Category: Diseases, Syndromes and Conditions

In Depth: As Schools Open, will Measles Outbreaks get Worse?

By Elri Voigt

In October last year, the National Institute for Communicable Diseases (NICD) alerted the public to a measles outbreak in Limpopo. Since then, four more provinces have reported outbreaks, and the number of positive cases in the country has climbed rapidly.

Last week’s measles report from the NICD indicated that between the first week of October 2022 and mid-week in the second week of January 2023, a total of 397 cases of measles were identified across the country. Of those, 382 cases were detected in five provinces – Limpopo 145, North West 125, Mpumalanga 79, Gauteng 18, and the Free State 15. These five provinces have all met the criteria for a measles outbreak (three or more cases in a district within a month).

The remaining 15 cases are spread around KwaZulu-Natal, Northern Cape, the Eastern Cape, and the Western Cape – none of which have so far met the criteria for an outbreak.

‘Biggest outbreak in 11 years’

Dr Kerrigan McCarthy, a pathologist from the Centre for Vaccines and Immunology at the NICD, tells Spotlight that this is the biggest outbreak in 11 years, surpassing the outbreak in 2017 when around 280 cases of measles were identified.

According to the NICD report, the total number of laboratory-confirmed measles cases and the total number of samples submitted for testing has decreased for the third consecutive week. However, McCarthy cautions that this apparent decline might actually be due to a decrease in the number of specimens sent to the NICD for testing, and not to the outbreak actually slowing down.

“The fact that we have seen a decrease in the number of positive cases could be attributed to the decrease in number of specimens that have been submitted, but there is a small possibility that it could represent a turnaround in the outbreak. However, a consensus amongst us in public health is that it is the former problem,” says McCarthy.

She adds that the true extent of this outbreak – and whether new cases have really declined or not – may only become clear in the next few weeks, as schools across the country resume activities.

While it isn’t possible to predict exactly where the outbreak is going, McCarthy says at the moment it is following a similar trend to the widespread measles outbreak that occurred just over a decade ago. “In 2009 to 2011 we had an outbreak of over 22 000 measles cases… and in fact, in that outbreak, we saw a similar pattern. The outbreak was declared in late 2009 and cases started increasing into December and then when the schools closed and December holidays happened, there was a lull in cases and then when the schools returned there was a massive increase in cases,” she says.

Fears of much larger outbreaks

In a Spotlight article published in July last year, Dr Haroon Saloojee, Professor and Head of the Division of Community Paediatrics at the University of the Witwatersrand, and other experts warned that low vaccination rates may lead to measles outbreaks of the type we are now seeing. Now they are concerned that things might get worse.

Saloojee agrees that it isn’t possible to predict exactly how this outbreak will behave. “There are obviously three possible outcomes,” he says, “An increase, levelling off, or decline. My fear and expectation [are] that the outbreak will continue to expand. There are more than a million unvaccinated children under five, and possibly about 2.5 million unvaccinated under 15 years.

“We should be greatly concerned. It is highly likely that the outbreak will extend beyond the five provinces and affect all provinces in the country,” he says.

He adds that children are protected from measles through vaccination and if 95% of children are vaccinated against measles, then this herd immunity will protect the 5% who are not vaccinated. But in South Africa, measles coverage is not at 95%.

“In South Africa, at best, about 80% of children are vaccinated [against measles]. The proportion is lower in some provinces. Thus, all children, but particularly unvaccinated children, are at risk of acquiring measles,” he says. “We haven’t had a serious problem [with] measles in South Africa for at least the last 20 years. But in other low- and middle-income countries, it is still one of the five major causes of child mortality.”

Mass measles immunisation campaign needed

Saloojee tells Spotlight the only way to curtail the outbreak at this point is through a national supplementary mass measles immunisation campaign.

“There is only one option at this stage, as we are facing a crisis. A national supplementary immunisation campaign is warranted, despite its high cost and resource demands,” he says. “Such activities have already commenced in the affected provinces and will be extended to other provinces if the outbreak continues to spread. The aim of the campaign is to boost measles vaccine coverage to the 95% mark in the short term, so that herd immunity can kick in.”

How did we get here?

While such an immunisation campaign should help mitigate the current spread of measles, the question remains how a widespread outbreak could occur in the first place given South Africa’s well-established childhood immunisation programme.

“The outbreak was entirely predictable and preventable,” says Saloojee. “We have had similar outbreaks [about] every five years since 2000. Paradoxically, COVID delayed this outbreak, which should have happened in 2020 because the isolation measures protected against measles spread too.”

“However, we cannot run away from the fact that too few children receive all their routine vaccinations, and there is little being done to systematically change this such as stopping vaccine stockouts, and clinics and hospitals reducing missed opportunities to vaccinate eligible children,” he says. “If nothing is done, we can count on another outbreak in 2028.”

Countries across the world are reporting measles outbreaks, according to the CDC, which is being attributed to a disruption in services like routine immunisation because of the COVID pandemic. However, according to Saloojee, South Africa’s outbreak cannot be attributed exclusively to the pandemic disrupting services, instead, it is also due to years of suboptimal measles vaccine coverage.

Spotlight previously reported in-depth on results from the 2019 Expanded Programme on Immunisation (EPI) National Coverage survey, which showed that only around 77% (76.8%) of the children surveyed had received all fourteen age-appropriate vaccines from birth to 18 months. This includes the two doses of the measles vaccine.

Dr Lesley Bamford, a child health specialist in youth and school health at the National Department of Health, provided Spotlight with a table showing measles vaccination coverage per province between 2017 and 2022.

graph - Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of HealthNote that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health

According to the figures provided by Bamford, national coverage for the first dose of the measles vaccine has improved from 80% in 2017-2018 to 88% in 2021-2022. However, coverage for the second measles dose remained stuck in a narrow band from 77% to 80%, until 2021-2022, when it improved to 84% – still well below the 95% coverage required for herd immunity.

Expanded vaccination campaign

The NICD report shows the highest number of measles cases so far have been in the five to nine-year age group, which represents 40% of cases. 29% of cases were in the one to four age group and 17% in the 10 to 14-year age group. The remaining cases occurred in children younger than one year and those aged 15 and older.

According to McCarthy, based on the distribution of cases in these age groups, the NICD recommended to the National Department of Health that it extend its planned mass measles vaccination campaign to include children between six months and 15 years of age – which the Department has agreed to do.

Bamford tells Spotlight that a mass measles immunisation campaign had already been planned across all provinces for February 2023. But for the five provinces experiencing outbreaks, the timeline has since moved up. The four remaining provinces will still start their campaigns in February as planned.

“The target age group for that campaign has been extended. So, the initial plan was targeting children under 5 years of age and now in most provinces, it has been extended to include all children six months to 15 years of age,” she says.

Spokesperson for the National Department of Health, Foster Mohale confirms that all children between the ages of six months and 15 years, regardless of documentation, are eligible to receive their measles vaccination in the catch-up drive. “Most provinces have been vaccinating all children between 6 months and 15 years, with [or] without documents because diseases have no discrimination. So, we haven’t received any concern or report about non-vaccination of children without documentation,” he says.

Bamford adds that a measles incident management team has been established by the National Department of Health, which meets with the NICD and the provinces on a weekly basis.

She says Limpopo started its campaign in November, Mpumalanga and North West started in December, and Gauteng and the Free State started in January. The campaigns have so far been conducted mainly at primary healthcare clinics and outreach to ECD centres but now that the school year has resumed, children will also be vaccinated at schools.

Because the provinces all started at different times, there is no specific timeline for the vaccination campaign to be completed, according to Bamford, but the expectation from the National Department is that all provinces will wrap up their campaigns by mid-February when the HPV vaccination campaign kicks off.

“We know that measles coverage is suboptimal, and that is why we were planning to run a campaign, but of course, that is the single biggest reason why we are now experiencing these outbreaks,” she says. “The only way really to stop measles outbreaks is to improve immunisation coverage.”

Republished from Spotlight under a Creative Commons 4.0 Licence.

Source: Spotlight

Turning M. Pneumoniae into ‘Living Medicine’

Pseudomonas
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr

Using a modified version of the bacterium Mycoplasma pneumoniae, researchers have designed the first ‘living medicine’ to treat lung infections. Their method is reported in the journal Nature Biotechnology. The treatment targets Pseudomonas aeruginosa, a common source of hospital-acquired infections and which is naturally multi-drug resistant.

Researchers removed the M. pneumoniae‘s ability to cause disease and repurposing it to attack P. aeruginosa instead. The modified bacterium is used in combination with low doses of antibiotics that would otherwise not work on their own.

Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The ‘living medicine’ doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.

P. aeruginosa infections are difficult to treat because the bacteria lives in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.

P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition affecting 9–27% of patients who require intubation. The incidence exceeds 50% for patients intubated because of severe COVID. VAP can extend the duration in intensive care unit for up to 13 days and kills 9–13% of patients.

The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth of Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.

“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr María Lluch, co-corresponding author of the study.

With the aim of using the ‘living medicine’ to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebuliser.

M. pneumoniae is one of the smallest known species of bacteria. Dr Luis Serrano first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.

One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.

By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers creating new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads – whether these are cytokines, nanobodies or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.

In addition to designing the ‘living medicine’, Dr. Serrano’s research team are also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team are using these proteins to target inflammation caused by P. aeruginosa infections.

Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which release mediator proteins such as cytokines. One type of cytokine, IL-10, has well-known anti-inflammatory properties and is of growing therapeutic interest.

Dr Serrano’s research group used protein-design software to engineer new versions of IL-10 purposefully optimised to treat inflammation. The cytokines were designed to be created more efficiently and to have higher affinity, meaning less cytokines are needed to have the same effect.

The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild type IL-10 cytokine.

According to Dr Ariadna Montero Blay, co-corresponding author of that study, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”

Source: Center for Genomic Regulation

Scientists Solve Epstein-Barr Virus Mystery

Photo by National Cancer Institute on Unsplash

Medical science has not yet been able to explain why the Epstein-Barr virus triggers infectious mononucleosis (IM) in some people with initial infections and not in others. But now researchers have identified a unusual T cell response to the virus as the cause, and as a potential target for the development of vaccines. The findings were recently published in the journal Blood.

T cells normally fight the proliferation of the Epstein-Barr virus (EBV) in humans as part of an antiviral immune response. In this response, certain EBV components (peptides) are presented to the T cells by a specific molecule (HLA-E), which is found on the surface of cells infected with EBV. This triggers a non-classical T-cell response that leads to the destruction of the infected cells. Due to a genetic variation (HLA-E*0103/0103), about one third of the population naturally has more HLA-E molecules on EBV-infected cells.

A recently published study has shown that the risk of developing IM following first-time infection with the Epstein-Barr virus depends strongly on this EBV-specific immune response.

“Our research revealed that people with the HLA-E*0103/0103 genetic variation have a lower risk of developing infectious mononucleosis than those who do not have the variation. Our experiments in the lab showed that this gene variation is associated with a highly pronounced EBV-specific -non-classical — immune response,” explained Hannes Vietzen from MedUni Vienna’s Center for Virology, the first author of the study.

Preventive and diagnostic possibilities

EBV is one of the most common viral infections in humans. On initial infection, the virus causes IM in some children and young adults; this disease is characterised by non-specific symptoms, such as fever, as well as exhaustion that in some cases can last for several months. Until now, it was unclear why a first-time EBV infection only leads to IM in a minority of people, while most do not present any symptoms whatsoever. The immune response that the researchers identified could also be a target for research into preventive measures: “This immune response was still measurable years after the initial EBV infection and generally provides long-lasting protection against reinfection with Epstein-Barr, so it might be worth focusing our attention on this mechanism with a view to developing new vaccines in future,” said Hannes Vietzen, looking ahead.

Another finding from the study could also open up new diagnostic options: “The combination of the unfavourable HLA-E genetic variation with certain EBV peptides also appears to play an important role in the development of EBV-associated lymphomas in transplant recipients,” Hannes Vietzen commented. “Analysis of the EBV strains found in these patients could be helpful in identifying high-risk patients at an early stage and treating them in good time.”

Source: Medical University of Vienna

Curing an Incurable Liver Disease

Female scientist in laboratory
Photo by Gustavo Fring on Pexels

Research published in the Proceedings of the National Academy of Sciences has shown for the first time that the effects of Alagille syndrome, an incurable genetic disorder that affects the liver, could be reversed with a single drug. The study has the potential to transform treatment for this rare disease and may also have implications for more common diseases.

More than 4000 babies each year are born with Alagille syndrome Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with a wide variety of clinical manifestations. The clinical manifestations are variable, even within the same family, and commonly include hepatic (cholestasis, characterised by bile duct paucity on liver biopsy), cardiac (primarily involving the pulmonary arteries), skeletal (butterfly vertebrae), ophthalmologic (posterior embryotoxon), and facial abnormalities.

“Alagille syndrome is widely considered an incurable disease, but we believe we’re on the way to changing that,” says Associate Professor Duc Dong, PhD, who led the study. “We aim to advance this drug into clinical trials, and our results demonstrate its effectiveness for the first time.”

Children with ALGS frequently require a liver transplant, but donor livers are limited, and not all children with ALGS qualify. Without a transplant, the disease has a 75% mortality rate by late adolescence.

“Duc and his team continue to do thrilling research on Alagille syndrome, and these breakthroughs certainly offer hope for families living with this very complicated and complex disorder,” says Roberta Smith, CNMT, president of the Alagille Syndrome Alliance. “We have been longtime supporters of Duc’s work and have come to know him as a driven, dedicated scientist who is passionate about moving the needle one step closer toward a cure.”

Their new drug, called NoRA1, activates the Notch pathway, a cell-to-cell signaling system present in nearly all animals. Notch signaling helps orchestrate fundamental biological processes and plays a role in many diseases in addition to Alagille syndrome. In children with Alagille syndrome, a genetic mutation causes a reduction in Notch signaling, which results in poor liver duct growth and regeneration.

The researchers found that in animals with mutations in the same gene affected in ALGS, NoRA1 increases Notch signaling and triggers duct cells to regenerate and repopulate in the liver, reversing liver damage and increasing survival.

“The liver is well known for its great capacity to regenerate, but this doesn’t happen in most children with Alagille syndrome because of compromised Notch signaling,” says first author Chengjian Zhao, a postdoctoral researcher in Dong’s lab. “Our research suggests that nudging the Notch pathway up with a drug could be enough to restore the liver’s normal regenerative potential.”

The researchers are currently testing the drug on lab-grown liver orgnelles cultured made with stem cells derived from the cells of ALGS patients.

“Instead of forcing the cells to do something unusual, we are just encouraging a natural regenerative process to occur, so I’m optimistic that this will be an effective therapeutic for Alagille syndrome,” adds Dong.

Source: Sanford Burnham Prebys

Festive Season Sees Widening of SA’s Measles Outbreak

Source: CDC

Over the festive season, the South African measles outbreak has now extended to five provinces, including Gauteng as of epidemiological week (epiweek) 51, the National Institute for Communicable Diseases (NICD) has reported.

From samples collected in epiweek 40 (end 8 Oct 2022) to epiweek 51 (end 24 Dec 2022), a total of 297 cases of laboratory-confirmed measles cases have been reported in South Africa. From epiweek 40 to mid-week 51, 2022, a total of 285 laboratory-confirmed cases were reported from five provinces with declared measles outbreaks in Limpopo (128 cases), Mpumalanga (68), North West (69), Gauteng (13), and Free State (7). The NICD classifies a measles outbreak as three or more confirmed laboratory measles cases reported within 30 days of disease onset, within a district.

The number of cases continues to increase daily as blood and throat swabs are submitted to the NICD for measles serology and PCR testing.

The age of laboratory-confirmed cases across the five provinces ranges from two months to 42 years. Of these, 41% were ages 5–9, followed by 28% for ages 1–4 and 15% for ages 10–14 . Vaccination status of 84 cases (29%) was known, of whom 33 (39%) were vaccinated.

Data on hospital admission rates and measles mortality rates are not yet known. Whilst cases that are seen at hospitals may not necessarily be admitted, this figure gives us an indication of the severity of illness, as patients consulted tertiary care facilities. The number of admitted patients will be a subset of these cases.

Source: National Institute for Communicable Diseases

Why do Humans Catch Diseases from Rodents?

Mouse
Photo by Kanasi on Unsplash

A need to better understand zoonotic transmission was highlighted by the COVID pandemic. In a global study published in Nature Communications, researchers have identified that most reservoirs of rodent-borne diseases tend to live exclusively or occasionally in or near human dwellings, show large fluctuations in their numbers, and/or are hunted for meat or fur.

Rodents’ ‘fast life’ with sexual maturity at early age, many litters per year and numerous young per litter is an important explanation why rodents are important reservoirs for pathogens. But why do humans get infected by rodent-borne pathogens?

“Most rodents that spread zoonotic pathogens, meaning pathogens spreading between animals and humans, show large population fluctuations, move at least occasionally indoors, or are hunted for meat or fur. Our results were consistent among pathogen types ie, virus, bacteria, fungi, and parasites. And with transmission modes, ie, intermediate, involvement of vectors or non-close and close contact, with close contact including inhalation of contaminated aerosols,” says Frauke Ecke, project leader and Professor at University of Helsinki, Finland and senior lecturer at Swedish University of Agricultural Sciences (SLU).

Global study on 436 rodent species

In the study, researchers from SLU, University of Helsinki and Cary Institute of Ecosystem Studies, USA, performed a global quantitative study based on data collected from research papers and databases. The study includes 436 rodent species of which 282 are all known reservoirs of zoonotic pathogens. The researchers studied the linkage among the rodents’ choice of environment, variation in numbers i.e., population fluctuations, humans’ hunting of rodents, and the status of rodents as reservoirs.

“It is remarkable how consistent the results are among continents, disease systems and rodent species,” says Rick Ostfeld, co-leader of the study.

Greater risk of rodent zoonotic transmission in some parts of the world

In addition, the researchers have identified regions where transmission risk between rodents and humans is high. Large parts of Europe, especially central and northern Europe, a wide stretch extending from eastern Europe to eastern Asia, eastern China, parts of South America, south-east Australia, and eastern regions in North America are at high risk.

“If people encounter a rodent in these regions, there is a high risk that this rodent carries zoonotic pathogens,” says Ecke.

Examples of such pathogen carrying rodents include the bank vole in Europe, the North American deer mouse, and Azara’s Grass Mouse in South America. These species show large population fluctuations and can also move indoors.

“It is especially the large population fluctuations together with the disturbance of the rodents’ natural habitat that can explain why rodents move nearby and into human dwellings. This movement behaviour is typical for so-called generalists, which are species that can cope with many different environments. These generalists are the most important reservoirs of pathogens,” explains Ecke.

Source: University of Helsinki

Cluster Headaches are Linked to other Medical Conditions

Photo by Alex Green on Pexels

People with cluster headaches may be more than three times more likely to have other medical conditions such as heart disease, mental disorders and other neurologic diseases, according to a study published in Neurology.

Cluster headaches are short but extremely painful headaches that can occur many days, or even weeks, in a row. The headaches can last anywhere from 15 minutes to three hours.

“Around the world, headaches have an incredibly negative impact on people’s quality of life, both economically and socially,” said study author Caroline Ran, PhD, of the Karolinska Institutet in Stockholm, Sweden. “Our results show that people with cluster headaches not only have an increased risk of other illnesses, those with at least one additional illness missed four times as many days of work due to sickness and disability than those with just cluster headaches. They also have a higher chance of a long-term absence from work.”

The study involved 3240 people with cluster headaches ages 16–64 in Sweden who were compared to 16 200 matched controls. The majority were men, typical of cluster headache.

Researchers looked at work records and disability benefits to determine how many days during a year people were absent from work due to sickness and disability.

Among those with cluster headaches, 92%, or 2977 people, had at least one additional illness. Of those without cluster headaches, 78%, or 12 575 people, had two or more illnesses.

Of those with cluster headaches, more women had additional illnesses than men, 96% and 90% respectively.

The average number of days a person was absent due to sickness and disability was nearly twice as high among people with cluster headaches with 63 days compared to those without cluster headaches with 34 days.

People with cluster headaches and at least one additional illness had four times as many absence days compared to people with cluster headaches who did not have an additional illness.

“Increasing our understanding of the other conditions that affect people with cluster headache and how they impact their ability to work is very important,” added Ran. “This information can help us as we make decisions on treatments, prevention and prognoses.”

A limitation of the study was that information on personal data, such as smoking, alcohol consumption and BMI, which could affect the occurrence of diseases, was not available.

Source: American Academy of Neurology

New Version of Fexaramine Reverses Gut Inflammation in Mouse Models

Anatomy of the gut
Source: Pixabay CC0

FexD, a new version of fexaramine developed by Salk Institute researchers, acts like a master reset switch in the intestines and has previously been found to lower cholesterol, burn fat, and ward off colorectal cancer in mice. Now, the team reports in Proceedings of the National Academy of Sciences that FexD can also prevent and reverse intestinal inflammation in mouse models of inflammatory bowel disease.

“The Salk-developed drug FexD provides a new way to restore balance to the digestive system and treat inflammatory diseases that are currently very difficult to manage,” says senior author and Salk Professor Ronald Evans, director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.

Inflammatory bowel disease (IBD), which includes both Crohn’s disease and ulcerative colitis, is characterised by an excess of immune cells and inflammatory signalling molecules known as cytokines in the gut. Existing treatments, which mostly work by either suppressing the entire immune system or by targeting individual cytokines, are only effective for some patients and carry a host of side effects.

For more than two decades, Evans’s lab has studied Farnesoid X receptor (FXR), a master regulator protein that senses the bile acids delivered to the digestive system to help digest food and absorb nutrients. When FXR detects a shift in bile acids at the beginning of a meal, it prepares the body for an influx of food by flipping on and off dozens of cellular programs related to digestion, blood sugar, and fat metabolism.

In 2015, Evans and his colleagues developed a pill called fexaramine that activates FXR in the gut. The pill, they initially showed, can stop weight gain and control blood sugar in mice. In 2019, they showed that FexD – an updated version of fexaramine – also prevented cancer-associated changes to stem cells in the gut. Their work suggested that FXR also played a role in regulating inflammation.

“Every time you eat, you’re causing small amounts of inflammation in your gut as your intestinal cells encounter new molecules. FXR makes sure inflammation stays under control during normal feeding,” says Senior Staff Scientist Michael Downes, co-corresponding author of the new paper.

In the new work, Evans’ group discovered that activating FXR can be used to ease symptoms in inflammation-driven diseases. When the researchers gave mice with IBD a daily dose of oral FexD, either before or after the onset of intestinal inflammation, the drug prevented or treated the inflammation. By activating FXR, FexD reduced the infiltration of a class of highly inflammatory immune cells called innate lymphoid cells. In turn, levels of cytokines already implicated in IBD decreased to levels normally seen in healthy mice.

“When we activate FXR, we restore appropriate signalling pathways in the gut, bringing things back to a homeostatic level,” says Senior Research Scientist Annette Atkins, co-author of the study.

Since FXR acts more like a reset button than an off switch for the immune system, cytokines are not completely blocked by FexD. This means that the immune system continues functioning in a normal way after a dose of FexD. The compound still must be optimised for use in humans and tested in clinical trials, but the researchers say their findings provide important information about the complex links between gut health and inflammation and could eventually lead to an IBD therapeutic.

“In people with IBD, our strategy could potentially be very effective at preventing flare-ups and as a long-term maintenance drug,” says first author Ting Fu, previously a postdoctoral fellow at Salk and now an assistant professor at the University of Wisconsin-Madison.

Source: Salk Institute

Light Therapy Relieves MS Fatigue Symptoms

Photo by Stormseeker on Unsplash

Multiple Sclerosis (MS) is almost always accompanied by fatigue, a massive tiredness that is described by the vast majority of patients as the most distressing symptom. Researchers have now identified light therapy as a promising nonpharmaceutical treatment option: patients included in the study showed a measurable improvement after just 14 days of use. Their study’s results were published in the Multiple Sclerosis Journal – Experimental, Translational and Clinical.

The research team led by Stefan Seidel from the Department of Neurology at MedUni Vienna and AKH Vienna, relied not only on surveys but also on objective measurements when selecting the test persons – the first study of its kind to do so. For example, sleep-wake disorders were ruled out in the 26 participating MS patients, particularly with the assistance of various sleep medicine examinations. “In this manner, for example, we ensured that MS patients with fatigue do not suffer from sleep apnoea or periodic leg movements during sleep. Both are sleep disorders that can lead to fatigue in everyday life,” elaborated study leader Stefan Seidel.

Performance improvement

The test persons – all patients of the Neurology Department at MedUni Vienna and AKH Vienna – were equipped with commercially available light sources for self-testing at home: Half of the participants received a daylight lamp with a brightness of 10 000 lux (equivalent not to a cloudy day but not direct sunlight), while the other half received an identical lamp that emitted a red light with an intensity of <300 lux due to a filter (about the intensity of an office working environment). While the red light used by the control group showed no effect, the researchers were able to observe measurable successes in the other group after only 14 days: The participants who used their 10 000 lux daylight lamp for half an hour every day showed improved physical and mental performance after only a short period of time. In addition, the group of participants who had consumed bright light displayed less daytime sleepiness in comparison with the other group.

A nonpharmaceutical approach

Fatigue is a severe form of tiredness and fatigability that occurs in 75 to 99 percent of people with MS and is described as particularly distressing. Nerve damage triggered by MS is one possible cause. In addition to behavioural measures, such as regular rest breaks, various medications are currently available to alleviate fatigue, but some of these are associated with severe side effects. “The findings from our study represent a promising non-drug therapeutic approach,” Stefan Seidel said. However, the results still need to be confirmed in a subsequent larger-scale study. The reinvigorating mechanism of light therapy on MS patients will also be the subject of further scientific research.

Source: Medical University of Vienna

Scientists Uncover Three Genes Linked to Multiple Sclerosis

Genetics
Image source: Pixabay

New research published in the Annals of Clinical and Translational Neurology has identified three genes and their expressed proteins that may be involved in the pathogenesis of multiple sclerosis.

By comparing information on the genes and proteins expressed in the brains of thousands of individuals with and without multiple sclerosis, investigators discovered different expression levels of the SHMT1FAM120B, and ICA1L genes (and their proteins) in brain tissues of patients versus controls.

Protein abundance alteration in human brain has linked to MS. For instance, protein abundance of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP)3 and thymosin β-46 was dysregulated in lesions from MS patients’ brain, and these proteins have been used for disease severity prediction and targeted therapy lately. In addition, compared to bodily fluid samples like cerebrospinal fluid and plasma, human brain tissue directly reflects the pathophysiology changes of MS and has become increasingly important in disease biomarker identification. However, few studies focused on specific subregions of the brain, ignoring the possible differences in protein types and abundance between subregions with distinct functions.

Studying the functions of these genes may uncover new information on the mechanisms involved in the development and progression of multiple sclerosis. “Our findings shed new light on the pathogenesis of MS and prioritised promising targets for future therapy research,” the authors wrote.

Source: Wiley