Category: Diseases, Syndromes and Conditions

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Reduced Risk of Relapse in MS Sufferers Taking Cladribine

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A healthy neuron.
A healthy neuron. Credit: NIH

A study using real-world data has shown that multiple sclerosis (MS) sufferers taking cladribine were less likely to experience disease relapse than those who took other oral disease-modifying therapies.

Relapse and discontinuation outcomes favoured cladribine tablets over oral fingolimod, dimethyl fumarate, and teriflunomide. The findings were reported Helmut Butzkueven, PhD, of Monash University at ACTRIMS Forum 2022, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

For the study, researchers drew on data from the MSBase registry of more than 79 000 people with MS worldwide. Few clinical trials or real-world studies are available that compare the effectiveness of cladribine tablets to other oral disease-modifying therapies, the researchers noted.

“Many treatment choices that patients and their care teams have to make are not or not yet examined in classical randomised trials,” Dr Butzkueven told MedPage Today. “Sophisticated analysis of data gathered systematically and prospectively in clinical care is proving a valuable alternative to examine and compare the outcomes of different treatment choices in all kinds of scenarios.”

“Oral agents for use in relapsing MS are very convenient and effective treatment choices,” he added. “This work directly compares outcomes for people with MS who chose cladribine tablets versus other oral drugs.”

The chemotherapy drug cladribine, was recently approved by the FDA for active secondary progressive disease and relapsing MS. This was based on results from trial data showing that cladribine significantly decreased the number of MS relapses and reduced the progression of disability compared with placebo.

GLIMPSE was a longitudinal study that included data for 3475 MS patients on either cladribine, fingolimod, dimethyl fumarate or teriflunomide.

The 633 patients taking cladribine were propensity-score matched with those taking oral comparators on various factors such as age, sex and country.

In pairwise comparisons, cladribine versus fingolimod had 520 matched participants per group: the annualised relapse rate (ARR) was 0.09 compared with 0.15, respectively, the hazard ratio (HR) for time to first relapse was 0.60, and the HR for time to discontinuation was 0.22.

For cladribine versus dimethyl fumarate (450 people per group), the ARR was 0.10 compared with 0.15 the HR for time to first relapse was 0.58, and the HR for time to discontinuation was 0.10.

The cladribine versus teriflunomide (458 people per group) comparisons showed that the ARR was 0.09 compared with 0.17, the HR for time to first relapse was 0.33, and the HR for time to discontinuation was 0.10.

Source: MedPage Today

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Link Between Consuming Dairy Products and MS Flareups Explained

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The reason why multiple sclerosis (MS) sufferers often complain of more severe disease symptoms after consuming dairy products may be down to the milk protein casein, which can trigger inflammation targeting the myelin sheath, according to a study published in the journal PNAS.

This link was demonstrated in mice, but there was evidence of a similar mechanism in humans. The researchers therefore recommend that certain groups of MS sufferers avoid dairy products.

“We hear again and again from sufferers that they feel worse when they consume milk, cottage cheese or yoghurt,” explained Professor Stefanie Kürten from the Institute of Anatomy at University Hospital Bonn. “We are interested in the cause of this correlation.”

The professor of neuroanatomy is considered a renowned expert on multiple sclerosis. “We injected mice with different proteins from cow’s milk,” she said. “We wanted to find out if there was a constituent that they were responding to with symptoms of disease.”

When they administered the cow’s milk constituent casein together with an effect enhancer to the animals, the mice went on to develop neurological disorders. Electron microscopy showed damage to the insulating myelin sheath, which normally prevents short circuits and significantly accelerates stimulus conduction.

In multiple sclerosis, the body’s immune system destroys the myelin sheath. Consequences range from paresthaesia and vision problems to movement disorders. With patients ending up in a wheelchair. In mice, the myelin sheath was also massively perforated, apparently triggered by casein administration. “We suspected that the reason was a misdirected immune response, similar to that seen in MS patients,” explained Rittika Chunder, a postdoctoral fellow in Prof. Kürten’s research group. “The body’s defenses actually attack the casein, but in the process they also destroy proteins involved in the formation of myelin.”

Such cross-reactivity can occur when two molecules share some similar parts, causing the immune system to mistake them for each other. “We compared casein to different molecules that are important for myelin production,” Dr Chunder said. “In the process, we came across a protein called MAG. It looks markedly similar to casein in some respects – so much so that antibodies to casein were also active against MAG in the lab animals.”

This means that in the casein-treated mice, the body’s own defences were also directed against MAG, destabilising the myelin. But to what extent can the results be transferred to people with MS? To answer this question, the researchers added casein antibodies from mice to human brain tissue. These did indeed accumulate in the cells responsible for myelin production in the brain.

The study found that the antibody-producing B cells in the blood of people with MS respond particularly strongly to casein. It is possible that at some point while consuming milk, the affected individuals developed an allergy to casein. Now, on consuming dairy products, the immune system produces masses of casein antibodies, which due to cross-reactivity with MAG, also damage the myelin sheath.

However, this only affects MS patients who are allergic to cow’s milk casein. “We are currently developing a self-test with which affected individuals can check whether they carry corresponding antibodies,” said Prof Kürten. “At least this subgroup should refrain from consuming milk, yogurt, or cottage cheese.”

It is possible that cow’s milk also increases the risk of developing MS in healthy individuals. Because casein can also trigger allergies in them – which is probably not even that rare. Once such an immune response exists, cross-reactivity with myelin can in theory occur. However, this does not mean that hypersensitivity to casein necessarily leads to the development of multiple sclerosis, Prof Kürten stressed. This would presumably require other risk factors. This connection is concerning worrying, said Prof Kürten, as “Studies indicate that MS rates are elevated in populations where a lot of cow’s milk is consumed.”

Source: University of Bonn

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

Azithromycin in Infant RSV Does Not Prevent Wheezing, May be Harmful

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Photo by William-Fortunato on Pexels

A recent study on the impact of the antibiotic azithromycin during severe respiratory syncytial virus (RSV) bronchiolitis overwhelmingly supports current bronchiolitis guidelines in the US, which recommend against antibiotics during acute bronchiolitis.

The anti-inflammatory properties of azithromycin can be beneficial in some chronic lung diseases, such as cystic fibrosis. With that in mind, researchers investigated its potential to prevent future recurrent wheezing among infants hospitalised with RSV. With such babies at increased risk of developing asthma later in childhood, the scientists hoped to find a therapy to reduce this risk.

The study, published in NEJM Evidence, also provided considerable evidence that severe RSV bronchiolitis in early life increases the likelihood of repeated wheezing episodes in early childhood, often leading to asthma.

“The major message is that antibiotics don’t have a role, either in the management of acute RSV bronchiolitis or to reduce subsequent wheezing,” said co-corresponding author Leonard Bacharier, MD, professor of Pediatrics at Monroe Carell Jr Children’s Hospital at Vanderbilt. “As a matter of fact, we found that antibiotics in general in our study of severe RSV bronchiolitis increased the risk of subsequent recurrent wheezing over the following two to four years.”

“We need to discourage the use of this therapy, as it is potentially harmful,” he said.

The study examined children hospitalised with RSV bronchiolitis during a single-center, double-blind, placebo-controlled trial.

An earlier pilot trial enrolled 40 infants hospitalised with RSV bronchiolitis where treatment with azithromycin, and this showed a reduction in the likelihood of recurrent wheeze over the following year.

In the current study, 200 otherwise healthy 1- to 18-month-old children who were hospitalised for RSV bronchiolitis were prospectively randomised to either oral azithromycin or a placebo for 14 days. The group was broadly representative of the population of children who experience severe RSV bronchiolitis.

Antibiotics are sometimes used in the treatment of RSV because co-occurring complications lead medical teams to prescribe them, thinking there is a bacterial component to the illness, Prof Bacharier said.
“This condition can be managed by supportive care – oxygen, fluids, observation, time and love,” he stressed. “If a clinician is going to use an antibiotic in the setting of RSV bronchiolitis, there needs to be a very strong rationale for doing so. There is substantial evidence to suggest that children who receive antibiotics early in life are at an increased risk of developing asthma, and this study is consistent with that evidence.”

Source: EurekAlert!

Categories : Diseases, Syndromes and Conditions Medical Research & TechnologyTags :

Sanofi’s Rare Disease Database Aids Healthcare Practitioners

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Image source: CDC/Unsplash

Sanofi’s rare disease database that helps healthcare practitioners tackle their unique challenges – and knowing that treatments are available directly improves patients’ wellbeing. This comprehensive database has also aided rare disease research.

Johannesburg, 28 February 2022: Patients with rare diseases present unique challenges to healthcare practitioners (HCPs). Obstacles to caring for them include diagnostic delays and a lack of information, expertise, and treatment options for many rare diseases. HCPs play a vital role in enhancing the quality of life for patients and families living with a rare disease by making appropriate referrals to specialists, helping to coordinate care, and assisting patients in obtaining the proper support.1,2

A disease is defined as ‘rare’ when it affects fewer than 1 in 2000 people.3

Over 7000 rare diseases have been described to date, affecting over 350 million people worldwide.3,4 While most (70-80%) of rare diseases are genetic and inherited, some may be acquired, and 70% are exclusively paediatric in onset.5

Recent surveys showed that those living with rare diseases had a significantly higher prevalence of anxiety and depression compared to the general population.5,6 Levels of high stress can become even worse for carers when the person they are supporting has a diagnosis with no available treatment option.5,6

Monique Nel, Medical Advisor – Rare Diseases at Sanofi says: “Sanofi has been dedicated to researching and developing innovative treatments for rare diseases for 40 years. Currently, Sanofi has one of the largest rare diseases pipelines in the industry, across multiple diseases and modalities.7”

“Our rare disease patient registries have grown to represent one of the largest collections of real-world data for rare diseases collected over the past 30 years. We have a presence in 68 countries worldwide, with more than 920 participating sites and more than 17 800 patients enrolled.”

These registries have helped researchers to publish studies describing the underlying biology of disease, identify risk factors impacting treatment outcomes, and share guidelines for monitoring and treatment.

A further useful resource for HCPs and patients is the list of rare diseases maintained by the Genetic and Rare Diseases Information Center (GARD) of the US National Institutes of Health.8          

Says Nel: “We understand the difficulty that healthcare professionals face when it comes to patient diagnosis of a rare disease, and that a coordinated approach to diagnosis and care for people living with rare diseases is needed. Rare diseases deserve the same amount of time, resources and dedication to finding effective treatments and therapies as any other conditions, which is a mission that Sanofi strives to promote every day, to help HCPs to improve diagnosis.”

References:

  1. Elliott E, Zurynski Y. Rare diseases are a ‘common’ problem for clinicians. Aust Fam Physician. 2015 Sep;44(9):630. http://www.ncbi.nlm.nih.gov/pubmed/26488039
  2. Dudding-Byth T. A powerful team: the family physician advocating for patients with a rare disease. Aust Fam Physician. 2015 Sep;44(9):634. http://www.ncbi.nlm.nih.gov/pubmed/264880401. NIH.
  3. Genetic and Rare Disease Information Center. FAQs About Rare Diseases. Available at: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases
  4. Bogart KR, Irvin VL. Health-related quality of life among adults with diverse rare disorders. Orphanet J Rare Dis. 2017 Dec 7;12(1):177. doi: 10.1186/s13023-017-0730-1. PMID: 29212508; PMCID: PMC5719717.
  5. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165–173. https://doi.org/10.1038/s41431-019-0508-0
  6. National Alliance for Caregiving. Rare Disease Caregiving in America. Available at: https://www.caregiving.org/wp-content/uploads/2020/05/NAC-RareDiseaseReport_February-2018_WEB.pdf
  7. Sanofi Your Health webpage. Rare Disease. https://www.sanofi.com/en/your-health/specialty-care/rare-diseases
  8. National Institutes of Health, Genetic and Rare Diseases Information Center. Caring for your patient with a rare disease.  Available at: https://rarediseases.info.nih.gov/guides/pages/122/caring-for-your-patient-with-a-rare-disease
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Study Reveals the Intricacy of C. Diff’s Armour

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The spectacular structure of the protective armour of superbug C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like chain mail. This assembly prevents molecules getting in and provides a new target for future treatments, according to the scientists at Newcastle, Sheffield and Glasgow Universities who have uncovered it. Credit: Newcastle University, UK

The spectacular structure of the protective armour of C. difficile has been revealed for the first time showing the close-knit yet flexible outer layer – like a mediaeval knight’s chain mail.

This tight arrangement keeps molecules from getting in and provides a new target for future treatments, according to the scientists who have uncovered it.

Published in Nature Communications, the team of scientists outlined the structure of the main protein, SlpA, that forms the links of the chain mail and how they link up to form a pattern and create this flexible armour.
One of the many ways that Clostridioides difficile has to protect itself from antibiotics is a special layer that covers the cell of the whole bacteria – the surface layer or S-layer. This flexible armour protects against the entry of drugs or molecules released by our immune system to fight bacteria.

Using a combination of X-ray and electron crystallography, the team determined the structure of the proteins and their arrangement.

Corresponding author and lead researcher Dr Paula Salgado said: “I started working on this structure more than 10 years ago, it’s been a long, hard journey but we got some really exciting results! Surprisingly, we found that the protein forming the outer layer, SlpA, packs very tightly, with very narrow openings that allow very few molecules to enter the cells. S-layer from other bacteria studied so far tend to have wider gaps, allowing bigger molecules to penetrate. This may explain the success of C.diff at defending itself against the antibiotics and immune system molecules sent to attack it.

“Excitingly, it also opens the possibility of developing drugs that target the interactions that make up the chain mail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell and kill it.”

Antimicrobial resistance (AMR), a growing problem, was declared by WHO as one of the top 10 global public health threats facing humanity.
One of the many bacteria that have evolved resistance to antibiotics, C. diff infects the human gut and is resistant to all but three current drugs. Antibiotics only compound the problem, as the good bacteria in the gut are killed alongside those causing an infection and, as C. diff is resistant, it can grow and cause diseases ranging from diarrhoea to death due to massive lesions in the gut. Since the only way to treat C.diff is to take antibiotics, it creates a vicious cycle of recurrent infections.

This knowledge could lead to the development of C. diff specific drugs that break the protective layer, creating holes to allow drug molecules to penetrate and kill the cell.

Dr Rob Fagan, who helped carry out the electron crystallography work, said: “We’re now looking at how our findings could be used to find new ways to treat C. diff infections such as using bacteriophages to attach to and kill C. diff cells – a promising potential alternative to traditional antibiotic drugs.”

Source: EurekAlert!

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Investigating Vaping’s Impact on Gum Disease

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Photo by Chiara summer on Unsplash

A series of new studies investigates how e-cigarettes alter oral health and may be contributing to gum disease. The latest, published in mBio, finds that e-cigarette users have a distinctive oral microbiome that is less healthy than nonsmokers but potentially healthier than cigarette smokers, and measures worsening gum disease over time.

“To our knowledge, this is the first longitudinal study of oral health and e-cigarette use. We are now beginning to understand how e-cigarettes and the chemicals they contain are changing the oral microbiome and disrupting the balance of bacteria,” said co-lead researcher Prof Deepak Saxena.

While cigarette smoking is known to increase gum disease risk, much less is known about the impact of e-cigarette use on oral health, especially in the long term.

The researchers studied the oral health of 84 adults from three groups: cigarette smokers, e-cigarette users, and people who have never smoked. Gum disease was assessed through two dental exams six months apart, during which plaque samples were taken to analyse the bacteria present.

Gum health changes
All participants had some gum disease at the start of the study, with cigarette smokers having the most severe disease, followed by e-cigarette users. After six months, the researchers observed that gum disease had worsened in some participants in each group, including several e-cigarette users.

Clinical attachment loss is a key indicator of gum disease, measured by gum ligament and tissue separating from a tooth’s surface, leading the gum to recede and form pockets. These pockets are bacterial breeding grounds and can lead to worsening gum disease. In a study of the same participants published in Frontiers in Oral Health, the research team found that clinical attachment loss was significantly worse only in the e-cigarette smokers after six months.

A unique microbiome
Analysis of the bacteria in plaque samples showed that e-cigarette users had a different oral microbiome than smokers and nonsmokers, in line with their earlier results.

While all groups shared roughly a fifth of the types of bacteria, the bacterial makeup for e-cigarette users had strikingly more in common with cigarette smokers than nonsmokers. Several types of bacteria, including Selenomonas, Leptotrichia, and Saccharibacteria, were abundant in both smokers and vapers compared to nonsmokers. Several other bacteria – including Fusobacterium and Bacteroidales, linked to gum disease – were particularly dominant in the mouths of e-cigarette users.

When plaque samples were gathered and analysed in the six-month follow-up, the researchers found greater diversity in bacteria for all groups studied, yet each group maintained its own distinct microbiome.

“Vaping appears to be driving unique patterns in bacteria and influencing the growth of some bacteria in a manner akin to cigarette smoking, but with its own profile and risks to oral health,” said Fangxi Xu, study co-first author.

An altered immune response
The researchers found that the distinct microbiome in e-cigarette users was correlated with clinical measures of gum disease and changes to the host immune environment. In particular, vaping was associated with different levels of cytokines. Certain cytokines are linked to an imbalance in oral bacteria and can worsen gum disease by making people prone to inflammation and infection.

TNFα, a cytokine that causes inflammation, was significantly elevated among e-cigarette users. In contrast, cytokines IL-4 and IL-1β were lower among e-cigarette users; because IL-4 tends to be reduced in people with gum disease and increases after treatment, it suggests that certain bacteria in the mouths of e-cigarette users are worsening inflammation.

The researchers concluded that the distinct oral microbiome of e-cigarette users elicits altered immune responses, which along with clinical markers for gum disease illustrate how vaping presents its own challenge to oral health.

“E-cigarette use is a relatively new human habit,” said Scott Thomas, study co-first author. “Unlike smoking, which has been studied extensively for decades, we know little about the health consequences of e-cigarette use and are just starting to understand how the unique microbiome promoted by vaping impacts oral health and disease.”

Source: New York University

Categories : Diseases, Syndromes and Conditions GeneticsTags :

A Life-changing Genetic Cure for Sickle Cell Patient

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Sickle cell disease occurs in people who inherit two copies of the sickle cell gene, one from each parent. This produces abnormal haemoglobin, called haemoglobin S. Credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health

Jimi Olaghere, who had suffered all his life from the chronic pain of sickle cell disease, recently received a genetic cure decades sooner than he would have believed possible.

Mr Olaghere is one of the first seven sickle cell patients who received a new gene-editing treatment going through its first clinic trials in the US. “It’s like being born again,” he said, adding that it has changed his life. “When I look back, it’s like, ‘Wow, I can’t believe I lived with that.'”

Mr Olaghere, 36 said: “You always have to be in a war mindset, knowing that your days are going to be filled with challenges.”

Sickle cell disease is caused by a mutated gene that results in abnormal haemoglobin, leading to blood cells becoming more rigid and taking on their characteristic sickle shape. These malformed cells often get stuck in blood vessels, giving rise to ischaemias and an increase in cardiovascular disease risk and organ damage. Mr Olaghere may need a hip replacement due to avascular necrosis.

The disease also causes chronic pain, which he likened to “shards of glass flowing through your veins or someone taking a hammer to your joints.”

Severe pain episodes known as crises are the hallmark of sickle cell disease. For years, Mr Olaghere was hospitalised on a monthly basis. Winters worsened the problem as the cold restricted surface blood vessels, increasing the risk of blockages. He moved to a warmer city, and became a tech entrepreneur as he didn’t think any employer would be sympathetic to going to the hospital so often.

His family urged him to participate in clinical trials or receive a bone marrow transplant. However, he thought it would take too much time and instead pinned his hopes on DNA editing “in the future, probably 20 to 50 years from now”.

But in 2019 he read about a new gene editing therapy and emailed the medical team right away. When he learned he was accepted, he said it was “the best Christmas present ever”. As the pandemic hit and flights were cancelled, he was still able to make the four-hour drive for treatment appointments.
In order to genetically edit his stem cells the stem cells were flushed out of his bone marrow and into the bloodstream for collection.

“You sit there for eight hours and this machine is literally just sucking all the blood out of you,” he said.

The process left him physically and mentally drained, and still needed  blood transfusions. Mr Olaghere had to go through this process, the most difficult of all for him, four times. 

The key to the treatment lies not in correcting the genetic defect that produces the cell but rather sidestepping it by getting the body to use an alternative: foetal haemoglobin 

Ordinarily, at around 40 weeks of pregnancy, a genetic switch called BCL11A is flipped and the body starts producing adult haemoglobin – which is the only form affected by sickle cell disease. 

“Our approach is to turn that switch off and increase the production of foetal haemoglobin again, basically turning the clock back,” explained Dr Haydar Frangoul, who treated Mr at the Sarah Cannon Research Institute.

Mr Olaghere’s stem cells were sent to Vertex Pharmaceuticals’ laboratories for genetic editing. By September 2020, the engineered cells were ready to be infused into his body. “It was the week of my birthday, actually. So it was almost like getting a new life,” he recalled.

The original faulty stem cells that remained in his body were killed off with chemotherapy, and then genetically engineered replacements were infused into his body to produce sickle-free blood.

“I remember waking up without any pain and feeling lost,” he said. “Because my life is so associated with pain, it’s just a part of who I am. It’s weird now that I don’t experience it any more.'”

Dr Frangoul said that the first seven patients’ results have been “nothing short of amazing” and represented a “functional cure” for their disease.
“What we are seeing is patients are going back to their normal life, none have required admission to hospital or doctor visits because of sickle cell related complications,” Dr Frangoul said.

So far, the genetic technique has been conducted on 45 patients with either sickle cell disease or beta thalassaemia. However, the data are still being gathered.

Source: BBC News

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In MS, Twin Study Reveals Disease-causing T Cells

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By studying the immune system of pairs of monozygotic twins to rule out genetics in cases of multiple sclerosis, researchers may have discovered a smoking gun: precursor cells of the disease-causing T cells.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system CNS and the most common cause of neurological impairment in young adults. In MS, the patient’s own immune system attacks the CNS, resulting in cumulative neurological damage. The cause of MS still unclear but a variety of genetic risk factors and environmental influences have already been linked to the disease.

Genetics have already been found to be a necessary condition for developing multiple sclerosis. “Based on our study, we were able to show that about half of the composition of our immune system is determined by genetics,” said Florian Ingelfinger, a PhD candidate at the UZH Institute of Experimental Immunology. The study shows that these genetic influences, while always present in MS patients, are not on their own sufficient to trigger multiple sclerosis. In the study, 61 pairs of monozygotic twins where one twin is affected by MS whereas the co-twin is healthy were examined. From a genetic point of view, the twins were thus identical. “Although the healthy twins also had the maximum genetic risk for MS, they showed no clinical signs of the disease,” said Lisa Ann Gerdes.

With this cohort of twins, the researchers were  tease out environmental differences. “We are exploring the central question of how the immune system of two genetically identical individuals leads to significant inflammation and massive nerve damage in one case, and no damage at all in the other,” explained Professor Burkhard Becher, leader of the research team. Using identical twins let the researchers block out the genetic influence and focus on the immune system changes that were ultimately responsible for triggering MS in one twin.

The researchers harnessed state-of-the-art technologies to describe the immune profiles of the twin pairs in great detail. “We use a combination of mass cytometry and the latest methods in genetics paired with machine learning to not only identify characteristic proteins in the immune cells of the sick twin in each case, but also to decode the totality of all the genes that are switched on in these cells,” Florian Ingelfinger explained. 

“Surprisingly, we found the biggest differences in the immune profiles of MS affected twins to be in the cytokine receptors, ie the way immune cells communicate with one another. The cytokine network is like the language of the immune system,” said Ingelfinger. Increased sensitivity to certain cytokines leads to greater T cell activation in the bloodsteams of patients with multiple sclerosis. These T cells are more likely to migrate into the CNS and cause damage there. The identified cells were found to have the characteristics of recently activated cells, which were in the process of developing into fully functional T cells. “We may have discovered the cellular big bang of MS here – precursor cells that give rise to disease-causing T cells,” said Prof Becher.

“The findings of this study are particularly valuable in comparison to previous studies of MS which do not control for genetic predisposition,” said Prof Becher. “We are thus able to find out which part of the immune dysfunction in MS is influenced by genetic components and which by environmental factors. This is of fundamental importance in understanding the development of the disease.”

The study findings were reported in Nature.

Source: University of Zurich

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New Insights Into Atopic Dermatitis Yield Possible Therapy

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Atopic dermatitis (AD) is often thought of as an inflammatory disease that arises from a breakdown in the barrier function of the skin. Now a new study pinpoints a cascade of inflammatory signalling that precedes the appearance of skin ulcers, shedding light on the early stages of the condition and possible new drug targets.

The work, published in the journal Science Translational Medicine, was the result of a cross-school and cross-institutional collaboration among researchers.

“You have researchers in the dental school noticing a skin condition, broadening their work to the medical school and experts on computational systems biology,” said Professor Dana Graves, a co-corresponding author on the paper. “Without this interdisciplinary collaboration, that initial finding would not have gone anywhere.”

John Seykora, a co-corresponding author and professor of dermatology, agreed. “This shows one of the benefits of being part of a university with experts across fields,” he says. “Our dental school colleagues developed a mouse that manifested a particular skin phenotype, and the question was, What was this and did it resemble any disease we might know? And in the end it did, and it’s providing some novel insights into a very common skin condition in humans.”

The work began with an exploration of the role of inflammatory signalling in bone fracture healing in diabetes. A focus was on nuclear factor kappa-B (NF-kB), a master regulator of inflammatory responses. As part of that work, researchers developed a mouse model lacking an activator of NF-kB signalling, IKKB. The researchers noticed that these animals developed skin lesions as they became young adults.

“That was interesting to us because these ulcerations looked like an inflammatory event, but we had effectively turned off the activity of NF-kB, which should reduce inflammation,” said Prof Graves. “So this was a paradox.”

To better understand what was driving this response, they sought expertise in skin diseases from Prof Seykora. When they examined the mice, they noted several features quite similar to AD, “albeit the mouse version” said Prof Graves.

In particular, they noted skin thickening and an infiltration of certain types of white blood cells that are also seen in human AD. Delving deeper into how the loss of IKKB was driving these effects, the team performed single-celled RNA analysis combined with a new analysis method. The team learned that fibroblasts were the culprit, a major component of the skin’s dermis layer and typically thought to support the structural integrity of skin.

Though NF-kB typically promotes inflammation, here, decreased NF-kB activity was paradoxically leading to recruitment of immune cells and associated inflammation. Data from the team’s single-cell RNA analysis pointed to high activities of a protein transcription factor called CEBPB, as well as a signalling molecule, CCL11, “We worked out the mechanism in the mouse,” Prof Sekora said, “then showed that much of it applied in human tissue as well.”

When the researchers compared what they had seen in the mouse cells to skin samples from people with AD, they found similar patterns; CCL11 and CEBPB were both found at higher levels in the affected skin than in unaffected skin.

Testing a monoclonal antibody against CCL11 in mice tamped down the inflammatory response they had initially seen in animals lacking IKKB, suggesting that this could be a target to reduce AD-associated inflammation.

The researchers say the work also highlights a developing appreciation that fibroblasts play important roles in immune processes in the skin, indicating that they are important regulators of white blood cells.

AD  typically emerges in childhood, often manifesting along with asthma. Indeed, in the mice, too, the signalling abnormalities the researchers observed occurred in a period corresponding to the animals “childhood.” The group’s findings suggest that fibroblasts may be involved during this period in helping to establish appropriate immune signalling in the skin.

“We have viewed NF-kB as a factor that stimulates inflammation, but it could be that, during development, its activation might be important for maintaining homeostasis,” said Prof Graves.

The team’s next steps are to further explore NF-kB signalling in fibroblasts.

Source: University of Pennsylvania

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A Simple Technique to Reduce Light-headedness upon Standing Up

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Light-headedness upon standing up due to initial orthostatic hypotension (IOH) is a common but poorly understood condition. A new study offers two simple  techniques to effectively manage symptoms of IOH and improve quality of life by activating lower body muscle before or after standing. The research appears in Heart Rhythm.

IOH is a transient decrease in blood pressure and increase in heart rate. Syncope, light-headedness, dizziness, or loss of consciousness from IOH, affects up to 40% of the general population (all ages), while presyncope is probably even more common. However, the condition is under-studied and there are very few options currently available to patients with IOH and no pharmacological treatments. The most common recommendations have been to stand up slowly or sit up first before standing.

IOH symptoms often present during an active stand but not with a passive tilt-table test, suggesting that a muscle activation response plays an important role in the pathophysiology of IOH. This muscle activation response refers to the rapid and excessive vasodilation that occurs in response to the brief lower body muscle contraction required to stand due to local mechanisms. Additional factors involved in this response include the increase in heart rate, initially due to the muscle heart reflex and secondarily in response to the arterial baroreflex triggered by the drop in BP as well as the increase in peripheral resistance, which is also triggered by the arterial baroreflex.

This study investigated physical manoeuvres before or after standing and their efficacy in reducing the drop in blood pressure as well as the symptoms typically seen in IOH patients upon standing. Study participants included 24 young women with a history of IOH. Two participants had inadequate heart rate recordings and were excluded from the analysis. The interventions tested consisted of lower body muscle pre-activation (thighs) through repeated knee raises prior to standing (PREACT) and lower body muscle tensing (thighs and buttocks) through leg crossing and tensing immediately after standing (TENSE).

The 22 study participants completed three sit-to-stand manoeuvres including a stand with no intervention (control), and two interventions. Researchers found that both PREACT and TENSE effectively improve the blood pressure drop. This led to a reduction in symptoms upon standing. They found that the PREACT manoeuvre accomplished this by increasing cardiac output, while the TENSE manoeuvre did so by increasing stroke volume.

“Our study provides a novel and cost-free symptom management technique that patients with IOH can use to manage their symptoms,” noted first author Nasia A. Sheikh, MSc. “Since it is a physical manoeuvre, it simply requires the lower body limbs, which patients can utilise at any time and from anywhere to combat their symptoms.”

Source: Elsevier