The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Pathogenesis.

Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER-nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis.

Modulating sphingosine 1-phosphate receptor signaling skews intrahepatic leukocytes and attenuates murine nonalcoholic steatohepatitis.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid associated with nonalcoholic steatohepatitis (NASH). Immune cell-driven inflammation is a key determinant of NASH progression. Macrophages, monocytes, NK cells, T cells, NKT cells, and B cells variably express S1P receptors from a repertoire of 5 receptors termed S1P1 - S1P5. We have previously demonstrated that non-specific S1P receptor antagonism ameliorates NASH and attenuates hepatic macrophage accumulation. However, the effect of S1P receptor antagonism on additional immune cell populations in NASH remains unknown. We hypothesized that S1P receptor specific modulation may ameliorate NASH by altering leukocyte recruitment. A murine NASH model was established by dietary feeding of C57BL/6 male mice with a diet high in fructose, saturated fat, and cholesterol (FFC) for 24 weeks. In the last 4 weeks of dietary feeding, the mice received the S1P1,4,5 modulator Etrasimod or the S1P1 modulator Amiselimod, daily by oral gavage. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by flow cytometry, immunohistochemistry, and mRNA expression. Alanine aminotransferase, a sensitive circulating marker for liver injury, was reduced in response to Etrasimod and Amiselimod treatment. Liver histology showed a reduction in inflammatory foci in Etrasimod-treated mice. Etrasimod treatment substantially altered the intrahepatic leukocyte populations through a reduction in the frequency of T cells, B cells, and NKT cells and a proportional increase in CD11b+ myeloid cells, polymorphonuclear cells, and double negative T cells in FFC-fed and control standard chow diet (CD)-fed mice. In contrast, FFC-fed Amiselimod-treated mice showed no changes in the frequencies of intrahepatic leukocytes. Consistent with the improvement in liver injury and inflammation, hepatic macrophage accumulation and the gene expression of proinflammatory markers such as Lgals3 and Mcp-1 were decreased in Etrasimod-treated FFC-fed mice. Etrasimod treated mouse livers demonstrated an increase in non-inflammatory (Marco) and lipid associated (Trem2) macrophage markers. Thus, S1P1,4,5 modulation by Etrasimod is more effective than S1P1 antagonism by Amiselimod, at the dose tested, in ameliorating NASH, likely due to the alteration of leukocyte trafficking and recruitment. Etrasimod treatment results in a substantial attenuation of liver injury and inflammation in murine NASH.

Diagnosing Joubert Syndrome in Two Adult Siblings: A Very Rare Case Report.

Joubert syndrome (JS) is a rare genetic disorder usually diagnosed during childhood. Adult Joubert syndrome is rare, and that too in siblings from a non-consanguineous marriage in their adulthood is extremely rare, with very few cases reported worldwide. The need for expensive imaging modality to aid diagnosis has also been cited as a drawback in diagnosing the condition in resource-poor areas. We describe the case of two adult siblings who came for other diseases and were diagnosed with Joubert syndrome.

Efficacy of Vitamin D Supplementation in the Improvement of Clinical Status in Patients Diagnosed with Fibromyalgia Syndrome: A Systematic Review.

BACKGROUND: Fibromyalgia syndrome is characterised by extensive muscular pain and chronic fatigue. Among the pharmacologic and other nutrient supplements that have been studied, Vitamin D has garnered attention owing to the critical role it plays in inflammatory and pain pathways. We conducted a systematic literature review to examine the efficacy of vitamin D supplementation in improving the clinical status of the patients and alleviating the symptoms of fibromyalgia. METHODS: We searched Cochrane CENTRAL, PubMed, Science Direct, Scopus, grey literature (medrXiv and biorXiv) for observational studies, randomized controlled trials, case-control studies, and case reports published in English from January 2011 to May 2021, using the terms vitamin D and fibromyalgia or FMS. References were reviewed manually and articles were only included if they were specific about the diagnosis of fibromyalgia. RESULTS: 2651 studies were retrieved, with 12 studies fulfilling the inclusion criteria. 11 out of these 12 studies were of high quality and showed low risk of bias. 11 of these also demonstrated definitive improvement in clinical status and various outcome measures following supplementation with Vitamin D. CONCLUSION: Our study emphasises an association between supplementation of vitamin D and improvement of the clinical condition of fibromyalgia through a systematic review of high-quality studies. The study also identified areas for future scope for research needed for standardising the detection and treatment of this chronic condition through cost-effective supplements such as Vitamin D.

Wilson's Disease: Diagnosis in Novel Way.

Wilson's disease first described by Kinnier Wilson in 1912, is a rare autosomal recessive genetic disorder involving a defect in copper metabolism. This disease affects between one in 30,000 to one in 100,000 individuals and has a carrier frequency of one in every 90. It is characterized by hepatic and neurological symptoms. The usual age of presentation is 4 to 40 years but this disorder has been detected in children as young as three years and adults as old as 70 years with males and females being equally affected. Diagnosing Wilson's disease at the earliest is crucial as it is not only progressive and fatal if untreated, but also responds promptly to medication. Here we are going to present a novel way to diagnose a case of Wilson disease in a resource-limited setting. The diagnosis was possible with detailed present and past history raising strong clinical suspicion of environmental or genetically related disease. The diagnosis was done in a novel way by first diagnosing in daughter thereafter confirming the same diagnosis in patient.

Efficacy and Safety of Vedolizumab in Management of Moderate to Severe Ulcerative Colitis: A Systematic Review.

Ulcerative colitis (UC) is an inflammatory bowel disease and causes inflammation and ulcer of the colon. Vedolizumab is a newer biological agent with an inhibitory effect on α4ß7 integrin approved for moderate to severe UC patients. Our study reviewed the clinical response, clinical remission, and mucosal healing of vedolizumab in moderate to severe UC management. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search in PubMed, Google Scholar, and Science Direct, and nine studies were included in the systematic review. At week six, vedolizumab showed a significant clinical response. At week 52, vedolizumab showed significant mucosal healing and clinical remission. The most commonly associated adverse effects are nasopharyngitis, oropharyngeal infection, and gastrointestinal infection. However, additional clinical trials and observational studies with longer follow-ups are required to study the efficacy and safety of the drug.

The Impact of Rheumatoid Arthritis on Bone Loss: Links to Osteoporosis and Osteopenia.

Rheumatoid arthritis (RA) is an autoimmune chronic connective tissue disease that produces persistent systemic inflammation, with joint inflammation leading to function loss and joint destruction. Low bone mass causes skeletal bone loss, commonly referred to as osteopenia or osteoporosis.  We conducted this literature review to examine the relationship between RA and osteoporosis and the variables contributing to this connection. We used articles from the US National Library of Medicine (PubMed), Google Scholar, Science Direct to access the required information. Eventually, our results concluded that RA could result in local periarticular and generalized bone loss. Many risk factors contribute to this association, such as chronic joints inflammation, glucocorticoid use, genetics, and estrogen hormone effects. Still, it is not clear yet whether this is due to a consequence of treatment, immobility, or the activity of the disease. There are many recommendations by the American College of Rheumatology for RA patients during the disease course to reduce the risk of osteoporosis development, which include early starts of disease-modifying anti-inflammatory drugs (DMARDs), doing a dual-energy x-ray (DXA) or quantitative ultrasound (QUS) for identifying a patient at risk of osteoporosis, taking vitamin D, calcium, and bisphosphonates. Further prospective studies and clinical trials are essential to provide a solid evidence-based recommendation that will help to prevent bone loss in RA patients.

Sofosbuvir/Velpatasvir - A Promising Treatment for Chronic Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infection is a disease that affects millions of people worldwide and has an enormous global public health impact. Chronic HCV is a long-term infection that goes unnoticed until the virus destroys the liver enough to induce liver disease symptoms. The inadequate and poorly tolerated treatment contributes to the burden of chronic HCV. Treatments have improved over time - direct-acting antivirals (DAAs) that targeted different hepatitis C virus genomic sites have shown to be more effective and well-tolerated. Patients recover to a greater extent following a treatment regimen based on DAAs. We conducted this literature review to investigate the effectiveness of these medications in treating chronic HCV infection. Relevant articles were identified by searching PubMed and Google scholar databases. Our primary goal was to analyze the efficacy and safety of the DAA, sofosbuvir plus velpatasvir, with or without ribavirin, in cirrhotic or non-cirrhotic, naïve or previously treated, chronic HCV patients. We found that treating patients with sofosbuvir-velpatasvir for 12 weeks was highly effective with fewer adverse events, including those with compensated cirrhosis. The outcomes aided in improving HCV treatment, lowering the disease's burden and fatality rate.

Gaucher's Disease in an Adult Female: A Rare Entity.

Gaucher's disease is a rare inborn error of metabolism with an autosomal recessive pattern of inheritance. With over 26 million births occurring per annum, extrapolation of this figure would give us an estimated burden of 17,000 babies born with lysosomal storage disorder (LSD). Given the large population of India and the high rates of consanguineous marriage that takes place in the subcontinent, LSD might not be as rare as we perceive it to be. We report a rare occurrence of type-1 Gaucher's disease in an adult female patient born of a non-consanguineous marriage, belonging to the tropical area of Chhattisgarh, India where there is a predominance of malaria, thalassemia, and sickling. The diagnosis was challenging in this case since we needed to work out all the differential diagnoses of pancytopenia with hepatomegaly and massive splenomegaly. The key part was her medical history where there was documentation of her elder brother's death due to some mental illness of undiagnosed etiology. Being a difficult time due to coronavirus disease 2019 ( COVID-19) , we were able to diagnose the patient with a bone marrow biopsy followed by glucocerebrosidase enzyme level suggestive of Gaucher's disease.

Stem Cell Therapy for the Treatment of Myocardial Infarction: How Far Are We Now?

Myocardial infarction is one of the leading causes of death worldwide. Poor functional recovery of the myocardium is noticed after an event of myocardial infarction. Researchers and clinicians around the world have been engaged to regenerate the damaged human heart for a long time. Stem cell therapy is an exciting newer therapy to treat cardiovascular diseases. Various types of stem cells have been used to revive the damaged myocardium after myocardial infarction, and they have overall demonstrated safety and moderate efficacy. The specific mechanisms by which these cells help in improving cardiac function are still not completely known. There is growing evidence that intracoronary bone marrow cell transplantation in patients with myocardial infarction beneficially affects the remodeling of the damaged myocardium. Our systematic review article aims to assess the effects and the future of stem cell therapy in patients with myocardial Infarction. We searched articles in PubMed, ScienceDirect, and Google Scholar. Thirty-one studies that included 2171 patients in total were analyzed. Most of these studies showed stem cell therapy is safe and well tolerated in patients, and modest improvements are seen in left ventricular functions with no major adverse effects. However, some studies showed no positive and clinically significant outcomes. So, more high-quality studies on a larger scale are required to support and confirm its efficacy in remodeling damaged myocardium after myocardial infarction. We should also perform studies to determine the timing of cell delivery that is best suited for stem cell therapy.

The Relationship Between Vitamin D and Asthma Exacerbation.

Asthma is a chronic airway inflammatory condition that affects millions of people worldwide. It presents with reversible bronchoconstriction that makes it difficult for patients to breathe. Asthma flare-ups have several triggers, but the symptoms are similar, including wheezing, coughing, shortness of breath, and chest tightness. Severe asthma exacerbation is described as symptomatic asthma that is unresponsive to inhaled asthma medications and is only responsive to steroids in oral or intravenous forms. Asthma-related deaths occur during episodes of asthma exacerbation. Vitamin D is a steroid-derived vitamin produced by the body and found in some foods. Administration of doses of vitamin D can also help maintain an adequate level of the vitamin. Vitamin D plays a vital role in regulating the level of calcium in the body and bone remodeling processes. It also has an immunomodulatory effect on innate and adaptive immunity within the body and that partially explains its links to inflammation-induced epithelial changes seen in asthma. We conducted this literature review by selecting articles from PubMed and Cumulated Index to Nursing and Allied Health Literature (CINAHL) Plus databases to investigate the relationship between vitamin D level and asthma exacerbation. From the studies, we found that asthmatic patients have low vitamin D levels during an asthma exacerbation. However, supplementing vitamin D may not reduce the rates of asthma exacerbation except in adult asthmatic patients with low levels of vitamin D.

Magic of a Common Sugar Pill in Cancer: Can Metformin Raise Survival in Pancreatic Cancer Patients?

Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.

Are We Jumping the Gun with Itolizumab in India? A Situational Analysis from the Pre-COVID Era.

Itolizumab, an anti-CD6 monoclonal antibody, has been recently approved for the off-label indication of cytokine release syndrome in the background of COVID-19, by the Drug Controller General of India. However, this drug has not been included in the National Clinical Management Protocol for COVID-19 yet. The limited-to-no experience of the Indian health workforce with the drug urged us to conduct a situational analysis in the pre-COVID era to analyse the degree of use of the drug and the indications for which it has been employed.

Role of Dupilumab in Approved Indications of COVID-19 Patient: an Efficacy-Based Nonsystematic Critical Analysis.

With many drugs being tried in the management and treatment of COVID-19, dupilumab is one such monoclonal antibody that has come under the limelight for its possible role as an adjunct therapy in COVID-19 position. There are isolated case reports and series that document a milder course of COVID-19 infection in patients who have already been on dupilumab therapy for treatment of conditions such as atopic dermatitis and chronic rhino-sinusitis with nasal polyp. There is also an ongoing debate regarding the continuation of biologicals in the COVID patient. In this article, a non-systematic critical analysis of dupilumab was performed to delve into this hypothesis further.

Can HCQ Be Considered a "Safe Weapon" for COVID-19 in the Indian Population?

With no drugs currently approved for treatment and cure of COVID-19 (coronavirus disease 2019), hydroxychloroquine is one of the many first-line drugs used in the management. However, given the life-threatening adverse effects of HCQ that have been reported, its use as a prophylactic treatment remains debated. HCQ has long been used in India for the treatment of malaria, auto-immune and inflammatory diseases, and even type 2 diabetes mellitus recently. We aimed to review existing literature and relevant Web sites regarding the safety profile of HCQ in the Indian subcontinent. A non-systematic critical analysis of all published literature/studies focused on the Indian population, recording on the use of HCQ for various indications up till April 2020 was done and frequency of occurrence of HCQ related life-threatening and cardiac side effects were noted. Results from PubMed database showed an incidence of 0.6% of cardiac-related side effects and 7.42% of other self-limiting and minor side effects among the Indian population on HCQ. Considering its minimal risk and favorable safety profile, cost-effectiveness, availability, and affordability in India, the use of hydroxychloroquine in the fight against COVID-19 appears rationale. Following the results of our study, we hypothesize that Indians might be less likely to suffer from cardiac-related side effects given their genetic make-up. However, this would need further studies, clinical trials, and a pharmacogenomic understanding of the subject.