Identification of effective drug targets in treating Glutaric aciduria type 1 disease

Glutaric aciduria type I (GA‐I) is an autosomal recessive cerebral organic aciduria,caused by a defective GCDH enzyme. This protein lies in the common final catabolic pathway of L‐lysine, L‐hydroxy lysine and L‐tryptophan. Individuals possessing GCDH enzyme deficiency are biochemically characterized by the accumulation of neurotoxic metabolites glutaryl‐CoA, GA, 3‐OH‐GA as well as non‐toxic C5DC in their tissues and body fluids. If untreated, most of the individuals develop an acute encephalopathic crisis causing striatal damage during a finite period of brain growth, resulting in complex movement disorder with predominant dystonia, most commonly between 3 months to 3 years of age. Individuals, diagnosed before the onset of irreversible neurologic symptoms can be prevented from striatal damage, if they are treated with a special diet consisting of low L‐lysine content,supplementation with carnitine and essential amino acids as well as emergency treatment on demand. Even though the currently followed metabolic treatment is predicted to be safe and effective, a significant number of patients still suffer from striatal damage despite early diagnosis and treatment. In addition, recent findings report on extra‐striatal, extra cerebral and non‐neurologic abnormalities despite the current regimen followed. This highlights the prerequisite for the discovery of novel,safe and more efficient long‐term treatment strategies. In this thesis, we hypothesize that pharmacological inhibition of upstream enzymatic steps of the lysine degradation pathway, prior to GCDH, will prevent toxic metabolite accumulation and, consequently, induction of clinical disease phenotype in Glutaric aciduria Type I. To this end, Dehydrogenase E1 and transketolase domain containing 1 (DHTKD1)(approach1) and Aminoadipate amino transferase (AADAT) (alternate approach 2) are targeted and our hypothesis is tested in genetically modified cell models,Glutaric aciduria type I patient cell lines, and knockout mouse models. We therefore,developed a Dhtkd1‐/‐/ Gcdh‐/‐ mouse model and studied its characteristics biochemically and clinically after giving high lysine (4.7% (w/w) or 235mg of Llysine in food) in diet. Our studies showed that DHTKD1 knockout was unable to rescue GA‐I phenotype in Dhtkd1+/+/ Gcdh‐/‐ mice as seen by the accumulated GA levels on GCMS measurement. Since our in vivo data strongly suggested that DHTDK1 is not a suitable drug target in GA‐I, we did not proceed with drug testing.Next, we evaluated the commercially available, patented AADAT inhibitor PF04859989 in GCDH‐deficient cells. Indeed, the inhibitor treatment significantly reduced GA accumulation in these cells. Overall this thesis suggests that,pharmacological inhibition of AADAT is a novel therapeutic strategy for GA‐I

A Cross-Sectional Study on Knowledge about Swine Flu among First-Year MBBS Students in Mamata Medical College, Khammam

Introduction: An outbreak of the H1N1 swine flu virus, in march 2009, spread rapidly through the world, leading to the declaration of an influenza pandemic by WHO on 11th June 2009.Objective: To assess the knowledge about swine flu among first-year MBBS students.Materials and Methods: A cross-sectional study was conducted among first-year MBBS students of Mamata Medical College, Khammam, Telangana, during April 2015. Data were collected by using pilot-tested, self-administered questionnaire and results were analyzed by using SPSS version 19.Results: Majority 110 (96.5%) of the students are having correct knowledge regarding symptoms of swine flu. Around 58 (50.9%) students are having knowledge regarding spread/ mode of transmission of swine flu. Majority 74 (64.9%) of the students are having knowledge regarding availability of medication for swine flu.Conclusion: The awareness regarding H1N1 infection was adequate among the students who participated in this study and this can be attributed to the immediate training given to these students as well as to the mass media campaign which is important in epidemic situations to avoid its spread and complication

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Schizophrenia – Insight, Depression: A Correlation Study

Background: Schizophrenia is one of the severe forms of mental illness which demands enormous personal and economical costs. Recent years have attracted considerable interest in the dual problem of depression in schizophrenia and its relation to insight. Most clinicians believe that poor insight in patients with schizophrenia, though problematic for treatment adherence, may be protective with respect to suicide. The assumption is that patients who do not believe that they are ill are less likely to be suicidal. Alternatively, those patients with schizophrenia who recognize and acknowledge the illness will be more of a suicidal nature. Aim of the Study: The aim of the study is to find out the correlation between insight and depression in schizophrenic population. Materials and Methods: This study is a cross-sectional, single-centred, correlation study done in a total of 60 subjects. Inclusion Criteria - Subjects between 20-60 years, who were diagnosed to have schizophrenia as per International clasification of diseases-10 and who have given written consent to participate in the study. Exclusion Criteria - Subjects who have other diagnosis such as mood disorder, schizoaffective disorder, mental retardation, epilepsy or detectable organic disease and co morbid substance abuse are excluded from the study. Schizophrenics who have acute exacerbation are also excluded. Instruments - For insight assessment, schedule for assessment of insight, a three item rating scale, is used. For depressive symptoms assessment a nine item rating scale, Calgary depression rating scale, is administrated. Results: Insight and depression are strongly correlated in schizophrenic population with a Pearson correlation coefficient of 0.758. The correlation between insight and depression is high in subjects with less duration of illness. Conclusion: Better insight was significantly correlated with lower mood. In addition, it suggests that poor insight may protect against depression in the early stages of recovery from schizophrenia.The correlation between insight and depression is high in subjects with less duration of illness