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  • 1
    Language: English
    In: Frontiers in behavioral neuroscience, 2013, Vol.7, pp.82
    Description: Numerous environmental factors have been identified as influential in the development of schizophrenia. Some are byproducts of modern life, yet others were present in our evolutionary past and persist to a lesser degree in the current era. The present study brings together published epidemiological data for schizophrenia and data on variables related to photic input for places of residence across geographical regions, using rainfall as an inverse, proxy measure for light levels. Data were gathered from the literature for two countries, the former Yugoslavia and Ireland, during a time in the early 20th century when mobility was relatively limited. The data for Yugoslavia showed a strong correlation between hospital census rates for schizophrenia (by place of birth) and annual rain (r = 0.96, p = 0.008). In Ireland, the hospital census rates and first admissions for schizophrenia (by place of permanent residence) showed a trend for correlation with annual rain, reaching significance for 1st admissions when the rainfall data was weighted by the underlying population distribution (r = 0.71, p = 0.047). In addition, across the years 1921-1945, birth-year variations in a spring quarter season-of-birth effect for schizophrenia in Ireland showed a trend for correlation with January-March rainfall (r = 0.80, p ≤ 0.10). The data are discussed in terms of the effect of photoperiod on the gestation and behavior of offspring in animals, and the premise is put forth that vestigial phenotypic plasticity for such photic cues still exists in humans. Moreover, genetic polymorphisms of risk identified for psychotic disorders include genes modulated by photoperiod and sunlight intensity. Such a relationship between phenotypic plasticity in response to a particular environmental regime and subsequent natural selection for fixed changes in the environmentally responsive genes, has been well studied in animals and should not be discounted when considering human disease.
    Keywords: Epidemiology ; Melanotropin ; Natural Light ; Photoperiod ; Prenatal ; Pyschoses ; Schizophrenia ; Vitamin D
    ISSN: 1662-5153
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  • 2
    In: Addiction, October 2017, Vol.112(10), pp.1882-1883
    Description: Byline: Christine L. Miller Keywords: Cannabis; causal; clinically administered I.sub.9-tetrahydrocannabinol; family history; gene-environment; other drugs; psychosis; recovery; schizophrenia; siblings ***** No abstract is available for this article. *****
    Keywords: Cannabis ; Causal ; Clinically Administered Δ 9 ‐Tetrahydrocannabinol ; Family History ; Gene‐Environment ; Other Drugs ; Psychosis ; Recovery ; Schizophrenia ; Siblings
    ISSN: 0965-2140
    E-ISSN: 1360-0443
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  • 3
    In: Nature, 2011, Vol.478(7368), p.197
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    In: Nature, 2005, Vol.434(7035), p.904
    Description: Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase 2 (Hyal2), which is not functional as a receptor in mice but is functional in humans. Sheep are immunotolerant of JSRV because of the expression of closely related endogenous retroviruses, which are not present in humans and most other species, and this may facilitate oncogenesis. Here we show that expression of the JSRV envelope (Env) protein alone in lungs of mice, by using a replication-incompetent adeno-associated virus vector, results in tumours with a bronchiolo-alveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumour development was almost entirely blocked in immunocompetent mice. Our results provide a rare example of an oncogenic viral structural protein, show that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicate that immune recognition of Env can protect against JSRV tumorigenesis. ; Includes references ; p. 904-907.
    Keywords: Mice ; Viral Proteins ; Carcinogenesis ; Adenocarcinoma ; Structural Proteins ; Adenoma ; Jaagsiekte Sheep Retrovirus ; Lung Neoplasms ; Lungs ; Histopathology ; Gene Expression ; Pathogenesis ; Envelope Proteins;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Language: English
    In: European Neuropsychopharmacology, March 2015, Vol.25(3), pp.435-440
    Description: Two kynurenine metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are known to inhibit melanin polymer formation in reactions catalyzed by tyrosinase. The present study expands that finding to include inhibition of chlorpromazine-stimulated melanin formation from the endogenous melanin precursor adrenochrome. Several kynurenine pathway metabolites tested had no measurable effect on the reaction: tryptophan, kynurenine, kynurenic acid, quinolinic acid and nicotinic acid. However, at a concentration of 0.5 mM in a pH 7.4 reaction mix, 3-hydroxykynurenine exerted~72% inhibition on product formation and the same concentration of 3-hydroxyanthranilic acid caused complete inhibition. Two other classes of antipsychotic drugs were evaluated in this paradigm, represented by olanzapine and minocycline. Although the adrenochrome reaction of both drugs was strongly inhibited by 3-hydroxyanthranilic acid, 3-hydroxykynurenine inhibited product formation from only the minocycline reaction. The results are discussed in terms of the well-studied kynurenine pathway upregulation in psychotic disorders and how such upregulation may either influence the efficacy of antipsychotic drug treatment or relate to the mechanism of action of these drugs.
    Keywords: Antipsychotic Efficacy ; Chemical Reactions ; Neuromelanin ; Quinones ; Cataract ; Psychosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0924-977X
    E-ISSN: 1873-7862
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  • 6
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e38171
    Description: Borrelia burgdorferi , the agent of Lyme disease, is a spirochetal pathogen with limited metabolic capabilities that survives under highly disparate host-specific conditions. However, the borrelial genome encodes several proteins of the mevalonate pathway (MP) that utilizes acetyl-CoA as a substrate leading to intermediate metabolites critical for biogenesis of peptidoglycan and post-translational modifications of proteins. In this study, we analyzed the MP and contributions of acetate in modulation of adaptive responses in B. burgdorferi . Reverse-transcription PCR revealed that components of the MP are transcribed as individual open reading frames. Immunoblot analysis using monospecific sera confirmed synthesis of members of the MP in B. burgdorferi . The rate-limiting step of the MP is mediated by HMG-CoA reductase (HMGR) via conversion of HMG-CoA to mevalonate. Recombinant borrelial HMGR exhibited a K m value of 132 µM with a V max of 1.94 µmol NADPH oxidized minute −1 (mg protein) −1 and was inhibited by statins. Total protein lysates from two different infectious, clonal isolates of B. burgdorferi grown under conditions that mimicked fed-ticks (pH 6.8/37°C) exhibited increased levels of HMGR while other members of the MP were elevated under unfed-tick (pH 7.6/23°C) conditions. Increased extra-cellular acetate gave rise to elevated levels of MP proteins along with RpoS, CsrA Bb and their respective regulons responsible for mediating vertebrate host-specific adaptation. Both lactone and acid forms of two different statins inhibited growth of B. burgdorferi strain B31, while overexpression of HMGR was able to partially overcome that inhibition. In summary, these studies on MP and contributions of acetate to host-specific adaptation have helped identify potential metabolic targets that can be manipulated to reduce the incidence of Lyme disease.
    Keywords: Research Article ; Biology ; Medicine ; Infectious Diseases ; Microbiology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Brain Research, Feb 16, 2006, Vol.1073-1074, p.25(13)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.brainres.2005.12.056 Byline: Christine L. Miller (a), Ida C. Llenos (b), Jeannette R. Dulay (b), Serge Weis (b) Keywords: Tryptophan dioxygenase; Tryptophan pyrrolase; Gene expression; Metabolic pathway; Psychosis; HPLC; RT-PCR; Immunohistochemistry; Mental disorder Abstract: Upregulation of the kynurenine pathway has been associated with several etiologies of psychosis, an indication that increased levels of pathway intermediates might be involved in eliciting some psychotic features. In schizophrenia, tryptophan 2,3-dioxygenase (TDO2) was previously identified in postmortem frontal cortex as the enzyme likely responsible for the reported increase in pathway activity in the brain. For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product. The results were unaffected by neuroleptic status or smoking history. To make the distinction between mental disorders with psychosis and those without, this study included patients with bipolar disorder and major depression. Compared to the control group, the HPLC, RT-PCR, and immunohistochemistry results show significant elevation of (1) kynurenine in schizophrenia (1.9-fold, P = 0.02), and in bipolar disorder (1.8-fold, P = 0.04), primarily in the bipolar subgroup with psychosis (2.1-fold, P = 0.03); (2) TDO2 mRNA in schizophrenia (1.7-fold; P = 0.049); and (3) the immunohistochemistry values for the density of TDO2-positive white matter glial cells in schizophrenia (P = 0.01) and in major depression (P = 0.03) as well as the density and intensity of glial cells (in both gray and white matter) stained for TDO2 in bipolar disorder (P = 0.02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration. Author Affiliation: (a) Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University, 600 N. Wolfe St./Blalock 1105, Baltimore, MD 21287, USA (b) Stanley Laboratory for Brain Research and Neuropathology, The Stanley Medical Research Institute, Departments of Psychiatry and Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA Article History: Accepted 11 December 2005
    Keywords: Messenger Rna ; Immunohistochemistry ; Tryptophan ; Bipolar Disorder ; Gene Expression ; Brain ; Schizophrenia ; Enzymes
    ISSN: 0006-8993
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: Cardiovascular Pathology, July-August, 2012, Vol.21(4), p.361(4)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.carpath.2011.11.001 Byline: Silvia Bosio, Surbhi Leekha, Scott I. Gamb, Alan J. Wright, Christine L. Terrell, Dylan V. Miller Keywords: Biofilm; Prosthetic valve; Endocarditis; Mycobacterium fortuitum Abstract: Prosthetic valve endocarditis presents unique challenges for both diagnosis and treatment. A potential role of biofilm has been hypothesized in the pathogenesis of these infections. Article History: Received 18 March 2011; Revised 21 October 2011; Accepted 2 November 2011
    Keywords: Endocarditis ; Prostheses And Implants ; Valves
    ISSN: 1054-8807
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: Schizophrenia Research, April 2014, Vol.154(1-3), pp.119-120
    Keywords: Family Health ; Marijuana Abuse -- Complications ; Schizophrenia -- Complications;
    ISSN: 0920-9964
    E-ISSN: 1573-2509
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  • 10
    Language: English
    In: Schizophrenia Research, September 2009, Vol.113(2-3), pp.259-267
    Description: Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. A single nucleotide polymorphism (SNP) in each of six genes, TDO2, HM74, HM74A, MCHR1, MCHR2 and MC5R, was tested for association with phenotype (475 Caucasians, 88 African Americans with schizophrenia; 97 Caucasians, 3 African Americans with bipolar disorder; 191 Caucasian, 49 African American controls). An A allele in HM74 was significantly associated with schizophrenia and with schizophrenia plus bipolar disorder combined, odds ratios (OR) of 1.48, = 0.011 and 1.50, = 0.007, respectively. Augmentation of disease risk was found for the complex genotype HM74[A,any] + MCHR1[T,any] + MCHR2[C,any] which conferred an OR maximal for the combined diagnostic category of schizophrenia plus bipolar disorder (1.70, = 0.003), carried by 30% of the cases. TDO2[CC] + MC5R[G, any] + MCHR2[GC] conferred an OR maximal for schizophrenia alone (4.84, = 0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melanotropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.
    Keywords: Psychosis ; Gene–Gene Interactions ; Metabolic ; Niacin Receptor ; Tryptophan 2,3-Dioxygenase
    ISSN: 0920-9964
    E-ISSN: 1573-2509
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