GWAS for executive function and processing speed suggests involvement of the CADM2 gene

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

Effect of Feeding a Reduced-protein Diet Supplemented with Crystalline Amino acids to Broiler Breeders during Post-molt on Performance, Reproductive, and Immune Responses

One experiment was conducted with a total of 2000 broiler breeders (Lohman strain) at 74 weeks of age, which lasted for 10 weeks. Birds were randomly assigned to two dietary treatments varying in dietary crude protein (CP). The reduced-CP diet had dietary CP level approximately 1.5 percentage units lower than the control (15.5 vs 14.0%). By supplementing 0.13 and 0.1% of DL-methionine and L-HCl-lysine to the reduced-CP diet, respectively, the sulfur amino acids to lysine ratio was kept similar between the control and the reduced-CP diet. Data were subjected to one-way ANOVA in a completely randomized design with 2 treatments and 4 replicates. Results showed that egg shell thickness, hatchability, and the Hemagglutination Inhibision (HI) response against New Castle and Influenza from reduced-CP group were not significantly different from the control group. Hen-day egg production was also remained unchanged throughout the experiment. Nevertheless, it was numerically higher in the low-protein group than the control group. In conclusion, egg production, hatchability and the immune response of broiler breeders can be maintained on a reduced-CP diet (90% of the industry norm) when the contents and ratio of sulfur amino acids to lysine kept constant

Prevalence of congenital malformations observed in neonates in Shariati Hospital (1381-1383)

Background: Congenital malformations are one of the most important problems in pediatrics. The estimation of the prevalence of malformations and some probable determinants were the purpose of this study. Methods: In this retrospective study, all of the newborns that were born during three years (2002-4) were included. Hospital files of 3840 newborns were studied retrospectively and the data were collected in checklist. Finding: 118 cases had at least a major or minor malformation. Over all the prevalence of malformations was 3.1%. Male newborns showed a higher prevalence of malformations than females but with no statistical significance. The skeletal system had the highest rate of malformations, while the genitourinary system and the head and neck deformities were in the second and third position. There were no significant relations between the prevalence of malformations and the maternal age, the height and weight of the newborns and the season of birth. Conclusion: The prevalence of malformations in this study was similar to previous studies

Treatment of the patient with acute ischemic stroke

Stroke is a cerebrovascular injury that occurs when blood flow to the brain is interrupted. It is the third leading cause of death and the commonest cause of disability in North America. There are many treatable risk factors for ischemic stroke, including high blood pressure, smoking, and high cholesterol. In addition, stroke in the acute stage can be treated with thrombolytic agents, and secondary prevention measures include antiplatelet drugs and anticoagulation in selected patients. The role of the physician in ischemic stroke management is first to establish a specific diagnosis. Stroke can be secondary to paradoxical embolus, cardiogenic embolism, atheroma of the ascending and transverse aorta, atheroma of the carotid vessels or its major branches, or lacunar infarct. About 5 % of all strokes are the result of rare causes, chiefly a complication of other medical problems. Appropriate investigation will attach a precise diagnostic label to each stroke in the majority of cases and help lay out a plan for management. Each diagnostic label carries with it specific implications in terms of acute management, as well as secondary prevention. Appropriate management of the ischemic stroke patient includes a specific diagnosis, specific treatment, and a long-term management plan

The exact science of stroke thrombolysis and the quiet art of patient selection.

The science of metric-based patient stratification for intravenous thrombolysis, revolutionized by the landmark National Institute of Neurological Disorders and Stroke trial, has transformed acute ischaemic stroke therapy. Recanalization of an occluded artery produces tissue reperfusion that unequivocally improves outcome and function in patients with acute ischaemic stroke. Recanalization can be achieved mainly through intravenous thrombolysis, but other methods such as intra-arterial thrombolysis or mechanical thrombectomy can also be employed. Strict guidelines preclude many patients from being treated by intravenous thrombolysis due to the associated risks. The quiet art of informed patient selection by careful assessment of patient baseline factors and brain imaging could increase the number of eligible patients receiving intravenous thrombolysis. Outside of the existing eligibility criteria, patients may fall into therapeutic 'grey areas' and should be evaluated on a case by case basis. Important factors to consider include time of onset, age, and baseline blood glucose, blood pressure, stroke severity (as measured by National Institutes of Health Stroke Scale) and computer tomography changes (as measured by Alberta Stroke Programme Early Computed Tomography Score). Patients with traditional contraindications such as wake-up stroke, malignancy or dementia may have the potential to receive benefit from intravenous thrombolysis if they have favourable predictors of outcome from both clinical and imaging criteria. A proportion of patients experience complications or do not respond to intravenous thrombolysis. In these patients, other endovascular therapies or a combination of both may be used to provide benefit. Although an evidence-based approach to intravenous thrombolysis for acute ischaemic stroke is pivotal, it is imperative to examine those who might benefit outside of protocol-driven practice