Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a ...multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate the reliability and validity of a semistructured measure of obsessive-compulsive symptom severity in children and adolescents with obsessive-compulsive disorder (OCD).
Sixty-five children ...with OCD (25 girls and 40 boys, aged 8 to 17 years) were assessed with the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Interrater agreement was assessed by four raters in a subsample (n = 24). Discriminant and convergent validity were assessed by comparing CY-BOCS scores to self-ratings of depression, anxiety, and obsessive-compulsive symptoms.
Internal consistency was high, measuring .87 for the 10 items. The intraclass correlations for the CY-BOCS Total, Obsession, and Compulsion scores were .84, .91, and .68, suggesting good to excellent interrater agreement for subscale and total scores. The CY-BOCS Total score showed a significantly higher correlation with a self-report of obsessive-compulsive symptoms (r = .62 for the Leyton survey) compared with the Children's Depression Inventory (r = .34) and the Children's Manifest Anxiety Scale (r = .37) (p = .02 and .05, respectively).
The CY-BOCS yields reliable and valid subscale and total scores for obsessive-compulsive symptom severity in children and adolescents with OCD. Reliability and validity appear to be influenced by age of the child and the hazards associated with integrating data from parental and patient sources.
Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for ...13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this randomized study, the addition of lixisenatide, a glucagon-like peptide 1–receptor agonist, to usual care in patients with type 2 diabetes and a recent cardiovascular event did not alter the ...rate of subsequent major cardiovascular or other serious adverse events.
Randomized trials involving patients with new or established type 2 diabetes have shown that improved glucose control reduces the risk of microvascular complications,
1
–
3
with modest cardiovascular benefits suggested by meta-analyses and extended follow-up of clinical trials.
4
–
7
However, various studies indicate that, despite being effective in lowering the glucose and glycated hemoglobin levels, some hypoglycemic medications may increase, rather than reduce, the risk of cardiovascular events.
8
–
10
These unexpected findings prompted the reexamination of the regulatory approval processes for new antidiabetic therapies, which had been based primarily on the surrogate measure of glucose lowering with limited clinical-outcomes data. Since . . .
•Developments in composting technology enable dairy farms to produce compost bedding.•Measured emissions at on-farm manure-separator, composter, and compost-storage.•Active composting had low ...emissions of N2O and CH4 and higher loss of CO2 and NH3.•Compost storage had higher emissions of CH4 and N2O emissions, and lower NH3.•Solid-liquid separation and composting reduced GHG emissions vs liquid manure storage.
Recent developments in composting technology enable dairy farms to produce their own bedding from composted manure. This management practice alters the fate of carbon and nitrogen; however, there is little data available documenting how gaseous emissions are impacted. This study measured in-situ emissions of methane (CH4), carbon dioxide (CO2), nitrous oxide (N2O), and ammonia (NH3) from an on-farm solid-liquid separation system followed by continuously-turned plug-flow composting over three seasons. Emissions were measured separately from the continuously-turned compost phase, and the compost-storage phase prior to the compost being used for cattle bedding. Active composting had low emissions of N2O and CH4 with most carbon being emitted as CO2-C and most N emitted as NH3-N. Compost storage had higher CH4 and N2O emissions than the active phase, while NH3 was emitted at a lower rate, and CO2 was similar. Overall, combining both the active composting and storage phases, the mean total emissions were 3.9×10−2gCH4kg−1 raw manure (RM), 11.3gCO2kg−1 RM, 2.5×10−4g N2O kg−1 RM, and 0.13g NH3 kg−1 RM. Emissions with solid-separation and composting were compared to calculated emissions for a traditional (unseparated) liquid manure storage tank. The total greenhouse gas emissions (CH4+N2O) from solid separation, composting, compost storage, and separated liquid storage were reduced substantially on a CO2-equivalent basis compared to traditional liquid storage. Solid-liquid separation and well-managed composting could mitigate overall greenhouse gas emissions; however, an environmental trade off was that NH3 was emitted at higher rates from the continuously turned composter than reported values for traditional storage.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
There is an independent progressive epidemiologic relation between glycemia and cardiovascular disease (CVD) events; however, whether lowering glucose levels with currently available therapies can ...reduce CVD events remains unknown. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to answer this question in high-risk patients with type 2 diabetes mellitus. In ACCORD, 10,251 patients with type 2 diabetes and other CVD risk factors or CVD were randomly allocated to intensive glycemic control, targeting a glycosylated hemoglobin (HbA1c ) level <6%, or standard glycemic control, targeting an HbA1c level of 7.0%–7.9%. All participants are provided with diabetes education, glucose-monitoring equipment, and antidiabetic medications. All participants in the intensive glycemic control group are started on ≥2 classes of agents. Doses are intensified or a new medication class is added every month if HbA1c levels are ≥6% or if >50% of premeal or postmeal capillary glucose readings are >5.6 mmol/L (100 mg/dL) or >7.8 mmol/L (140 mg/dL), respectively. All drug combinations are permitted, and drugs are reduced only because of side effects or contraindications. Annual training, menus of approaches for intensification, regular electronic messaging, audits of achieved glycemia, and central feedback to sites support glycemic intensification strategies in intensive participants. In participants in the standard glycemic control group, therapy is intensified whenever HbA1c is ≥8%, and antihyperglycemic drugs that promote hypoglycemia (ie, insulin or insulin secretagogues) are reduced if HbA1c persistently decreases to <7% in the setting of hypoglycemia. ACCORD addresses the hypothesis that aggressive glucose lowering prevents CVD events in patients with type 2 diabetes. It is focused on the levels of glycemia achieved using a variety of strategies, not on the specific therapies used. It will also provide information on how to safely approach near-normal levels of glucose control in clinical practice and evidence to support future clinical guidelines for diabetes management in older adults.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
18.
Homeobox genes in obsessive-compulsive disorder Nestadt, G.; Wang, Y.; Grados, M.A. ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
January 2012, Volume:
159B, Issue:
1
Journal Article
This study investigates the relationship of specific anxiety and affective disorders to obsessive-compulsive disorder (OCD) in a blind, controlled family study.
Eighty case and 73 control probands, ...as well as 343 case and 300 control first-degree relatives of these probands, participated in the study. Subjects were examined by psychologists or psychiatrists using the Schedule for Affective Disorder and Schizophrenia-Lifetime Anxiety version (SADS-LA). Two experienced psychiatrists independently reviewed all clinical materials, and final diagnoses were made according to DSM-IV criteria, by consensus procedure.
Except for bipolar disorder, all anxiety and affective disorders investigated were more frequent in case than control probands. Substance dependence disorders were not more frequent. Generalized anxiety disorder (GAD), panic disorder, agoraphobia, separation anxiety disorder (SAD) and recurrent major depression were more common in case than control relatives. These disorders occurred more frequently if the relative was diagnosed with OCD. Only GAD and agoraphobia were more frequent in case relatives independent of OCD.
GAD and agoraphobia share a common familial aetiology with OCD. The other anxiety and affective disorders, when comorbid with OCD, may emerge as a consequence of the OCD or as a more complex syndrome.
Objective:
The authors evaluated the efficacy, safety, and tolerability of extended-release venlafaxine in the treatment of pediatric generalized anxiety disorder.
Method:
Two randomized, ...double-blind, placebo-controlled trials were conducted at 59 sites in 2000 and 2001. Participants 6 to 17 years of age who met DSM-IV criteria for generalized anxiety disorder received a flexible dosage of extended-release venlafaxine (N=157) or placebo (N=163) for 8 weeks. The primary outcome measure was the composite score for nine delineated items from the generalized anxiety disorder section of a modified version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children, and the primary efficacy variable was the baseline-to-endpoint change in this composite score. Secondary outcome measures were overall score on the nine delineated items, Pediatric Anxiety Rating Scale, Hamilton Anxiety Rating Scale, Screen for Child Anxiety Related Emotional Disorders, and the severity of illness and improvement scores from the Clinical Global Impression scale (CGI).
Results:
The extended-release venlafaxine group showed statistically significant improvements in the primary and secondary outcome measures in study 1 and significant improvements in some secondary outcome measures but not the primary outcome measure in study 2. In a pooled analysis, the extended-release venlafaxine group showed a significantly greater mean decrease in the primary outcome measure compared with the placebo group (-17.4 versus -12.7). The response rate as indicated by a CGI improvement score <3 was significantly greater with extended-release venlafaxine than placebo (69% versus 48%). Common adverse events were asthenia, anorexia, pain, and somnolence. Statistically significant changes in height, weight, blood pressure, pulse, and cholesterol levels were observed in the extended-release venlafaxine group.
Conclusions:
Extended-release venlafaxine may be an effective, well-tolerated short-term treatment for pediatric generalized anxiety disorder.
PDF
