Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and ConditionsTags :

How the Influenza Virus Hijacks Our Cells’ Mechanisms

On By ModernMedia
Photo by Andrea Piacquadio on Unsplash

Influenza epidemics, caused by influenza A or B viruses, result in acute respiratory infection. New research published in published in the journal PNAS has identified how the influenza A virus manages to penetrate cells to infect them. By attaching itself to a receptor on the cell surface, it hijacks the iron transport mechanism to start its infection cycle. By blocking the receptor involved, the researchers were also able to significantly reduce its ability to invade cells. These results highlight a vulnerability that could be exploited to combat the virus.

Influenza viruses represent a major risk to human and animal health. Their potential for mutation makes them particularly elusive. ”We already knew that the influenza A virus binds to sugar structures on the cell surface, then rolls along the cell surface until it finds a suitable entry point into the host cell. However, we did not know which proteins on the host cell surface marked this entry point, and how they favoured the entry of the virus,” explains study leader Mirco Schmolke, Associate Professor at University of Geneva (UNIGE).

A receptor as a key to infection

The scientists first identified cell surface proteins present in the vicinity of the viral haemagglutinin, the protein used by the influenza A virus to enter the cell. One of these proteins stood out: transferrin receptor 1. This acts as a revolving door transporting iron molecules into the cell, which are essential for many physiological functions.

“The influenza virus takes advantage of the continuous recycling of the transferrin receptor 1 to enter the cell and infect it,” explains first author Béryl Mazel-Sanchez, a former post-doctoral researcher in Mirco Schmolke’s lab. “To confirm our discovery, we genetically engineered human lung cells to remove the transferrin receptor 1, or on the contrary to overexpress it. By deleting it in cells normally susceptible to infection, we prevented influenza A from entering. Conversely, by overexpressing it in cells normally resistant to infection, we made them easier to infect.”

Inhibiting this mechanism

The research team then succeeded in reproducing this mechanism by inhibiting the transferrinreceptor 1 using a chemical molecule. ”We tested it successfully on human lung cells, on human lung tissue samples and on mice with several viral strains,” says Béryl Mazel-Sanchez. ”In the presence of this inhibitor, the virus replicated much less. However, in view of its potentially oncogenic characteristics, this product cannot be used to treat humans.” On the other hand, anti-cancer therapies based on the inhibition of the transferrin receptor are under development and could also be interesting in this context.

”Our discovery was made possible thanks to the excellent collaboration within the Faculty of Medicine as well as with the University Hospitals of Geneva (HUG) and the Swiss Institute of Bioinformatics (SIB),” the authors add. In addition to the transferrin receptor 1, scientists have identified some 30 other proteins whose role in the influenza A entry process remains to be deciphered. It is indeed likely that the virus uses a combination involving other receptors. ”Although we are still far from a clinical application, blocking the transferrin receptor 1 could become a promising strategy for treating influenza virus infections in humans and potentially in animals.”

Source: Université de Genève

Categories : Diseases, Syndromes and ConditionsTags :

Nonalcoholic Fatty Liver Disease Comes with an Increased Infection Risk

On By ModernMedia
Source: CC0

A Swedish study of more than 12 000 patients with nonalcoholic fatty liver disease (NAFLD) revealed a significantly increased risk of severe infections requiring hospital admission. The study was published in Clinical Gastroenterology and Hepatology.

NAFLD is considered a manifestation of the metabolic syndrome in the liver and with the global rise in obesity, NAFLD has emerged as the most common chronic liver disease affecting around one quarter of all adults worldwide. Being such a wide-spread disease, it has also become the fastest growing cause of end-stage liver disease, primary liver cancer and liver transplantation. In recent years, NAFLD is increasingly viewed as a multifaceted disease affecting multiple organ systems.

In the ESPRESSO study, involving 12 133 individuals with biopsy-proven NAFLD, and 57 516 matched controls from the general population, NAFLD was associated with a 71% higher risk for severe infections requiring hospital admission. The researchers found that individuals with NAFLD exhibited the same spectrum of infection sites as compared with the general population – with respiratory and urogenital tract infections being the two most common sites of infection.

“Our work is important as the first nationwide study assessing the risk of infections in individuals diagnosed with NAFLD”, says lead author Dr Fahim Ebrahimi, MD, MSc, postdoctoral researcher at Karolinska Institutet and gastroenterologist at Clarunis University Center for Gastrointestinal and Liver Diseases in Basel, Switzerland. “Our findings highlight the importance of NAFLD as a multisystem disorder that increases the risk of infections independent from other underlying risk factors such as diabetes mellitus.”

Risk differences for infections

The researchers were intrigued by previous experimental studies that suggested that NAFLD is associated with impaired function of several immune cells which may lead to higher susceptibility towards various viral, bacterial, and fungal infections. “The liver plays a significant role in the human immune system with immune cells, such as macrophages (Kupffer cells) and lymphocytes, constituting up to 20% of all liver cells”, adds Dr. Ebrahimi. “We were surprised to find that the risk of severe infections was increased even in people with simple fatty liver disease without evidence of any liver inflammation or fibrosis. However, when individuals had evidence of the inflammatory subtype nonalcoholic steatohepatitis (NASH), or had developed fibrosis, they were at even higher risks with the highest risks among those with cirrhosis.”

“The absolute risk difference at 20 years after NAFLD diagnosis was 17.3%, equal to one extra severe infection in every 6 patients with NAFLD, therefore, our findings underline the importance of early diagnosis and treatment to reverse the disease at all stages”, says corresponding author Jonas F Ludvigsson, paediatrician at Örebro University Hospital, and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.

“To date, clinical guidelines on NAFLD have not yet included specific recommendations for preventing and managing infections”, says Dr Ebrahimi. “Based on our results, prevention of infections should become one of the main public health efforts to tackle NAFLD associated morbidities.”

Source: Karolinksa Insitutet

Categories : Diseases, Syndromes and ConditionsTags :

Gauteng Cholera Deaths Rise as Government Sets up Field Hospital

On By ModernMedia

As of Sunday, reports indicate that 23 people have died so far in the recent cholera outbreak in Hammanskraal, a direct result of the town’s neglected water sanitation infrastructure. A further 48 have been hospitalised, with six emergency field tents being set up to prop up the overburdened Jubilee Hospital, which has seen 215 patients since 19 May, as reported in the most recent Gauteng Department of Health bulletin.

The temporary field hospital has been set up to immediately attend to cases of dehydration, supplying oral rehydration solution (IRS) as well as intravenous fluids. More critical patients are taken to Tshwane hospitals.

The Gauteng Department of Health also notes that as of Friday, 27 of the 75 confirmed cholera cases had recovered and been discharged. The Gauteng Department of Education has said that it will intensify efforts to supply schools in Hammanskraal with clean drinking water.

South Africa’s most serious outbreak of cholera in recent history was from November 2008, when a massive cholera outbreak occurred in Zimbabwe and spread to South Africa. Within the first 5 months of the outbreak, more than 73 000 cases and 3500 deaths (case fatality rate of >4.7%) had been reported, and it spread to South Africa through Musina. Between 15 November 2008 and 30 April 2009, a total of 12 706 cases of cholera were reported by the National Department of Health. Of the total number of cases, 1114 (9.0%) were laboratory-confirmed cases, and 65 deaths (case fatality rate of 0.5%) were recorded. In this outbreak, microbial analysis published in the Journal of Infectious Diseases found the emergence of antimicrobial resistance in Vibrio cholerae 01 strains.

The National Institute of Communicable Diseases has posted guidelines [PDF] for the management of suspected cholera chases.

Categories : Diseases, Syndromes and ConditionsTags :

Death Toll Rises to 17 as Gauteng Cholera Outbreak Continues

On By ModernMedia
Scanning electron micrograph image of Vibrio cholerae. Source: Wikimedia CC0

The Hammanskraal cholera outbreak continues with 17 deaths from the disease reported so far. Poverty is exacerbating the situation, with residents being advised to drink bottled water – but unable to afford it. According to GroundUp, the microbiological compliance (a measure of faecal bacteria) at sewage treatment plants was as low as 2% and 0%, where below 50% is considered ‘bad’.

Characterised by watery diarrhoea and dehydration, cholera is caused by infection by the bacterium Vibrio cholerae and in some cases can cause death within hours. It is spread through contaminated water, and asymptomatic individuals can contribute to the spread by shedding bacteria in faeces for seven to 14 weeks.

The National Institute for Communicable Diseases (NICD) says that treatment is with oral rehydration solution (ORS), with intravenous ringer’s lactate for severe dehydration and antibiotics recommended in hospitalised patients.

For acute cases of watery diarrhoea, the National Institute for Communicable Diseases (NICD) advises the following course of action:

– Collect a stool or rectal swab specimen and request culture for cholera (in addition to other microbiological tests etc. as indicated). Where possible, collect specimens before antibiotic treatment is given. Guidance on the collection of specimens can be found here (https://www.nicd.ac.za/wp-content/uploads/2023/01/Guidelines-for-specimen-collection-Cholera-Janury2023.pdf)

– Notify the case as suspected cholera by completing a Notifiable Medical Conditions case notification form. Do this immediately; don’t wait for laboratory results.

For management of suspected cholera cases, NICD provides the following guidance:

Rehydration is the mainstay of treatment.

1. Assess and reassess the degree of dehydration frequently.

2. Replace fluid and maintain hydration status based on the degree of dehydration (see flowchart)

3. Antibiotic therapy is recommended for hospitalised patients. Ciprofloxacin is currently the antibiotic of choice:
Paediatric dose: 20 mg/kg (max 1g) po stat
Adult dose: 1g po stat

4. Children < 5 years of age should be given zinc supplementation.

5. Patients should be fed as soon as they can tolerate food

6. Patients who are no longer dehydrated and can take ORS and have decreased frequency of diarrhoea may be discharged.

7. Don’t prescribe anti-motility drugs (eg loperamide)

8. Isolate patient if possible and apply contact precautions

The guidance also covers laboratory sampling and infection control procedures. Further resources are available on their website.

Categories : Diseases, Syndromes and ConditionsTags :

Brepocitinib Promising in Treatment of Psoriatic Arthritis

On By ModernMedia
Photo by Towfiqu barbhuiya

Brepocitinib is an oral drug that inhibits certain enzymes involved in inflammation (called tyrosine kinase 2 and Janus kinase 1) and is being tested for the treatment of several immunological diseases. A phase IIb randomised clinical trial published in Arthritis & Rheumatology recently generated promising efficacy and safety data for the use of brepocitinib in adults with moderately-to-severely active psoriatic arthritis.

Psoriatic arthritis is a type of arthritis that affects some people with psoriasis. It typically causes affected joints to become swollen, stiff and painful. Like psoriasis, psoriatic arthritis is a long-term condition that can get progressively worse.

Overall, 218 participants were randomised to receive either a low or high dose of brepocitinib or placebo for 1 year. After 16 weeks of treatment, 30 and 60mg daily doses of brepocitinib were superior to placebo at reducing signs and symptoms of psoriatic arthritis. Response rates were maintained or improved through week 52. Side effects were mostly mild or moderate.

“These data demonstrate striking efficacy and confirm the relevance of multiple signaling pathways dependent on the kinases targeted by brepocitinib in psoriatic arthritis,” said corresponding author Philip Mease, MD, of Swedish Medical Center/Providence St. Joseph Health and the University of Washington, in Seattle. “The safety is also reassuring for brepocitinib in this study.”

Source: Wiley

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

FDA Approves First Drug Designed to Treat Indolent Systemic Mastocytosis

On By ModernMedia
Photo by Rodion Kutsaiev on Unsplash

Systemic mastocytosis (SM) is a rare haematologic disorder that can lead to a range of debilitating symptoms across multiple organ systems and a significant impact on patients’ quality of life, and now the first medicine has been approved to specifically treat the most common form of the disease. On Monday 22 May, the US Food and Drug Administration (FDA) approved AYVAKIT® (avapritinib) to treat indolent systemic mastocytosis (ISM) in adults.

ISM represents the vast majority of SM cases, and AYVAKIT is now available for adults with ISM at the recommended dose of 25mg once daily. AYVAKIT was designed to potently and selectively inhibit KIT D816V, the primary underlying driver of the disease. AYVAKIT has been FDA approved for the treatment of advanced SM since June 2021.

“After decades of caring for people with indolent systemic mastocytosis, I have seen firsthand its profound impact on patients’ underlying mast cell burden, symptoms, physical and mental health, and ability to work and participate in daily activities,” said investigator Cem Akin, MD, PhD, Professor of Medicine at the University of Michigan. “Despite the use of multiple supportive care treatments, a considerable number of patients with indolent systemic mastocytosis continue to experience a substantial disease burden. AYVAKIT advances the treatment of indolent systemic mastocytosis by targeting KIT D816V, the primary underlying cause of the disease, and establishes a new standard of care for a broad population of patients with this disorder. AYVAKIT delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those affected by the disease.”

The approval of AYVAKIT in ISM is based on data from the double-blind, placebo-controlled PIONEER trial – the largest study ever conducted for this disease – in which patients received AYVAKIT 25mg once daily plus best supportive care (AYVAKIT) or placebo plus best supportive care (placebo). AYVAKIT demonstrated significant improvements versus placebo in the primary and all key secondary endpoints, including overall symptoms and measures of mast cell burden.

AYVAKIT was well-tolerated with a favourable safety profile compared to placebo, and most adverse reactions were mild to moderate in severity. The most common adverse reactions for AYVAKIT (≥10%) were eye oedema, dizziness, peripheral oedema and flushing. Serious adverse reactions and discontinuations due to adverse reactions occurred in less than 1% of patients.

Detailed results from the PIONEER trial, including open-label extension study data showing the clinical benefits of AYVAKIT through 48 weeks of treatment, were presented in February 2023 at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

Source: Blueprint Medicines

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Ripping Through Biofilms in Chronic Treatment-resistant Wounds

On By ModernMedia
Methicillin-resistant-Staphylococcus-aureus-MRSA

Researchers have developed a new method that combines palmitoleic acid, gentamicin, and non-invasive ultrasound to help improve drug delivery in chronic wounds that have been infected with Staphylococcus aureus and protected by thick biofilms. Their results were published in Cell Chemical Biology.

Chronic wounds are notoriously challenging to treat because of bacterial infections like S. aureus, which can also be resistant to antibiotics.

To defend itself from the immune system and other threats, S. aureus can band together, creating a slick, slimy biofilm around itself. The biofilm barrier is so thick that neither immune cells nor antibiotics can penetrate through and neutralise the harmful bacteria.

Using a new strategy, researchers at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering were able to reduce the challenging MRSA infection in the wounds of diabetic mice by 94%. They were able to completely sterilise the wounds in several of the mice, and the rest had significantly reduced bacterial burden.

“When bacteria are not completely cleared from chronic wounds, it puts the patient at high risk for the infection recurring or of developing a secondary infection,” said senior author Sarah Rowe-Conlon, PhD. “This therapeutic strategy has the potential to improve outcomes and reduce relapse of chronic wound infections in patients. We are excited about the potential of translating this to the clinic, and that’s what we’re exploring right now.”

Biofilms act as a physical barrier to many classes of antibiotics. Virginie Papadopoulou, PhD, was curious to know if non-invasive cavitation-enhanced ultrasound could create enough agitation to form open spaces in the biofilm to facilitate drug-delivery.

Liquid droplets which can be activated by ultrasound, called phase change contrast agent (PCCA), are applied topically to the wound. An ultrasound transducer is focused on the wound and turned on, causing the liquid inside the droplets to expand and turn into microscopic gas-filled microbubbles, when then move rapidly.

The oscillation of these microbubbles agitates the biofilm, both mechanically disrupting it as well as increasing fluid flow. Ultimately, the combination of the biofilm disruption and the increased permeation of the drugs through the biofilm allowed the drugs to come in and kill the bacterial biofilm with very high efficiency.

“Microbubbles and phase change contrast agents act as local amplifiers of ultrasound energy, allowing us to precisely target wounds and areas of the body to achieve therapeutic outcomes not possible with standard ultrasound,” said Dayton. “We hope to be able to use similar technologies to locally delivery chemotherapeutics to stubborn tumours or drive new genetic material into damaged cells as well.”

When the bacterial cells are trapped inside the biofilm, they are left with little access to nutrients and oxygen. To conserve their resources and energy, they transition into a dormant or sleepy state. The bacteria, which are known as persister cells in this state, are extremely resistant to antibiotics.

Researchers chose gentamicin, a topical antibiotic typically ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells. The researchers also introduced a novel antibiotic adjuvant, palmitoleic acid, to their models.

Palmitoleic acid, an unsaturated fatty acid, is a natural product of the human body that has strong antibacterial properties. The fatty acid embeds itself into the membrane of bacterial cells, and the authors discovered that it facilitates the antibiotic’s successful entry into S. aureus cells and is able to kill persistent cells and reverse antibiotic resistance.

Overall, the team is enthusiastic about the new topical, non-invasive approach because it may give scientists and doctors more tools to combat antibiotic resistance and to lessen the serious adverse effects of taking oral antibiotics.

“Systemic antibiotics, such as oral or IV, work very well, but there’s often a large risk associated with them such as toxicity, wiping out gut microflora and C. difficile infection,” said Rowe-Conlon. “Using this system, we are able to make topical drugs work and they can be applied to the site of infection at very high concentrations, without the risks associated with systemic delivery.”

Source: University of North Carolina Health Care

Categories : Ageing Diseases, Syndromes and ConditionsTags :

Possible Explanation for Why More Men Develop Hearing Loss in Old Age

On By ModernMedia
Photo by Kindel Media on Pexels

A new study led by Yale School of Medicine scientists and published in BMC has pinpointed why some adults – by some estimates, at least 50% of the population after 75 years of age – develop hearing problems.

While congenital hearing impairment – usually presenting in childhood – result from rare mutations, hearing problems in adults are likely due to the cumulative effect of polygenic risk and environmental factors.

Recent genome-wide association studies have uncovered several risk genes that are implicated in hearing problems in adults, however some factors still have not adequately been investigated by large-scale genetic studies.

For instance, there is limited information about why hearing problems among older adults are more common, more severe, and with earlier onset in men than in women. It is uncertain how hearing-related polygenic risk translates among people of diverse ancestral backgrounds.

While environmental risk factors such as noise exposure and tobacco smoking are known to increase the risk of hearing problems, the molecular mechanisms underlying these associations are unclear.

Researchers sampled nearly 750 000 adults and identified 54 risk variants – including 12 novel variants – that could contribute to hearing problems. They also highlighted how hormonal regulation may play a role in the differences between hearing problems in men and women.

Analysing multiple ancestry groups, the researchers demonstrated that polygenic risk in hearing problems is shared across human populations. They also determined genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their associations with hearing problems.

“Our results support that large-scale genetic studies are useful instruments to understand the biology and the epidemiology of hearing problems in adults,” said Renato Polimanti, PhD, associate professor of psychiatry at Yale School of Medicine and senior author of the study.

Overall, the findings contribute to identifying possible molecular targets for drug development and define novel strategies to identify older adults at risk of losing their hearing.

The study could lead to changes in how older adults with hearing problems are assessed and treated. Hearing loss can impair communications, and that can result in social isolation with major health, psychosocial, and economic consequences, reducing the quality of life of those affected.

Source: Yale University

Categories : Diseases, Syndromes and ConditionsTags :

Solriamfetol is Best for Banishing Excessive Daytime Sleepiness

On By ModernMedia

New research in the Annals of Internal Medicine reports that the drug solriamfetol is the most effective treatment for excessive daytime sleepiness (EDS) for people with obstructive sleep apnoea (OSA).

The standard treatment for OSA is a positive airway pressure (PAP) mask that uses compressed air to support lung airways during sleep. However, some people with OSA still experience EDS and may benefit from anti-fatigue medication.

“The most important thing that people with OSA should do is use their PAP machine, but if they are still sleepy there are options in the form of medications that can reduce their tiredness,” said first author Tyler Pitre, a resident physician in internal medicine at McMaster University and incoming respirology fellow at the University of Toronto.

“Fifteen to 30 per cent of people in North America have a diagnosis of OSA and the prevalence could be much higher as many others are undiagnosed. Many people have symptoms as the condition is highly associated with obesity, which affects a large and increasing number of people in Canada, the United States and other high-income countries,” he said.

“Among those patients, many will have EDS, which affects their quality of life, making them less productive and also puts them at risk of other psychological issues. Improving this situation is of paramount importance to physicians.”

Pitre said that OSA affects nearly one billion people globally, leaving many of them at risk of EDS.

Zeraatkar and Pitre made their findings by conducting a systematic review of 14 clinical trials of anti-fatigue medications involving 3085 people, as well as analysing data from MEDLINE, CENTRAL, EMBASE and ClinicalTrials.gov in a specific network meta-analysis. They conducted their research from October 2022 to January 2023.

Senior author Zeraatkar said that while solriamfetol is likely the best medication for EDS, the drugs armodafinil-modafinil and pitolisant are also effective in combatting fatigue.

Solriamfetol can also raise blood pressure, especially risky for people with OSA, as many of them also have cardiovascular issues.

“It would be interesting to see how effective these anti-fatigue medications will be for treating related illnesses such as chronic fatigue syndrome and long COVID, now that we know they work for a similar condition,” said Zeraatkar, an assistant professor of the Department of Anesthesia.

Source: McMaster University

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Autoimmune Disorders Now Affect Roughly One in Ten Individuals

On By ModernMedia
Photo by Jacek Dylag on Unsplash

A population-based study of 22 million people in the UK estimates that around one in ten individuals in the UK now live with an autoimmune disorder. The findings, published in The Lancet, also highlight important socioeconomic, seasonal and regional differences for several autoimmune disorders, providing new clues as to what factors may be involved in these conditions.

There are more than 80 known autoimmune diseases, including conditions like rheumatoid arthritis, type 1 diabetes and multiple sclerosis, some of which have been increasing in the last few decades.

This has raised the question whether overall incidence of autoimmune disorders is on the rise and what factors are involved, such as environmental factors or behavioural changes in society. The exact causes of autoimmune diseases remain largely unknown, including how much can be attributed to a genetic predisposition to disease and how much is down to exposure to environmental factors.

The study used anonymised electronic health data from 22 million individuals in the UK to investigate 19 of the most common autoimmune diseases. The authors examined whether incidence of autoimmune diseases is rising over time, who is most affected by these conditions and how different autoimmune diseases may co-exist with each other.

They found that the 19 autoimmune diseases studied affect around 10% of the population. This is higher than previous estimates, which ranged from 3–9% and often relied on smaller sample sizes and included fewer autoimmune conditions. The analysis also highlighted a higher incidence in women (13%) than men (7%).

The research discovered evidence of socioeconomic, seasonal and regional disparities for several autoimmune disorders, suggesting that these conditions are unlikely to be caused by genetic differences alone. This observation may point to the involvement of potentially modifiable risk factors such as smoking, obesity or stress. It was also found that in some cases a person with one autoimmune disease is more likely to develop a second, compared to someone without an autoimmune disease.

Dr Nathalie Conrad at the University of Oxford said: “We observed that some autoimmune diseases tended to co-occur with one another more commonly than would be expected by chance or increased surveillance alone. This could mean that some autoimmune diseases share common risk factors, such as genetic predispositions or environmental triggers. This was particularly visible among rheumatic diseases and among endocrine diseases. But this phenomenon was not generalised across all autoimmune diseases. Multiple sclerosis, for example, stood out as having low rates of co-occurrence with other autoimmune diseases, suggesting a distinct pathophysiology.”

These findings reveal novel patterns that will inform the design of further research into the possible common causes of different autoimmune diseases.

Professor Geraldine Cambridge at UCL Medicine said: “Our study highlights the considerable burden that autoimmune diseases place upon individuals and the wider population. Disentangling the commonalities and differences within this large and varied set of conditions is a complex task. There is a crucial need, therefore, to increase research efforts aimed at understanding the underlying causes of these conditions, which will support the development of targeted interventions to reduce the contribution of environmental and social risk factors.”

Source: University College London