published earlier this year, Grimson and collaborators used a technology called single cell RNA sequencing to examine and identify all the circulating immune cells in ME/CFS patients. In the current paper, they used that data to examine which of the different types of T cells, including CD8+ T cells, were most altered in ME/CFS patients.

“That pointed us in the direction of CD8+ cells,” Grimson said. After purifying those cells, they used additional advanced technologies to precisely determine which genes were being expressed and pinpoint which genes were getting switched on or off. 

“When we looked at all of the differences [compared to normal functioning], they really pointed us towards an exhaustion-like state for the CD8+ T cells,” Grimson said. 

Meanwhile, in Hanson’s lab, Maya led a different approach of purifying patients’ T cells and then determining expression patterns of proteins on the surface of these cells. The team examined two series of different markers on the various proteins, one of which allowed them to subdivide all the different types of CD8+ T cells, while the other allowed them to detect proteins known to be involved in exhaustion.

“Immune cells from ME/CFS patients exhibited higher levels of proteins on their surface that are characteristic of cells that have become exhausted, which can be caused by long-term exposure to a virus protein or by continuous stimulation of the immune system, a state that is also found in cancer patients,” Hanson said. 

Future work will try to determine whether a virus is in fact involved, which is currently not known. “We need to understand what is pushing them to this exhausted state,” Grimson said.

The team also plans to take cells from patients and controls, purify those cells and treat patients with drugs that reverse exhaustion and see if the immune cells resume normal function. If CD8+ T cell exhaustion can be reversed, the next question is whether such reversal actually benefits a patient, as exhaustion can have protective qualities. 

Another future line of inquiry will include distinguishing T cell receptors in exhausted cells from patients, to try to find which molecules those T cell receptors are recognising, and if from those clues, they can work out whether specific pathogens are involved. 

Source: Cornell University

Categories : Pain ManagementTags :

fMRI Brain Scan Predicts the Effectiveness of Spinal Cord Surgery

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A 10-minute brain scan can predict the effectiveness of a risky spinal surgery to alleviate intractable pain. The Kobe University result gives doctors a much-needed biomarker to discuss with patients considering spinal cord stimulation.

For patients with chronic pain that cannot be cured in any other way, a surgical procedure called “spinal cord stimulation” is seen as a method of last resort. The treatment works by implanting leads into the spine of patients and electrically stimulating the spinal cord. Because the spinal cord transmits sensations to the brain from all over the body, the position of the leads is adjusted so that the patients feel the stimulation at the site of the pain. The Kobe University anaesthesiologist Ueno Kyohei says: “A big issue is that the procedure is effective for some but not for other patients, and which is the case is usually evaluated in a short trial of a few days to two weeks prior to permanent implantation. Although this trial is short, it is still an invasive and risky procedure. Therefore, clinicians have long been interested in the possibility of predicting a patient’s responsiveness to the procedure through non-invasive means.”

Functional magnetic resonance imaging, or fMRI, has become a standard tool to visualize how the brain processes information. More precisely, it can show which parts of the brain are active in response to a stimulus, and which regions are thus functionally connected with each other. “In an earlier study, we reported that for the analgesic ketamine, pain relief correlates negatively with how strongly connected two regions of the default mode network are before the drug’s administration,” explains Ueno. The default mode network, which plays an important role in self-related thought, has previously been implicated in chronic pain. Another relevant factor is how the default mode network connects with the salience network, which is involved in regulating attention and the response to stimuli. Ueno says, “Therefore, we wanted to examine whether the correlation of the activities within and between these networks could be used to predict responsiveness to spinal cord stimulation.”

He and his team published their results in the British Journal of Anaesthesia. They found that the better patients responded to spinal cord stimulation therapy, the weaker a specific region of the default mode network was connected to one in the salience network. Ueno comments, “Not only does this offer an attractive biomarker for a prognosis for treatment effectiveness, it also strengthens the idea that an aberrant connection between these networks is responsible for the development of intractable chronic pain in the first place.”

Undergoing an fMRI scan is not the only option. Combining pain questionnaires with various clinical indices has been reported as another similarly reliable predictor for a patient’s responsiveness to spinal cord stimulation. However, the researchers write that “Although the cost of an MRI scan is controversial, the burden on both patients and providers will be reduced if the responsiveness to spinal cord stimulation can be predicted by one 10-minute resting state fMRI scan.”

In total, 29 patients with diverse forms of intractable chronic pain participated in this Kobe University study. On the one hand, this diversity is likely the reason why the overall responsiveness to the treatment was lower compared to similar studies in the past and also made it more difficult to accurately assess the relationship between brain function and the responsiveness. On the other hand, the researchers also say that, “From a clinical perspective, the ability to predict outcomes for patients with various conditions may provide significant utility.” Ueno adds: “We believe that more accurate evaluation will become possible with more cases and more research in the future. We are also currently conducting research on which brain regions are strongly affected by various patterns of spinal cord stimulation. At this point, we are just at the beginning of this research, but our main goal is to use functional brain imaging as a biomarker for spinal cord stimulation therapy to identify the optimal treatment for each patient in the future.”

Categories : Neurology UrogenitalTags :

Scientists Identify a Type of Brain Cell That is a Master Controller of Urination

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Researchers have identified a subset of brain cells in mice that act as the master regulators of urination.

The research, published as a Reviewed Preprint in eLife, is described by editors as an important study with convincing data showing that oestrogen receptor 1-expressing neurons (ESR1+) in the Barrington’s nucleus of the mouse brain coordinate both bladder contraction and relaxation of the external urethral sphincter.

Urination requires the coordinated function of two units of the lower urinary tract. The detrusor muscle of the bladder wall relaxes to allow the bladder to fill and empty, while the external sphincter opens when it’s appropriate to allow urine to flow out, but otherwise keeps tightly shut.

“Impairment of coordination between the bladder muscle and the sphincter leads to various urinary tract dysfunctions and can significantly degrade a person’s quality of life,” says first author Xing Li, Advanced Institute for Brain and Intelligence, School of Physical Science and Technology, Guangxi University, Nanning, China. “But although we know the individual nerve signalling pathways that control each of these urinary tract components, we don’t know which brain areas ensure they cooperate at the right time.”

To explore this, the authors used state-of-the-art live cell imaging to study the activity of brain cells in anaesthetised and awake mice during urination. They focused on a brain region called the pontine micturition centre (PMC), otherwise known as the Barrington’s nucleus, and compared the activity of different PMC nerve cell subtypes.

In their first experiments, they measured the activity of the cells as the bladder empties by measuring changes in levels of calcium. This revealed that the electrical firing rate of a subset of PMC cells expressing estrogen receptors (PMCESR1+ cells) was tightly linked to bladder emptying. When they combined this with monitoring bladder physiology, they found that it was not only the timing of PMCESR1+ cell activity that correlated with bladder emptying, but the strength of cell electrical activity, too.

Next, they tested what happened to urination if they blocked or triggered the PMCESR1+ cells. They found that when PMCESR1+ cell activity was blocked, the amount of urine the mice passed was significantly reduced and ongoing urination was suspended from the moment the cells were inactive. To understand the mechanism behind this, they measured the activity of the bladder muscle and sphincter. They discovered that both increase of bladder pressure and sphincter muscle bursting activity associated with bladder emptying both stopped when PMCESR1+ cell activity was blocked during an ongoing voiding even. Similarly, when PMCESR1+ cells were artificially activated using light, bladder emptying occurred 100% of the time. This suggests that PMCESR1+ cells work as a reliable master switch that either initiates or suspends bladder emptying.

To test whether PMCESR1+ cells can influence bladder emptying independently of controlling the sphincter, they disconnected either the nerve carrying messages from the brain to the sphincter, or the nerve carrying messages from the brain to the bladder. They found that PMCESR1+ cell control of the bladder was fully operational even when communication to the sphincter was blocked, and vice versa. This showed the cells could control the bladder and sphincter independently of one another, but the question remained: could they coordinate the action of the bladder muscle and sphincter together? That is, operate them in a controlled, perfectly timed manner, to trigger bladder emptying when appropriate?

To explore this, they simultaneously recorded bladder pressure and electromyography measurements of sphincter activity. The timing of bladder pressure changes immediately before sphincter bursting activity was consistent for both spontaneous bladder emptying and emptying caused by activating the PMCESR1+ cells, showing that these cells can coordinate the two steps in a precisely temporal sequence and controlled way.

“Our study shows that a subset of cells in the Barrington’s nucleus of the brain can initiate and suspend bladder emptying with 100% accuracy when needed, for example, to release only a small volume for landmarking by animals, or for a human to urinate into a small sample tube for a health check,” concludes senior author Xiaowei Chen, Third Military Medical University, and Chongqing Institute for Brain and Intelligence, China. “While other cells will no doubt be involved in perfect urination control, our pinpointing of PMCESR1+ cells’ crucial role in bladder–sphincter coordination will aid the development of targeted therapies for treating urination dysfunction caused by brain or spinal cord injury or peripheral nerve damage.”

Source: eLife

Categories : Diet and NutritionTags :

Five Years of Vitamin D Supplements Fails to Prevent Diabetes

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Using significantly higher doses of vitamin D than recommended for five years did not affect the incidence of type 2 diabetes in elderly men and women, according to a new study from the University of Eastern Finland which appears in Diabetologia.

In population studies, low levels of vitamin D in the body have been associated with a higher risk of type 2 diabetes, but such observational studies cannot directly prove a causative link. Experimental studies have shown that the use of significantly higher doses of vitamin D than recommended slightly reduces the risk of developing type 2 diabetes in individuals with impaired glucose metabolism, ie, those with prediabetes. In contrast, no effects have been observed in individuals without prediabetes. However, the studies with non-prediabetic subjects have used relatively small doses of vitamin D or have been short-term. Until now, there has been no research data on the effects of long-term use of high doses of vitamin D on the risk of type 2 diabetes in individuals without glucose metabolism disorders.

In the Finnish Vitamin D Trial (FIND) conducted at the University of Eastern Finland from 2012 to 2018, 2 495 men aged 60 and older and women aged 65 and older were randomised for five years into either a placebo group or groups receiving either 40 or 80 micrograms of vitamin D3 per day. In the statistical analyses of the now-published sub-study, 224 participants who were already using diabetes medications at the start of the study were excluded. Comprehensive information was collected from the participants on lifestyle, nutrition, diseases, and their risk factors. Data was also obtained from national health registers. About one-fifth were randomly selected for more detailed examinations, and blood samples were taken from them.

During the five years, 105 participants developed type 2 diabetes: 38 in the placebo group, 31 in the group receiving 40 micrograms of vitamin D3 per day, and 36 in the group receiving 80 micrograms of vitamin D3 per day. There was no statistically significant difference in the number of cases between the groups.

In the more closely studied group of 505 participants, the blood calcidiol level, which describes the body’s vitamin D status, was on average 75nmol/L at the start, and only 9% had a low level, ie, below 50nmol/L. After one year, the calcidiol level was on average 100nmol/L in the group that used 40 micrograms of vitamin D per day and 120nmol/L in the group that used 80 micrograms of vitamin D per day. There was no significant change in the placebo group. The effects of vitamin D on blood glucose and insulin levels, body mass index, and waist circumference were examined during the first two years of the study, but no differences were observed between the groups.

The findings of the FIND study reinforce the view that the use of higher doses of vitamin D than recommended does not significantly affect the risk of developing type 2 diabetes in individuals without prediabetes and who already have a good vitamin D status. So far, there is no research data on whether high doses of vitamin D can be beneficial in preventing type 2 diabetes in individuals without prediabetes but with vitamin D deficiency.

Source: University of Eastern Finland

Categories : Diseases, Syndromes and ConditionsTags :

Why are Humans Susceptible to Hepatitis B Virus – But not Monkeys?

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Hepatitis B virus (HBV) infection is a leading cause of chronic liver diseases, that spreads among individuals through blood or body fluids. According to the World Health Organization, globally 1.2 million new HBV infections are reported every year – most in low- and middle-income countries. HBV infections are limited to a few species, including humans and chimpanzees. Despite their close evolutionary relationship with these animals, old-world monkeys are not susceptible to HBV infections.

In a new study published in Nature Communications, scientists led by Visiting Professor Koichi Watashi from the Tokyo University of Science to uncover why monkeys are naturally resistant to HBV infection.

Using cryo-electron microscopy, scientists solved the structure of a membrane receptor found in liver cells called the sodium taurocholate co-transporting polypeptide (NTCP) in macaques. HBV binds to human NTCP using its preS1 region in the surface protein. Prof Watashi explains, “We identified a binding mode for NTCP-preS1 where two functional sites are involved in human NTCP (hNTCP). In contrast, macaque NTCP (mNTCP) loses both binding functions due to steric hindrance and instability in the preS1 binding state.”

To understand this ‘interspecies barrier’ against viral transmission, Prof Watashi and his team compared the structures of hNTCP and mNTCP, identifying differences in amino acid residues critical for HBV binding and entry into liver cells. hNTCP and mNTCP share 96% amino acid homology, with 14 amino acids distinct between the two receptors. A key distinction among these differences is the bulky side chain of arginine at position 158 in mNTCP, which prevents deep preS1 insertion into the NTCP bile acid pocket. For successful viral entry into liver cells, a smaller amino acid like glycine, as found in hNTCP, is necessary.

Interestingly, the substitution of Glycine by Arginine in mNTCP was at a position far away from the binding site for bile acid. Prof Watashi adds, “These animals probably evolved to acquire escape mechanisms from HBV infections without altering their bile acid transport capacity. Consistently, phylogenetic analysis showed strong positive selection at position 158 of NTCP, probably due to pressure from HBV. Such molecular evolution driven to escape virus infection has been reported for other virus receptors.” Further lab experiments and simulations revealed that an amino acid at position 86 is also critical for stabilising NTCP’s bound state with HBV’s preS1 domain. Non-susceptible species lack lysine at this position, which has a large side chain; macaques instead have asparagine, which contributes to HBV resistance.

The researchers also noted that bile acids and HBV’s preS1 competed to bind to NTCP, where the long tail-chain structure of the bile acid inhibited the binding of preS1. Commenting on these findings, Prof Watashi stated, “Bile acids with long conjugated chains exhibited anti-HBV potency. Development of bile acid-based anti-HBV compounds is underway and our results will be useful for the design of such anti-HBV entry inhibitors.”

By unravelling the structure of mNTCP and pinpointing the amino acids that facilitate viral entry into liver cells, researchers have opened the door to new therapeutic avenues. Furthermore, the implications extend beyond HBV, offering critical insights into other viruses, including SARS-CoV-2, and their potential to cross species barriers. This research not only enhances our understanding of viral dynamics but also serves as a crucial tool in the ongoing quest to predict and prevent future pandemics.

The future of global health hinges on these revelations, promising a path toward more equitable access to treatments and a stronger defence against emerging viral threats.

Source: Tokyo University of Science