Explore the vast range of titles available.

Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are known to be abnormal in schizophrenia. To test the hypothesis that these phenomena are related, we measured presynaptic dopaminergic function simultaneously with regional cerebral blood flow during the Wisconsin Card Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and matched controls. We show that the dopaminergic uptake constant K i in the striatum was significantly higher for patients than for controls. Patients had significantly less WCST-related activation in PFC. The two parameters were strongly linked in patients, but not controls. The tight within-patient coupling of these values, with decreased PFC activation predicting exaggerated striatal 6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction may lead to dopaminergic transmission abnormalities.

Background/Aims: To associate neuropsychology test performance with perfusion on single-photon emission computed tomography (SPECT) among 12 patients with cerebral small vessel disease. Methods: The easy Z score imaging system (eZIS) was used to compare patient images to those of normal controls. Scores from neuropsychological tests commonly used to screen for dementia were associated with SPECT resting perfusion image values using the statistical parametric mapping (SPM) program. Results: Immediate Memory and Delayed Memory index scores, as well as memory subtests of the Repeatable Battery for Assessment of Neuropsychological Status showed cluster- and voxelwise positive correlations with hypoperfusion in frontal, temporal and cerebellar regions. Negative correlations, primarily in frontal regions, were interpreted as compensatory hyperperfusion. Conclusion: eZIS and SPM analyses of SPECT images showed perfusion correlations with neuropsychological tests with small vessel disease.

Freed, Miletich, Bankiewicz and others dispute Lindvall and others' findings on the effects of fetal brain tissue transplantation on patients with Parkinson's disease. Lindvall and others respond.

While circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P<5x10(-8)), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1x10(-29)) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes.

While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5x10(-8)) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism-including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles-all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay.

Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants have been found to influence the risk of type 2 diabetes mellitus, relatively few studies have focused on genes associated with glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8-12 weeks. Epidemiologic studies and randomized clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk and cardiovascular disease. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study that evaluated 337,343 SNPs in 14,618 apparently healthy Caucasian women. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P = 2.8 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 10(-9)) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel. We were able to replicate this novel association in an independent validation sample of 455 additional non-diabetic men and women. HK1 encodes the enzyme hexokinase, the first step in glycolysis and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 polymorphisms paves the way for further studies of the role of HK1 in hemoglobin glycation, glucose metabolism, and diabetes.

Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction Genomewide Analysis Among 18 245 Initially Healthy Women From the Women’s Genome Health Study Paul M. Ridker, MD, MPH ; Guillaume Paré, MD, MSc ; Alex N. Parker, PhD ; Robert Y.L. Zee, PhD, MPH ; Joseph P. Miletich, MD and Daniel I. Chasman, PhD From the Center for Cardiovascular Disease Prevention (P.M.R., G.P., R.Y.L.Z., D.I.C.) and The Donald W Reynolds Center for Cardiovascular Research (P.M.R., R.Y.L.Z., D.I.C.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.; and Amgen, Inc (A.N.P., J.P.M.), Cambridge Mass. Correspondence to Daniel I. Chasman, PhD or Paul M Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman{at}rics.bwh.harvard.edu Received August 25, 2008; accepted December 3, 2008. Background— Recent trial data have challenged the hypothesis that cholesteryl ester transfer protein (CETP) and high-density lipoprotein cholesterol (HDL-C) have causal roles in atherothrombosis. One method to evaluate this issue is to examine whether polymorphisms in the CETP gene that impact on HDL-C levels also impact on the future development of myocardial infarction. Methods and Results— In a prospective cohort of 18 245 initially healthy American women, we examined over 350 000 singe-nucleotide polymorphisms (SNPs) first to identify loci associated with HDL-C and then to evaluate whether significant SNPs within these loci also impact on rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had 1 or more SNPs associated with HDL-C at genome-wide statistical significance ( P <5 x 10 –8 ). However, only SNPs near or in the CETP gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the CETP gene was associated with a per-allele increase in HDL-C levels of 3.1 mg/dL and a concordant 24% lower risk of future myocardial infarction (age-adjusted hazard ratio, 0.76; 95% CI, 0.62 to 0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDL-C and incident myocardial infarction were also observed at the CETP locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects. Conclusion— In this prospective cohort of initially healthy women, SNPs at the CETP locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway. Key Words: HDL-cholesterol • myocardial infarction • atherosclerosis • genetic association   CLINICAL PERSPECTIVE Guest Editor for this article was Donna K. Arnett, PhD. Related Article Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction: Genomewide Analysis Among 18 245 Initially Healthy Women From the Women’s Genome Health Study Paul M. Ridker, Guillaume Paré, Alex N. Parker, Robert Y.L. Zee, Joseph P. Miletich, and Daniel I. Chasman Circ Cardiovasc Genet 2009 2: 26-33. [Abstract] [Full Text] [PDF]

Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study Guillaume Paré, MD, MSc, FRCP(C) * ; Daniel I. Chasman, PhD * ; Alexander N. Parker, PhD ; Robert R.Y. Zee, PhD, MPH ; Anders Mälarstig, PhD ; Udo Seedorf, PhD ; Rory Collins, MBBS, MSc, FRCP ; Hugh Watkins, MD, PhD, FRCP ; Anders Hamsten, MD, PhD, FRCP ; Joseph P. Miletich, MD and Paul M Ridker, MD, MPH From the Center for Cardiovascular Disease Prevention (G.P., D.I.C., R.R.Y.Z., P.M.R.) and the Donald W. Reynolds Center for Cardiovascular Research (G.P., D.I.C., R.R.Y.Z., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Amgen, Inc (A.N.P., J.P.M.), Cambridge, Mass; Atherosclerosis Research Unit (A.M., A.H.), Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Leibniz-Institut für Arterioskleroseforschung an der Universität Münster (U.S.), Münster, Germany; Clinical Trial Service Unit and Epidemiological Studies Unit (R.C.), and Department of Cardiovascular Medicine (H.W.), University of Oxford, Oxford, United Kingdom; and the PROCARDIS Consortium, www.procardis.org. Correspondence to Guillaume Paré, MD, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave East, 3rd Floor, Boston, MA 02215. E-mail gpare{at}rics.bwh.harvard.edu Received October 20, 2008; accepted February 9, 2009. Background— Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown. Methods and Results— To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with MTHFR (1p36.22; rs1801133; P =8.1 x 10 –35 ) and CBS (21q22.3; rs6586282; P =3.2 x 10 –10 ), we found novel associations with CPS1 (2q34; rs7422339; P =1.9 x 10 –11 ), MUT (6p12.3; rs4267943; P =2.0 x 10 –9 ), NOX4 (11q14.3; rs11018628; P =9.6 x 10 –12 ), and DPEP1 (16q24.3; rs1126464; P =1.2 x 10 –12 ). The associations at MTHFR , DPEP1 , and CBS were replicated in an independent sample from the PROCARDIS study, whereas the association at CPS1 was only replicated among the women. Conclusions— These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease. Key Words: genetics • metabolism • amino acids   CLINICAL PERSPECTIVE The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/2/2/142/DC1. *The first 2 authors contributed equally to this work. Related Article Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study Guillaume Paré, Daniel I. Chasman, Alexander N. Parker, Robert R.Y. Zee, Anders Mälarstig, Udo Seedorf, Rory Collins, Hugh Watkins, Anders Hamsten, Joseph P. Miletich, and Paul M Ridker Circ Cardiovasc Genet 2009 2: 142-150. [Abstract] [Full Text] [PDF]