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Sodium benzoate is one of the widely used food preservatives and its metabolism in the human body has been studied only with the host perspective. Despite the human gut microbiome being considered as a virtual human organ, its role in benzoate metabolism is yet to be elucidated. The current study uses a multi-omic approach to rationalize the role of human gut microbes in benzoate metabolism. Microbial diversity analysis with multiple features synchronously indicates the dominance of Bacteroidetes followed by Firmicutes, Actinobacteria, and Proteobacteria. Metagenomic exploration highlights the presence of benzoate catabolic protein features. These features were mapped on to the aerobic and anaerobic pathways of benzoate catabolism. Benzoate catabolism assays identified statistically significant metabolites ( P  < 0.05) associated with the protocatechuate branch of the beta-ketoadipate pathway of the benzoate metabolism. Analysis of the 201 human gut metagenomic datasets across diverse populations indicates the omnipresence of these features. Enrichment of the benzoate catabolic protein features in human gut microbes rationalizes their role in benzoate catabolism, as well as indicates food-derived microbiome evolution.

The Autism Dysmorphology Measure is designed for non-expert clinicians. It uses an algorithm to assess 12 body regions and categorizes Autism on the number of dysmorphic regions identified; Essential (≤ 3), Equivocal (4–5) or Complex (≥ 6). We evaluated 200 Indian children with Autism (mean age 3.7 years) in a hospital-based cross-sectional study and compared inter-group profiles. We found 31% Essential, 49% Equivocal and 20% Complex Autism. On comparing results with existing literature, it appeared that genetic ancestry and age significantly influenced dysmorphism and hence categorization. No significant differences were observed between complex and essential autism in epilepsy, severity of autism or development, as reported earlier. These shortcomings make the present tool unsuitable for use in young Indian children with Autism.

Abstract INTRODUCTION: Patients with tuberculosis (TB) may have depression as a comorbidity, which may be associated with poor treatment outcomes. Increased production of pro-inflammatory cytokines activating enzyme indoleamine 2,3-dioxygenase (IDO) has been reported in TB. We studied the association of IDO activity and comorbid depression in TB patients. MATERIALS AND METHODS: Newly diagnosed, treatment-naïve TB patients were evaluated for symptoms of depression using the Patient Health Questionnaire (PHQ)-9 scale. A PHQ-9 score of ≥5 was taken as an indicator for depression. Patients were further categorized into two groups based on their PHQ-9 scores, Group-I with a PHQ-9 score of <5 and Group-II with a PHQ-9 score ≥5. The serum kynurenine (KYN) and tryptophan (TRP) levels were determined using liquid chromatography-mass spectrometry (LC-MS) and the KYN/TRP ratio was taken as a measure for IDO activity. RESULTS: A total of 106 TB patients and 106 healthy controls were enrolled in this study. Over 73.5% of TB patients had PHQ-9 scores of above 5 with an average score of 7.09 ± 2.83, a significant difference (P < 0.05) as compared to the average PHQ-9 scores of healthy controls (2.93 ± 1.20). Group-II TB patients had lower serum TRP 539.55 ± 194.31 ng/mL versus 1109.45 ± 186.04 ng/mL (P < 0.01) in Group-I; higher serum KYN 425.81 ± 65.51 ng/mL versus 250.06 ± 40.28 ng/mL (P < 0.01) and higher K/T ratio 0.906 ± 0.56 versus 0.251 ± 0.052 (P < 0.01). There was a significant linear correlation between PHQ-9 and serum KYN (r: 0.969; P: <0.01; R2: 0.909); serum TRP (r: 0.841; P: <0.01; R2: 0.745); and KYN/TRP ratio (r: 0.745; P < 0.01; R2: 0.618). CONCLUSION: These findings suggest that in TB patients, induction of IDO activity may be relevant to the development of comorbid depression.

Background: Biodosimetry is the quantification of absorbed radiation dose using biological material obtained from an exposed individual. Radiation can cause different types of chromosomal aberrations, including stable aberrations like translocations and unstable ones like micronuclei, dicentric chromosomes (DC), acentric, and ring forms. Dicentric chromosome assay has become the \"gold standard\" for cytogenetic biodosimetry due to its reproducibility, specificity (low baseline rates), and sensitivity to low doses. Using existing calibration curves and models obtained from in vitro irradiation of blood, the yield of DCs can be used to estimate the average whole-body absorbed dose. Purpose: To evaluate and compare the in vivo dose-response relation of DC aberration formation in peripheral blood lymphocytes of head and neck cancer (HNC) patients undergoing radiotherapy (RT) alone, cisplatin-based chemoradiation (CCRT), accelerated fractionation RT (AFRT), and CCRT with gefitinib (GCRT). Methodology: This prospective observational and analytical study was conducted from 2018 to 2021 in the Department of Radiation Oncology and Genetic Lab of tertiary care, teaching hospital after approval from the Institutional Ethics Committee. Biodosimetric analysis was done weekly in patients undergoing RT (n = 20) versus CCRT (n = 20), CCRT (n = 12) versus AFRT (n = 12), and CCRT (n = 6) versus GCRT (n = 6). The yield of DCs was measured in blood samples taken before starting treatment, that is, day 0 and during RT on days 6, 11, and 16 in RT alone versus CCRT; on days 7 and 13 in CCRT versus AFRT; and days 6 and 11 in CCRT versus GCRT from a blood sample drawn 1-2 h after RT. Phytohemagglutinin-stimulated lymphocytes were cultured using heparinized blood in RPMI-1640 medium supplemented with fetal bovine serum. Cells were arrested at metaphase using demecolcine, harvested by centrifugation, mounted, and stained with Giemsa. Cytogenetic analysis was performed by analyzing at least 100 metaphases with well-spread chromosomes. DC aberrations and acentric fragments were identified and recorded. To standardize the findings as per the customized field for every patient, the mean DC yield per cm2 of the irradiated area was calculated and compared. Results: The mean yield of DC/cm2 in the CCRT group was greater than the RT alone group by 16.33%, 28.57%, and 18.68% on days 6, 11, and 16 of treatment, respectively. This difference between the two groups at day 6 (P = 0.001), day 11 (P < 0.001), and day 16 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the AFRT group by 7.9% and 18.3% on days 7 and 13 of treatment, respectively. This difference at day 7 (P < 0.001) and day 13 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the GCRT group by 22.7% and 21.8% on days 6 and 11 of treatment, respectively. The difference at day 6 (P = 0.01) was statistically significant but, on day 11 (P = 0.065) this difference was found insignificant. Conclusion: There is a dose-dependent increase in the yield of DCs in lymphocytes of HNC patients undergoing RT with subsequent fractions. Cisplatin-based chemoradiation is the superior method of treatment intensification radio-biologically proven by higher DC yield.

Background Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort ( N  = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases ( N  = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy ( N  = 291/885, 32.9%), trinucleotide repeat expansion disorders ( N  = 242/885; 27.3%) and spinal muscular atrophy ( N  = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia ( N  = 120/149, 80.5%) and cystic fibrosis ( N  = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease ( GBA :c.1448T > C), β-thalassemia ( HBB :c.92.+5G > C), non-syndromic hearing loss ( GJB2 :c.71G > A), albinism ( TYR :c.832 C > T), congenital adrenal hyperplasia ( CYP21A2 :c.29–13 C > G) and progressive pseudo rheumatoid dysplasia ( CCN6 :c.298T > A) were observed in the present study. Conclusion The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Integrating health interventions in a growing economy like India, with a birth cohort of 27 million/year, one-fifth of all childbirths, and approximately one-third of neonatal deaths globally, is a challenge. While mortality statistics are vital, intact survival and early preventive healthcare, such as newborn screening (NBS), are paramount. The appalling lack of information about the precise burden of metabolic errors at the state/national level or a mandated program encouraged a feasibility study of NBS in a prospective newborn cohort recruited in Delhi State (November 2014–April 2017) using a public–private partnership mode. The major determinants for effective implementation of universal NBS at the national level and limitations encountered are discussed in this report. Data to generate the ‘core’ panel for screening, sustained training of healthcare personnel, dissemination of the power of NBS to ensure neonatal/societal health to the public, and a ‘national policy’ emerge as priorities in a developing country.

BackgroundC-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models.MethodsExome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.ResultsTwo homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.ConclusionIn conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Background Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase ( GBA1 ) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients. Methods The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients’ whole GBA gene coding region using bidirectional Sanger sequencing. Results The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes. Conclusions The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.

To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. Detailed phenotyping and next-generation sequencing (panel and exome). Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello–Carey syndrome–like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

ABSTRACT Background and Aims: Genetic polymorphisms contribute to patients' variability in pain perception and response to opioid treatment. The present study evaluated the association of calcitonin gene-related peptide (CGRP) 4218T/C polymorphisms with fentanyl consumption over 24 h postoperatively in patients after major abdominal surgery. Methods: Eighty-five patients undergoing major abdominal surgery under general anaesthesia were recruited. For postoperative analgesia, epidural fentanyl and intravenous paracetamol were provided. The CGRP 4218T/C genotype was analysed, and the association between the genotype of the patient and the total consumption of fentanyl in the first 24 h after surgery was assessed. The association between different genotypes, the severity of postoperative pain and the side effects of opioids were also studied. Results: Our study population distribution included 52.9% of the T/T genotype (wild homozygote), 35.3% of the T/C genotype (heterozygote) and 11.8% of the C/C genotype (mutant homozygote). Mean (standard deviation) total fentanyl consumption in the first 24 h was found to be highest in the C/C group (212.0 [7.5] μg), followed by the T/T group (182.8 [9.9] μg) and was the least in the T/C group (159.6 [7.5] μg). The C/C group reported higher pain scores in all the study periods. There was no significant difference in the side effects of opioids, such as nausea, vomiting, sedation among different genotypes of CGRP 4218T/C. Conclusion: The polymorphism of CGRP 4218T/C affects postoperative pain perception and analgesic consumption. Patients with the C/C genotype had higher postoperative fentanyl consumption and pain scores.