New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy.

We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides-Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be associated with Nicolaides-Baraitser syndrome and adds to chromatin remodeling as a pathway for epileptogenesis. © 2016 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

Beryllium-10 in australasian tektites: evidence for a sedimentary precursor.

Each of seven Australasian tektites contains about 1 x l0(8) atoms of beryllium-10 (half-life, 1.53 x 10(6) years) per gram. Cosmic-ray bombardment of the australites cannot have produced the measured amounts of beryllium-10 either at the earth's surface or in space. The beryllium-10 contents of these australites are consistent with a sedimentary precursor that adsorbed from precipitation beryllium-10 produced in the atmosphere. The sediments must have spent several thousand years at the earth's surface within a few million years of the tektite-producing event.

A rapid appraisal of functioning of district programme management units under NRHM in Madhya Pradesh.

OBJECTIVES: To study the functioning of District Programme Management Units in the delivery of health services in various districts of Madhya Pradesh. METHODOLOGY: A cross-sectional descriptive study was conducted in seven districts of Madhya Pradesh selected randomly. The study subjects were Chief Medical and Health Officers, programme managers, assistant managers and data officers at state and district levels. Datawas collected from the respondents in a pre-designed, pre-tested in-depth interview schedule. RESULTS: Around 70% of districts submitted their Programme Implementation Plan (PIP) on time, 30% were unable to do so because of inadequate staff and frequent changing of the reporting format. The District Programme Managers (DPMs) were not satisfied with their fixed salary. But they were satisfied with their job. In some districts the space available for the functioning of District Programme Management Unit (DPMU) are rather too small. CONCLUSION: Standardized uniform formats and guidelines should be made available to all DPMUs at the beginning of planning process. A comprehensive pre-service training for the DPMU staff including practical sessions, field exposure on district health planning, financial management, technical and administrative issues needs to be ensured.

Screening for diabetes among tuberculosis patients registered under revised national tuberculosis control program, Bhopal, India.

CONTEXT: Tuberculosis (TB) and diabetes mellitus (DM) remain a global public health problem. India has the largest number of TB cases; in 2015, out of total global annual incidence of 9.6 million TB cases, 2.2 million were estimated from India. There are 62.4 million people with type 2 diabetes and 77 million people with prediabetes in India, and these numbers are projected to increase to 101 million by the year 2030. Diabetes and TB affect each other at many levels. Screening for diabetes in patients with TB will not only help in early case detection but also better management of both comorbidities. AIMS: (i) To determine the prevalence of diabetes and prediabetes among diagnosed cases of TB registered under RNTCP in Bhopal district. (ii) To determine additional yield of previously unknown DM and the number needed to screen (NNS) to find out a new case of DM. (iii) To find out the factors associated with diabetes among patients diagnosed with TB registered under RNTCP in Bhopal district. SETTINGS AND DESIGN: This study was a cross-sectional study conducted on registered patients with TB under RNTCP in two TB units of Bhopal district. MATERIALS AND METHODS: Participants were contacted and interview was conducted after obtaining consent using predesigned and pretested performa during the period of 1st October 2014 to 30th March 2015 for a period of 6 months. STATISTICAL ANALYSIS USED: Continuous variable were summarized as frequency, mean, and standard deviation. All variables were analyzed using Chi-square test of significance; P < 0.05 was taken as statically significant. RESULT: Of the total 528 patients with TB, 296 was male and 232 were female. Of the total, 63 (11.9%) patients were diagnosed as diabetic. NNS to diagnose a new case of DM was 22.1. Significant association was found with six variables which are age, sex, body mass index, type of TB, category of TB, and smoking. CONCLUSION: This study shows feasibility and importance of screening of patients with TB in existing program settings.

A Survey of Deaf Mutes.

BACKGROUND: Detection of hearing loss at birth or early childhood is difficult. This bears on the rehabilitation of the child as the golden period of learning is lost. Reliable statistics relating the average age for detection of hearing loss and fitting of hearing aids in children are not available in our country. A survey of 52 deaf mutes was therefore conducted to ascertain the probable causes that lead to deafness. METHODS: The study subjects were 42 deaf mutes from the Government run school for deaf mutes and 10 from ASHA School run by the Army Wives Welfare Association. A questionnaire prepared in Hindi was filled by the parents and data analysed. RESULTS: The average age of detection of hearing loss was 2.8 years and the average age for receiving a hearing aid was 7.6 years. Thus due to the significant reduction of sensory input at the 'golden period of learning' only 50% of those fitted with a hearing aid found it useful. In 42.3% the cause of deafness could not be identified. CONCLUSION: Greater emphasis is required on early diagnosis of childhood deafness and fitment of hearing aid.

Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.

Mutations in the N-methyl-D-aspartate receptor (NMDAR) gene GRIN2A cause epilepsy-aphasia syndrome (EAS), a spectrum of epileptic, cognitive and language disorders. Using bioinformatic and patient data we shortlisted 10 diverse missense mutations for characterisation. We used high-throughput calcium-flux assays and patch clamp recordings of transiently transfected HEK-293 cells for electrophysiological characterization, and Western blotting and confocal imaging to assay expression and surface trafficking. Mutations P79R, C231Y, G483R and M705V caused a significant reduction in glutamate and glycine agonist potency, whilst D731N was non-responsive. These mutants, along with E714K, also showed significantly decreased total protein levels and trafficking to the cell surface, whilst C436R was not trafficked at all. Crucially this reduced surface expression did not cause the reduced agonist response. We were able to rescue the phenotype of P79R, C231Y, G483R and M705V after treatment with a GluN2A-selective positive allosteric modulator. With our methodology we were not able to identify any functional deficits in mutations I814T, D933N and N976S located between the glutamate-binding domain and C-terminus. We show GRIN2A mutations affect the expression and function of the receptor in different ways. Careful molecular profiling of patients will be essential for future effective personalised treatment options.

Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). CONCLUSIONS: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Antibacterial activity of Cuscuta reflexa stem and Corchorus olitorius seed.

The methanol extracts of Cuscuta reflexa stem and Corchorus olitorius seed showed a broad spectrum of antibacterial activity.

Clinical characteristics of renal cell carcinoma: Five years review from a tertiary hospital in Eastern India.

BACKGROUND: Renal cell carcinoma (RCC) is the one of the dreadful urological carcinoma. In comparison to the West, it is very rarely seen in Asia as well in India. Very small number of studies is available in this geographical area. AIMS: We studied the demographic pattern, presentation, risk factors and survival of RCC in an Eastern Indian institution. We characterized and compared these data with available literature Settings and Design: Retrospective study. MATERIALS AND METHODS: A total of 81 patients of RCC from January 2008 to December 2012 were enrolled. Their pre-operative data were reviewed. They were followed as per institutional follow-up protocol. STATISTICAL ANALYSIS USED: Kaplan-Meier plot was constructed for survival analysis. Comparison of survival curves was performed by Logrank test. P < 0.05 was considered to be significant. RESULTS: A total of 75 patients were analyzed with a mean follow-up of 26.3 ± 17.7 months. The mean age of presentation in our study was 52.79 years with a peak at 5th decade. Nearly 73.33% patients having one or more risk factors. 9 out of 10 had presented with some symptoms. The survival for localized RCC was 100% and significantly greater than advanced RCC (P < 0.0001). Similarly in the stage III, significant greater survival (P < 0.0001) was noted compare to stage IV. CONCLUSIONS: The age of presentation of RCC in India has been found in 5th decade, which is a decade earlier than the western countries. Symptomatic RCC is still majority in India. Organ confined tumors have good prognosis. When it metastasizes to lymph node or distant organ, the outcome is poor. Our results may form the basis for further studies and it may be used as future reference.

Effect of misspecification of gene frequency on the two-point LOD score.

In this study, we used computer simulation of simple and complex models to ask: (1) What is the penalty in evidence for linkage when the assumed gene frequency is far from the true gene frequency? (2) If the assumed model for gene frequency and inheritance are misspecified in the analysis, can this lead to a higher maximum LOD score than that obtained under the true parameters? Linkage data simulated under simple dominant, recessive, dominant and recessive with reduced penetrance, and additive models, were analysed assuming a single locus with both the correct and incorrect dominance model and assuming a range of different gene frequencies. We found that misspecifying the analysis gene frequency led to little penalty in maximum LOD score in all models examined, especially if the assumed gene frequency was lower than the generating one. Analysing linkage data assuming a gene frequency of the order of 0.01 for a dominant gene, and 0.1 for a recessive gene, appears to be a reasonable tactic in the majority of realistic situations because underestimating the gene frequency, even when the true gene frequency is high, leads to little penalty in the LOD score.

Methodologic issues in assessing risk factors for epilepsy in an epidemiologic study in India.

OBJECTIVES: To test a field questionnaire for epilepsy risk factors in rural India. BACKGROUND: Case-control studies are necessary to plan appropriate prevention and intervention strategies against epilepsy but difficult to mount in developing countries for various logistic and cultural reasons. Recent studies have proposed nutritional and infective risk factors not reported in Western studies. METHODS: A structured questionnaire including known and putative risk factors was administered to parents of 61 children with epilepsy and 59 randomly selected population control subjects in rural West Bengal. ORs of effect were calculated using a multiple logistic regression model with 95% CIs. RESULTS: Socioeconomic status, febrile convulsions, and reproductive history were easily assessable. Ages, dates, and some proxy infection markers were unreliable. Febrile convulsions were an independent risk factor (OR 6.45; 95% CI, 1.45 to 28.66). Associations with family history and infective symptoms were suggested. No association was demonstrated with socioeconomic status or reproductive factors. CONCLUSIONS: Known risk factors were confirmed, and novel factors were suggested. A retrospective questionnaire does not allow accurate study of infective exposures. Greater statistical power is needed to study weaker associations and interacting effects.

Comparison of key informant and survey methods for ascertainment of childhood epilepsy in West Bengal, India.

BACKGROUND: This study aimed to compare efficacy and cost of key informants and survey for ascertainment of childhood epilepsy within a treatment context in rural India. METHODS: The study was set in a non-governmental, community programme for the functional and socioeconomic rehabilitation of children with disabilities in rural West Bengal, India. Ascertainment was by two methods: house-to-house survey of 15000 households and also by 430 key informants including village leaders, health workers and 670 schoolchildren. Methods were compared for positive predictive value, and sensitivity by capture-recapture technique. Ninety four children were enrolled into treatment. Predictors of treatment success were determined by multiple logistic regression analysis, giving adjusted odds ratios for remission. The costs of identifying one case and one treatment success were measured by costing personnel, materials and overheads. RESULTS: The survey was four times as sensitive as key informants although the positive predictive values were similar (36%, 40%). The survey had an absolute sensitivity of only 59%. Identification by key informants strongly predicted successful treatment outcome (odds ratio [OR] = 4.74, 95% confidence interval [CI] : 1.19-18.85). The cost of finding one case was US$11 and US$14, and of finding one successful treatment outcome US$35 and US$67 for informants and survey respectively. Key informants were essential in attaining longer term programme objectives. CONCLUSIONS: In the context of a treatment programme, key informants were the more cost-effective method, but community involvement was traded against low sensitivity in the short term. Overall ascertainment costs were significant in the context of primary health care in India.

PIP: Epilepsy is the most important neurological problem in developing countries, with a total of 50 million people worldwide having the condition. 33 million of these cases are children in developing countries, of whom 90% are untreated. To determine the number of children with active epilepsy in a given developing country community, previous studies have either ascertained information directly from key informants in the community or through more broad-based two-stage surveys. Findings are reported from a study conducted in 46 villages of district 24 Parganas South, a rural district south of Calcutta, comparing the two approaches' sensitivity, efficacy, and costs. Village leaders, health workers, and students were interviewed as key informants, while house-to-house surveys were conducted in 15,000 households. The survey was 4 times as sensitive as the key informant approach, although the approaches had similar positive predictive values. The survey had an absolute sensitivity of 59%. Case identification by key informants strongly predicted successful treatment outcomes. The cost of finding 1 case was US$11 and US$14, and of finding one successful treatment outcome US$35 and US$67 for informants and survey, respectively. The use of key informants was essential to attaining longer-term program objectives.

Quality of life assessment in children: a review of conceptual and methodological issues in multidimensional health status measures.

STUDY OBJECTIVE: To clarify concepts and methodological problems in existing multidimensional health status measures for children. DESIGN: Thematic review of instruments found by computerised and manual searches, 1979-95. SUBJECTS: Nine health status instruments. MAIN RESULTS: Many instruments did not satisfy criteria of being child centered or family focussed; few had sufficient psychometric properties for research or clinical use; underlying conceptual assumptions were rarely explicit. CONCLUSIONS: Quality of life measures should be viewed cautiously. Interdisciplinary discussion is required, as well as discussion with children and parents, to establish constructs that are truly useful.

Neonatal hypoglycaemia in Nepal 1. Prevalence and risk factors.

AIMS: To measure the prevalence of hypoglycaemia among newborn infants in Nepal, where classic risk factors prevail, and to evaluate their importance. METHODS: A cross sectional study was done of 578 term newborn infants aged 0 to 48 hours on the postnatal wards of a government maternity hospital in Kathmandu, with unmatched case-control analysis of risk factors for moderate hypoglycaemia (less than 2.0 mmol /l). RESULTS: Two hundred and thirty eight (41%) newborn infants had mild (less than 2.6 mmol/l) and 66 (11%) moderate hypoglycaemia. Significant independent risk factors for moderate hypoglycaemia included postmaturity (OR 2.62), birthweight under 2.5 kg (OR 2.11), small head size (OR 0.59), infant haemoglobin >210 g/l (OR 2.77), and raised maternal thyroid stimulating hormone (TSH) (OR 3.08). Feeding delay increased the risk of hypoglycaemia at age 12-24 hours (OR 4.09). Disproportionality affected the risk of moderate hypoglycaemia: lower with increasing ponderal index (OR 0.29), higher as the head circumference to birthweight ratio increased (OR 1.41). Regression expressing blood glucose concentration as a continuous variable revealed associations with infant haemoglobin (negative) and maternal haemoglobin (positive), but no other textbook risk factors. CONCLUSIONS: Neonatal hypoglycaemia is more common in a developing country, but may not be a clinical problem unless all fuel availability is reduced. Some textbook risk factors, such as hypothermia, disappear after controlling for confounding variables. Early feeding could reduce moderate hypoglycaemia in the second 12 hours of life. The clinical significance of raised maternal TSH and maternal anaemia as prenatal risk factors requires further research.

Neonatal hypoglycaemia in Nepal 2. Availability of alternative fuels.

AIMS: To study early neonatal metabolic adaptation in a hospital population of neonates in Nepal. METHODS: A cross sectional study was made of 578 neonates, 0 to 48 hours after birth, in the main maternity hospital in Kathmandu. The following clinical and nutritional variables were assessed: concentrations and age profiles of blood glucose, hydroxybutyrate, lactate, pyruvate, free fatty acids (FFA) and glycerol; associations between alternative fuel levels and hypoglycaemia; and regression of possible risk factors for ketone availability. RESULTS: Risk factors for impaired metabolic adaptation were common, especially low birthweight (32%), feeding delays, and cold stress. Blood glucose and ketones rose with age, but important age effects were also found for risk factors like hypothermia, thyroid hormone activities, and feeding practices. Alternative fuel concentrations, except FFA, were significantly reduced in infants with moderate hypoglycaemia during the first 48 hours after birth. Unlike earlier studies, small for gestational age (SGA) infants had significantly higher hydroxybutyrate:glucose ratios which suggested counter regulatory ketogenesis. Hypoglycaemic infants were not hyperinsulinaemic. Regression analysis showed risk factors for impaired counter regulation which included male and large infants, hypothermia, and poorer infant thyroid function. SGA infants and those whose mothers had received no antenatal care had increased counter regulation. CONCLUSIONS: Alternative fuels are important in the metabolic assessment of neonates, and they might provide effective cerebral metabolism even during moderate hypoglycaemia. Hypoglycaemic infants generally had lower concentrations of alternative fuels through either reduced availability or increased consumption. SGA and post term infants increased counter regulatory ketogenesis with early neonatal hypoglycaemia, but hypothermia, male gender, and low infant T4 were associated with impaired counter regulation after birth.

Association of enterotoxigenic Bacteroides fragilis with childhood diarrhoea.

This study was conducted in a hospital setting to determine whether enterotoxigenic strains of Bacteroides fragilis (ETBF) were associated with childhood diarrhoea. ETBF was isolated from 6 (2.6%) of 226 patients and 3 (1.7%) of 172 controls and was found mostly in children between 1-5 yr of age. The syndrome associated with ETBF was secretory in nature with watery diarrhoea and of mild severity. ETBF may be associated with diarrhoeal illness in children but is not a major problem in this part of the country.

Case-control and qualitative study of attrition in a community epilepsy programme in rural India.

Dropout from epilepsy programmes is a serious problem in developing countries and has not been systematically studied before. We set up a community-based programme for children with epilepsy in rural India. The aim of this study was to assess reasons for dropout. We assessed medical and sociodemographic variables for their effect on dropout at 12 months using an unmatched case-control design on 32 cases and 62 controls. We also interviewed the parents of 32 children who dropped out of treatment, using a topic schedule. Two-thirds of the dropouts occurred within the first 6 months of treatment. Severely impaired children were more likely to drop out (odds ratio 4.60, 95% CI: 1.0-21.0) and families who had tried AEDs before were less likely to do so (odds ratio 0.12, 95% CI: 0.015-0.88). Denial of diagnosis, access problems and symptom resolution were the other main reasons underlying attrition. Active ascertainment methods should be reconsidered in community programmes. Very poor families without a male head or with long journey times are at high risk of dropout. People with severe impairments need appropriate integrated rehabilitation.

Onset of puberty and ovarian steroidogenesis following adminstration of methanolic extract of Cuscuta reflexa Roxb. stem and Corchorus olitorius Linn. seed in mice.

The effect of methanolic extract (ME) of Cuscuta reflexa stem Roxb. and Corchorus olitorius Linn. seed on the onset of reproductive maturity and the ovarian steroidogenesis was studied by means of biochemical techniques. ME of Cuscuta reflexa stem and Corchorus olitorius seed treatment causes a remarkable delay in sexual maturation as evidenced by the age at vaginal opening and appearance of first estrus (cornified smear). The same treatment also results in a significant diminution of Delta(5)-3beta-hydroxysteroid dehydrogenase (HSD) and glucose-6-phosphate dehydrogenase (G-6-PD) activity along with a reduction in the weight of ovary, uterus and pituitary. On the basis of above data, it is assumed that the probable cause of delayed maturation in ME of Cuscuta reflexa stem and Corchorus olitorius seed treated mice is due to the suppressed ovarian steroidogenesis.

Synthesis of a new ion exchanger, zirconium vanadate, and its application to the separation of barium and cesium radionuclides at tracer levels.

A new inorganic ion exchanger, zirconium vanadate, has been synthesized and characterized. Elemental analysis suggests that the probable formula of the compound is ZrO2, V2O5, 2H2O. The exchanger is highly stable in thermal, radiation and chemical environments. Radiochemical separation schemes for the 134Cs and 133Ba pair and also for separating the short-lived daughter 137Ba from its parent 137Cs using this newly synthesized ion exchanger have been developed.

Separation of 90Y from 90Sr using zirconium vanadate as the ion exchanger.

The sorption and desorption behaviour of several radionuclides, including 241Am, 152,154Eu, 233U, 137Cs, 90Sr and 90Y was studied under varying acidities using zirconium vanadate as ion exchanger. The sorption follows the order: Cs > Eu > Am >Y > U, while Sr was not taken up by the ion exchanger. A radiochemical separation scheme for the 90Y daughter from its 90Sr parent using zirconium vanadate ion exchanger has been developed. The exchanger was synthesized and characterized in our laboratory.