GIS for spatial decision-making

Please read the abstract in the section 00front of this documentDissertation (MSc)--University of Pretoria, 2001.Geography, Geoinformatics and MeteorologyMScUnrestricte

Epigenetic management of major psychosis

Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders

GAD1 mRNA Expression and DNA Methylation in Prefrontal Cortex of Subjects with Schizophrenia

Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia

Neuropathological Similarities and Differences between Schizophrenia and Bipolar Disorder: A Flow Cytometric Postmortem Brain Study

Recent studies suggest that schizophrenia (SCH) and bipolar disorder (BPD) may share a similar etiopathology. However, their precise neuropathological natures have rarely been characterized in a comprehensive and quantitative fashion. We have recently developed a rapid, quantitative cell-counting method for frozen unfixed postmortem brains using a flow cytometer. In the present study, we not only counted stained nuclei, but also measured their sizes in the gray matter of frontopolar cortices (FPCs) and inferior temporal cortices (ITCs) from patients with SCH or BPD, as well as in that from normal controls. In terms of NeuN(+) neuronal nuclei size, particularly in the reduced densities of small NeuN(+) nuclei, we found abnormal distributions present in the ITC gray matter of both patient groups. These same abnormalities were also found in the FPCs of SCH patients, whereas in the FPCs of BPD patients, a reduction in oligodendrocyte lineage (olig2(+)) cells was much more common. Surprisingly, in the SCH FPC, normal left-greater-than-right asymmetry in neural nuclei densities was almost completely reversed. In the BPD FPC, this asymmetry, though not obvious, differed significantly from that in the SCH FPC. These findings indicate that while similar neuropathological abnormalities are shared by patients with SCH or BPD, differences also exist, mainly in the FPC, which may at least partially explain the differences observed in many aspects in these disorders

Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

<p>Abstract</p> <p>Background</p> <p>The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC).</p> <p>Results</p> <p>This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged.</p> <p>Conclusion</p> <p>The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.</p

Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance.Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003–2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups.Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p &lt; 0.01).Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia

In recent years, numerous substances have been identified as so-called “endocrine disruptors” because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed

Tourism Management Plan for Concession Area CH/12 : GIS Plan

This document represents the Tourism Management Plan for CH/12 concession area residing in the Nunga Wildlife Management Area (WMA). Its purpose is to provide a framework for management of the values and use of CH/12 that is approved by relevant authorities, notably Botswana Tourism Organisation and Chobe Land Board. This Plan sets objectives for the concession area, recommends management prescriptions both as policy and as management actions to realise the objectives, and advises on a monitoring system to evaluate whether the objectives are being achieved. It also proposes the management framework within which subsequent implementation and further detailed planning will take place.The Tourism Management Plan for CH/12 has been developed against the backdrop of the planning system in Botswana and to a very large extent, draws guidance and direction from the new Final Draft Wildlife Management Area Regulations of 2010. These have been complemented by reviews of other relevant Management Plans and Reports, field surveys, stakeholder consultations and interviews, as well as, the remits of the Terms of Reference (ToR) as issued by Botswana Tourism Organisation