Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Quantum signatures of chaos in a kicked top.

Chaotic behaviour is ubiquitous and plays an important part in most fields of science. In classical physics, chaos is characterized by hypersensitivity of the time evolution of a system to initial conditions. Quantum mechanics does not permit a similar definition owing in part to the uncertainty principle, and in part to the Schrödinger equation, which preserves the overlap between quantum states. This fundamental disconnect poses a challenge to quantum-classical correspondence, and has motivated a long-standing search for quantum signatures of classical chaos. Here we present the experimental realization of a common paradigm for quantum chaos-the quantum kicked top- and the observation directly in quantum phase space of dynamics that have a chaotic classical counterpart. Our system is based on the combined electronic and nuclear spin of a single atom and is therefore deep in the quantum regime; nevertheless, we find good correspondence between the quantum dynamics and classical phase space structures. Because chaos is inherently a dynamical phenomenon, special significance attaches to dynamical signatures such as sensitivity to perturbation or the generation of entropy and entanglement, for which only indirect evidence has been available. We observe clear differences in the sensitivity to perturbation in chaotic versus regular, non-chaotic regimes, and present experimental evidence for dynamical entanglement as a signature of chaos.

Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria.

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end-stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Tenocyte proliferation on collagen scaffolds protects against degradation and improves scaffold properties.

Tissue engineering scaffolds encourage cell proliferation whilst degrading to facilitate tissue regeneration. Their mechanical properties therefore change, decreasing due to scaffold degradation and increasing due to extracellular matrix deposition. This work compares the changing properties of collagen scaffolds incubated in culture medium, with and without human tenocytes, in order to investigate the relationship between degradation and tenocyte proliferation. The material properties of scaffolds are compared over 26 days using mechanical testing, differential scanning calorimetry, infra-red spectroscopy, and histology and biochemical assays. For medium-only scaffolds, the mechanical properties decrease rapidly, while culture medium sulfhydryl content increases significantly, with no significant changes in the denaturation temperature of scaffold collagen content. Conversely, the mechanical properties and collagen content of tenocyte-seeded scaffolds increase significantly while culture medium sulfhydryl content decreases and denaturation temperature remains the same. These results indicate that tenocytes proliferation both reduces the degradation of collagen scaffolds incubated in culture medium and produces scaffolds with improved properties.

Selective, Ultra-Sensitive, and Rapid Detection of Serotonin by Optimized ZnO Nanorod FET Biosensor.

BACKGROUND: Fluctuation in serotonin (5-HT) level is an essential manifestation of several neurological disorders. In view of such importance, it is necessary to monitor the levels of 5-HT with good sensitivity, selectivity, affordability and low response time. Zinc oxide (ZnO) based field effect transistors (FET) with attributes like minimized noise levels and large on-off ratio are regarded as emerging high performance biosensor platforms. However, their response is significantly non-linear and there has been no appreciable endeavor for improving the non-linearity. METHOD: In this paper, we have introduced embedded gate electrode encompassing the channel of the FET which improves the uniformity in electric field line distribution through the electrolyte and proportionately enhances the capture of target biomolecule at ultra-low concentrations, thereby increasing the linearity. Further, we have incorporated the optimized parameters of ZnO nanorods reported previously, for rapid and selective detection of 5-HT. RESULTS: It has been observed that the fabricated ZnO FET biosensor lowers the detection limit down to 0.1fM which is at least one order of magnitude lower than the existing reports. The sensor also has wide linear range from 0.1fM to 1nM with a detection time of about 20 minutes. CONCLUSION: The proposed zinc oxide nanorod-based sensor can be used as an excellent tool for future diagnosis of neurological disorders.

A Study of Psychological Correlates after Amputation.

BACKGROUND: Amputation of a limb affects almost all aspects of an individual's life. Psychological aspects are important factors for adjustment with the disability. METHODS: The present study was carried out on 50 consecutive male patients admitted to the Artificial Limb Centre. Base line and post therapy psychological assessment was carried out on Hospital Anxiety and Depression Scale (HADS). Trauma Symptom Inventory (TSI) was administered along with Millon Index of personality styles (MIPS). Psychological intervention was given to them on a therapy module proposed by authors. Data was analyzed with the help of SPSS. RESULT: Findings revealed significant differences in scores on HADS, before and after therapy (p<0.05). On Trauma symptom Inventory defensive avoidance and depression were noted to be above cut off level of (>65). Predominant personality styles were self indulgence and internally focused in motivating styles (mean prevalence score <50) and thought guided in thinking styles, dominating and controlling in behaving styles. The analysis of prevalence score of above 50 and less than 50 indicated Confident/Asserting (9B), Submissive / Yielding (11A), having significant change after therapy on score of anxiety (P<0.05). The personality dimension of dutiful and conforming had shown significant influence after therapy (P<0.05) on score of depression. CONCLUSION: The findings indicated psychological assessment and intervention is to be included as a part of the management after amputation.

Risk Factors for Suicide in Wives of Military Personnel.

BACKGROUND: An increasing trend in attempted and completed suicide amongst wives of serving personnel was observed. METHODS: A questionnaire designed to elicit the known risk-factors for suicide, suicide attempts and suicidal ideation by women in the Indian context was administered to 222 wives of Indian military personnel living in a garrison with their husbands. RESULT: A large number (28%) of the sample were child-less. Alcoholism in husband was reported by 22 women and domestic violence by four. Six had been bereaved in the past year. Chronic illness was reported by 10 women and psychiatric illness by four. CONCLUSION: Wives of military personnel may need targeted community interventions focusing on the risk factors for suicide.

Psychiatric Morbidity Pattern in a Child Guidance Clinic.

BACKGROUND: There is a paucity of Indian studies on psychiatric morbidity in children. Present work was undertaken in a child guidance clinic in armed forces. METHODS: Retrospective analysis of 213 patients who attended a child guidance clinic was done. RESULTS: Majority (n=138) were boys. 55.9% were referred from paediatric outpatient department while medical officers in periphery referred 38.5%. The diagnoses was mental retardation in 30.97%, behavioral and emotional disorders in 23.06% and neurotic, stress related and somatoform disorders in 15.98% cases.

Reduction in Drug Prescription using Biofeedback Relaxation in Neurotic and Psychosomatic Disorders.

BACKGROUND: There is a paucity of Indian studies on effectiveness of biofeedback in reducing drug prescription in neurotic and stress related disorders. METHODS: Study sample of generalized anxiety disorders (GAD), mixed anxiety depression, obssessive compulsive disorder (OCD), dissociative disorder and headache were assigned to three groups of 28, 23 and 27 patients respectively. Group 1 were subjected to drug therapy, Group 2 to biofeedback and Group 3 to drugs and biofeedback for 12 weeks. All were followed up at six months and one year. RESULT: At the end of one year, in Group 1, 60.71 % had mild and 17.86 % had moderate anxiety levels, while 21.43% required no further follow up. In Group 2, 39.13 % showed mild and 43.48 % had moderate anxiety levels, while 17.39 % required no follow up. In Group 3, 22.22% had mild and 11.13% had moderate levels of anxiety, while 66.66% required no further treatment. CONCLUSIONS: Biofeedback relaxation with pharmacotherapy is useful in select group of neurotic and psychosomatic cases.

Psychological Well-being of Medical Students.

BACKGROUND: Training in medicine is emotionally demanding. Psychological well being of medical students is a matter of concern. There is lack of Indian studies in this area. METHODS: A total of 105 medical student of one batch were assessed utilizing psychophysiological state inventory, Institute for personality and ability testing (IPAT) anxiety and depression scale, achievement motivation scale, scale for locus of control and 16 PF in three phases at one-year intervals. RESULT: Majority of the students had average achievement, motivation and adaptability. Anxiety and depression scores fell within normal limits. In personality profile factor 'B', 'M' and 'Q41' had changed significantly. Achievement motivation showed significant decreases and CSS1 and PO1 scores showed significant increase during the years of medical education. CONCLUSION: The results demonstrate that over satisfaction and relaxed attitude may have poor academic outcome.

Changing Pattern of Alcohol Abuse in the Army before and after AO 3&11/2001.

BACKGROUND: The Army Order 3&11/2001 was introduced to curb alcoholism and to weed out habitual alcoholics. Hence a study was carried out in a zonal referral hospital from 01 Jan 2001 to 30 Jun 2003 to assess its effectiveness. METHODS: The subjects consisted of officers, junior commisioned officers and other ranks who satisfied the International Classification of Diseases (ICD) 10 criteria for alcohol dependence. RESULT: Out of 1023 consecutive admissions, alcohol dependent cases numbered 245 (23.95%). They were disposed as under: 57/ 245 (23.6%) in S1 (fit for all duties), 67/245 (27.35%) in S2 (fit for duties with few restrictions), 72/245 (29.39%) in S3 (fit for duties with more restrictions), and 32/245 (13.06%) in S5 (unfit for further service.). CONCLUSION: The data showed that the percentage of cases disposed under fit for all duties had risen four times (23.80 vs 5.86), those invalided out increased by two times (12.70 vs 6.64) and those retained in S2 had reduced (26.46 vs 41.21) after the new policy.

Study of Behaviour Problems in a Paediatric Outpatient Department.

BACKGROUND: Behaviour problems in children still needs precise definition, explicit criterion and assessment on multiple paradigms. METHODS: Fifty children of the age group 6-14 years, from paediatric outpatient department, selected after randomisation were assessed for behaviour problems with the child behaviour checklist. The data collected was analysed using appropriate statistical tests. RESULTS: 40% children were above cutoff score. Mean child behaviour check list (CBCL) score was 40.6. Total of 72% children were from armed forces background of whom 9% were siblings of officers. 30.6% children from the armed forces background were above the cutoff score. There was no significant difference in the behaviour problems between different age groups and sex. There was no significant difference in behaviour problems between children of officers, other ranks or various income groups. Female children had behaviour problems like "too concerned with neatness or cleanliness", "feels has to be perfect" and "argues a lot" where as male children had behaviour problems like "Does not feel guilty after misbehaving", "argues a lot" and "restless". CONCLUSION: Behaviour problems in the subjects were externalizing ones. No specific trend was found in children of defence personnel vis-a-vis children of civilian population.

Psychological Correlates of Outcome after Coronary Artery Bypass Graft.

BACKGROUND: Psychological effects of Coronary Artery Bypass graft (CABG) have been of interest all over the world but there is a paucity of Indian work. METHODS: 30 patients undergoing CABG at a service hospital were included. All patients filled a specially designed proforma. Mini Mental Status Examination, Hospital anxiety and depression scale, Coronary scale, Seattle angina questionnaire and Euro-QOL 5D were performed before and seven days after CABG. RESULTS: 43.3% had significant anxiety and 30% had significant depression before CABG. Following CABG, 36.67% of the patients had significant anxiety while 40% had significant depression. On the Seattle angina questionnaire, physical limitation reduced from 71.6 ± 7.9 to 53.1 ± 14.6. There was significant improvement in treatment satisfaction from 37.8 ± 6.1 to 59.4 ± 4.2 following CABG. On th euro quality of life scale (EQ5D) health status improved from 38.17 ± 9.51 before CABG to 68.5 ± 5.28 after CABG. CONCLUSION: There is a significant incidence of anxiety and depression in patients undergoing CABG, both before and after surgery.

Norms of the Rorschach Test for Indian Subjects.

BACKGROUND: The clinical utility of the Rorschach test in Indians is hampered by the absence of reliable normative data. Method : The Rorschach by Dlopfer's method was administrated to 1256 subjects consisting of 300 normal army personnel, 300 normal civilians, 250 schizophrenics, 300 neurotics and 106 patients with organic disorders. RESULTS: The Rorschach protocols of normal Indian army personnel and normal civilians showed significant differences from one another and also from the western norms. These differences are culturally determined and are not indicative of low intelligence or psychopathology. Patients with schizophrenia, neurosis, head injury and epilepsy show significant differences from the records of normal subjects. The protocols of army schizophrenics show significant deviations from those of normal army personnel and these changes revert to normal with clinical recovery. CONCLUSION: The Rorschach test is not a culture fee test as claimed earlier. In view of the differences from Western norms, Rorschach protocols of Indians should be interpreted using the norms for Indians. In the case of army personnel the norms for army personnel should be used. While the use of the Rorschach to study the personality patterns of normal individuals and as an aid to clinical diagnosis was strongly supported, the findings of the study indicate that the test can also be employed to assess therapeutic response of patients with schizophrenia.

Stimulation of tubulin synthesis by thyroid hormone in the developing rat brain.

The effect of triiodothyronine on the biogenesis of tubulin has been studied in the developing rat brain. In organ cultures of brains from newborn rats, the hormone stimulates the incorporation of [14C]leucine into tubulin by 60-80% within 2 h in the absence of any significant change in total protein synthesis. This stimulation is strictly age-dependent (only brains from late fetal or newborn rats are sensitive), dose-dependent (stimulation increases progressively and reaches a maximum level with physiological dose of the hormone) and displays tissue specificity. The temporal correspondence of the sensitivity of the rat brain to triiodothyronine with the period of normal rise in the level of tubulin and that of the maximal level of nuclear triiodothyronine receptors in the brain strongly suggests the involvement of the hormone in regulating the biogenesis of tubulin during the differentiation and maturation of neonatal rat brain.

Effect of thyroid hormone on the abundance of Na,K-adenosine triphosphatase alpha-subunit messenger ribonucleic acid.

The effects of thyroid hormone on Na,K-ATPase alpha-subunit mRNA (mRNA alpha) content and Na,K-ATPase activity were measured in renal cortex, heart, and cerebrum of hypothyroid rats 24 and 72 h after injection of diluent or T3. Use of a cDNA probe complementary to rat brain mRNA alpha in Northern blot analysis revealed a single 26-27 S band in RNA isolated from these three tissues regardless of thyroid status. Tissue mRNA alpha content was estimated by dot blot analysis of whole cell extracts and isolated total RNA. Injection of T3 augmented mRNA alpha content by 2.1- to 2.5-fold in kidney cortex and myocardium at 24 h. After three daily injections of T3, the increases in mRNA alpha were evident despite a global increase in RNA content associated with hypertrophy of these target tissues. Furthermore, the increases in abundance of mRNA alpha after 72 h of T3 treatment correlated with enhancement of Na,K-ATPase activity. In contrast, both mRNA alpha and enzyme activity were invariant in the cerebrum. These data suggest that T3-induced augmentation of Na,K-ATPase activity is mediated, at least in part, by increased mRNA alpha content in target tissues.

Cannabis Use in Psychiatrie Patients.

BACKGROUND: Cannabis abuse has been associated with psychiatric disorders. METHODS: The pattern of cannabis use and incidence of cannabis dependence and cannabis psychosis among 471 consecutive patients admitted to a tertiary care psychiatric center was investigated. RESULTS: Cannabis use was reported by 67 (14.23%) patients of whom 42 (8.92%) were occasional users, 18 (3.82%) were classified as frequent users while 7 (1.49%) fulfilled criteria for cannabis dependence. 3 (0.64%) patients showed symptoms which were characteristic of cannabis psychosis. Among the 67 cannabis users, 56 (83.58%) had their first exposure to cannabis before entering service at 13-19 years of age. The remaining 14 (16.09%) began consuming cannabis 1-5 years after joining service. CONCLUSION: The reasons given for using cannabis were curiosity about its effects 32 (47.76%), peer pressure 17 (25.37%) or traditional use during festivals 18 (26.87%).