Category: Diseases, Syndromes and Conditions

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Curing an Incurable Liver Disease

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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

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Festive Season Sees Widening of SA’s Measles Outbreak

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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

Categories : Diseases, Syndromes and Conditions

Why do Humans Catch Diseases from Rodents?

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Mouse
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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

Categories : Diseases, Syndromes and Conditions Pain ManagementTags :

Cluster Headaches are Linked to other Medical Conditions

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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

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New Version of Fexaramine Reverses Gut Inflammation in Mouse Models

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Anatomy of the gut
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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

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Light Therapy Relieves MS Fatigue Symptoms

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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

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Scientists Uncover Three Genes Linked to Multiple Sclerosis

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Genetics
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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 SHMT1, FAM120B, 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

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Promising New Treatment for Moderate to Severe Atopic Dermatitis

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Atopic dermatitis
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An international clinical trial of a new monoclonal antibody therapy showed promising results for patients moderate to severe atopic dermatitis both while taking the drug and up to 20 weeks after the therapy was stopped, according to Mount Sinai researchers in The Lancet.

The researchers said the results indicate that the new biologic, rocatinlimab, has the potential to change the genetic makeup of a person’s atopic dermatitis for the long term, and possibly help sustain lasting results without continued use. Rocatinlimab inhibits OX40. an immune molecule involved in activating inflammatory cells that play a key role in the development of atopic dermatitis and other inflammatory diseases.

“Atopic dermatitis, the most common type of eczema, is a debilitating chronic inflammatory skin disease that affects 1 in 10 Americans and millions of people worldwide,” said Emma Guttman, MD, PhD, Mount Sinai professor. “It often develops at a very young age, causing the skin to become inflamed, red, extremely itchy, painful, and very dry – all symptoms that greatly affect a patient’s quality of life. We are very optimistic about the results of this trial and the potential for disease modification and long-lasting effects to improve patients’ quality of life.”

In this phase 2b multicentre, double-blind, placebo-controlled study, 274 patients were recruited and (rocatinlimab: n = 217; placebo: n = 57) equally randomised to rocatinlimab every four weeks (150mg or 600mg) or every two weeks (300mg or 600mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up.

Percent change from baseline in the Eczema Area and Severity Index (EASI) score was assessed as the primary endpoint at week 16, and significance versus placebo was achieved with all active rocatinlimab doses (-48% to -61%) doses compared to placebo (-15%). All active dose cohorts also continued improving after week 16, and most patients maintained the response for at least 20 weeks off treatment.

The results support rocatinlimab as a safe and effective treatment for moderate to severe atopic dermatitis, with potentially long-lasting efficacy and disease modification. Adverse events reported were generally similar between rocatinlimab groups. Common adverse events during the double-blind period included fever, chills, headache, aphthous ulcers (canker sores), and nausea.

“At week 36, all participants had been on the treatment for at least 18 weeks,” added Dr Guttman, senior author of the study. “By this time, we saw that while the drug achieved the primary endpoints in all doses versus the placebo, it’s also a drug that improves over time, which is really unusual and unique among currently available treatment options.”

Researchers plan to continue this investigation in a phase 3 program in 2023. Future studies will also include a larger study population, longer follow-up, and explore combination therapy (eg with topical corticosteroids).

Source: Mount Sinai Hospital

Categories : Diseases, Syndromes and Conditions General InterestTags :

Celine Dion Reveals Her Rare Disease Diagnosis

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Celine Dion in 2008. Photo by Anirudh Koul. CC2.0

Canadian singer Celine Dion has revealed that she has been diagnosed with a very rare neurological disease called Stiff Person Syndrome (SPS), BBC News reports. The disease causes muscle spasms, interfering with daily activities. Injuries can be sustained from falls caused by spasms experienced while walking.

The 54-year-old singer had been battling with muscle spasms, and since the disease interferes with her singing, she has cancelled all of her concerts scheduled for 2023, putting them off to 2024.

SPS is an extremely rare disease, thought to affect only one in a million individuals. As such, relatively little is known about it and what causes it, although it is associated with autoimmune disorders and often misdiagnosed as Parkinson’s disease.

After a hiatus from 2014 to be with her husband while he battled cancer, she returned to the stage in 2019 with her new album Courage. This tour had a number of cancellations due to the COVID pandemic.

Speaking on an Instagram post, Dion said that she had “a great team of doctors working alongside me to help me get better” and had the support of her “precious children”.

The singer explained: “I’m working hard with my sports medicine therapist every day to build back my strength and my ability to perform again, but I have to admit it’s been a struggle.

“All I know is singing. It’s what I’ve done all my life and it’s what I love to do the most.

“I miss you so much. I miss seeing all of you [and] being on the stage, performing for you.

“I always give 100 per cent when I do my show but my condition is not allowing me to give you that right now.”

What is stiff person syndrome?

According to the National Institute for Neurological Disorders, SPS is characterised by “fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms. Abnormal postures, often hunched over and stiffened, are characteristic of the disorder. People with SPS can be too disabled to walk or move, or they are afraid to leave the house because street noises, such as the sound of a horn, can trigger spasms and falls. SPS affects twice as many women as men.”

A definitive diagnosis can be made by measuring the level of glutamic acid decarboxylase (GAD) antibodies in the blood, which is elevated in people with SPS. GAD is the rate-limiting enzyme that catalyses the conversion of glutamate to GABA

As for management, the symptoms can be well controlled. Pharmacological treatment includes IVIg, anti-anxiety drugs, muscle relaxants, anti-convulsants, and pain relievers.

Work continues for better treatments; so far rituximab proved ineffective. At present, research is focused on aetiology and the role of anti-GAD antibodies.

Categories : Dentistry Diseases, Syndromes and ConditionsTags :

Bacteria in Severe Oral Infections Linked to Other Diseases

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Dentist checking teeth
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To date, there has been little research into identifying the bacteria found in severe oral infections, despite long-suspected links to other diseases. Now, a study from Karolinska Institutet has characterised the microbial composition of these, with many known to be linked to other disease. The study is published in Microbiology Spectrum.

There is growing evidence linking oral health and common diseases, such as cancer, cardiovascular disease, diabetes and Alzheimer’s disease. However, there have been few longitudinal studies identifying which bacteria occur in infected oral- and maxillofacial regions.

Researchers at Karolinska Institutet have now analysed samples collected between 2010 and 2020 at the Karolinska University Hospital in Sweden from patients with severe oral infections and produced a list of the most common bacteria.

“We’re reporting here, for the first time, the microbial composition of bacterial infections from samples collected over a ten-year period in Stockholm County,” says Professor Margaret Sällberg Chen of the Department of Dental Medicine. “The results show that several bacterial infections with link to systemic diseases are constantly present and some have even increased over the past decade in Stockholm.”

A role in other diseases

The study shows that the most common bacterial phyla amongst the samples were Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, while the most common genera were Streptococcus spp, Prevotella spp, and Staphylococcus spp.

“Our results provide new insight into the diversity and prevalence of harmful microbes in oral infections,” says Professor Sällberg Chen. “The finding isn’t only of importance to dental medicine, it also helps us understand the role of dental infection in patients with underlying diseases. If a certain bacterium infects and causes damage in the mouth, it’s very likely that it can be harmful to tissues elsewhere in the body as the infection spreads.”

The research group has previously shown that the occurrence of oral bacteria in the pancreas reflects the severity of pancreatic tumours.

Improve diagnostics and therapy

The study was conducted using 1014 samples from as many patients, of whom 469 were women and 545 men, and a mass-spectrometric method called MALDI-TOF that rapidly identifies individual living bacteria in a sample, but that is rarely used in dental care.

“Our study was a single centre epidemiology study and to ensure the validity of the results we need to make more and larger studies,” says adjunct Professor Volkan Özenci at the Department of Laboratory Medicine. “We now hope that dentists will collaborate with clinical microbiology laboratories more to gain a better understanding of the bacteria that cause dental infections, to improve diagnostics and therapeutic management of oral infections.”

The study is part of Khaled Al-Manei’s doctoral thesis, the next step of which is a similar epidemiological study of fungal infections in the mouth that aims to identify new fungi and microbes and understand what causes their possible malignancy. 

Source: Karolinska Institutet