188 research outputs found
Die Wirkung von Resveratrol auf menschliche BlutplÀttchen
BlutplĂ€ttchen spielen eine wesentliche Rolle in der Entstehung arterieller Thromben. Im Rahmen kardiovaskulĂ€rer Erkrankungen erhöht sich die PlĂ€ttchenaktivitĂ€t und damit auch das Risiko fĂŒr thrombotische Ereignisse. StandardmĂ€Ăig werden Risikopatienten daher mit PlĂ€ttchen hemmenden Pharmaka wie AcetylsalicylsĂ€ure (ASS) behandelt. Dennoch kommt es bei einigen Patienten zu Herzinfarkt oder Schlaganfall. Das wachsende Thema âASS-Resistenzâ stellt die Medizin vor groĂe Probleme, da hierfĂŒr weder die genauen Ursachen bekannt sind noch exakte Diagnostikmöglichkeiten existieren. In den letzten Jahren erlangten sekundĂ€re Pflanzenstoffe immer mehr Aufmerksamkeit fĂŒr die Thrombose-prophylaxe. Insbesondere fĂŒr das in Rotwein enthaltene Polyphenol Resveratrol wurde in vielen Studien gezeigt, dass es die PlĂ€ttchenaggregation hemmen kann. Meist handelt es sich jedoch dabei um in vitro-Versuche. In dieser Arbeit sollte daher die systemische Wirkung eines oral eingenommenen pflanzlichen Resveratrol-Extrakts a) auf die AktivitĂ€t und b) auf die ASS-SensitivitĂ€t menschlicher BlutplĂ€ttchen untersucht werden. Dabei kamen folgende Tests gleichzeitig zum Einsatz:
1. Mit dem PADA (platelet adhesion assay) und dem PADA-RASS (platelet adhesion assay â Resistenz auf ASS) wurden zwei neuartige Tests verwendet, welche mit geringen Scher-krĂ€ften und ohne jegliche Zugabe von kĂŒnstlichen Aktivatoren funktionieren. Man erhĂ€lt das Ergebnis, indem die noch nicht adhĂ€rierten, freien PlĂ€ttchen gezĂ€hlt werden. Der PADA gibt dabei Auskunft ĂŒber die RuheaktivitĂ€t der PlĂ€ttchen. Beim PADA-RASS wird zusĂ€tzlich der Effekt einer in vitro-Zugabe von ASS auf die PlĂ€ttchenaktivitĂ€t gemessen. Zum ersten Mal wurden beide Tests mit Citrat-, Hirudin- und Heparinblut parallel durchgefĂŒhrt, um den Einfluss der Antikoagulation zu untersuchen.
2. Die zweite Methode war das Multiplate-System, das auf dem Prinzip der Impedanz-aggregometrie beruht. Hier induziert die Zugabe verschiedener Aktivatoren (ArachidonsĂ€ure, Kollagen, ADP = Adenosindiphosphat, TRAP = thrombin receptor activating peptide) eine Aggregation der PlĂ€ttchen. Das Ergebnis drĂŒckt aus, wie sich der elektrische Widerstand in der Blutprobe wĂ€hrend der Aggregation Ă€ndert. Der Effekt von ASS wurde durch einen in vitro-Zusatz von ASS getestet.
3. Im Gegensatz zu den oben genannten PlĂ€ttchenfunktionstests wurde mit der Durchflusszytometrie als dritte Methode einzig und allein die Expression des AdhĂ€sionsmolekĂŒls P-Selektin auf der PlĂ€ttchenmembran als MaĂ ihrer AktivitĂ€t bestimmt. Dabei wurde zum einen der Effekt von Resveratrol auf ruhende, unstimulierte PlĂ€ttchen gemessen und zum anderen auf TRAP-aktivierte PlĂ€ttchen
MRI of female genital tract congenital anomalies: European Society of Urogenital Radiology (ESUR) guidelines
OBJECTIVE: To develop imaging guidelines for the MR work-up of female genital tract congenital anomalies (FGTCA). METHODS: These guidelines were prepared based on a questionnaire sent to all members of the European Society of Urogenital Radiology (ESUR) Female Pelvic Imaging Working Group (FPI-WG), critical review of the literature and expert consensus decision. RESULTS: The returned questionnaires from 17 different institutions have shown reasonable homogeneity of practice. Recommendations with focus on patient preparation and MR protocol are proposed, as these are key to optimised examinations. Details on MR sequences and planning of uterus-orientated sequences are provided. CONCLUSIONS: The multiplanar capabilities and soft tissue resolution of MRI provide superb characterisation of the wide spectrum of findings in FGTCA. A standardised imaging protocol and method of reporting ensures that the salient features are recognised, contributing to a correct diagnosis and classification of FGTCA, associated anomalies and complications. These imaging guidelines are based on current practice among expert radiologists in the field and incorporate up to date information regarding MR protocols and essentials of recently published classification systems. KEY POINTS: * MRI allows comprehensive evaluation of female genital tract congenital anomalies, in a single examination. * A dedicated MRI protocol comprises uterus-orientated sequences and vaginal and renal evaluation. * Integration of classification systems and structured reporting helps in successful communication of the imaging findings
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Genome-wide association study identifies 30 loci associated with bipolar disorder.
Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with Pâ<â1âĂâ10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (Pâ<â5âĂâ10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder
Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and post-treatment depressive symptom trajectory
Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development
Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (nâ=â1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (nâ=â321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (pâ=â0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers
Common variants at 2q11.2, 8q21.3, and 11q13.2 are associated with major mood disorders
Bipolar disorder (BPD) and major depressive disorder (MDD) are primary major mood disorders. Recent studies suggest that they share certain psychopathological features and common risk genes, but unraveling the full genetic architecture underlying the risk of major mood disorders remains an important scientific task. The public genome-wide association study (GWAS) data sets offer the opportunity to examine this topic by utilizing large amounts of combined genetic data, which should ultimately allow a better understanding of the onset and development of these illnesses. Genome-wide meta-analysis was performed by combining two GWAS data sets on BPD and MDD (19,637 cases and 18,083 controls), followed by replication analyses for the loci of interest in independent 12,364 cases and 76,633 controls from additional samples that were not included in the two GWAS data sets. The single-nucleotide polymorphism (SNP) rs10791889 at 11q13.2 was significant in both discovery and replication samples. When combining all samples, this SNP and multiple other SNPs at 2q11.2 (rs717454), 8q21.3 (rs10103191), and 11q13.2 (rs2167457) exhibited genome-wide significant association with major mood disorders. The SNPs in 2q11.2 and 8q21.3 were novel risk SNPs that were not previously reported, and SNPs at 11q13.2 were in high LD with potential BPD risk SNPs implicated in a previous GWAS. The genome-wide significant loci at 2q11.2 and 11q13.2 exhibited strong effects on the mRNA expression of certain nearby genes in cerebellum. In conclusion, we have identified several novel loci associated with major mood disorders, adding further support for shared genetic risk between BPD and MDD. Our study highlights the necessity and importance of mining public data sets to explore risk genes for complex diseases such as mood disorders
Prediction of lithium response using genomic data
Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and WĂŒrzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures
Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for nâ=â2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD
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