Clinical factors and vascular endothelial growth factor as determinants of disease progression in Indian patients with amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Prognostication remains sub-optimally defined. We aimed to assess clinical determinants of disease progression rates in Indian patients with ALS and to assess the role of vascular endothelial growth factor (VEGF) in disease progression. METHODS: In this cross-sectional study, consecutive patients with clinically definite/probable ALS according to the revised El Escorial criteria and controls were included. Patients were classified into fast or slow progressors based on disease progression rate (DPR). Serum and CSF VEGF level was assessed for patients and controls. RESULTS: Of 142 patients recruited, 93 (65.5%) were male. Mean age at enrollment was 49.37 ± 12.65 years. Mean duration of symptoms was 20.53 ± 20.88 months. Mean DPR was 1.14 ± 0.94. Based on DPR, 81 (57%) patients were slow progressors and 61 (43%) were fast progressors. Univariate analysis demonstrated a statistically significant association of DPR with age at onset, symptom duration, time to spread, wasting of small muscles of the hand, frontal release signs, and neurophysiologic bulbar abnormalities. On multivariate analysis, age at onset and symptom duration had a significant association with disease progression. The CSF VEGF levels of ALS patients (46.18 ± 27.8) were significantly elevated compared to controls (25.95 ± 25.64 pg/ml) (p = 0.001), but not serum VEGF. CONCLUSION: Age at symptom onset and duration of disease had a significant impact on disease progression in Indian patients with ALS. CSF VEGF levels were significantly elevated in ALS compared to controls, indicating the role of CSF VEGF as a potential biomarker.

Val66Met polymorphism and BDNF levels in Alzheimer's disease patients in North Indian population.

Analysis of serum brain-derived neurotrophic factor (BDNF) levels in Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI) and controls with BDNF gene polymorphism and cognitive function were investigated. The study recruited 63 AD patients, 15 aMCI and 63 age- and sex-matched healthy controls from All India Institute of Medical Sciences, New Delhi, India. Patients with AD (12268.3 ± 7099.9 pg BDNF/ml) and aMCI (10780 ± 4184.2 pg BDNF/ml) had higher serum levels than had the controls (9362.833 ± 5883.32 pg BDNF/ml). Significant difference in BDNF levels was not found between the three groups. No significant difference was obtained between BDNF genotype and allele distribution between AD patients, aMCI versus controls; genotypic frequency: Chi-square = 3.21; p-value = 0.20 and allelic frequency: Chi-square = 0.412, p-value = 0.521, df = 1 (AD vs controls); Chi-square = 1.63, p-value = 0.201, df = 1 (aMCI vs controls). In conclusion, val66met polymorphism and BDNF serum level between the three groups and genotype did not significantly affect the serum BDNF level or age, Mini-Mental State Examination score in AD and aMCI. Further studies are necessary to elucidate the kinetics and the potential role of serum BDNF as a marker of disease progression in AD patients.

Correlation of serum SARS-CoV-2 IgM and IgG serology and clinical outcomes in COVID-19 patients: Experience from a tertiary care centre.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a pandemic for the last 2 years. Inflammatory response to the virus leads to organ dysfunction and death. Predicting the severity of inflammatory response helps in managing critical patients using serology tests IgG and IgM. AIM: To investigate the correlation of the serology (IgM and IgG) with reverse transcriptase polymerase chain reaction (RT-PCR) status, disease severity [mild to critical], intensive care unit (ICU) admission, septic shock, acute kidney injury, and in-hospital mortality. METHODS: We conducted a longitudinal study to correlate serum SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) serology with clinical outcomes in coronavirus disease 2019 (COVID-19) patients. We analyzed patient data from March to December 2020 for those who were admitted at All India Institute of Medical Sciences Rishikesh. Clinical and laboratory data of these patients were collected from the e-hospital portal and analyzed. A correlation was seen with clinical outcomes and was assessed using MS Excel 2010 and SPSS software. RESULTS: Out of 494 patients, the mean age of patients was 48.95 ± 16.40 years and there were more male patients in the study (66.0%). The patients were classified as mild-moderate 328 (67.1%), severe 131 (26.8%), and critical 30 (6.1%). The mean duration from symptom onset to serology testing was 19.87 ± 30.53 d. In-hospital mortality was observed in 25.1% of patients. The seropositivity rate (i.e., either IgG or IgM > 10 AU) was 50%. IgM levels (AU/mL) (W = 33428.000, P ≤ 0.001) and IgG levels (AU/mL) (W = 39256.500, P ≤ 0.001), with the median IgM/ IgG levels (AU/mL), were highest in the RT-PCR-Positive group compared to RT-PCR-Negative clinical COVID-19. There was no significant difference between the two groups in terms of all other clinical outcomes (disease severity, septic shock, ICU admission, mechanical ventilation, and mortality). CONCLUSION: The study showed that serology levels are high in RT-PCR positive group compared to clinical COVID-19. However, serology cannot be useful for the prediction of disease outcomes. The study also highlights the importance of doing serology at a particular time as antibody titers vary with the duration of the disease. In week intervals there was a significant correlation between clinical outcomes and serology on week 3.

Association of SUMOylation Pathway Genes With Stroke in a Genome-Wide Association Study in India.

OBJECTIVE: To undertake a genome-wide association study (GWAS) to identify genetic variants for stroke in an Indian population. METHODS: In a hospital-based case-control study, 8 teaching hospitals in India recruited 4,088 participants, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed with logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked. RESULTS: Associations of vascular risk factors with stroke were similar to previous reports and show modifiable risk factors such as hypertension, smoking, and alcohol consumption as having the highest effect. Single-marker-based association revealed 2 loci for cardioembolic stroke (1p21 and 16q24), 2 for small vessel disease stroke (3p26 and 16p13), and 4 for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at p < 5 × 10-8. The index single nucleotide polymorphism of 1p21 is an expression quantitative trait locus (p lowest = 1.74 × 10-58) for RWDD3 involved in SUMOylation and is associated with platelet distribution width (1.15 × 10-9) and 18-carbon fatty acid metabolism (p = 7.36 × 10-12). In gene-based analysis, we identified 3 genes (SLC17A2, FAM73A, and OR52L1) at p < 2.7 × 10-6. Eleven of 32 candidate gene loci studied in an Indian population replicated (p < 0.05), and 21 of 32 loci identified through previous GWAS replicated according to directionality of effect. CONCLUSIONS: This GWAS of stroke in an Indian population identified novel loci and replicated previously known loci. Genetic variants in the SUMOylation pathway, which has been implicated in brain ischemia, were identified for association with stroke.

Intravenous fluid regimen and hyponatraemia among children: a randomized controlled trial.

The aim of this study was to compare the effect of three different intravenous (i.v.) fluid regimes on the incidence of hyponatraemia in hospitalized children ranging in age from 3 months to 12 years. Children who required the administration of i.v. maintenance fluid for at least 24 h following hospitalization were eligible for inclusion. The children were randomized to three i.v. fluid groups: Group A, 0.9% saline in 5% dextrose at the standard maintenance rate; Group B, 0.18% saline in 5% dextrose at the standard maintenance rate; Group C, 0.18% saline in 5% dextrose at two-thirds of the standard maintenance rate. The primary outcome measure was incidence of hyponatraemia (plasma sodium < 130 mEq/L). Of the 167 patients enrolled, 58, 56 and 53 patients were randomized to Group A, B and C, respectively. We observed that 14.3% (8/56) of the children administered 0.18% saline in 5% dextrose at the standard maintenance rate (Group B) developed hyponatraemia compared with 1.72% of the children in Group A and 3.8% of those in Group C. Based on these results, we conclude that the administration of 0.9% saline in 5% dextrose as i.v. maintenance fluid helps in reducing the incidence of hospital-acquired hyponatraemia among children.

Apolipoprotein-E genotypes and myasthenia gravis.

Autoimmune myasthenia gravis (MG) is a disorder of neuromuscular junction. Possible role of multiple genes in the development of the MG has been documented. This case-control study, studied the association of apolipoprotein E (Apo-E) alleles with MG. Anti-AChR antibody was measured using radio receptor immunoassay. Apo-E genotypes were analyzed in 120 MG patients and 120 healthy subjects. Comparison between patients with MG and controls showed no significant association with Apo-E allelic variants. However, a significant association of Apo-E4 allele with AChR-antibody positive patients was observed (P = 0.007). Also, among seropositive patients, a significant association was seen between female gender and Apo-E4 allele (P = 0.023). Our results suggest that the presence of Apo-E4 allele might influence seropositive status in patients with MG and seems an associated susceptible factor in female patients.

Myocardial cell injury is common in children with septic shock.

OBJECTIVE: To determine the prevalence of myocardial cell injury in children with septic shock by estimating the levels of biochemical markers of myocardial injury, troponin I (TnI) and creatine kinase MB (CK-MB). PATIENTS: Children aged 3 months to 16 years were admitted to paediatric intensive care unit (PICU) with septic shock. Children with sepsis without shock and children with hypovolaemic shock were enrolled as controls. MEASUREMENTS AND MAIN RESULTS: Serum TnI and CK-MB levels were measured at admission and serially at 24 h, 48 h and 96 h in children with septic shock, while baseline measurement of the same markers was taken from the controls. In total, 88% (15/18) of children with septic shock had elevated TnI levels compared with 25% (5/20) with sepsis and 6.7% (1/15) with hypovolaemic shock (p < 0.001). Serial TnI levels at admission, 24 h, 48 h and 96 h were higher in the nonsurvivors. There was a positive correlation between the baseline TnI levels and the predicted mortality using the paediatric index of mortality (PIM2) scores at admission (r = 0.51, p = 0.03). CONCLUSION: A majority of children with septic shock have evidence of myocardial cell injury. The estimation of serum TnI levels may help in better prognostication of children with septic shock.

Adrenal status in children with septic shock using low-dose stimulation test.

OBJECTIVES: There is paucity of data on the magnitude of absolute or relative adrenal insufficiency in septic shock, especially in children. We conducted a prospective study to determine the prevalence of adrenal insufficiency in children with septic shock using a low-dose Synacthen (1 microg) stimulation test. DESIGN: Cross-sectional study. SETTING: Pediatric intensive care unit in a tertiary care hospital in northern India. PATIENTS: Children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed cortisol estimation at baseline and after low-dose Synacthen (1 microg) stimulation at 30 and 60 mins in children with fluid refractory septic shock admitted to our pediatric intensive care unit. Basal cortisol levels <7 microg/dL and peak cortisol level <18 microg/dL were used to define adrenal insufficiency. An increment of <9 microg/dL after stimulation was used to diagnose relative adrenal insufficiency. As there is lack of consensus on the cutoffs for defining relative adrenal insufficiency using the low-dose adrenocorticotropic hormone test, we evaluated different cutoff values (increment at 30 mins, increment at 60 mins, greater of the two increments) and evaluated their association with the incidence of catecholamine refractory shock and outcomes. Children with sepsis but without septic shock were sampled for baseline cortisol levels as a comparison. Thirty children (15 girls) with septic shock were included; median age (95% confidence interval) was 36.5 (9.39- 58.45) months. Median Pediatric Risk of Mortality score was 22.5 (14.13-24.87). Fifteen (50%) children survived. The median (95% confidence interval) cortisol values at baseline and 30 mins and 60 mins after stimulation were 71 (48.74-120.23) microg/dL, 78.1 (56.9-138.15) microg/dL, and 91 (56.17-166.44) microg/dL, respectively. The median baseline cortisol value in age- and gender-matched children with sepsis was 11.5 microg/dL. None of the children with septic shock fulfilled the criteria for absolute adrenal insufficiency. However, nine (30%) patients had relative adrenal insufficiency (increment in cortisol <9 microg/dL). Of these nine patients, five (56%) died; of the 21 patients with a greater increment in cortisol after stimulation, ten died (p = .69). Compared with patients in septic shock with normal adrenal reserve, those with relative adrenal insufficiency had a higher incidence of catecholamine refractory shock (p = .019) but no difference in mortality rate (p = .69). On the sensitivity and specificity analysis using various cutoffs of increment, the best discrimination for catecholamine refractory shock was obtained with a peak increment <6 microg/dL. CONCLUSIONS: Relative adrenal insufficiency is common in children with septic shock and is associated with catecholamine refractory shock.

Serial circulating vasopressin levels in children with septic shock.

BACKGROUND: Septic shock is an important cause of death in pediatric intensive care units. Initial evaluations have shown that vasopressin may have a role in catecholamine refractory shock in adults. It is important to determine whether children with septic shock have deficiency of vasopressin. This will help in defining the role of vasopressin in septic shock. DESIGN: Prospective cohort study. SETTING: Pediatric intensive care unit of a tertiary care hospital in north India. PATIENTS: Patients were children with septic shock, and controls were children with sepsis but no shock. STUDY DESIGN: Vasopressin levels in plasma were determined by enzyme-linked immunosorbent assay for children with septic shock at diagnosis (baseline) and thereafter at 24, 48, and 96 hrs to determine the time trends. The baseline vasopressin values for children with septic shock were compared with those for children without shock. RESULTS: The median (95% confidence interval) vasopressin level at baseline in children with septic shock was 116 (63.3-130.7) pg/mL, and in children with sepsis but no shock it was 106 (61.7-131.77) pg/mL. The median value for survivors was 76 (44.6-130.9) pg/mL, and for nonsurvivors, 118 (81.7-259) pg/mL (p = .16). The serial values also did not show any significant changes; the values at 24 hrs (n = 17), 48 hrs (n = 16), and 96 hrs (n = 15) were 105 (76.1-125.9), 105 (41.4-155.5), and 109.5 (54.9-154.8) pg/mL, respectively. CONCLUSIONS: The results of our study suggest that vasopressin levels are elevated in children with septic shock and that serial values up to 96 hrs do not show any decline.

Relationship between polymorphisms in beta -2 adrenergic receptor gene and ischemic stroke in North Indian Population: a hospital based case control study.

BACKGROUND: Stroke is a multi-factorial disease and influenced by both genetic and environmental factors. The purpose of the present case control study was to check the relationship between beta-2 adrenergic receptor (ADRB2) polymorphism and ischemic stroke in North Indian Population. METHODS: In a hospital based case control study, patients with ischemic stroke and control subjects from outpatient department and neurology ward of All India Institute of Medical Sciences New Delhi. Genotyping was performed by using Polymerase chain reaction-Restriction fragment length polymorphism. Frequency distributions of genotypes and alleles were compared between cases and controls using multivariate logistic regression. RESULTS: In this study, 224 patients and 224 age-and sex-matched control subjects were recruited. Mean age of cases and controls were 53.9 ± 13.4 and 53.6 ± 12.9 years respectively. Multivariate logistic regression analysis showed an independent association between Gln27Glu polymorphism and large vessel stroke (LVD) under a recessive model of inheritance (OR 3.9; 95% CI 1.3 to 11). An age-stratified analysis, suggested independent association between Gln27Glu polymorphism and ischemic stroke, large vessel disease and small vessel disease stroke who had onset of disease at an older age. CONCLUSIONS: The findings of the present study suggest that Gln27Glu polymorphism of the ADRB2 gene may confer higher risk of large vessel disease stroke in a North Indian population. Prospective studies with larger sample size are required for independent validation.

Genetic polymorphism of drug metabolizing enzymes (GSTM1 and CYP1A1) as risk factors for oral premalignant lesions and oral cancer.

AIMS: Polymorphisms in the genes that code for metabolic enzymes involved in either the activation (Phase I) or detoxication (Phase II) of chemical carcinogens in tobacco, may alter expression or function of carcinogenic compounds and hence alter risk of oral cancer. The present study investigates whether polymorphisms at CYP1A1 and GSTM1 gene loci act as risk factors for oral precancerous lesions and cancer. METHODS: For the present study, histopathologically confirmed cases of 90 oral precancerous lesions, 150 oral squamous cell carcinoma (SCC) and 150 control subjects were selected. Polymerase chain reaction and restriction fragment length polymorphism were performed using DNA from blood samples to determine the polymorphic genotypes at CYP1A1 and GSTM1 loci. RESULTS: CYP1A1 C (m2/m2) genotype conferred a 12.0 fold-increased risk (OR=12.0; 95% CI, 2.40-60.05) to oral SCC. GSTM1 null showed no significant association but the frequency was higher in oral SCC cases. Patients with genotype C and/or GSTM1 deficiency developed carcinoma after less tobacco consumption than those of other genotypes though the difference was not statistically significant. The frequency of the combined genotypes C and GSTM1 null was found to be 14% among oral SCC patients. On comparing the susceptibility of intraoral sites it was found that in the majority of cases (64%) in the study groups they were the buccal mucosa. CONCLUSION: Hence it was concluded that metabolic enzymes reported in the present study: CYP1A1 significantly alter oral cancer risk. GSTM1 null and CYP1A1 C (m2m2) show a predisposition to premalignant lesions and cancer of the buccal mucosa than other sites.