Effect of telmisartan on sub-acute model of inflammation in male Wistar rats - an experimental study

Background: Cardiovascular diseases remain the major cause of death and premature disability in developed societies.Current predictions estimate that by the year 2020 cardiovascular diseases, notably atherosclerosis and hypertension will become leading global causes of total disease burden. The objective of the study was to investigate the influence of telmisartan on sub-acute model of inflammation in adult male Wistar rats.Methods: After obtaining ethical clearance from Institutional Animal Ethics Committee, animals were allotted to the three groups i.e. control, aspirin and telmisartan (n=6 animals in each group). The effect of telmisartan on inflammation was studied using sub-acute (Cotton pellet granuloma and histopathologic examination of grass piths) models. Experiment was conducted according to the Committee for the purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines. Analysis was done using one way ANOVA followed by post hoc tests of Dunnett’s and Bonferroni’s. P<0.05 was considered as statistically significant.Results: In the present study telmisartan showed significant anti-inflammatory activity in sub-acute models of inflammation.Conclusions: In view of role of inflammation in the pathogenesis of atherosclerosis and their complications, treatment by telmisartan can reduce complications by virtue of its anti-inflammatory activity, in addition to its antihypertensive effect. Also this study may help to open new avenues for therapeutic indications of telmisartan.

Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study

Introduction: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. Methods: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as “poor” (κ ≤ 0.4), “moderate” or “good” (κ > 0.6). Results: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. Conclusion: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust

The India brain infections guidelines project: Global evidence for local application.

Background Brain infections are a major cause of morbidity and mortality globally. India lacks systematically evidence-informed guidelines for brain infections. Methods We had set up a group of experts in brain infections, evidence synthesis and guideline development to produce guidelines for hospital clinicians diagnosing and treating patients with suspected and confirmed brain infections in India. Questions are being drafted and prioritised, and a plan for GRADE-informed evidence synthesis and guideline development is in place, using methods to increase efficiency of the process where possible. Dissemination and outputs The guidelines will be disseminated through publication as well as on a dedicated website. Training of clinicians in evidence synthesis and guideline development, and setting up a network of institutions and professional societies, will provide lasting impact in terms of national capacity strengthening

CAG Repeats Determine Brain Atrophy in Spinocerebellar Ataxia 17: A VBM Study

Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17).To determine whether specific structural brain degeneration and rate of disease progression in SCA17 might be associated with the CAG repeat size, observer-independent voxel-based morphometry was applied to high-resolution magnetic resonance images of 16 patients with SCA17 and 16 age-matched healthy controls. The main finding contrasting SCA17 patients with healthy controls demonstrated atrophy in the cerebellum bilaterally. Multiple regression analyses with available genetic data and also post-hoc correlations revealed an inverse relationship again with cerebellar atrophy. Moreover, we found an inverse relationship between the CAG repeat length and rate of disease progression.Our results highlight the fundamental role of the cerebellum in this neurodegenerative disease and support the genotype-phenotype relationship in SCA17 patients. Genetic factors may determine individual susceptibility to neurodegeneration and rate of disease progression

Managing hyperemesis gravidarum: a multimodal challenge

Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Movement disorders of probable infectious origin

Background: Movement disorders (MDs) associated with infections remains an important debilitating disorder in the Asian countries. Objectives: The objective of the following study is to report the clinical and imaging profile of a large cohort of patients with MDs probably associated with infection. Materials and Methods: This was a chart review of 35 patients (F:M-15:20) presenting with MD in the Neurology services of National Institute of Mental Health and Neurosciences, India. The demographic profile, type of infection, time from infection to MD, phenomenology of MD and magnetic resonance imaging (MRI) findings were reviewed. Results: The mean age at presentation was 22.6 ± 13.3 years, (5-60), age of onset of MD was 15.7 ± 15 years, and duration of symptoms was 6.9 ± 8.1 years (42 days to 32 years). The mean latency of onset of MD after the infection was 5.9 ± 4.2 weeks. The phenomenology of MD were: (1) Pure dystonia-28.6%, (2) dystonia with choreoathetosis-22.9%, (3) Parkinsonism-14.6%, (4) pure tremor, hemiballismus, myoclonus and chorea-2.9% each, and (5) mixed MD-22.9%. Most often the MD was generalized (60%), followed by right upper limb (31.4%) and left upper limb (8.6%). A viral encephalitic type of neuroinfection was the most common infection (85.7%), which was associated with MD. Abnormalities of brain MRI, seen in 79.2%, included signal changes in (1) thalamus-52.0%, (2) putamen and subcortical white matter-16% each, (3) pons-12%, (4) striatopallidum, striatum and grey matter-8% each, and (5) caudate, cerebellum, lentiform nucleus, midbrain and subthalamic nucleus-4.0% each. Conclusions: MDs associated with infection were the most often post-encephalitic. Dystonia was the most common MD, and thalamus was the most common anatomical site involved

Japanese Encephalitis among Adults: A Review.

Japanese encephalitis (JE) is becoming an increasingly important issue among adults. The reasons for this are multifactorial. During the past decades, new areas of Japanese encephalitis virus (JEV) transmission have occurred in several locations, most notably in a markedly expanded area of Australia during 2021-2022. When JEV enters new areas, cases in adults frequently occur. This is unlike the typical pattern in endemic areas where the burden of disease is in children because most adults are protected through natural immunity following earlier exposure to the virus. Even in endemic areas, JEV has become relatively more important in adults because improved JE control through childhood immunization programs has resulted in a substantial decrease in pediatric JE cases and thus more prominence of adult JE cases. Finally, increases in tourism to JE risk areas have resulted in more exposure of adult travelers, who are usually non-immune, to infection in JE risk areas. In this review we describe the increasing importance of JE in adults in some areas and then consider the comparative clinical presentation and severity of illness among children and adults