Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naïve pluripotent stem cells.

Naïve pluripotent stem cells (nPSC) frequently undergo pathological and not readily reversible loss of DNA methylation marks at imprinted gene loci. This abnormality poses a hurdle for using pluripotent cell lines in biomedical applications and underscores the need to identify the causes of imprint instability in these cells. We show that nPSCs from inbred mouse strains exhibit pronounced strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming to pluripotency and upon culture with MAP kinase inhibitors, a common approach to maintain naïve pluripotency. Analysis of genetically highly diverse nPSCs from the Diversity Outbred (DO) stock confirms that genetic variation is a major determinant of epigenome stability in pluripotent cells. We leverage the variable DNA hypomethylation in DO lines to identify several trans-acting quantitative trait loci (QTLs) that determine epigenome stability at either specific target loci or genome-wide. Candidate factors encoded by two multi-target QTLs on chromosomes 4 and 17 suggest specific transcriptional regulators that contribute to DNA methylation maintenance in nPSCs. We propose that genetic variants represent candidate biomarkers to identify pluripotent cell lines with desirable properties and might serve as entry points for the targeted engineering of nPSCs with stable epigenomes. Highlights: Naïve pluripotent stem cells from distinct inbred mouse strains exhibit variable DNA methylation levels at imprinted gene loci.The vulnerability of pluripotent stem cells to loss of genomic imprinting caused by MAP kinase inhibition strongly differs between inbred mouse strains.Genetically diverse pluripotent stem cell lines from Diversity Outbred mouse stock allow the identification of quantitative trait loci controlling DNA methylation stability.Genetic variants may serve as biomarkers to identify naïve pluripotent stem cell lines that are epigenetically stable in specific culture conditions.

Does application of complexity theory simplify concepts of psychiatry: Analogies and insights.

Scientific curiosity has not been able to explain the cause of psychiatric illness based on primarily biological or social paradigm. Available literatures were explored to understand causality of psychiatric illness from perspective of physics. Theory of complexity and other relevant theories were extrapolated to address these questions. Mental illness appeared to be a complex interplay of reductionism and emergentism, genetic and epigenetics, stress and the vulnerability or the core and the periphery. Mental illness displayed complex interaction between biological trait and environmental state.

Adult attention-deficit Hyperactivity disorder: From clinical reality toward conceptual clarity.

There is ambiguity about the clinical picture and concept of attention-deficit hyperactivity disorder (ADHD) in adults. Relevant literature was extracted from various search engines, analyzed, and interpreted. Available literature suggests a significant prevalence of ADHD in the adult population affecting the quality of socio-occupational functioning. Inattentiveness was more commonly present than hyperactivity-impulsivity. Frequent comorbidities with other psychiatric disorders like anxiety disorders and substance use disorders were noted. Pharmacological management and psychotherapy have been found effective in its management. ADHD is a disorder across the lifespan and fairly prevalent among adults. Greater awareness and more research are required for a better understanding of Adult ADHD and its effective management.

Age at first drink and severity of alcohol dependence.

BACKGROUND: Early age at first drink (AFD) has been linked to early onset and increased severity of alcohol dependence in various studies. Few Indian studies on AFD have shown a negative correlation between AFD and severity of alcohol dependence. Our study aimed to explore this relationship in patients with alcohol dependence syndrome (ADS) diagnosed using ICD-10 criteria. METHODS: One hundred fifty-one consecutive patients freshly diagnosed with ADS were included in the study, which was conducted at the psychiatry unit of a tertiary care, multispecialty hospital. The Addiction Severity Index (ASI) was used to assess severity of alcohol dependence. RESULTS: Mean AFD was 24.85 years (range = 13-40 years). Median ASI score was 36 (range = 21 to 57). The study yielded a weak negative correlation (ρ = -.105) between AFD and ASI, which was statistically not significant. CONCLUSIONS: We found no correlation between AFD and severity of alcohol dependence at detection in Indian Armed Forces personnel, which is contrary to what has been reported worldwide and in previous Indian studies. Delayed initiation of alcohol use among those enrolling in the Indian Armed Forces and early detection of alcohol dependence within the military environment are possible explanations.

First-episode psychosis: How long does it last? A review of evolution and trajectory.

Study of first-episode psychosis (FEP), an episode of psychotic nature which manifests for the first time in an individual in the longitudinal continuum of his/her illness, has been study matter of research interest in recent years. A comprehensive review of the literature will help us understand the evolution and trajectory of this concept better. A literature review of available articles addressing the concept, phenomenology, evolution, identification, course, and outcome of FEP was done; the same was subsequently divided into broad topics for better clarity and analyzed. FEP constituted a clinical psychotic phenomenon with underlying significant heterogeneity in diagnosis, stability, course, and outcome. The study has attempted to view FEP both as horizontal spectrum across various diagnoses and longitudinally ranging from asymptomatic individual with unknown risk status to attenuated psychosis to multiple relapses/unremitting illness. Many risk and protective factors have been brought out with varying certainty ranging bio-psycho-social spectrum. Efforts have been made to calculate polygenic risk score based on genes involvement/sharing between various psychotic spectrum disorders; as well as biomarker panels to identify people at risk. FEP may prove to be an important concept to understand psychosis in general; without putting things into the diagnostic rubric. It may help understand multiple risk and protective factors for the course and outcome of psychotic illness and may clear the cloud to sharpen the evidence toward commonality and distinctiveness between various psychotic diagnoses in vogue for more comprehensive concept.

Is four-dimensional CT angiography as effective as digital subtraction angiography in the detection of the underlying causes of intracerebral haemorrhage: a systematic review.

PURPOSE: To determine whether the sensitivity and specificity of four-dimensional CTA (4D-CTA) are equivalent to digital subtraction angiography (DSA) in the detection of underlying vascular abnormalities in patients with intracerebral haemorrhage (ICH). METHODS: A systematic review of studies comparing 4D-CTA with DSA in the detection of the underlying structural causes of ICH was performed on the literature published between 1998 and 2019. RESULTS: We identified a total of 237 articles from PubMed, SCOPUS and Web of Science using the following Medical Subject Headings (MeSH) terms: primary intracerebral haemorrhage, 4D-CTA, DSA, cerebral haemorrhage, angiography, digital subtraction, arteriovenous malformations, 4D, CTA, dynamic-CTA and time-resolved CTA. Following the removal of duplicate publications and articles failing to meet our inclusion criteria, there were four articles potentially viable for analysis. Therefore, there were not sufficient studies to provide a statistically meaningful meta-analysis. CONCLUSION: The review of current literature has demonstrated that there are few published studies comparing 4D-CTA with DSA in spontaneous ICH, with only four suitable studies identified for potential analysis. However, due to the restricted number of patients and high sensitivity and specificity of 3 studies (100%), performing a meta-analysis was not meaningful. Qualitative analysis of the data concluded that 4D-CTA has the diagnostic potential to replace invasive DSA in certain cases with vascular abnormalities. However, further research studies directly comparing 4D-CTA with DSA using larger prospective patient cohorts are required to strengthen the evidence base.

Role of various lifestyle and behavioral strategies in positive mental health across a preventive to therapeutic continuum.

There is growing interest in lifestyle and behavioral strategies not only in prevention but also in the management of psychiatric morbidity. Available literature in this direction was accessed, and the role of various lifestyle and behavioral factors was explored. There is strong evidence of the role of good sleep, nutritious diet, exercise, social connectedness, enhanced self-esteem, sense of purpose in life, resilience, mindfulness, and environmental mastery in the promotion of mental well-being and prevention and management of psychiatric disorders. There is a significant scope of lifestyle and behavioral intervention in ensuring positive mental health spanning from preventive to therapeutic dimension.

Workplace based assessment: A review of available tools and their relevance.

Workplace-based assessment (WPBA) appears to be a promising tool for more comprehensive assessment of the learners. Relevant literature in this direction was collated and analyzed for its relevance, salience, and merit. Many WPBA tools are being used by various educational institutions which spans across multiple domains and over the entire duration of the workplace learning. It caters to holistic assessment with structured measures, real-time feedback, and continuous professional development. It is being used more for formative assessment and has limited utility in summative assessment as on date. WPBA tools have promising prospect in bringing novelty, objectivity, and holistic approach in assessment.

Intermittent plasticity in individual grains: A study using high energy x-ray diffraction.

Long-standing evidence suggests that plasticity in metals may proceed in an intermittent fashion. While the documentation of intermittency in plastically deforming materials has been achieved in several experimental settings, efforts to draw connections from dislocation motion and structure development to stress relaxation have been limited, especially in the bulk of deforming polycrystals. This work uses high energy x-ray diffraction measurements to build these links by characterizing plastic deformation events inside individual deforming grains in both the titanium alloy, Ti-7Al, and the magnesium alloy, AZ31. This analysis is performed by combining macroscopic stress relaxation data, complete grain stress states found using far-field high energy diffraction microscopy, and rapid x-ray diffraction spot measurements made using a Mixed-Mode Pixel Array Detector. Changes in the dislocation content within the deforming grains are monitored using the evolution of the full 3-D shapes of the diffraction spot intensity distributions in reciprocal space. The results for the Ti-7Al alloy show the presence of large stress fluctuations in contrast to AZ31, which shows a lesser degree of intermittent plastic flow.

Incidence and characteristics of Epidermal Growth Factor Receptor (EGFR) mutation in non-small-cell lung cancer (Adenocarcinoma histology): A report of 106 patients from Kolkata.

CONTEXT: Regional epidemiological data regarding the epidermal growth factor receptor (EGFR) mutation status in non-small-cell lung cancers (NSCLC) is an unmet need from the eastern part of India. AIMS: To report the incidence of EGFR mutation and its correlation with the phenotypical characteristics, in NSCLC patients from Kolkata. SUBJECTS AND METHODS: NSCLC patients, with adenocarcinoma histology, whose tissues had been tested for EGFR mutational status between March 2014 and February 2017, were considered for this study. The testing methods used were Real-time-based amplification refractory mutation system, polymerase chain reaction (ARMS PCR), PCR and gene sequencing, and cell-free DNA (CTDNA). Clinical characteristics and treatment details were collected from the patient's medical records in a de-identified manner. STATISTICAL ANALYSIS USED: Data were analyzed using simple descriptive statistical methods. RESULTS: Between March 2014 and February 2017, 108 samples were tested and two were deemed inadequate for reporting. Of the remaining 106 patients, 65 (61.3%) were males, and 41 (38.6%) were females. Median age was 56 years (42-72), 59 years for males and 52 years for females. 73.6% were nonsmokers. 87.7% tests were done using the real-time ARMS-PCR; 9.4% underwent PCR and gene sequencing and 2.8% using CT-DNA. Of 106 patients, 35 (33%) patients were found to be EGFR mutation positive. Ratio of male:female was 16 (45.7%):19 (54.3%). Ratio of nonsmoker: smoker was 30 (85.7%):5 (14.3%). 18 patients had exon 19 deletion (51.4%), 15 had L858R exon 21 mutation (42.9%), 1 patient (2.9%) had mutation in S7681 exon 20 along with L858R 21 and one patient (2.9%) had a T790m mutation without any other detectable EGFR mutation. CONCLUSIONS: The incidence of EGFR mutation in NSCLC is 33% from Kolkata and is typically more common in females and nonsmokers.

Management of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach.

A phaeochromocytoma (PC) is a rare, catecholamine-secreting neuroendocrine tumour arising from the adrenal medulla. Presenting symptoms of this rare tumour are highly variable but life-threatening multiorgan dysfunction can occur secondary to catecholamine-induced hypertension or hypotension and subsequent cardiovascular collapse. High levels of circulating catecholamines can induce an acute stress cardiomyopathy, also known as Takotsubo cardiomyopathy. Recent studies have focused on early diagnosis and estimation of the prevalence of acute stress cardiomyopathy in patients with PC, but very little is reported about management of these complex cases. Here, we report the case of a 38-year-old lady who presented with an acute Takotsubo or stress cardiomyopathy and catecholamine crisis, caused by an occult left-sided 5 cm PC. The initial presenting crisis manifested with symptoms of severe headache and abdominal pain, triggered by a respiratory tract infection. On admission to hospital, the patient rapidly deteriorated, developing respiratory failure, cardiogenic shock and subsequent cardiovascular collapse due to further exacerbation of the catecholamine crisis caused by a combination of opiates and intravenous corticosteroid. An echocardiogram revealed left ventricular apical hypokinesia and ballooning, with an estimated left ventricular ejection fraction of 10-15%. Herein, we outline the early stabilisation period, preoperative optimisation and intraoperative management, providing anecdotal guidance for the management of this rare life-threatening complication of PC. LEARNING POINTS: A diagnosis of phaeochromocytoma should be considered in patients presenting with acute cardiomyopathy or cardiogenic shock without a clear ischaemic or valvular aetiology.Catecholamine crisis is a life-threatening medical emergency that requires cross-disciplinary expertise and management to ensure the best clinical outcome.After initial resuscitation, treatment of acute catecholamine-induced stress cardiomyopathy requires careful introduction of alpha-blockade followed by beta-blockade if necessary to manage ß-receptor-mediated tachycardia.Prolonged α-adrenergic receptor stimulation by high levels of circulating catecholamines precipitates arterial vasoconstriction and intravascular volume contraction, which can further exacerbate hypotension. Invasive pressure monitoring can aid management of intravascular volume in these complex patients.

Maximizing the Tweet Engagement Rate in Academia: Analysis of the AJNR Twitter Feed.

The use of social media by medical professionals and organizations is increasing, with Twitter receiving the most attention. User engagement is an important goal of social media activity, and engagement metrics represent a viable gauge of value in social media. No thorough analysis of tweet characteristics that increase academic user engagement has yet been published. In this study, the authors analyzed the American Journal of Neuroradiology Twitter feed to determine the tweet characteristics that were associated with higher engagement rates.

Gender differential and implications in the epidemiology of stress fractures among cadets of Indian Armed Forces.

BACKGROUND: Most studies on stress fractures in India have been carried out among recruits as against officer trainees and limited to males. With the continuous induction of women in the Armed Forces, it was decided to carry out a study among officer trainees of the three services and compare the epidemiology among genders. METHODS: A prospective study was carried out in 2011-2012 at Training Institutes of the three services where male and female cadets train together. Baseline data was collected for all trainees who joined the academy during the study period. All cadets were followed up for development of stress fractures for which details were taken. Additional information was taken from the Training Institute. RESULTS: A total of 3220 cadets (2612 male and 608 female cadets) were included in the study. Overall 276 cadets were observed to have stress fractures during training - making an incidence of 6.9% for male cadets and 15.8% for female cadets. Females were found to have a significantly higher incidence of stress fractures. Further the distribution and onset of stress fractures in females was observed to be distinct from males. CONCLUSION: The significant gender differential observed in the study indicates differential role of intrinsic and extrinsic risk factors in the causation of stress fractures among male and female. Special consideration needs to be given to these while planning and implementing measures for prevention. Further studies may be carried out on subject and on the effect of interventions in stress fracture prevention.

Photocatalytic and antibacterial activity of cadmium sulphide/zinc oxide nanocomposite with varied morphology.

Nanocomposites with multifunctional application prospects have already dragged accelerating interests of materials scientists. Here we present CdS/ZnO nanocomposites with different morphology engineering the precursor molar ratio in a facile wet chemical synthesis route. The materials were structurally and morphologically characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray analysis (EDX) and high-resolution transmission electron microscopy (HRTEM). The growth mechanism of the composite structure with varying molar ratio is delineated with oriented attachment self assemble techniques. Photocatalytic activity of CdS/ZnO nanocomposites with varying morphology were explored for the degradation of rhodamine B (RhB) dye in presence of visible light irradiation and the results reveal that the best catalytic performance arises in CdS/ZnO composite with 1: 1 ratio. The antibacterial efficiency of all nanocomposites were investigated on Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia without light irradiation. Antibacterial activity of CdS/ZnO nanocomposites were studied using the bacteriological test-well diffusion agar method and results showed significant antibacterial activity in CdS/ZnO composite with 1:3 ratio. Overall, CdS/ZnO nanocomposites excel in different potential applications, such as visible light photocatalysis and antimicrobial activity with their tuneable structure.

Association of p53 codon72 Arg>Pro polymorphism with susceptibility to nasopharyngeal carcinoma: evidence from a case-control study and meta-analysis.

Tumor suppressor p53 is a critical player in the fight against cancer as it controls the cell cycle check point, apoptotic pathways and genomic stability. It is known to be the most frequently mutated gene in a wide variety of human cancers. Single-nucleotide polymorphism of p53 at codon72 leading to substitution of proline (Pro) in place of arginine (Arg) has been identified as a risk factor for development of many cancers, including nasopharyngeal carcinoma (NPC). However, the association of this polymorphism with NPC across the published literature has shown conflicting results. We aimed to conduct a case-control study for a possible relation of p53 codon72 Arg>Pro polymorphism with NPC risk in underdeveloped states of India, combine the result with previously available records from different databases and perform a meta-analysis to draw a more definitive conclusion. A total of 70 NPC patients and 70 healthy controls were enrolled from different hospitals of north-eastern India. The p53 codon72 Arg>Pro polymorphism was typed by polymerase chain reaction, which showed an association with NPC risk. In the meta-analysis consisting of 1842 cases and 2330 controls, it was found that individuals carrying the Pro allele and the ProPro genotype were at a significantly higher risk for NPC as compared with those with the Arg allele and the ArgArg genotype, respectively. Individuals with a ProPro genotype and a combined Pro genotype (ProPro+ArgPro) also showed a significantly higher risk for NPC over a wild homozygote ArgArg genotype. Additionally, the strength of each study was tested by power analysis and genotype distribution by Hardy-Weinberg equilibrium. The outcome of the study indicated that both allele frequency and genotype distribution of p53 codon72 Arg>Pro polymorphism were significantly associated with NPC risk. Stratified analyses based on ethnicity and source of samples supported the above result.

Psychiatric Advance Directives in India: What will the future hold?

Psychiatric Advance Directives (PADs) have been incorporated into India's Mental Health Care Bill, 2013. This is the first time any form of Advance Directive stands to receive legal sanction in India. PADs have numerous theoretical and empirically tenable therapeutic and financial advantages. Western experiences have shown high acceptance for the concept among psychiatric patients, and illustrated that most stable patients with severe mental illness retain the capacity to frame PADs consistent with community practice standards. However active psychopathology does impair this capacity, and therein, current subjective assessments of competence performed by Physicians without objective instruments are often inaccurate. Though PADs champion patient autonomy, when applied and studied, they have shown little significant advantage-there is currently not enough data to support evidence-based universal recommendations for PADs. PADs as incorporated into the Mental Health Care Bill model on existing Western statutes, and though many of the strengths of earlier systems have been subsumed, so have several of the shortcomings. The risks, benefits and applicability of PADs in India are complicated by the social re-calibration of patient autonomy, mental-healthcare delivery system weaknesses, and the relatively peripheral role the Psychiatrist is mandated to play in the entire advance directive process. Treating patients within the framework of their pre-stated wishes will be a much more intricate and arduous task than most of modern Psychiatric practice in India, but the difficulties, obstacles and inevitable failures encountered will provide evidence of the delivery system's weaknesses and thereby contribute to its strength.

Role of autologous platelet-rich plasma in treatment of long-bone nonunions: a prospective study.

PURPOSE: Fracture union is a complex biological process, which depends upon several systemic and local factors. Disturbance of any of these factors may lead to nonunion of the fracture. These nonunions have a huge impact on quality of life as well as socioeconomical aspects. The platelets on activation release a number of growth factors and differentiation factors, which play important role in fracture healing. This study aimed to look for efficacy of platelet-rich plasma in the treatment of established fracture nonunions of long bones. METHODS: A total of 94 patients with established nonunion of long bone (35 tibia, 30 femur, 11 humerus, 4 radius, 12 ulna, 2 with both radius and ulna) were included in this study. We injected 15-20 ml of autologous platelet-rich plasma (>2,000,000 platelets/µl) under image intensifier at each nonunion site. The fracture union was evaluated clinically and radiologically regularly at monthly interval till 4 months. RESULTS: Eighty-two patients had their fracture united at the end of 4 months. Thirty-four patients showed bridging trabeculae on X-rays at the end of 2 months, while 41 patients showed bridging trabeculae at the end of third month. Twelve patients did not show any attempt of union at 4 months and were labeled as failure of treatment. There were no complications. CONCLUSION: Platelet-rich plasma is a safe and effective treatment for the treatment of nonunions. More studies are needed to look into molecular mechanism of this fracture healing acceleration by platelet-rich plasma.