tbuckley/cabot-search huggingface dataset:
No Association Between Schizophrenia and Polymorphisms in COMT in Two Large Samples
Authors: Hywel J Williams, Beate Glaser, Nigel M Williams, Nadine Norton, Stanley Zammit, Stuart MacGregor, George K Kirov, Michael J Owen, Michael C O'Donovan
Journal: American Journal of Psychiatry (2005)

A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses.They reviewed data from more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples.The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects.The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies.
Effectiveness of the Diabetic Foot Risk Classification System of the International Working Group on the Diabetic Foot
Authors: Edgar J.G. Peters, Lawrence A. Lavery
Journal: Diabetes Care (2001)

OBJECTIVE—To evaluate the effectiveness of a diabetic foot risk classification system by the International Working Group on the Diabetic Foot to predict clinical outcomes. RESEARCH DESIGN AND METHODS—A total of 225 diabetic patients were initially evaluated as part of a prospective case-control study at the University of Texas Health Science Center at San Antonio. Complete records were available for 213 patients for follow-up evaluation after 29 months. Upon enrollment, subjects were stratified into four risk groups based on the presence of risk factors according to the consensus of the International Working Group on the Diabetic Foot. Group 0 consisted of subjects without neuropathy, group 1 consisted of patients with neuropathy but without deformity or peripheral vascular disease (PVD), group 2 consisted of subjects with neuropathy and deformity or PVD, and group 3 consisted of patients with a history of foot ulceration or a lower-extremity amputation. RESULTS—Upon enrollment, patients in higher-risk groups had longer duration of diabetes, worse glycemic control, vascular and neuropathic variables, and more systemic complications of diabetes. During 3 years of follow-up, ulceration occurred in 5.1, 14.3, 18.8, and 55.8% of the patients in groups 0, 1, 2, and 3, respectively (linear-by-linear association, P &amp;lt; 0.001). All amputations were found in Groups 2 and 3 (3.1 and 20.9%, P &amp;lt; 0.001). CONCLUSIONS—The foot risk classification of the International Working Group on the Diabetic Foot predicts ulceration and amputation and can function as a tool to prevent lower-extremity complications of diabetes.
A Swedish National Twin Study of Lifetime Major Depression
Authors: Kenneth S Kendler, Margaret Gatz, Charles O Gardner, Nancy L Pedersen
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: Substantial evidence supports the heritability of lifetime major depression. Less clear is whether genetic influences in major depression are more important in women than in men and whether genetic risk factors are the same in the two sexes. It is not known whether genetic effects on major depression are constant across historical cohorts. METHOD: Lifetime major depression was assessed at personal interview by modified DSM-IV criteria in 42,161 twins, including 15,493 complete pairs, from the national Swedish Twin Registry. Twin models were evaluated by using the program Mx. RESULTS: Model fitting indicated that the heritability of liability to major depression was significantly higher in women (42%) than men (29%) and the genetic risk factors for major depression were moderately correlated in men and women. No significant differences were seen in the etiologic roles of genetic and environmental factors in major depression in three cohorts spanning birth years 1900–1958. CONCLUSIONS: In the largest sample to date, lifetime major depression was moderately heritable, with estimates similar to those in prior studies. In accord with some but not other previous investigations, this study suggests both that the heritability of major depression is higher in women than in men and that some genetic risk factors for major depression are sex-specific in their effect. No evidence was found for differences in the roles of genetic and environmental risk factors in major depression in birth cohorts spanning nearly six decades.
CD40 Signaling Is Impaired in <i>L. major</i>–infected Macrophages and Is Rescued by a p38MAPK Activator Establishing a Host-protective Memory T Cell Response
Authors: Amit Awasthi, Ramkumar Mathur, Aslam Khan, Bimba N. Joshi, Nitya Jain, Sangeeta Sawant, Ramanamurthy Boppana, Debashis Mitra, Bhaskar Saha
Journal: The Journal of Experimental Medicine (2003)

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-gamma, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major-infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major-infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance.
Pathophysiology of impaired ovarian function in galactosaemia
Authors: T Forges, P Monnier-Barbarino, B Leheup, P Jouvet
Journal: Human Reproduction Update (2006)

Classical galactosaemia is an inherited inborn error of the major galactose assimilation pathway, caused by galactose-1-phosphate uridyltransferase (GALT) deficiency. Many GALT mutations have been described, with different clinical consequences. In severe forms, newborns present with a life-threatening, acute toxic syndrome that rapidly regresses under a galactose-restricted diet. However, long-term complications, particularly cognitive and motor abnormalities, as well as hypergonadotrophic hypogonadism in female patients are still unavoidable. The pathogenesis of galactose-induced ovarian toxicity remains unclear but probably involves galactose itself and its metabolites such as galactitol and UDP-galactose. Possible mechanisms of ovarian damage include direct toxicity of galactose and metabolites, deficient galactosylation of glycoproteins and glycolipids, oxidative stress and activation of apoptosis. As there is no aetiological treatment, clinical management of ovarian failure in galactosaemic patients principally relies on hormonal replacement therapy to induce pubertal development and to prevent bone loss and other consequences of estrogen deprivation. Further investigations will be necessary to better understand the metabolic flux of galactose through its biochemical pathways and the mechanisms of these secondary complications. The aim of this article is to present an extensive review on the pathogenesis and clinical management of galactose-induced premature ovarian failure.
PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice
Authors: Scott N. Mueller, Vijay K. Vanguri, Sang-Jun Ha, Erin E. West, Mary E. Keir, Jonathan N. Glickman, Arlene H. Sharpe, Rafi Ahmed
Journal: Journal of Clinical Investigation (2010)

The inhibitory receptor programmed death 1 (PD-1) is upregulated on antigen-specific CD8+ T cells during persistent viral infections. Interaction with PD-1 ligand 1 (PD-L1) contributes to functional exhaustion of responding T cells and may limit immunopathology during infection. PD-L1 is expressed on both hematopoietic and nonhematopoietic cells in tissues. However, the exact roles of PD-L1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear. Here we used bone marrow chimeric mice to examine the effects of PD-L1 deficiency in hematopoietic or nonhematopoietic cells during lymphocytic choriomeningitis virus clone 13 (LCMV CL-13) infection. We found that PD-L1 expression on hematopoietic cells inhibited CD8+ T cell numbers and function after LCMV CL-13 infection. In contrast, PD-L1 expression on nonhematopoietic cells limited viral clearance and immunopathology in infected tissues. Together, these data demonstrate that there are distinct roles for PD-L1 on hematopoietic and nonhematopoietic cells in regulating CD8+ T cell responses and viral clearance during chronic viral infection.
RESPIRATORY PLATEAUX IN "DAY-DREAMING" AND IN SCHIZOPHRENIA
Authors: WILLIAM CORWIN, HERBERT BARRY
Journal: American Journal of Psychiatry (1940)

A change in respiration herein termed "respiratory plateaux" has been noted in states of "day-dreaming" in normals and a similar tendency has been observed in schizophrenic patients. These periods of apnea appear to be more striking and more frequent in the latter. It is obviously difficult to be certain that experimental subjects are actually day-dreaming. Nevertheless certain individuals when instructed to day-dream manifested breathing characterized by recurrent periods of apnea. Periods of apnea or "respiratory plateaux" were relatively numerous among schizophrenic patients. Several college students with pronounced "respiratory plateaux" exhibited evidence of maladjustment. The findings are to be regarded as preliminary until repeated with a larger series of cases.
The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects
Authors: Cláudia C. Oliveira, Peter A. van Veelen, Bianca Querido, Arnoud de Ru, Marjolein Sluijter, Sandra Laban, Jan W. Drijfhout, Sjoerd H. van der Burg, Rienk Offringa, Thorbald van Hall
Journal: The Journal of Experimental Medicine (2010)

The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b-restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells.
Identification of the Transcription Factor Single-Minded Homologue 2 as a Potential Biomarker and Immunotherapy Target in Prostate Cancer
Authors: Mohamed S. Arredouani, Bin Lu, Manoj Bhasin, Miriam Eljanne, Wen Yue, Juan-Miguel Mosquera, Glenn J. Bubley, Vivian Li, Mark A. Rubin, Towia A. Libermann, Martin G. Sanda
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Identification of novel biomarkers and immunotherapy targets for prostate cancer (PCa) is crucial to better diagnosis and therapy. We sought to identify novel PCa tumor-associated antigens (TAA) that are expressed in PCa, absent in nonprostate human tissue, and immunogenic for immune responses restricted by human HLA. Experimental Design and Results: Using microarray analysis of normal and cancerous human prostate tissues, we identified 1,063 genes overexpressed in PCa. After validating 195 transcripts in publicly available array data sets, we interrogated expression of these TAAs in normal human tissues to identify genes that are not expressed at detectable levels in normal, nonprostate adult human tissue. We identified 23 PCa TAA candidates. Real-time PCR confirmed that 15 of these genes were overexpressed in PCa (P&amp;lt; 0.05 for each). The most frequently overexpressed gene, single-minded homologue 2 (SIM2), was selected for further evaluation as a potential target for immunotherapy. ELISA assay revealed that a fraction of PCa patients exhibited immune responsiveness to SIM2 as evidenced by the presence of autoantibodies to SIM2 in their sera. We next showed binding of putative HLA-A2.1–restricted SIM2 epitopes to human A2.1, and immunization of transgenic HLA-A2.1 mice showed induction of SIM2-specific CTL responses in vivo. Conclusions: Our findings that SIM2 is selectively expressed in PCa, that human HLA-A2.1–restricted SIM2 epitopes induce specific T cells in vivo, and that anti-SIM2 antibodies are detectable in PCa patients' sera implicate SIM2 as a PCa-associated antigen that is a suitable potential target for PCa immunotherapy. (Clin Cancer Res 2009;15(18):5794–802)
Successful Treatment of Primary and Disseminated Human Lung Cancers by Systemic Delivery of Tumor Suppressor Genes Using an Improved Liposome Vector
Authors: Rajagopal Ramesh, Tomoyuki Saeki, Nancy Smyth Templeton, Lin Ji, L. Clifton Stephens, Isao Ito, Deborah R. Wilson, Zheng Wu, Cynthia D. Branch, John D. Minna, Jack A. Roth
Journal: Molecular Therapy (2001)

Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP:Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.
Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers
Authors: A. Eisen, J. Lubinski, J. Gronwald, P. Moller, H. T. Lynch, J. Klijn, C. Kim-Sing, S. L. Neuhausen, L. Gilbert, P. Ghadirian, S. Manoukian, G. Rennert, E. Friedman, C. Isaacs, E. Rosen, B. Rosen, M. Daly, P. Sun, S. A. Narod
Journal: JNCI Journal of the National Cancer Institute (2008)

Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. We conducted a matched case–control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P = .03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P = .04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P = .21). Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.
Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance
Authors: Felicity Payne, Rita Colnaghi, Nuno Rocha, Asha Seth, Julie Harris, Gillian Carpenter, William E. Bottomley, Eleanor Wheeler, Stephen Wong, Vladimir Saudek, David Savage, Stephen O’Rahilly, Jean-Claude Carel, Inês Barroso, Mark O’Driscoll, Robert Semple
Journal: Journal of Clinical Investigation (2014)

Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5-6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2. Both mutations reduced NSMCE2 expression in patient cells. Primary cells from one patient showed increased micronucleus and nucleoplasmic bridge formation, delayed recovery of DNA synthesis, and reduced formation of foci containing Bloom syndrome helicase (BLM) after hydroxyurea-induced replication fork stalling. These nuclear abnormalities in patient dermal fibroblast were restored by expression of WT NSMCE2, but not a mutant form lacking SUMO-ligase activity. Furthermore, in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase-deficient NSMCE. Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.
Posture-induced airflow limitation in asthma: relationship to plasma catecholamines and an inhaled anticholinergic agent
Authors: K Larsson, S Bevegard, B Mossberg
Journal: European Respiratory Journal (1988)

Postural influence on ventilatory function was investigated in thirteen asthmatic subjects on three consecutive days starting at 10.00 am. Lung function was measured in the seated position before and after four hours lying supine. Peak expiratory flow (PEF) was measured every 0.5 h in the supine position. Blood samples for determination of plasma catecholamines were collected before, during and after lying supine. After the initial lung function testing, placebo or ipratropium bromide (0.125 mg) was inhaled. On the third day the whole trial was performed seated, without any drug, as a control experiment. On the placebo day lying supine induced an initial, rapid fall of PEF followed by a progressive decrease during the four hours. The progressive decrease in PEF was apparently caused by bronchoconstriction. Ipratropium bromide prevented this posture-induced bronchoconstriction. On the day seated there was also a tendency towards a decline of PEF though less pronounced than in the supine position on the placebo day. No significant alterations in plasma levels of catecholamines were observed. We conclude that the supine posture is a stimulus to bronchoconstriction in asthma, likely to be involved in nocturnal wheezing. Postural bronchoconstriction is not explained by lowered plasma levels of adrenaline, as has been suggested for nocturnal asthma. The results raise the question of whether cholinergic mechanisms are involved.
Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension
Authors: J. Suntharalingam, R. D Machado, L. D Sharples, M. R Toshner, K. K Sheares, R. J Hughes, D. P Jenkins, R. C Trembath, N. W Morrell, J. Pepke-Zaba
Journal: Thorax (2007)

<b>Background:</b> Although pulmonary endarterectomy (PEA) is potentially curative in chronic thromboembolic pulmonary hypertension (CTEPH), some patients have distally distributed disease that is not amenable to surgery. The aetiology and characteristics of this patient group are currently not well understood. <b>Objectives:</b> This study compares the baseline demographic features and outcomes in subjects with distal CTEPH, those with proximal CTEPH and those with idiopathic pulmonary arterial hypertension (IPAH) to determine whether these conditions represent separate entities or whether they exist along the same spectrum of disease. <b>Methods:</b> The medical history, clinical characteristics, bone morphogenetic protein receptor type II (BMPR2) mutation status and outcomes of 96 subjects with IPAH, 35 with distal CTEPH and 68 with proximal CTEPH referred to a single specialist centre between 1994 and 2005 were reviewed. <b>Results:</b> There were significant differences between the distal CTEPH, proximal CTEPH and IPAH groups in age (55.9 years vs 54.8 years vs 46.2 years, p&lt;0.001), proportion who were male (43% vs 69% vs 29%, p&lt;0.001), previous deep vein thrombosis (28.6% vs 30.9% vs 3.1%, p&lt;0.001), positive BMPR2 status (0% vs 0% vs 15%, p = 0.018), mean pulmonary artery pressure (47.3 mm Hg vs 45.4 mm Hg vs 54.8 mm Hg, p&lt;0.001) and total pulmonary resistance (12.9 WU vs 12.4 WU vs 18.1 WU, p&lt;0.001). Patients with distal CTEPH and those with IPAH were managed similarly and had comparable survival characteristics (1 year survival 77% vs 86%; 3 year survival 53% vs 60%; p = 0.68). <b>Conclusions:</b> Patients with distal CTEPH share certain demographic features with patients with proximal CTEPH that not only indicate a common aetiology but also help to differentiate them from patients with IPAH. Despite more favourable haemodynamic parameters in those with distal CTEPH, patients in this group had a poor long-term outcome which was similar to that of patients with IPAH.