Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

Limitations of fractional shortening as an index of contractility in pediatric patients infected with human immunodeficiency virus.

Left ventricular fractional shortening (FS) is dependent on left ventricular preload and afterload, as well as contractility. Contractility may therefore not be accurately described by FS, especially in infants and children infected with human immunodeficiency virus (HIV), who tend to have abnormal left ventricular preload and afterload. We therefore examined the magnitude and clinical impact of the discrepancy between FS and contractility by assessment of 177 echocardiograms from 76 HIV-infected pediatric patients (median age, 1.9 years). The studies included simultaneous measurements of left ventricular FS, contractility, preload, and afterload. The correlation between contractility and FS was modest (r = 0.70; p < 0.001), and was weaker in children less than 2 years of age (r = 0.52) than in older children (r = 0.84). FS incorrectly predicted contractility in 46% of the studies; 43% with depressed FS (< 28%) had either normal (17/42) or enhanced (1/42) contractility. For 67% of echocardiograms, FS and contractility differed by > 1 SD, and for 36% the difference was > 2 SD. These differences remained after adjustment of FS for age or body surface area. Afterload was abnormal in 42% and preload in 21% of all echocardiograms. High preload predicted that FS would overestimate contractility (p = 0.002); high afterload predicted that FS would underestimate contractility (p < 0.001). The discrepancy between FS and contractility was larger among children who were younger, had more advanced HIV disease, or were not sedated during echocardiography. One third of children with congestive symptoms had normal contractility and depressed FS; the discrepancy was primarily due to loading conditions. We conclude that the high incidence of abnormal loading conditions in HIV-infected infants and children limits the usefulness of load-dependent FS for assessing contractility. Measurements of loading conditions and load-independent indexes, which more directly reflect contractility, allow a more accurate determination of myocardial status and may lead to better clinical management.

Chronic low back pain patients around the world: cross-cultural similarities and differences.

OBJECTIVE: The current study sought to determine whether there were any significant cross-cultural differences in medical-physical findings, or in psychosocial, behavioral, vocational, and avocational functioning, for chronic low back pain patients. DESIGN: Partially double-blind controlled comparison of six different culture groups. SETTING: Subjects were selected from primarily ambulatory care facilities specializing in treating chronic pain patients. PATIENTS-SUBJECTS: Subjects consisted of 63 chronic low back pain patients and 63 healthy controls. Low back pain patients were randomly selected from six different culture groups (American, Japanese, Mexican, Colombian, Italian, and New Zealander). Ten to 11 were gathered per culture from a pool of patients treated at various pain treatment programs. Likewise, 10 or 11 control group subjects were obtained from each culture from a pool of healthy support staff. MAIN OUTCOME MEASURES: The Sickness Impact Profile and the Medical Examination and Diagnostic Information Coding System were used as primary outcome measures. RESULTS: Findings showed that (a) low back pain subjects across all cultures had significantly more medical-physical findings and more impairment on psychosocial, behavioral, vocational, and avocational measures than controls did; (b) Mexican and New Zealander low back pain subjects had significantly fewer physical findings than other low back pain groups did; (c) the American, New Zealander, and Italian low back pain patients reported significantly more impairment in psychosocial, recreational, and/or work areas, with the Americans the most dysfunctional; and (d) findings were not a function of working class, age, sex, pain intensity, pain duration, previous surgeries, or differences in medical-physical findings. CONCLUSIONS: It was concluded that there were important cross-cultural differences in chronic low back pain patients' self-perceived level of dysfunction, with the American patients clearly the most dysfunctional. Possible explanations included cross-cultural differences in social expectation; attention; legal-administrative requirements; financial gains; attitudes-expectations about usage, type, and availability of health care; and self-perceived ability and willingness to cope.