Categories : AgeingTags :

New Study Explains Why we Move More Slowly with Age

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It’s one of the inescapable realities of aging: The older we get, the slower we tend to move – whether we’re walking around the block or just reaching for the remote control. A new study led by CU Boulder engineers helps explain why.

The research is one of the first studies to experimentally tease apart the competing reasons why people over age 65 might not be as quick on their feet as they used to be. The group reported that older adults may move slower, at least in part, because it costs them more energy than younger people – perhaps not too shocking for anyone who’s woken up tired the morning after an active day.

The findings could one day give doctors new tools for diagnosing a range of illnesses, including Parkinson’s disease, multiple sclerosis and even depression and schizophrenia, said study co-author Alaa Ahmed. 

“Why we move the way we do, from eye movements to reaching, walking and talking, is a window into aging and Parkinson’s,” said Ahmed, professor in the Paul M. Rady Department of Mechanical Engineering. “We’re trying to understand the neural basis of that.”

She and her colleagues published their findings this month in the journal JNeurosci.

For the study, the group asked subjects age 18 to 35 and 66 to 87 to complete a deceptively simple task: to reach for a target on a screen, akin to playing a video game on a Nintendo Wii. By analysing patterns of these reaches, the researchers discovered that older adults seemed to modify their motions under certain circumstances to conserve their more limited supplies of energy. 

“All of us, whether young or old, are inherently driven to get the most reward out of our environment while minimising the amount of effort to do so,” said Erik Summerside, a co-lead author of the new study who earned his doctorate in integrative physiology from CU Boulder in 2018.

Using engineering to understand the brain

Ahmed added that researchers have long known that older adults tend to be slower because their movements are less stable and accurate. But other factors could also play a role in this fundamental part of growing up.

According to one hypothesis, the muscles in older adults may work less efficiently, meaning that they burn more calories while completing the same tasks as younger adults – like running a marathon or getting up to grab a soda from the refrigerator.

Alternatively, aging might also alter the reward circuitry in the human brain. Ahmed explained that as people age, their bodies produce less dopamine, a brain chemical responsible for giving you a sense of satisfaction after a job well done. If you don’t feel that reward as strongly, the thinking goes, you may be less likely to move to get it. People with Parkinson’s disease experience an even sharper decline in dopamine production.

In the study, the researchers asked more than 80 people to sit down and grab the handle of a robotic arm, which, in turn, operated the cursor on a computer screen. The subjects reached forward, moving the cursor toward a target. If they succeeded, they received a reward – not a big one, but still enough to make their brains happy.

“Sometimes, the targets exploded, and they would get point rewards,” Ahmed said. “It would also make a ‘bing bing’ sound.”

Moving slower but smarter

That’s when a contrast between the two groups of people began to emerge.

Both the 18 to 35-year-olds and 66 to 87-year-olds arrived at their targets sooner when they knew they would hear that ‘bing bing’ – roughly 4% to 5% sooner over trials without the reward. But they also achieved that goal in different ways.

The younger adults, by and large, moved their arms faster toward the reward. The older adults, in contrast, mainly improved their reaction times, beginning their reaches about 17 milliseconds sooner on average.

When the team added an 8-pound (3.6kg) weight to the robotic arm for the younger subjects, those differences vanished.

“The brain seems to be able to detect very small changes in how much energy the body is using and adjusts our movements accordingly,” said Robert Courter, a co-lead author of the study who earned his doctorate in integrative physiology from CU Boulder in 2023. “Even when moving with just a few extra pounds, reacting quicker became the energetically cheaper option to get to the reward, so the young adults imitated the older adults and did just that.”

The research seems to paint a clear picture, Ahmed said. Both the younger and older adults didn’t seem to have trouble perceiving rewards, even small ones. But their brains slowed down their movements under tiring circumstances.

“Putting it all together, our results suggest that the effort costs of reaching seem to be determining what’s slowing the movement of older adults,” Ahmed said.

The experiment can’t completely rule out the brain’s reward centres as a culprit behind why we slow down when we age. But, Ahmed noted, if scientists can tease out where and how these changes emerge from the body, they may be able to develop treatments to reduce the toll of aging and disease.

Source: University of Colorado Boulder

Categories : Diet and NutritionTags :

Social Media can Influence Young People to Eat More Healthily

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Photo by Alex Haney

Researchers from Aston University have found that people following healthy eating accounts on social media for as little as two weeks ate more fruit and vegetables and less junk food.

Previous research has shown that positive social norms about fruit and vegetables increases individuals’ consumption. The research team sought to investigate whether positive representation of healthier food on social media would have the same effect. The research was led by Dr Lily Hawkins, whose PhD study it was, supervised by Dr Jason Thomas and Professor Claire Farrow in the School of Psychology.

The researchers recruited 52 volunteers, all social media users, with a mean age of 22, and split them into two groups. Volunteers in the first group, known as the intervention group, were asked to follow healthy eating Instagram accounts in addition to their usual accounts. Volunteers in the second group, known as the control group, were asked to follow interior design accounts. The experiment lasted two weeks, and the volunteers recorded what they ate and drank during the time period.

Overall, participants following the healthy eating accounts ate an extra 1.4 portions of fruit and vegetables per day and 0.8 fewer energy dense items, such as high-calorie snacks and sugar-sweetened drinks, per day. This is a substantial improvement compared to previous educational and social media-based interventions attempting to improve diets.

Dr Thomas and the team believe affiliation is a key component of the change in eating behaviour. For example, the effect was more pronounced amongst participants who felt affiliated with other Instagram users.

The 2018 NHS Health Survey for England study showed that only 28% of the UK population consumed the recommended five portions of fruit and vegetables per day. Low consumption of such food is linked to heart disease, cancer and stroke, so identifying ways to encourage higher consumption is vital. Exposing people to positive social norms, using posters in canteens encouraging vegetable consumption, or in bars to discourage dangerous levels of drinking, have been shown to work. Social media is so prevalent now that the researchers believe it could be an ideal way to spread positive social norms around high fruit and vegetable consumption, particularly amongst younger people.

Dr Hawkins, who is now at the University of Exeter, said: “Our previous research has demonstrated that social norms on social media may nudge food consumption, but this pilot demonstrates that this translates to the real world. Of course, we would like to now understand whether this can be replicated in a larger, community sample.”

Source: Aston University

Categories : Cardiovascular DiseaseTags :

Study Finds Positive Effects with Anaesthetic Drug after Cardiac Arrest

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Photo by Mat Napo o Unsplash

If a patient is successfully resuscitated after a cardiac arrest and circulation resumes, they are not out of the woods yet. A number of factors can influence whether and how they survive the trauma in the subsequent phase. But a multicentre study of 571 patients has shown that the administration of the anaesthetic midazolam has a positive effect.

In cases where the patient required anaesthesia after successful resuscitation, midazolam improved the chances of optimal oxygen saturation and CO2 levels in the blood. The risk of a renewed drop in blood pressure or a renewed circulatory arrest didn’t increase. “This specific group of patients who have been successfully resuscitated should definitely be included in the guidelines for pre-hospital anaesthesia. Midazolam has proven to have a particularly positive effect in this group,” concludes Dr Gerrit Jansen, lead author of the study, which was published in the journal Deutsches Ärzteblatt International.

In the event of a cardiac arrest, rapid intervention is essential: If first aiders carry out resuscitation measures in good time, the patient’s circulation can be restarted in the best-case scenario. “However, it’s often the case that the patient hasn’t yet regained consciousness,” explains Gerrit Jansen. In this phase, there are various factors that can affect the chances of survival and subsequent permanent limitations due to the circulatory arrest.

“Some patients display protective reflexes after resuscitation, such as coughing or defensive movements, which make the emergency responders’ work more difficult. They often have to perform extended airway management, for example by intubating the patient in the same way as during surgery. This frequently requires sedation or anaesthesia,” explains Jansen. Until now, there has been concern that anaesthetic drugs could have a negative impact on the circulatory system, which has only just been restored. According to the study, however, this is not the case.

Of the 571 people included in the study who survived a cardiac arrest and were admitted to hospital, 395 were sedated, 249 of them with midazolam. The chance that their blood oxygen saturation levels were in the optimal range following a cardiac arrest increased twofold when midazolam was administered. The chance that carbon dioxide was effectively exhaled increased by a factor of 1.6 with the drug. “Our statistical methods confirmed a correlation between these results and the administration of midazolam, without any indication of negative circulatory effects,” says Gerrit Jansen.

“The European guidelines of the European Resuscitation Council don’t yet set out any specific recommendations for possible anesthetic drugs,” explains Jansen. “The German guideline for pre-hospital anaesthesia for patients with cardiovascular risk doesn’t mention patients in cardiac arrest. We’ve therefore carried out pioneering research in this field, the results of which should be incorporated into the recommendations for the benefit of the patients.”

Source: Ruhr-University Bochum

Categories : Neurology Surgeries & ProceduresTags :

Spinal Surgeons can Now Monitor their Procedure’s Effects Mid-surgery

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Photo by Natanael Melchor on Unsplash

With technology developed at UC Riverside, scientists can, for the first time, make high resolution images of the human spinal cord during surgery. The advancement could help bring real relief to millions suffering chronic back pain.

The technology, known as fUSI or functional ultrasound imaging, not only enables clinicians to see the spinal cord, but also enables them to map the cord’s response to various treatments in real time. A paper published today in the journal Neuron details how fUSI worked for six people undergoing electrical stimulation for chronic back pain treatment.

“The fUSI scanner is freely mobile across various settings and eliminates the requirement for the extensive infrastructure associated with classical neuroimaging techniques, such as functional magnetic resonance imaging (fMRI),” said Vasileios Christopoulos, assistant professor of bioengineering at UCR who helped develop the technology. “Additionally, it offers ten times the sensitivity for detecting neuroactivation compared to fMRI.”

Until now, it has been difficult to evaluate whether a back pain treatment is working since patients are under general anaesthesia, unable provide verbal feedback on their pain levels during treatment. “With ultrasound, we can monitor blood flow changes in the spinal cord induced by the electrical stimulation. This can be an indication that the treatment is working,” Christopoulos said.

The spinal cord is an “unfriendly area” for traditional imaging techniques due to significant motion artifacts, such as heart pulsation and breathing. “These movements introduce unwanted noise into the signal, making the spinal cord an unfavorable target for traditional neuroimaging techniques,” Christopoulos said.

By contrast, fUSI is less sensitive to motion artifacts, using echoes from red blood cells in the area of interest to generate a clear image. “It’s like submarine sonar, which uses sound to navigate and detect objects underwater,” Christopoulos said. “Based on the strength and speed of the echo, they can learn a lot about the objects nearby.”

Christopoulos partnered with the USC Neurorestoration Center at Keck Hospital to test the technology on six patients with chronic low back pain. These patients were already scheduled for the last-ditch pain surgery, as no other treatments, including drugs, had helped to ease their suffering. For this surgery, clinicians stimulated the spinal cord with electrodes, in the hopes that the voltage would alleviate the patient’s discomfort and improve their quality of life.

“If you bump your hand, instinctively, you rub it. Rubbing increases blood flow, stimulates sensory nerves, and sends a signal to your brain that masks the pain,” Christopoulos said. “We believe spinal cord stimulation may work the same way, but we needed a way to view the activation of the spinal cord induced by the stimulation.”

The Neuron paper details how fUSI can detect blood flow changes at unprecedented levels of less than 1mm/s. For comparison, fMRI is only able to detect changes of 2cm/s.

“We have big arteries and smaller branches, the capillaries. They are extremely thin, penetrating your brain and spinal cord, and bringing oxygen places so they can survive,” Christopoulos said. “With fUSI, we can measure these tiny but critical changes in blood flow.”

Generally, this type of surgery has a 50% success rate, which Christopoulos hopes will be dramatically increased with improved monitoring of the blood flow changes. “We needed to know how fast the blood is flowing, how strong, and how long it takes for blood flow to get back to baseline after spinal stimulation. Now, we will have these answers,” Christopoulos said.

Moving forward, the researchers are also hoping to show that fUSI can help optimise treatments for patients who have lost bladder control due to spinal cord injury or age. “We may be able to modulate the spinal cord neurons to improve bladder control,” Christopoulos said.

“With less risk of damage than older methods, fUSI will enable more effective pain treatments that are optimised for individual patients,” Christopoulos said. “It is a very exciting development.”

Source: University of California Riverside

Categories : AntibioticsTags :

Useless Antibiotic Prescriptions are Getting out of Hand

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Photo from Pixabay CCO

According to a massive new medical insurance database study, the U.S. is going the wrong way with antibiotic stewardship, with 1 in 4 prescriptions going to patients who have conditions that the drugs simply won’t work on. In fact, the percentage of all antibiotic prescriptions given to treat conditions they’re useless against was even higher in December 2021 than it was before the pandemic began, the study shows – increasing the rate of antibiotic resistance development.

The percentage inappropriate prescriptions actually fell slightly in the early months of the pandemic, when far fewer people sought medical care for infectious or non-infectious reasons, the new research shows. But this trend was soon reversed.

The study, published in the journal Clinical Infectious Diseases by a team from the University of Michigan, Northwestern University and Boston Medical Center, is based on data from more than 37.5 million children and adults covered by private insurance or Medicare Advantage plans from 2017 to 2021. Patients received antibiotic prescriptions from both in-person and telehealth visits.

The team looked back at any new diagnosis given to each patient on the day they received a prescribed antibiotic or in the three days before getting the prescription. If none of these diagnoses justified the use of antibiotics, they classified the prescription as inappropriate.

Key findings:

  • In all, 60.6 million antibiotic prescriptions were dispensed in the five years of the study period from January 2017 to December 2021. The share that were inappropriate rose from 25.5% to 27.1% during this period.
  • The proportion of people getting inappropriate antibiotics was 1.7% in December 2019, dipped to 0.9% in April 2020 – largely because fewer people get antibiotics in general – and returned to 1.7% by December 2021.
  • Some groups of people were more likely to receive inappropriate antibiotics. At the end of 2021, 30% of antibiotics for older adults with Medicare Advantage coverage were inappropriate, compared with 26% of antibiotics for adults with private health insurance and 17% of antibiotics for children with private insurance.
  • Among the diagnoses listed for people who received antibiotics for inappropriate reasons, “contact with and suspected exposure to COVID-19” was one of top two most common reasons from March 2020 through December 2021. There is no evidence that taking antibiotics after an exposure can reduce risk of developing COVID-19.
  • Of all the inappropriately prescribed antibiotics dispensed in the last half of 2021, 15% were for a COVID-19 infection. And COVID-19 infections accounted for 2% of all antibiotic prescribing – regardless of appropriateness – from March 2020 through December 2021.
  • Telehealth appointments accounted for 9% of all inappropriate antibiotic prescriptions in the latter half of 2021, down somewhat from 2020. There were almost no telehealth-based antibiotic prescriptions before March 2020.
  • For 28% to 32% of the antibiotic prescriptions filled by patients in the study period, there was no diagnosis available to judge appropriateness, potentially because the patient received the prescription at an appointment that didn’t get billed to their insurance, or it was a refill of a past prescription. The percentage was especially high in the first months of the pandemic.
  • 45% of all the patients in the study received antibiotics at least once in the five years, and 13% received them four or more times.

Source: University of Michigan

Categories : Ageing NeurologyTags :

Essential Tremor Increases Cognitive Impairment Risks over Time

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Photo by Matthias Zomer on Pexels

Essential tremor, a nervous system disorder that causes rhythmic shaking, is one of the most common movement disorders. A new study published in the Annals of Neurology reveals details on the increased risk of mild cognitive impairment (MCI) and dementia that individuals with essential tremor may face.

The research represents the longest available longitudinal prospective study of rates of MCI and dementia in people with essential tremor. The study enrolled 222 patients, 177 of whom participated in periodic evaluations over an average follow-up of 5 years.

Investigators observed a cumulative prevalence of 26.6% and 18.5% for MCI and dementia, respectively. They also noted a cumulative incidence of 18.2% and 11.2% for MCI and dementia, respectively. Each year, 3.9% of patients with normal cognition “converted” to having MCI, and 12.2% of those with MCI “converted” to having dementia.

“We know from related research that the presence of cognitive impairment in patients with essential tremor has meaningful clinical consequences. For example, patients with essential tremor who are diagnosed with dementia are more likely to need to use a walker or wheelchair, to employ a home health aide, and to reside in non-independent living arrangements than are patients with essential tremor without dementia,” said corresponding author Elan D. Louis, MD, MS, of the University of Texas Southwestern Medical Center. “With this in mind, the findings of the present study highlight the importance of cognitive screening and monitoring in patients with essential tremor. Early detection of impairment may provide opportunities for interventions that may slow further cognitive decline and improve the quality of life of patients and their families.”

Source: Wiley

Categories : Metabolic DisordersTags :

Study Links Emulsifiers and Type 2 Diabetes Risk

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Emulsifiers, commonly used additives for improving the texture of food products and extending their shelf life, may be associated with the onset of type 2 diabetes, according to a large cohort study of over 100 000 people in France.

Researchers from Inserm, INRAE, Université Sorbonne Paris Nord, Université Paris Cité and Cnam, as part of the Nutritional Epidemiology Research Team (CRESS-EREN), studied the possible links between the dietary intake of food additive emulsifiers and the onset of type 2 diabetes between 2009 and 2023. They analysed the dietary and health data of 104 139 adults participating in the French NutriNet-Santé cohort study, specifically evaluating their consumption of this type of food additive using dietary surveys conducted every six months. The findings suggest an association between the chronic consumption of certain emulsifier additives and a higher risk of diabetes. The study is published in Lancet Diabetes & Endocrinology.

In Europe and North America, 30 to 60% of dietary energy intake in adults comes from ultra-processed foods. An increasing number of epidemiological studies suggest a link between higher consumption levels of ultra-processed foods with higher risks of diabetes and other metabolic disorders.

Emulsifiers are among the most commonly used additives. They are often added to processed and packaged foods such as certain industrial cakes, biscuits and desserts, as well as yoghurts, ice creams, chocolate bars, industrial breads, margarines and ready-to-eat or ready-to-heat meals, in order to improve their appearance, taste and texture and lengthen shelf life. These emulsifiers include for instance mono- and diglycerides of fatty acids, carrageenans, modified starches, lecithins, phosphates, celluloses, gums and pectins.

As with all food additives, the safety of emulsifiers had been previously evaluated by food safety and health agencies based on the scientific evidence that was available at the time of their evaluation.
However, some recent studies suggest that emulsifiers may disrupt the gut microbiota and increase the risk of inflammation and metabolic disruption, potentially leading to insulin resistance and the development of diabetes.

For the first time worldwide, a team of researchers in France has studied the relationships between the dietary intakes of emulsifiers, assessed over a follow-up period of maximum 14 years, and the risk of developing type 2 diabetes in a large study in the general population.

The results are based on the analysis of data from 104 139 adults in France (average age 43 years; 79% women) who participated in the NutriNet-Santé web-cohort study (see box below) between 2009 and 2023.

The participants completed at least two days of dietary records, collecting detailed information on all foods and drinks consumed and their commercial brands (in the case of industrial products). These dietary records were repeated every six months for 14 years, and were matched against databases in order to identify the presence and amount of food additives (including emulsifiers) in the products consumed. Laboratory assays were also performed in order to provide quantitative data. This allowed a measurement of chronic exposure to these emulsifiers over time.

During follow-up, participants reported the development of diabetes (1056 cases diagnosed), and reports were validated using a multi-source strategy (including data on diabetes medication use). Several well-known risk factors for diabetes, including age, sex, weight (BMI), educational level, family history, smoking, alcohol and levels of physical activity, as well as the overall nutritional quality of the diet (including sugar intake) were taken into account in the analysis.

After an average follow-up of seven years, the researchers observed that chronic exposure – evaluated by repeated data – to the following emulsifiers was associated with an increased risk of type 2 diabetes:

  • carrageenans (total carrageenans and E407; 3% increased risk per increment of 100 mg per day)
  • tripotassium phosphate (E340; 15% increased risk per increment of 500 mg per day)
  • mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids (E472e; 4% increased risk per increment of 100 mg per day)
  • sodium citrate (E331; 4% increased risk per increment of 500 mg per day)
  • guar gum (E412; 11% increased risk per increment of 500 mg per day)
  • gum arabic (E414; 3% increased risk per increment of 1000 mg per day)
  • xanthan gum (E415; 8% increased risk per increment of 500 mg per day)

This study constitutes an initial exploration of these relationships, and further investigations are now needed to establish causal links. The researchers mentioned several limitations of their study, such as the predominance of women in the sample, a higher level of education than the general population, and generally more health-promoting behaviours among the NutriNet-Santé study participants. Therefore caution is needed when extrapolating the conclusions to the entire French population.

The study is nevertheless based on a large sample size, and the researchers have accounted for a large number of factors that could have led to confounding bias. They also used unique, detailed data on exposure to food additives, down to the commercial brand name of the industrial products consumed. In addition, the results remain consistent through various sensitivity analyses, which reinforces their reliability.

“These findings are issued from a single observational study for the moment, and cannot be used on their own to establish a causal relationship,”explain Mathilde Touvier, Research Director at Inserm, and Bernard Srour, Junior Professor at INRAE, lead authors of the study. “They need to be replicated in other epidemiological studies worldwide, and supplemented with toxicological and interventional experimental studies, to further inform the mechanisms linking these food additive emulsifiers and the onset of type 2 diabetes. However, our results represent key elements to enrich the debate on re-evaluating the regulations around the use of additives in the food industry, in order to better protect consumers.”

Among the next steps, the research team will be looking at variations in certain blood markers and the gut microbiota linked to the consumption of these additives, to better understand the underlying mechanisms. The researchers will also look at the health impact of additive mixtures and their potential ‘cocktail effects.’

They will also work in collaboration with toxicologists to test the impact of these exposures in in vitro and in vivo experiments, to gather more arguments in favour of a causal link.

Categories : Hospitals PaediatricsTags :

Refurbished School for Paediatric Patients Bridges Critical Learning Gaps

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Photo by Mary Taylor on Pexels

April 16 2024 – The Chris Hani Baragwanath Hospital School officially opened in its new location today, marking a key milestone in the partnership between Wits University and the academic hospital. The school caters for all learners in need of longer-term and chronic treatment for various paediatric conditions. Learners between Grades R and 12 are taught.  

“Sick children have multiple needs, and it’s our duty to ensure that they don’t miss out on any schooling. Everyone deserves the right to be educated and to contribute meaningfully to their communities as adults,” said Professor Shabir Madhi, Dean of the Wits Faculty of Health Sciences. 

Professor Madhi noted that the previous school building will be used as a campus for medical students and to grow the university’s teaching and learning footprint at Chris Hani Baragwanath Academic Hospital.  

The school district representative for Johannesburg Central, Ronica Ramdath, said that often sick children forfeit their education, which can be mitigated through the correct teaching approach and through supportive facilities. “When I first came to the school some years back, I was amazed at the teachers’ dedication. I remember seeing a teacher load all their educational resources in a bag and walk to the paediatric ward to teach sick children. Today, these children all benefit from such support,” she said.  

The Wits Faculty of Health Sciences heads of schools were present, together with hospital and teaching representatives.  

Meanwhile, Professor Madhi said that the university’s wifi is available at Chris Hani Baragwanath Hospital, underpinning Wits’ commitment to invest in a world-class academic hospital facility. “We are very proud of our footprint at the hospital and hope to continue to add value through research and clinical work,” he said. 

Source: University of the Witwatersrand – Faculty of Health Sciences

Categories : Immune SystemTags :

How Glucocorticoids Reprogram Immune Cells to Slow them Down

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Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID

Cortisone and other related glucocorticoids are extremely effective at curbing excessive immune reactions. But previously, astonishingly little was known about how they exactly do that. A team of researchers have now explored the molecular mechanism of action in greater detail. As the researchers report in the journal Nature, glucocorticoids reprogram the metabolism of immune cells, activating the body’s natural “brakes” on inflammation. These findings lay the groundwork for development of anti-inflammatory agents with fewer and less severe side effects.

The glucocorticoid cortisone is naturally present in the body as the stress hormone cortisol, which is released to improve the body’s responses to stress. Cortisol intervenes in sugar and fat metabolism and affects other parameters, including blood pressure and respiratory and heart rate. At higher doses, it also inhibits immune system activity, making it it useful for medical purposes. Due to their excellent efficacy, synthetic glucocorticoid derivates that inhibit inflammation even more strongly are used to treat a wide range of immune-mediated inflammatory diseases.

Glucocorticoids affect not only genes, but also cellular energy sources

Glucocorticoid-based medications come with side effects, especially at higher doses and when administered for longer periods. These side effects are related to the other effects of the body’s own cortisol, and include hypertension, osteoporosis, diabetes, and weight gain. With the aim of developing anti-inflammatory agents with fewer and less severe side effects, a team of researchers from from Charité – Universitätsmedizin Berlin, Uniklinikum Erlangen and Ulm University has now conducted a closer study of how the immunosuppressive effects of glucocorticoids exactly works.

Lead researcher Prof Gerhard Krönke, director of the Department of Rheumatology and Clinical Immunology at Charité, explains: “It was previously known that glucocorticoids activate a number of genes in different cells of the body. But through this mechanism, they mainly activate the resources present in the body. This does not adequately explains its strong immunosuppressive effect. In our study, we have now been able to show that glucocorticoids affect more than just the gene expression in immune cells. It also affects the cell´s powerhouses, the mitochondria. And that this effect on cell metabolism is in turn crucial to the anti-inflammatory effects exerted by glucocorticoids.”

Swords to plowshares

For the study, the research team focused on macrophages, a type of immune cell responsible for eliminating intruders such as viruses and bacteria. These cells can also play a role in the emergence of immune-mediated inflammatory diseases. In a mouse model, the researchers studied how these immune cells responded to inflammatory stimuli in a laboratory setting and what effects additional administration of a glucocorticoid had. The researchers observed that in addition to its effect on gene expression, glucocorticoids had a major effect in reversing changes in the cell metabolism that had been initiated by the inflammatory stimuli.

“When macrophages are put into ‘fight’ mode, they redirect their cellular energy into arming for a fight. Instead of supplying energy, their mitochondria produce the components needed to fight intruders,” Krönke says, describing the processes involved. “Glucocorticoids reverse the process, switching the ‘fight’ mode back off and turning swords into plowshares, so to speak. A tiny molecule called itaconate plays an especially important role in this.”

Itaconate mediates anti-inflammatory effect of glucocorticoids

Itaconate is an anti-inflammatory substance that the body naturally produces inside its mitochondria. Macrophages produce it early on when they are activated so that the inflammatory reaction will subside after a certain period. Generation of this natural immune “brake,” however, requires sufficient fuel. When the cell´s powerhouses are arming up for a fight, that is no longer the case, so itaconate production dwindles to a halt after a while. With normal, short-term inflammation, this timing is effective because the immune response has also subsided in the meantime.

“With a persistent inflammatory stimulus, the drop-off in itaconate production is an issue because there is then no immune ‘brake’ even though the immune system is still running on all cylinders, eventually contributing to chronic inflammation,” explains Dr Jean-Philippe Auger, a scientist at the Department of Medicine 3 – Rheumatology and Immunology at Uniklinikum Erlangen and the first author of the study. “This is where glucocorticoids intervenes. By reprogramming the mitochondrial function, they ramp up the formation of itaconate in the macrophages, restoring its anti-inflammatory effect.”

The search for new active substances

Using animal models for asthma and rheumatoid arthritis, the researchers showed how much the anti-inflammatory effect of glucocorticoids depends on itaconate. Glucocorticoids had no effect in animals unable to produce itaconate. So, if itaconate mediates the immunosuppressant effect of cortisone, what about administering itaconate directly, instead of glucocorticoids?

“Unfortunately, itaconate isn’t a particularly good candidate as an anti-inflammatory drug, because it’s unstable, and due to its high reactivity, it could cause side effects if administered systemically,” Krönke explains. “Aside from that, we assume the processes in humans to be a bit more complex than those in mice. So our plan is to look for new synthetic compounds that are just as effective as glucocorticoids at reprogramming the mitochondrial metabolism inside immune cells, but have fewer and less severe side effects.”

Source: Charité – Universitätsmedizin Berlin

Categories : Metabolic Disorders VaccinesTags :

Metabolic Health before Flu Vaccination Determines Its Effectiveness

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A four-week healthy diet improved the effectiveness of a flu vaccine given to obese mice

Photo by Gustavo Fring on Pexels

Scientists at St. Jude Children’s Research Hospital have shown that improving metabolic health in obese mice before vaccination, but not after, protects against influenza virus.

Metabolic health (normal blood pressure, blood sugar and cholesterol levels, among other factors) influences the effectiveness of influenza vaccinations. Vaccination is known to be less effective in people with obesity compared to those with a healthier body mass index (BMI), but St. Jude Children’s Research Hospital scientists have found that the difference is attributable not to obesity itself, but rather metabolic dysfunction. In a study published in Nature Microbiology, the researchers found that switching obese mice to a healthy diet before flu vaccination, but not after, completely protected the models from a lethal dose of flu, despite BMI.

“We found that the vaccines worked effectively if at the time of vaccination an animal is metabolically healthy,” said corresponding author Stacey Schultz-Cherry, PhD, St. Jude Department of Host-Microbe Interactions and Center of Excellence for Influenza Research and Response co-director. “And the opposite was also true: regardless of what the mice looked like on the outside, if they had metabolic dysfunction, the vaccines did not work as well.”

Prior research has shown that 100% of obese mice succumbed to influenza after exposure, even after vaccination. Contrary to the scientists’ original expectations, when mice who were vaccinated while obese returned to a healthy weight, outcomes did not improve. These now outwardly healthy mice still all succumbed to disease when exposed to the real virus. Only switching to a healthy diet four weeks before vaccination improved survival, with drastic effect, despite high BMI.

“We were excited to see this effect because mice with obesity are so susceptible to severe disease and succumbing to the infection,” Schultz-Cherry said. “Getting 100% survival with the vaccine where we had only seen 0% survival was impressive.” The improved survival suggests the researchers have discovered a greater underlying principle determining influenza vaccine efficacy.

Metabolic dysfunction hinders the immune system

While studying how metabolic function influences influenza vaccine responses, the scientists found that poor metabolic health causes immune system dysfunction. T cells, the primary immune cells involved in anti-viral responses, failed to act in animals that had been in an unhealthy metabolic state at the time of vaccination, even during later viral exposure. Even when the animals ate a healthy diet after vaccination and maintained a normal BMI, the anti-flu T cells were “frozen” in that dysfunctional state.

However, a healthy diet before vaccination improved T-cell function, which resulted in a robust anti-flu response during later exposure.

“The T cells were better able to do their job in the metabolically healthy mice at the time of vaccination,” Schultz-Cherry said. “It wasn’t a matter of the numbers of them or the types of them. It was their functional activity. There were plenty of them in the lungs, not working. The healthy diet switched them from not working to functioning properly, but only if the switch occurred before vaccination.”

The earlier healthy diet also improved inflammation. Pro-inflammatory cytokines are upregulated in obese animals. Schultz-Cherry’s team found that models also returned to a lower basal cytokine level when switched to a healthy diet before vaccination.

“A healthy diet lowered some of the systemic meta-inflammation in these animals, and they regained some of the epithelial innate immune responses,” said Schultz-Cherry. “We started seeing better signalling of things like interferons, which we know is problematic in obesity and in general saw the immune system starting to function the way that it should.”

Improving metabolic health may improve influenza vaccine effectiveness

“What we found and are emphasising is that it’s not the phenotype of obesity that matters; it’s really about metabolic health,” Schultz-Cherry said. “It’s metabolic health at that moment of vaccination that really makes a difference.”

The study was restricted to mice, but it does open research opportunities to improve influenza vaccine efficacy in humans. The findings suggest methods of improving metabolic health may also improve subsequent influenza vaccinations. Given the recent introduction of metabolic improvement drugs, especially glucagon-like peptide 1 (GLP-1) agonists, there may be potential for a cooperative effect.

“We don’t know for sure, but if the outcome of using GLP-1 drugs is weight loss and improved metabolic health, we would hypothesise that it will help,” Schultz-Cherry said. “But we do know that we can do better protecting our vulnerable populations, and this study is a start for understanding how.”

Source: St. Jude Children’s Research Hospital