Aspartame-induced cognitive dysfunction: Unveiling role of microglia-mediated neuroinflammation and molecular remediation.

Aspartame, an artificial sweetener, is consumed by millions of people globally. There are multiple reports of aspartame and its metabolites affecting cognitive functions in animal models and humans, which include learning problems, headaches, seizures, migraines, irritable moods, anxiety, depression, and insomnia. These cognitive deficits and associated symptoms are partly attributed to dysregulated excitatory and inhibitory neurotransmitter balance due to aspartate released from aspartame, resulting in an excitotoxic effect in neurons, leading to neuronal damage. However, microglia, a central immunocompetent cell type in brain tissue and a significant player in inflammation can contribute to the impact. Microglia rapidly respond to changes in CNS homeostasis. Aspartame consumption might affect the microglia phenotype directly via methanol-induced toxic effects and indirectly via aspartic acid-mediated excitotoxicity, exacerbating symptoms of cognitive decline. Long-term oral consumption of aspartame thus might change microglia's phenotype from ramified to activated, resulting in chronic or sustained activation, releasing excess pro-inflammatory molecules. This pro-inflammatory surge might lead to the degeneration of healthy neurons and other glial cells, impairing cognition. This review will deliberate on possible links and research gaps that need to be explored concerning aspartame consumption, ecotoxicity and microglia-mediated inflammatory cognitive impairment. The study covers a comprehensive analysis of the impact of aspartame consumption on cognitive function, considering both direct and indirect effects, including the involvement of microglia-mediated neuroinflammation. We also propose a novel intervention strategy involving tryptophan supplementation to mitigate cognitive decline symptoms in individuals with prolonged aspartame consumption, providing a potential solution to address the adverse effects of aspartame on cognitive function.

Cerebrotendinous Xanthomatosis, a Treatable Disorder Often Missed: Case Series of Three Patients Confirmed by Genetic Testing.

ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is a treatable autosomal recessive disorder with varied clinical manifestations and age of onset and is often diagnosed late. We report three cases of CTX who presented at our center with clinical features of frequent diarrhea, early cataracts, xanthomas, cognitive decline, ataxia, neuropathy, and other manifestations of CTX. Magnetic resonance imaging (MRI) brain in all three patients revealed abnormalities consistent with CTX. Diagnosis was confirmed by next-generation sequencing. Chenodeoxycholic acid (CDCA) is recommended as the drug of choice, as it can halt the disease progression and reverse some of the symptoms. In addition to late diagnosis, nonavailability of CDCA in our part of world adds to the problem of management of such patients; therefore, they are often started on alternative therapies, which are less effective.

Comparison of aspartate aminotransferase platelet ratio index score and insulin resistance in type 2 diabetes mellitus with non-alcoholic fatty liver disease.

Objective. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases characterized by the presence of ectopic fat in the liver and steatosis, which cannot be explained by alcohol consumption. The association between NAFLD and type 2 diabetes mellitus (T2DM) is well established. As liver fibrosis progresses in a patient with NAFLD, insulin resistance (IR) increases and may worsen diabetes control. The aspartate aminotransferase platelet ratio index (APRI) score is a simple and inexpensive bedside marker that can detect liver fibrosis and cirrhosis. Several studies have shown an association between APRI and NAFLD. However, there is a gap in correlation with IR in patients with diabetes. In this study, we sought to correlate IR and NAFLD in diabetes using the APRI score. Methods. This observational hospital-based cross-sectional study was conducted in the Department of General Medicine, one of the tertiary care hospitals in North India, from February 2019 to July 2020. A total of 70 patients were taken for the study. Patients with T2DM, aged >30 years, who had no history of alcohol use and who had or were newly diagnosed with NAFLD were enrolled in the study. Results. Significant differences in mean HbAc1, AST, serum insulin, APRI score and homeo-static model assessment-2 (HOMA2) IR between NAFLD grade 1, grade 2, and grade 3 groups were found. Pearson correlation between APRI score and HOMA2 IR total values revealed a significant positive correlation between them. Conclusions. The data of the present study indicate that the APRI score can be used to assess the IR degree and provide important information for improving glycemic control in T2DM patients with NAFLD.

Host-Erythrocytic Sphingosine-1-Phosphate Regulates Plasmodium Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation.

The evolution of resistance to practically all antimalarial drugs poses a challenge to the current malaria elimination and eradication efforts. Given that the epigenome of Plasmodium falciparum governs several crucial parasite functions, pharmaceutical interventions with transmission-blocking potential that target epigenetic molecular markers and regulatory mechanisms are likely to encounter drug resistance. In the malaria parasite, histone deacetylases (HDACs) are essential epigenetic modulators that regulate cellular transcriptional rearrangements, notably the molecular mechanisms underlying parasite proliferation and differentiation. We establish "lipid sequestration" as a mechanism by which sphingolipids, specifically Sphingosine-1-Phosphate (S1P) (a metabolic product of Sphingosine Kinase 1 [SphK-1]), regulate epigenetic reprogramming in the parasite by interacting with, and modulating, the histone-deacetylation activity of PfHDAC-1, thereby regulating Plasmodium pathogenesis. Furthermore, we demonstrate that altering host S1P levels with PF-543, a potent and selective Sphk-1 inhibitor, dysregulates PfHDAC-1 activity, resulting in a significant increase in the global histone acetylation signals and, consequently, transcriptional modulation of genes associated with gametocytogenesis, virulence, and proliferation. Our findings point to a hitherto unrecognized functional role for host S1P-mediated sphingolipid signaling in modulating PfHDAC-1's enzymatic activity and, as a result, the parasite's dynamic genome-wide transcriptional patterns. The epigenetic regulation of parasite proliferation and sexual differentiation offers a novel approach for developing host-targeted therapeutics to combat malaria resistance to conventional regimens. IMPORTANCE Sphingolipid is an 18-carbon amino-alcohol-containing lipid with a sphingosine backbone, which when phosphorylated by sphingosine kinase 1 (SphK-1), generates sphingosine-1-phosphate (S1P), an essential lipid signaling molecule. Dysregulation of S1P function has been observed in a variety of pathologies, including severe malaria. The malaria parasite Plasmodium acquires a host S1P pool for its growth and survival. Here, we describe the molecular attuning of histone deacetylase-1 (PfHDAC-1), a crucial epigenetic modulator that contributes to the establishment of epigenetic chromatin states and parasite survival, in response to S1P binding. Our findings highlight the host lipid-mediated epigenetic regulation of malaria parasite key genes.

Miller Fisher syndrome associated with COVID 19.

Miller Fisher syndrome (MFS), is an acute peripheral neuropathy, a variant of Guillain-Barre syndrome, that develops following exposure to different viral, bacterial, and fungal pathogens. Patients usually present with a triad of ophthalmoplegia, ataxia, and areflexia. During Covid pandemic MFS has been described associated with novel coronavirus disease 2019 (COVID-19). Here we describe the clinical course, Cerebrospinal fluid (CSF) findings, nerve conduction studies, treatment and outcome of the patient having MFS concurrent with COVID 19.

Delineating meta-quantitative trait loci for anthracnose resistance in common bean (Phaseolus vulgaris L.).

Anthracnose, caused by the fungus Colletotrichum lindemuthianum, is one of the devastating disease affecting common bean production and productivity worldwide. Several quantitative trait loci (QTLs) for anthracnose resistance have been identified. In order to make use of these QTLs in common bean breeding programs, a detailed meta-QTL (MQTL) analysis has been conducted. For the MQTL analysis, 92 QTLs related to anthracnose disease reported in 18 different earlier studies involving 16 mapping populations were compiled and projected on to the consensus map. This meta-analysis led to the identification of 11 MQTLs (each involving QTLs from at least two different studies) on 06 bean chromosomes and 10 QTL hotspots each involving multiple QTLs from an individual study on 07 chromosomes. The confidence interval (CI) of the identified MQTLs was found 3.51 times lower than the CI of initial QTLs. Marker-trait associations (MTAs) reported in published genome-wide association studies (GWAS) were used to validate nine of the 11 identified MQTLs, with MQTL4.1 overlapping with as many as 40 MTAs. Functional annotation of the 11 MQTL regions revealed 1,251 genes including several R genes (such as those encoding for NBS-LRR domain-containing proteins, protein kinases, etc.) and other defense related genes. The MQTLs, QTL hotspots and the potential candidate genes identified during the present study will prove useful in common bean marker-assisted breeding programs and in basic studies involving fine mapping and cloning of genomic regions associated with anthracnose resistance in common beans.

The Assessment of Fatigue in Rheumatoid Arthritis Patients and Its Impact on Their Quality of Life.

Introduction: Rheumatoid arthritis (RA) is a common autoimmune illness that manifests mostly as chronic, symmetric, and progressive polyarthritis with a global frequency of 0.3−1.0%. RA is a disease that affects people all over the world. In India, the prevalence is estimated to be 0.7%, with around 10 million persons suffering from RA. Most people with rheumatoid arthritis experience fatigue on most days, with over 70% experiencing symptoms similar to chronic fatigue syndrome. Patients rate fatigue as a top priority and believe this unmanageable symptom is ignored by clinicians; a systematic review shows the biological agents for RA inflammation have only a small effect on fatigue. Fatigue predicts and reduces the quality of life, and it is as difficult to cope with as pain. Physicians have traditionally concentrated on the inflammatory aspects of the illness (e.g., synovitis), whereas RA patients have prioritized pain, exhaustion, sleep difficulties, and other quality-of-life issues. Aims and Objectives: The basic aim of the study was to access the incidence of fatigue in rheumatoid arthritis and evaluate its impact on the quality of life in these patients using the MAF scale (multidimensional assessment of fatigue) after prior permission for the first time in an Asian population. Results: A total of 140 subjects and 100 controls were included in the study. Age was closely matched between the study subjects and controls. Among study subjects with the disease, 94 (67%) had a disease duration ≤ 5 years, 26 (19%) had a disease duration between 6−10 years, 10 (7%) had a duration of 11−15 years and 10 (7%) had >10 years disease duration. Among the sample, 31 (25%) study subjects had a DAS score ≤ 4.0, 63 (50%) study subjects had a DAS score (disease activity score) between 4.01 and 6.0, and in the remaining 31 (25%) study subjects, the DAS score was >6.0. The mean DAS score among study subjects was 4.96, and the study subjects had a mean activity of daily living (ADL) score of 11.64; controls had a mean score of 2.42 with a statistically significant p-value. The global fatigue index was higher in study subjects, with a mean of 33.16 in contrast with a mean of 14.41 in the controls with a significant p-value. Conclusion: Our study fatigue was a persistent problem, despite treatment. The median level of fatigue experienced by study subjects with RA was high. Therefore, as persistent fatigue is associated with functional loss, fatigue in RA remains an 'unmet need' and continues to be ignored by clinicians.

G6PD deficiency: imbalance of functional dichotomy contributing to the severity of COVID-19.

Human COVID-19 has affected more than 491 million people worldwide. It has caused over 6.1 million deaths and has especially perpetrated a high number of casualties among the elderly and those with comorbid illnesses. COVID-19 triggers a pro-oxidant response, leading to the production of reactive oxygen species (ROS) as a common innate defense mechanism. However, ROS are regulated by a key enzyme called G6PD via the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which controls the generation and removal of ROS in a tissue-specific manner. Therefore, a deficiency of G6PD can lead to the dysregulation of ROS, which causes a severe inflammatory response in COVID-19 patients. This report highlights the G6PD dichotomy in the regulation of ROS and inflammatory responses, as well as its deficiency in severity among COVID-19 patients.

Interleukin 32 gene promoter polymorphism: A genetic risk factor for multiple sclerosis in Kashmiri population.

OBJECTIVE: Although the exact cause of multiple sclerosis is not known, there are a number of factors involved mainly environmental and genetic factors. The present study was done to determine association between IL-32 gene promoter polymorphism and IL-32 levels with multiple sclerosis. METHODS: 48 relapsing remitting multiple sclerosis patients and 60 healthy controls were compared for IL-32 gene promoter polymorphism and IL-32 levels. RESULTS: There was no significant difference in genotype CT between the MS patients and healthy controls (p 0.130) where as a significant difference in genotype (CC) frequencies among MS patients and healthy controls (p 0.039) was observed. The difference in C allele frequency was also statistically significant between two study groups (p 0.01). Multivariate regression analysis revealed that the CC genotype might impact the risk of disease susceptibility up to 3.71 times and the presence of C allele might increase the risk of susceptibility to multiple sclerosis by 2.26 fold. The serum IL-32 levels were not statistically different multiple sclerosis patients and healthy controls and between wild and mutant genotypes. CONCLUSIONS: IL-32 gene promoter polymorphism is a genetic risk factor for multiple sclerosis patients particularly women.

Obesity as an Important Marker of the COVID-19 Pandemic.

INTRODUCTION: In December 2019, the emergence of the new coronavirus disease 2019 (COVID-19) began in Wuhan, China. Thereafter, the disease has been spreading rapidly across the world, with about 300 million registered cases worldwide, and the numbers are also exponentially increasing in India, with about 34 million registered cases by the end of 2021. Among the comorbidities, obesity may increase the risk of hospitalization due to COVID-19 infection as it is related to immune system dysfunction. Since the epidemiological picture of COVID-19 is changing very rapidly. Therefore, it is very important to discuss the pattern of clinical manifestation and association with comorbidities. Hence, we have conducted this observational study in one of the tertiary care centers in North India.  Methods and Materials: We conducted a hospital-based prospective observational study in dedicated COVID-19 wards and ICU of a tertiary care center in North India with a sample size of 400 positive patients (males: 260, females: 140). We divided the patients in this study into three different age groups (less than 40 years, 40-60 years, and more than 60 years). The patients with age ≤ 18 years and BMI 18.5 kg/m2 were excluded from the study.  Results: Out of these 400 patients, 55 (13.8%) developed severe COVID-19. There was a fewer number of patients who developed severe COVID-19 in the normal and over-weight group. Moreover, obese patients progressed to more severe cases (34.5%). This also shows that after adjusting for age, compared to the normal-weight group, those who were overweight had a 1.48-fold chance of developing severe COVID-19 (OR 1.48, P 0.0455), while those who were obese had a 1.73-fold chance of developing the disease (ORs 1.73, P 5 0.0652). Regarding gender distribution, the association appeared to be stronger in men than in women. After similar adjustment, the ORs for overweight and obese patients compared to normal-weight patients were 1.39 (p 0.5870) and 3.55 (p 0.0113) in females and 1.36 (0.5115) and 6.19 (0.0001) in males, respectively.  Conclusion: Our study shows that obese patients with a BMI of greater than or equal to 27.5 are at higher risk of developing COVID-19 severity, especially in the male population. Moreover, severity may be related to other comorbid conditions. However, in our study, patients with chronic obstructive pulmonary disease (COPD) and GI/liver diseases were less obese, and severity was relatively low. So, the conclusion is that obese male patients with comorbidities are more likely to develop severe COVID-19 infection.

Isolated neurobrucellosis-characteristic clinical and laboratory features.

To report various neurological syndromes, CSF findings, imaging and diagnostic methods used in neurobrucellosis patients admitted in our Neurology department over a period of 6 years. Case records of patients admitted to our department from August 2014 to May 2020 were searched for neurobrucellosis and data were obtained. A total of 19 patients were diagnosed as neurobrucellosis over a period of 6 years. Ten patients had chronic meningitis, five had VIII nerve involvement, one had optic neuritis, two had acute meningitis, one had subacute meningitis, four had myelopathy, five had polyradiculitis and two had spondylodiscitis. CSF was abnormal in 17 patients. Neutrophilic pleocytosis was seen in 12 patients who included nine patients with chronic symptomatology. Brain imaging was abnormal in three chronic meningitis patients. One had diffuse meningeal enhancement, another had hydrocephalus while the third patient had meningeal enhancement with basal exudates and contrast enhancement of bilateral VIII nerve. One of the patients of acute meningitis had hydrocephalus while the other one had bilateral T2/FLAIR hyperintensities with enhancement of meninges and leptomeningeal vessels. Elevated antibody titers only in serum was seen in six patients while elevated antibody titers only in CSF was seen in seven patients. Four patients had elevated antibody titers in both serum and CSF. CSF culture was positive in three patients. Neurobrucellosis is a rare clinical complication of brucellosis but may pose a problem in diagnosis as it can mimic tuberculosis. Involvement of VIII nerve and neurophilic pleocytosis in CSF despite chronic symptomatology can be diagnostic clues favoring neurobrucellosis.

Role of glucose 6-phosphate dehydrogenase (G6PD) deficiency and its association to Autism Spectrum Disorders.

Autism Spectrum Disorder (ASD) is a common group of neurodevelopmental disorders which causes significant alterations in social and communication skills along with repetitive behavior and limited interests. The physiological understanding of ASD is ambiguous. Several reports suggested that environmental, genetic and epigenetic changes, neuroinflammation, mitochondrial dysfunction and metabolic alterations orchestrate the pathological outcomes of ASD. A recent report from Saudi Arabia found a mutation in X-chromosomal housekeeping glucose 6-phosphate dehydrogenase (G6PD) gene in two male ASD patients. Although, the involvement of G6PD-deficiency in the pathogenesis of ASD is poorly understood. Several reports suggested that G6PD deficiency impedes cellular detoxification of reactive oxygen species (ROS), which may result in neuronal damage and neuroinflammation. A deficiency of G6PD in newborn children may play a fundamental role in the pathogenesis of ASD. In this review, we will discuss the implications of G6PD deficiency in pathogenesis, male biasness and theranostics in ASD patients.

Clinico-radiological and Pathological Characteristics of Inflammatory Myofibroblastic Tumors in Children: A Retrospective Study.

PURPOSE: Inflammatory myofibroblastic tumors (IMTs) are rare, benign lesions most often seen in the lung of young adults but can occur in children, in various sites. They mimic, clinically and radiologically, malignant tumors - especially sarcomas and lymphomas. The aim was to review the clinical, radiological, and pathological data of children with a diagnosis of IMT referred to our department. MATERIALS AND METHODS: This retrospective study was conducted at the Department of Medical and Paediatric Oncology, Regional Cancer Centre, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India from January 2014 to December 2015. RESULTS: Among 288 pediatric tumors registered during the study, 5 (1.73%) had the diagnosis of IMTs. The main symptoms were abdominal distension and pain in 60% (three cases), breathlessness and cough in 20% (one case), and right axillary area swelling in 20% (one case). In three patients, complete surgical excision was done, whereas another patient with retroperitoneal mass had the residual disease and received chemotherapy followed by complete second surgery. In the case of mediastinal IMT, surgery was followed by local radiotherapy. At present, four patients are disease-free and one patient with mediastinal IMT has the residual progressive disease. CONCLUSION: On presentation, IMT can constitute a formidable challenge, from diagnosis through to treatment.

Uncommon Adverse Effects of Commonly Used Chemotherapeutic Agents in Medical Oncology Practice: A Series of Two Cases of Hand-Foot Syndrome.

Chemotherapy has an increasing potential for cure and palliation of most forms of cancer in different stages. However, its use is associated with a multitude of side effects some very common and few very rare. We present two patients of metastatic nonsmall lung cancer who had severe forms of hand-foot syndrome with two different classes of antineoplastic drugs and have to discontinue chemotherapy.

Novel risk factors and early detection of anti tubercular treatment induced liver injury-Looking beyond American Thoracic Society Guidelines.

INTRODUCTION: ATT remains the standard treatment for tuberculosis. Drug-induced liver injury (DILI) has been a long-standing concern in the treatment of tuberculosis (TB) infection. AIMS AND OBJECTIVES: To study the occurrence and risk factors of DILI in patients on ATT by regular clinical and biochemical monitoring. MATERIALS AND METHODS: 200 patients, in whom ATT was started, were enrolled in the study. None of the patients with established risk factor for DILI as recognized by ATS guidelines was included in our study population. Regular clinical and liver function test monitoring was done at the commencement of ATT and then at 2, 4, and 8 weeks in the intensive phase subsequently at 4 and 6 months. RESULTS: DILI developed in 16 patients. Among those, 10 patients (62.5%) developed early DILI and 6 patients (37.5%) developed late DILI. Female gender and extrapulmonary tuberculosis were found to be associated with increased risk of ATT-induced DILI, whereas age, BMI, and serum albumin were not found to significantly increase DILI risk. CONCLUSION: DILI is a common problem among patients on ATT in our population. Early detection not only reduces the risk of developing Hepatic Failure but also prevents mortality.