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Abnormal choline phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus (31P) MRS is able to non-invasively detect these water-soluble metabolites of choline as well as ethanolamine phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, Pbonferroni<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. [ABSTRACT FROM AUTHOR]

Both migraine and bipolar affective disorder (BPAD) are complex phenotypes with significant genetic and nongenetic components. Epidemiological and clinical studies have showed a high degree of comorbidity between migraine and BPAD, and overlapping regions of linkage have been shown in numerous genome-wide linkage studies. To identify susceptibility factors for the BPAD/migraine phenotype, we conducted a genome-wide association study (GWAS) in 1001 cases with bipolar disorder collected through the NIMH Genetics Initiative for Bipolar Disorder and genotyped at 1m single-nucleotide polymorphisms (SNPs) as part of the Genetic Association Information Network (GAIN). We compared BPAD patients without any headache ( n = 699) with BPAD patients with doctor diagnosed migraine ( n = 56). The strongest evidence for association was found for several SNPs in a 317-kb region encompassing the uncharacterized geneKIAA0564 {e.g. rs9566845 [OR = 4.98 (95% CI: 2.6-9.48), P = 7.7 × 10−8] and rs9566867 ( P = 8.2 × 10−8)}. Although the level of signficance was significantly reduced when using the Fisher's exact test (as a result of the low count of cases with migraine), rs9566845 P = 1.4 × 10−5 and rs9566867 P = 1.5 × 10−5, this region remained the most prominent finding. Furthermore, marker rs9566845 was genotyped and found associated with migraine in an independent Norwegian sample of adult attention deficit hyperactivity disorder (ADHD) patients with and without comorbid migraine ( n = 131 and n = 324, respectively), OR = 2.42 (1.18-4.97), P = 0.013. This is the first GWAS examining patients with bipolar disorder and comorbid migraine. These data suggest that genetic variants in the KIAA0564 gene region may predispose to migraine headaches in subgroups of patients with both BPAD and ADHD. [ABSTRACT FROM AUTHOR]

A personal narrative is presented which explores the author's experience of working in the kitchen area while serving time in prison.

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 × 10−6) and rs10193871 in NAP5 at 2q21.2 (P=9.8 × 10−6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 × 10−6) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 × 10−5). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 × 10−6), rs4657247 in RGS5 at 1q23.3 (P=4.1 × 10−6), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 × 10−6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.Molecular Psychiatry (2009) 14, 755–763; doi:10.1038/mp.2009.43; published online 2 June 2009 [ABSTRACT FROM AUTHOR]

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania 18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.Molecular Psychiatry (2009) 14, 376–380; doi:10.1038/mp.2008.144; published online 30 December 2008 [ABSTRACT FROM AUTHOR]

The dopamine transporter (DAT) is the site of action of stimulants, and variations in the human DAT gene (DAT1) have been associated with susceptibility to several psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and bipolar disorder. We have previously reported the association of bipolar disorder to novel SNPs in the 3′ end of DAT1. We now report the identification of 20 additional SNPs in DAT1 for a total of 63 variants. We also report evidence for association to bipolar disorder in a second independent sample of families. Eight newly identified SNPs and 14 previously identified SNPs were analyzed in two independent samples of 50 and 70 families each using the transmission disequilibrium test. Two of the eight new SNPs, one in intron 8 and one in intron 13, were found to be moderately associated with bipolar disorder, each in one of the two independent samples. Analysis of haplotypes comprised of all 22 SNPs in sliding windows of five adjacent SNPs revealed an association to the region near introns 7 and 8 in both samples (empirical P-values 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed in the gene in our previous study was confirmed in this sample with greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. Together, these data are consistent with the presence of multiple variants in DAT1 that convey susceptibility to bipolar disorder.Molecular Psychiatry (2006) 11, 125–133. doi:10.1038/sj.mp.4001764; published online 1 November 2005 [ABSTRACT FROM AUTHOR]

Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required. Molecular Psychiatry (2003) 8, 299–308. doi:10.1038/sj.mp.4001290. [ABSTRACT FROM AUTHOR]

Smoking cessation continues to be one of the most cost-effective preventive measures for work-site disease management. The US Public Health Service Clinical Practice Guideline, entitled ‘Treating Tobacco Use and Dependence,’ provides guidance for evaluating and choosing smoking cessation programs for work sites. Smoking cessation interventions can be characterized by the resource intensity of the effort, the format and methods of interacting with patients and the focus and objectives of the content. These features are compared with typical group, phone and Internet-based program options. Pharmacotherapy treatment recommendations are reviewed as well as characteristics of first-line nicotine replacement therapy (NRT) medications (e.g. nicotine patch, gum, spray and inhaler) and bupropion. It is suggested that work-site recruitment and participation campaigns may fail for a variety of reasons including: too narrowly cast recruitment messages; inadequate exposure to campaign messages; lack of immediate and accessible enrollment mechanisms; and passive rather than active outreach. Four broad issues to consider when comparing outcomes data from potential smoking cessation programs are: at what follow-up point(s) is the quit rate measured?; is there a comparison group?; how was quit status determined?; and how is the status of participants who are lost to follow-up calculated in the outcomes data? [ABSTRACT FROM AUTHOR]

A prospective study was made of sequential changes in serum creatine kinase (CK) and CK-MB isoenzyme activity within the 12 hours following admission to the coronary care unit on 65 patients with recent chest pain. CK determinations were performed in the laboratory or in the coronary care unit using a dry reagent strip analyser. Slope values for log CK/hour and log CK-MB/hour were calculated, used to confirm or exclude the diagnosis of myocardial infarction, and compared with diagnosis by conventional means. Compared with retrospective diagnosis using all available information, the CK slope had a sensitivity of 100% and a specificity of 94%. This compared with a sensitivity of 94% and specificity of 90% for diagnosis using upper reference limits alone. Determination of CK slope permits very rapid and accurate biochemical confirmation or exclusion of myocardial infarction and the possibility of performing the measurements on the coronary care unit. It additionally offers the prospect of major cost savings resulting from early discharge or transfer from the coronary care unit. [ABSTRACT FROM PUBLISHER]

A system has been developed to measure the PO2 and PCO2 of gases and liquids under hyperbaric conditions for use with a pure oxygen, 'single patient' hyperbaric chamber (Vickers Medical Ltd). The measuring equipment is mounted outside the chamber.Conventional electrodes are used for the measurement of PO2 and PCO2 (Radiometer E5046, E5036), they are mounted in stainless steel cuvettes and used in conjunction with a digital pH meter (Radiometer PHM72). The cuvettes are maintained at 2Ata, but the rest of each electrode is at ambient pressure. Blood, saline, or gas samples from a specially designed tonometer can be introduced into the cuvettes under hyperbaric conditions.Linearity and reproducibility of oxygen were checked over the range 1100–1400 mm Hg (146–186 kPa) using gas mixtures. The means of a series of determinations for each mixture were within 4 mm Hg (0.53 kPa) of a line based on a two-point calibration using white spot nitrogen and 100% oxygen. For each mixture the standard deviation never exceeded 5.1 mm Hg (0.68 kPa).A gas-liquid difference exists under hyperbaric conditions which is about 5% for saline, 9% for blood, and 12% for 30% glycerol.The PCO2 of gas mixtures in the range 20–85 mm Hg (2.7–11.3 kPa) can be measured to within ± 1 mm Hg (0.13 kPa) of the values calculated from Haldane analysis. A gas-liquid difference for CO2 also exists under hyperbaric conditions, the liquid reading about 8% higher than gas of the same PCO2. This difference has not been explained, and is not found when the same system is used under normobaric conditions.The equipment is now being used for clinical studies. [ABSTRACT FROM PUBLISHER]

A diagram detailing the linkage disequilibrium across the dopamine transporter gene is presented.