Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Evaluation of the diagnostic performance of laboratory-based c-reactive protein as a triage test for active pulmonary tuberculosis.

INTRODUCTION: A highly sensitive triage test that captures most symptomatic patients at increased likelihood of having pulmonary tuberculosis (PTB) would 'rule-out' lower-risk patients from expensive confirmatory testing. Although studies have assessed the diagnostic accuracy of a C-reactive protein (CRP) triage test for PTB in HIV+ patients, limited data are available from HIV- cohorts. MATERIALS AND METHODS: In this retrospective case-control study, 765 serum samples were selected from FIND's biobank. Each sample had been collected from an adult presenting with respiratory symptomatology to district hospitals in South Africa and referral hospitals in Cambodia, Peru, Georgia and Vietnam between 2007-2017. Serum CRP measurements were obtained using a laboratory-based assay. CRP cutoff-points of ≥8mg/L and ≥10mg/L were predefined as a positive triage test result. The PTB reference standard was two contemporaneously collected sputum liquid culture results. RESULTS: CRP demonstrated an overall sensitivity for PTB of 79.8% (95%CI 75.5-83.5) and 77.7% (95%CI 73.4-81.6) for cutoff-points of 8mg/L and 10mg/L respectively. Specificity was 62.8% (95%CI 57.8-67.6%) and 66.6% (95%CI 61.1-70.7) respectively. Area-under-the-curve using Receiver Operating Characteristic analysis was 0.77 (95%CI 0.74-0.81). Threshold analysis showed optimal CRP cutoff-points were higher in HIV+ than HIV- participants. An algorithm in which CRP triage was followed by confirmatory Xpert MTB/Rif testing achieved a sensitivity of 75.1% (95%CI 69.0-80.4%) whilst decreasing Xpert usage by 40.6%. DISCUSSION: CRP may not meet the challenge of a catch-all TB triage test. However, it shows promise in HIV+ individuals. Further research is required in a prospective study using point-of-care platforms to further evaluate its capabilities

Investigation of photoplethysmographic signals and blood oxygen saturation values obtained from human splanchnic organs using a fiber optic sensor

Objective A reliable, continuous method of monitoring splanchnic organ oxygen saturation could allow for the early detection of malperfusion, and may prevent the onset of multiple organ failure. Current monitoring techniques have not been widely accepted in critical care monitoring. As a preliminary to developing a continuous indwelling device, this study evaluates a new handheld fiber optic photoplethysmographic (PPG) sensor for estimating the blood oxygen saturation (SpO2) of splanchnic organs during surgery. Methods A fiber optic splanchnic PPG sensor, instrumentation system and virtual instrument were developed to facilitate PPG and SpO2 measurement from splanchnic organs. Following Local Research Ethics Committee approval, the sensor was evaluated on seventeen ASA 1 and 2 patients undergoing open laparotomy. PPG signals were obtained from the large bowel, small bowel, liver and stomach. Simultaneous PPG signals from the finger were also obtained using an identical fiber optic sensor. Results Good quality PPG signals with high signal-to-noise (SNR) ratios were obtained from all splanchnic sites under investigation. Analysis of the ac and dc amplitudes of the red and infrared PPG signals showed there to be a statistically significant difference between PPG signals obtained from splanchnic organs with those obtained from the finger (using fiber optic sensors). Estimated SpO2 values from the splanchnic organs show good agreement with those obtained from the finger using both a fiber optic sensor and a commercial device. Furthermore, the results of a Bland and Altman analysis indicate that fiber optic splanchnic pulse oximetry, particularly of the bowel, may provide a suitable method for monitoring splanchnic organ perfusion. Conclusion The evaluation of a new fiber optic sensor on anaesthetized patients undergoing laparotomy demonstrated that good quality PPG signals and SpO2 estimates can be obtained from splanchnic organs. Such a sensor may provide a useful tool for the intraoperative assessment of splanchnic perfusion

Pramipexole effects on startle gating in rats and normal men

Dopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague–Dawley rats. Acoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague–Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans. Pramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10–20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude. The preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating

Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are Causal for Schnyder Crystalline Corneal Dystrophy

Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage

Treating breast cancer through novel inhibitors of the phosphatidylinositol 3'-kinase pathway

Recent studies indicate that constitutive signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is a cause of treatment resistance in breast cancer patients. This implies that patients with tumors that exhibit aberrant PI3K signaling may benefit from targeted pathway inhibitors. The first agents to make it to the clinic are the rapamycin analogs. These compounds inhibit the downstream PI3K effector mTOR (mammalian target of rapamycin). A study presented in this issue of Breast Cancer Research suggests that recently developed inhibitors of phosphoinositide-dependent protein kinase 1, a more proximal target of the PI3K pathway, may provide an alternative route to effective PI3K pathway inhibition for breast cancer treatment

Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats

Rationale The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ∆9-tetrahydrocannabinol (∆9-THC). However, we have previously shown that a cannabis extract devoid of ∆9-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour. Objectives The objective of the study was to assess the effects of CBG on food intake and feeding pattern microstructure. Methods Male Lister hooded rats were administered CBG (30–120 mg/kg, per ora (p.o.)) or placebo and assessed in open field, static beam and grip strength tests to determine a neuromotor tolerability profile for this cannabinoid. Subsequently, CBG (at 30–240 mg/kg, p.o.) or placebo was administered to a further group of pre-satiated rats, and hourly intake and meal pattern data were recorded over 2 h. Results CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120–240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased. Conclusions Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted

Role of Acetyl-Phosphate in Activation of the Rrp2-RpoN-RpoS Pathway in Borrelia burgdorferi

Borrelia burgdorferi, the Lyme disease spirochete, dramatically alters its transcriptome and proteome as it cycles between the arthropod vector and mammalian host. During this enzootic cycle, a novel regulatory network, the Rrp2-RpoN-RpoS pathway (also known as the σ54–σS sigma factor cascade), plays a central role in modulating the differential expression of more than 10% of all B. burgdorferi genes, including the major virulence genes ospA and ospC. However, the mechanism(s) by which the upstream activator and response regulator Rrp2 is activated remains unclear. Here, we show that none of the histidine kinases present in the B. burgdorferi genome are required for the activation of Rrp2. Instead, we present biochemical and genetic evidence that supports the hypothesis that activation of the Rrp2-RpoN-RpoS pathway occurs via the small, high-energy, phosphoryl-donor acetyl phosphate (acetyl∼P), the intermediate of the Ack-Pta (acetate kinase-phosphate acetyltransferase) pathway that converts acetate to acetyl-CoA. Supplementation of the growth medium with acetate induced activation of the Rrp2-RpoN-RpoS pathway in a dose-dependent manner. Conversely, the overexpression of Pta virtually abolished acetate-induced activation of this pathway, suggesting that acetate works through acetyl∼P. Overexpression of Pta also greatly inhibited temperature and cell density-induced activation of RpoS and OspC, suggesting that these environmental cues affect the Rrp2-RpoN-RpoS pathway by influencing acetyl∼P. Finally, overexpression of Pta partially reduced infectivity of B. burgdorferi in mice. Taken together, these findings suggest that acetyl∼P is one of the key activating molecule for the activation of the Rrp2-RpoN-RpoS pathway and support the emerging concept that acetyl∼P can serve as a global signal in bacterial pathogenesis