RESUMO
Schizophrenic psychoses are the result of a multifactorial process in which not only environmental influences but also genetic factors play an important role. These factors are based on a complex mode of inheritance that involves a large number of genetic variants. In the last three decades, biological psychiatric research has focused closely on molecular genetic aspects of the hereditary basis of schizophrenic psychoses. In particular, international consortia are combining cohorts from individual researchers, creating continuously increasing sample sizes and thus increased statistical power. As part of the Psychiatric Genomics Consortium (PGC), genome-wide association studies with tens of thousands of patients and controls have for the first time found robustly replicable markers for schizophrenic psychoses. Through intensive phenotyping, first approaches to a transdiagnostic clinical reclassification of severe mental illnesses have been established in the longitudinal PsyCourse study of the UMG Göttingen and the LMU Munich, allowing new biologically validated disease subgroups with prognostic value to be identified. For the first time environmental factors could even be examined in an African cohort that contribute to the development of the psychosis. In the coming years, the enormous technical progress in the area of genomic high-throughput technologies (next-generation sequencing) is expected to provide new knowledge not only about the influence of frequently occurring single nucleotide polymorphisms but also about rare variants. For the successful use of this technological revolution an exchange of data between research groups is essential.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Disseminação de Informação , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genéticaRESUMO
OBJECTIVE: To undertake a large-scale clinical study of predictors of lithium (Li) response in bipolar I disorder (BD-I) and apply contemporary multivariate approaches to account for inter-relationships between putative predictors. METHODS: We used network analysis to estimate the number and strength of connections between potential predictors of good Li response (measured by a new scoring algorithm for the Retrospective Assessment of Response to Lithium Scale) in 900 individuals with BD-I recruited to the Consortium of Lithium Genetics. RESULTS: After accounting for co-associations between potential predictors, the most important factors associated with the good Li response phenotype were panic disorder, manic predominant polarity, manic first episode, age at onset between 15-32 years and family history of BD. Factors most strongly linked to poor outcome were comorbid obsessive-compulsive disorder, alcohol and/or substance misuse, and/or psychosis (symptoms or syndromes). CONCLUSIONS: Network analysis can offer important additional insights to prospective studies of predictors of Li treatment outcomes. It appears to especially help in further clarifying the role of family history of BD (i.e. its direct and indirect associations) and highlighting the positive and negative associations of different subtypes of anxiety disorders with Li response, particularly the little-known negative association between Li response and obsessive-compulsive disorder.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Adolescente , Adulto , Transtorno Bipolar/complicações , Comorbidade , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Assuntos
Caderinas/genética , Transtornos do Humor/genética , Adulto , Tonsila do Cerebelo/fisiopatologia , Transtorno Bipolar/genética , Encéfalo/fisiopatologia , Caderinas/metabolismo , Cognição/fisiologia , Dendritos , Espinhas Dendríticas , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal , Neurônios , Personalidade/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Sinapses/genética , Sinapses/metabolismoRESUMO
PURPOSE: The aim of this long-term study was the comparison of appendiceal stump closure with polymeric clips or staplers with respect to perioperative costs and surgical outcome under routine conditions in a university centre. METHODS: For this retrospective chart review, a total of 618 patients undergoing laparoscopic appendectomy for suspected acute appendicitis between 2010 and 2017 were reviewed: 410 patients in the stapler group and 208 patients in the clip group. The database contained demographic data, operation time, inflammation parameters, closure method of the stump, surgeon status, length of hospital stay, and complications as well as histology reports. The costs were also compared. RESULTS: Clip application was more likely among younger patients (mean age 33.6 years vs. 41.7 years). Histopathological evidence for appendiceal pathology was found in 96.6% of patients in the clip group and 99.5% of patients in the stapler group. Laparoscopic appendectomy in the clip group was more frequently performed by resident physicians (69.2%) than in the stapler group (57.8%). The mean postoperative stay was 2.9 days in the clip group and 3.7 days in the stapler group. The use of the polymeric clip resulted in considerable cost savings (19.94 vs. 348.70). CONCLUSIONS: The use of polymeric clips for appendiceal stump closure during appendectomy is safe and effective. The base of the appendix is amenable to clipping in 32% of appendectomies in adult patients. This study supports the use of polymeric clips over staplers to decrease cost and environmental impact.
Assuntos
Apendicectomia/métodos , Apendicite/cirurgia , Laparoscopia/métodos , Instrumentos Cirúrgicos , Suturas , Técnicas de Fechamento de Ferimentos/instrumentação , Adulto , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.
Assuntos
Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Farmacogenética/métodos , Transtornos Psicóticos/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/farmacocinética , Antidepressivos Tricíclicos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Povo Asiático/genética , Transtorno Bipolar/genética , Carbamazepina/efeitos adversos , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo/genética , Previsões , Variação Genética/genética , Genótipo , Antígeno HLA-B15/genética , Humanos , Compostos de Lítio/efeitos adversos , Compostos de Lítio/farmacocinética , Farmacogenética/tendências , Transtornos Psicóticos/genéticaRESUMO
Bipolar disorder (BD) has a multifactorial etiology. Its development is influenced by genetic as well as environmental factors. Large genome-wide association studies (GWAS), in which genetic risk allelic variants for the disorder could be replicated for the first time, marked the breakthrough in the identification of the responsible risk genes. In addition to these common genetic variants with moderate effects identified by GWAS, rare variants with a higher penetrance are expected to play a role in disease development. The results of recent studies suggest that copy number variants might contribute to BD development, although to a lesser extent than in other psychiatric disorders, such as schizophrenia or autism. Results from the initial next generation sequencing studies indicate an enrichment of rare variants in pathways and genes that were previously found to be associated with BD. In the field of pharmacogenetics, a risk gene that influences the individual variance in the response to lithium treatment was identified for the first time in a recent large international GWAS. Currently the reported risk alleles do not sufficiently explain the phenotypic variance to be used for individual prediction of disease risk, disease course or response to medication. Future genetic research will provide important insights into the biological basis of BD by the identification of additional genes associated with BD. This knowledge of genetics will help identify potential etiological subgroups as well as cross-diagnostic disease mechanisms.
Assuntos
Transtorno Bipolar/genética , Alelos , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Compostos de Lítio/uso terapêutico , FarmacogenéticaRESUMO
Violence, flight, famine, and natural disasters as well as the absence of a psychosocial healthcare system are major psychological burdens for refugees. The level of provision of mental healthcare is particularly low in developing countries. Internally displaced people and refugees place high demands on the healthcare system because they often suffer from psychiatric disorders, such as depression, posttraumatic stress disorder, and substance use disorders. We present first initiatives to improve psychiatric care in refugee camps in Ethiopia, Kenya, and Sudan. Moreover, we provide first insights into a project based in Northern Iraq and Germany aimed at the treatment of people who were severely traumatized by the terror regime of the so-called Islamic State (IS).
Assuntos
Transtorno Depressivo/terapia , Países em Desenvolvimento , Refugiados/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos Relacionados ao Uso de Substâncias/terapia , África/etnologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/etnologia , Transtorno Depressivo/psicologia , Previsões , Acessibilidade aos Serviços de Saúde/tendências , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Serviços de Saúde Mental/tendências , Oriente Médio/etnologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/etnologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/etnologia , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
People with a migration background are a risk group for psychiatric disorders. Innovative, transnational and sustainable projects are necessary to ensure adequate care for refugees and asylum seekers. Selected projects of the University of Munich, the Charité Berlin and the University of Konstanz show promising approaches in addition to other initiatives.
Assuntos
Atenção à Saúde/organização & administração , Transtornos Mentais/terapia , Programas Nacionais de Saúde , Refugiados/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia , Doença Aguda , Assistência Ambulatorial/organização & administração , Serviços Médicos de Emergência/organização & administração , Etnopsicologia/organização & administração , Alemanha , Hospitais Psiquiátricos , Hospitais Universitários , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Psicoterapia/organização & administração , Encaminhamento e Consulta/organização & administração , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
One hundred years after its conceptual definition as 'Dementia Praecox' by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients' cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.
Assuntos
Transtornos Cognitivos/etiologia , Degeneração Neural/etiologia , Regeneração/fisiologia , Esquizofrenia/complicações , Esquizofrenia/história , Animais , História do Século XIX , História do Século XX , História do Século XXI , HumanosRESUMO
Worldwide the renewable energy sector is expanding at sea to address increasing demands. Recently the race for space in heavily used areas such as the North Sea triggered the proposal of co-locating other activities such as aquaculture or fisheries with passive gears in offshore wind farms (OWFs). Our interdisciplinary approach combined a quantification of spatial overlap of activities by using Vessel Monitoring System and logbook data with a stakeholder consultation to conclude and verify on the actual feasibility of co-location. In the German Exclusive Economic Zone (EEZ) of the North Sea up to 90% of Danish and 40% of German annual gillnet fleet landings of plaice overlapped with areas where OWFs are developed. Our results indicated further that the international gillnet fishery could lose up to 50% in landings within the North Sea German EEZ when OWF areas are closed entirely for fisheries. No spatial overlap was found for UK potters targeting brown crab in the German EEZ. We further identified a number of key issues and obstacles that to date hinder an actual implementation of co-location as a measure in the marine spatial planning process: defining the legal base; implementation of safety regulations; delineation of minimum requirements for fishing vessels such as capacities, quotas, technical equipment; implementation of a licensing process; and scoping for financial subsidies to set up business. The stakeholder consultation verified the scientific findings and highlighted that all those points need to be addressed in a planning process. In the German EEZ we have shown that the socio-economic importance of spatial overlap varies within planning boundaries. Therefore we recommend an interdisciplinary bottom-up approach when scoping for suitable areas of co-location. Hence, an informed marine spatial planning process requires comprehensive and spatial explicit socio-economic viability studies factoring in also ecological effects of OWFs on target species.
Assuntos
Pesqueiros , Energia Renovável , Vento , Animais , Alemanha , Mar do Norte , Opinião Pública , Fatores SocioeconômicosRESUMO
Mental disorders are among the greatest medical and social challenges facing us. They can occur at all stages of life and are among the most important commonly occurring diseases. In Germany 28 % of the population suffer from a mental disorder every year, while the lifetime risk of suffering from a mental disorder is almost 50 %. Mental disorders cause great suffering for those affected and their social network. Quantitatively speaking, they can be considered to be among those diseases creating the greatest burden for society due to reduced productivity, absence from work and premature retirement. The Federal Ministry of Education and Research is funding a new research network from 2015 to 2019 with up to 35 million euros to investigate mental disorders in order to devise and develop better therapeutic measures and strategies for this population by means of basic and translational clinical research. This is the result of a competitive call for research proposals entitled research network for mental diseases. It is a nationwide network of nine consortia with up to ten psychiatric and clinical psychology partner institutions from largely university-based research facilities for adults and/or children and adolescents. Furthermore, three cross-consortia platform projects will seek to identify shared causes of diseases and new diagnostic modalities for anxiety disorders, attention deficit hyperactivity disorders (ADHS), autism, bipolar disorders, depression, schizophrenia and psychotic disorders as well as substance-related and addictive disorders. The spectrum of therapeutic approaches to be examined ranges from innovative pharmacological and psychotherapeutic treatment to novel brain stimulation procedures. In light of the enormous burden such diseases represent for society as a whole, a sustainable improvement in the financial support for those researching mental disorders seems essential. This network aims to become a nucleus for long overdue and sustained support for a German center for mental disorders.
Assuntos
Centros Médicos Acadêmicos/organização & administração , Pesquisa Biomédica/organização & administração , Relações Interinstitucionais , Transtornos Mentais/diagnóstico , Transtornos Mentais/terapia , Pesquisa Translacional Biomédica/organização & administração , Alemanha , Programas Governamentais/organização & administração , Humanos , Modelos OrganizacionaisRESUMO
Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Alelos , Povo Asiático/genética , Encéfalo/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Estudos de Casos e Controles , Cognição , Bases de Dados Genéticas , Regulação para Baixo , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Personalidade/genética , Polimorfismo de Nucleotídeo Único/genética , Mapas de Interação de Proteínas/genética , População Branca/genéticaRESUMO
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Hipocampo/patologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Fenótipo , RNA Mensageiro/metabolismo , População Branca/genéticaRESUMO
BACKGROUND: Schizophrenia is a heterogeneous disorder. Over the years, different approaches have been proposed to approach this heterogeneity by categorizing symptom patterns. The study aimed to compare positive/negative and system-specific approaches to subtyping. METHODS: We used the Positive and Negative Syndrome Scale (PANSS) and Bern Psychopathology Scale (BPS), which consists of subscales for three domains (language, affect and motor behavior) that are hypothesized to be related to specific brain circuits, to assess cross-sectional psychopathological characteristics in a sample of 100 inpatients with schizophrenia spectrum disorders. We then categorized participants into positive/negative and system-specific subgroups to allow comparisons of the two approaches. RESULTS: The analyses revealed correlations between the PANSS positive subscore and the BPS affective subscore (r=.446, p<.001) and between the PANSS negative subscore and the BPS motor behavior subscore (r=.227, p=.023). As regards the positive and negative subtype, more participants were classified as positive in the language-dominant subtype (30.3%) and affect-dominant subtype (30.3%), whereas more were classified as negative in the motor behavior-dominant subtype (44.4%). However, most patients met the criteria for the mixed subtype. CONCLUSIONS: The results suggest that the positive/negative and system-specific approaches can be regarded as complementary. Future studies should examine both approaches in a longitudinal assessment of psychopathological symptoms and link them with qualitative-phenomenological approaches.
Assuntos
Escalas de Graduação Psiquiátrica , Esquizofrenia/classificação , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Avaliação de Sintomas , Adulto , Estudos Transversais , Feminino , Humanos , MasculinoRESUMO
Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes.
Assuntos
Transtornos de Ansiedade/complicações , Canais de Cálcio Tipo L/genética , Depressão , Predisposição Genética para Doença , Personalidade/genética , Caracteres Sexuais , Adulto , Idoso , Transtornos de Ansiedade/genética , Estudos de Coortes , Planejamento em Saúde Comunitária , Depressão/complicações , Depressão/genética , Depressão/psicologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neuroticismo , Inventário de Personalidade , Estudos Retrospectivos , Apoio Social , Estatística como AssuntoRESUMO
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of â¼750,000 high-quality genetic markers on a combined sample of â¼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of â¼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the â¼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Assuntos
Transtorno Bipolar/etnologia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Anquirinas/genética , Anquirinas/metabolismo , Antidepressivos/farmacologia , Povo Asiático/genética , Linhagem Celular Transformada , Citocinas/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Lectinas/genética , Lectinas/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , RNA Mensageiro/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Fatores de Tempo , Ácido Valproico/farmacologia , População Branca/genéticaRESUMO
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, P(bonferroni)<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.
Assuntos
Transtorno Bipolar/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Cerebelo/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
One of the simplest microscopic models for a thermally driven first-order phase transition is an Ising-type lattice system with nearest-neighbour interactions, an external field, and a degeneracy parameter. The underlying lattice and the interaction coupling constant control the anisotropic energy of the phase boundary, the field strength represents the bulk latent heat, and the degeneracy quantifies the difference in communal entropy between the two phases. We simulate the (stochastic) evolution of this minimal model by applying rejection-free canonical and microcanonical Monte Carlo algorithms, and we obtain caloric curves and heat capacity plots for square (2D) and face-centred cubic (3D) lattices with periodic boundary conditions. Since the model admits precise adjustment of bulk latent heat and communal entropy, neither of which affect the interface properties, we are able to tune the crystal nucleation barriers at a fixed degree of undercooling and verify a dimension-dependent scaling expected from classical nucleation theory. We also analyse the equilibrium crystal-melt coexistence in the microcanonical ensemble, where we detect negative heat capacities and find that this phenomenon is more pronounced when the interface is the dominant contributor to the total entropy. The negative branch of the heat capacity appears smooth only when the equilibrium interface-area-to-volume ratio is not constant but varies smoothly with the excitation energy. Finally, we simulate microcanonical crystal nucleation and subsequent relaxation to an equilibrium Wulff shape, demonstrating the model's utility in tracking crystal-melt interfaces at the atomistic level.
RESUMO
In Germany, over half a million operations are done in dermatologic surgery in a hospital setting every year, as well as a less well quantified number of procedures in private offices. In spite of this large number, specific guidelines concerning the use of perioperative antibiotics in dermatologic surgery are sparse. In contrast to procedures in general, visceral or gynecological surgery, general guidelines on perioperative antibiotics issued by the Paul-Ehrlich Institutes and the AWMF do not specifically consider dermatologic operations. Several surveys indicate that familiarity with current recommendations on perioperative antibiotics is suboptimal and resulted in a considerable overuse of perioperative antibiotics in dermatologic surgery. Given the increasing antimicrobial resistance among important pathogens and the inherent risks of antibiotic administration, the decision for the use of prophylactic antibiotics should be based on the individual risk profile of the patient and of the surgical procedure. In the following, we will critically discuss the evidence for perioperative antibiotics in dermatologic surgery.
Assuntos
Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Dermatopatias Bacterianas/prevenção & controle , Infecções dos Tecidos Moles/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Dermatológicos/efeitos adversos , Humanos , Dermatopatias Bacterianas/etiologia , Infecções dos Tecidos Moles/etiologia , Infecção da Ferida Cirúrgica/etiologiaRESUMO
BACKGROUND: The current situation in hospitals is characterized by financial limitations and simultaneously by increasing demands on quality and safety. The operative interface between anesthesia and transfusion medicine affects both factors. AIM: A detailed analysis was performed to evaluate the process quality at this operative interface at the University Hospital of Göttingen. The aim of the project was to revise und develop the structures and responsibilities at this interface, to dispose of weak points and to realize the optimization potential in the supply of blood products. MATERIAL AND METHODS: A databank-based electronic data processing solution was established with the clear definition of responsibilities for the various workflow procedures and the written documentation of these definitions in standard operating protocols. In order to guarantee the necessary transparency a routine reporting system to the department of surgery was established. In addition, a continuous further development of the blood supply standard based on electronic report data was implemented. RESULTS: By implementing the above named measures the rate of supplied to transfused blood products could be increased from 43.1 % to 55.7 %. The compliance with the blood supply standard improved continually over the first 18 months from 60.3 % to 92.3 %. The rate of supplied blood product deliveries without subsequent operation could be reduced from 9.0 % to 4.6 %. As a result of this optimization the supply costs in the internal cost allocation were reduced from 9,406