We tested 3 ild Asian elephants (Elephas maximus) in southern India and confirmed infection in 3 animals with Mycobacterium tuberculosis, an obligate human pathogen, by PCR and genetic sequencing. Our results indicate that tuberculosis may be spilling over from humans (reverse zoonosis) and emerging in wild elephants.

Introduction:A paucity of literature exists on genotype-phenotype correlates of 'unknown-etiology' infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE Methods:An observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016)(2017)(2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented. Results:Pathogenic/likely pathogenic variants were identified in 26 (31.7%) out of 82 children with DEE. These included those variants responsible for primarily DEE-21(76.7%); neuro-metabolic disorders-3(18.6%) and chromosomal deletions-2(4.7%). Of these patients, early-infantile epilepsy onset ≤ 6months age was noted in 22(84.6%). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50% (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3% (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67% (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32% (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N=33) had variants in SCN1A (N=10), SCN1B, CHD2; yield of 36.4% (12/33 tested; 57.1% from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy. Conclusions:Our study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.

bWe report the annotated genome sequence of two clinical isolates of Mycobacterium tuberculosis isolated from Kerala, India.

ABSTRACTThe success ofMycobacterium tuberculosisdepends on its ability to withstand and survive the hazardous environment inside the macrophages that are created by reactive oxygen intermediates, reactive nitrogen intermediates, severe hypoxia, low pH, and high CO2levels. Therefore, an effective detoxification system is required for the pathogen to persistin vivo. The genome ofM. tuberculosiscontains a new family of hemoproteins named truncated hemoglobin O (trHbO) and truncated hemoglobin N (trHbN), encoded by theglbOandglbNgenes, respectively, important in the survival ofM. tuberculosisin macrophages. Mycobacterial heat shock proteins are known to undergo rapid upregulation under stress conditions. The expression profiles of the promoters of these genes were studied by constructing transcriptional fusions with green fluorescent protein and monitoring the promoter activity in both free-living and intracellular milieus at different time points. WhereasglbNshowed an early response to the oxidative and nitrosative stresses tested,glbOgave a lasting response to lower concentrations of both stresses. At all time points and under all stress conditions tested,groEL2showed higher expression than both trHb promoters and expression of both promoters showed an increase while inside the macrophages. Real-time PCR analysis of trHb andgroEL2mRNAs showed an initial upregulation at 24 h postinfection. The presence of theglbOprotein imparted an increased survival toM. smegmatisin THP-1 differentiated macrophages compared to that imparted by theglbNandhsp65proteins. The comparative upregulation shown by both trHb promoters while grown inside macrophages indicates the importance of these promoters for the survival ofM. tuberculosisin the hostile environment of the host.

Background: Sporadic nonlesional intractable visual-sensitive epilepsies of childhood represent a challenging subset of epilepsies in terms of management and prognostication given a propensity to evolve as epileptic encephalopathy. Objective: To study the genetic heterogeneity of drug-resistant visual sensitive epilepsy of childhood. Methods: A retrospective chart review was conducted on patients in the pediatric age group between 2016 and 2018, with drug-resistant epilepsy (DRE) and video electro encephalography (VEEG) documented reflex photosensitivity, eye-condition sensitivity. Those patients who underwent genetic testing with targeted next-generation sequencing using an epilepsy gene panel were selected. Results: During the study period, out of 96 patients who underwent genetic testing, 4 patients (4.17%) with sporadic DRE presented with clinical phenotypes ranging from myoclonic-atonic epilepsy, generalized epilepsy with eyelid myoclonia as well as febrile and unprovoked seizures, along with visual sensitivity. Video EEG documented abnormalities ranged from occipital, posterior-cortex and generalized discharges with “eyes-closed state” triggered, self-induced “smart-phone” triggered, photosensitive focal-onset and generalized myoclonic seizures. Accompanying developmental impairment was noted. These patients who were investigated with clinical exome sequencing were detected to have mutations in not only SCN1A genes (pathogenic exonic and intronic variants) but also CHD2 (pathogenic) and CACNA1H genes (a familial febrile-seizure susceptibility variant of unknown significance). Conclusions: The series highlights the complex genetics of drug-resistant visual-sensitive epilepsy of childhood. Such genotype–phenotype associations throw light on the role of ion-channel and non-ion channel genes on reflex epileptogenesis in this group of patients.