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Sökning: WFRF:(Mwinyi Jessica) > Övrigt vetenskapligt/konstnärligt

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  • Ciuculete, Diana-Maria, et al. (författare)
  • Response to Leusink et al.
  • 2017
  • Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 566-566
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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  • Mohammad, Salahuddin (författare)
  • Investigating mental health disorders in relation to job and living related factors
  • 2023
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Job satisfaction plays an important role for life quality and health of working individuals. While studies have shown that self-reported mental health conditions such as stress, anxiety and depression are associated with job satisfaction, a large population-based study exploring and comparing self-reported physician posed diagnosed conditions and their association with job satisfaction and job tenure is missing. First study addresses the gap along with exploring the impact of the neurotic personality trait and other possible contributing factors.Individuals with autism spectrum disorder (ASD) experience lower well-being as demonstrated epidemiologically mostly for children and adolescents. Further etiological investigation of inclusive wellbeing, in terms of five wellbeing spectrum (5-WBS) traits including neuroticism, depression, loneliness, life satisfaction and positive affect, among adults with ASD may deepen the understanding. Seond study aims to investigate if a genetic predisposition for ASD is associated with 5-WBS traits using polygenic risk score (PRS) analysis.In the first study, sixteen mental health disorders diagnosed by physicians, categorized into four major groups were investigated in relation to employment status (108,711 participants) and in relation to job satisfaction and job tenure (34,808 participants). Analyses were performed using linear regression adjusted for age, sex, TDI, BMI, education, physical activity, work hours and neuroticism. In the second study, PRS for ASD were constructed in the UK Biobank (N = 337,423), based on the GWAS conducted by Psychiatric Genetics Consortium (18,381 cases, 27,969 comparisons) using PRSice-2. First study showed Neurotic & Stress Disorders, Eating Disorders and Other Mental Health Disorders were strongly associated with lower job satisfaction and shorter job tenure in both unadjusted and adjusted analyses. Neuroticism was strongly linked to job satisfaction but was not associated with job tenure. Second study showed, ASD PRS significantly predicted associations with all 5-WBS traits, showing a positive association with the negative WBS traits, neuroticism (max R2 = 0.04%, P < 1x10-4, AUC 0.51), depression (max R2 = 0.06%, P < 1x10-4, AUC 0.51), loneliness (max R2 = 0.04%, P < 1x10-4, AUC 0.51) and a negative association with the positive WBS traits, life satisfaction (max R2 = 0.08%, P < 1x10-4, AUC 0.56), positive affect (max R2 = 0.10%, P < 1x10-4, AUC 0.53).Findings of first study clarify the complex relationship of mental health with job satisfaction and job tenure which is very important to understand in designing measures to improve working life participation of individuals with mental health issues. The findings of second study suggest that adults carrying a high load of susceptible SNPs for ASD are more likely to show a decreased well-being.
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  • Mwinyi, Jessica (författare)
  • CYP2C19 and CYP2C9 : new aspects of pharmacogenetics and transcriptional regulation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Cytochrome P450s (CYPs) are responsible for approximately 75% of the phase I-dependent drug metabolism. Several important polymorphisms in these enzymes are known to significantly affect the individual drug response. CYP2C9 and CYP2C19 are polymorphically expressed CYP family members which are responsible for the metabolism of many different clinically important drugs, e.g. anticoagulants, antidepressants and antiulcer drugs. This thesis focuses on novel aspects with regard to the regulation of CYP2C9 and CYP2C19 gene expression. The influence of the recently found common allele variant CYP2C19*17 on CYP2C19 enzyme activity towards two CYP2C19 substrates was investigated in the frame of two pharmacokinetic in vivo studies. The studies compared the single-dose pharmacokinetics of omeprazole and the steady-state kinetics of escitalopram in healthy CYP2C19*17/*17 carriers with the pharmacokinetic outcome obtained for CYP2C19 wild-type subjects. While no significant differences in the metabolic efficacy were observed for escitalopram, CYP2C19*17/*17 subjects showed significantly lower plasma levels of omeprazole compared to CYP2C19 wild type carriers. This observation suggests that CYP2C19*17/*17 carriers might be at a higher risk for therapy failure during treatment with proton pump inhibitors. The transcriptional regulation of CYP2C9 and CYP2C19 gene expression by GATA transcription factors and by estrogen receptor α (ERα) was investigated in vitro. In the proximal promoter regions of both the CYP2C9 and the CYP2C19 gene, two adjacent putative GATA-binding sites with an ER-binding half-site in their vicinity were predicted in silico and initially studied by luciferase gene reporter assay. HepG2 and Huh-7 hepatoma cells were transfected with CYP2C9 or CYP2C19 promoter fragment carrying pGL3basic-constructs along with expression vectors for the transcription factors GATA-2, GATA-4, or ERα. Luciferase activities driven by wild-type CYP2C19 or CYP2C9 promoter were highly increased by GATA-4 and GATA-2 in both cell lines, whereas mutations introduced into the GATA binding sites or the co-transfection of the GATA-4 antagonist FOG-2 caused a significant loss of luciferase activity. In contrast, treatment with estradiol derivatives of ERα-transfected cells caused a significant inhibition of CYP2C19 and CYP2C9 promoter activity that was antagonized by site-directed mutagenesis of the putative ERα-binding half-sites. Additionally, estradiol derivatives significantly suppressed both CYP2C9 and CYP2C19 mRNA expression in human hepatocytes, as measured by real time PCR. Electrophoretic mobility shift assays revealed sequence-specific binding of GATA-4, GATA-6, and ERα to the two adjacent GATA binding sites and to the predicted ER binding half sites, respectively. ChIP assay in the cultured cells furthermore confirmed the association of both GATA-4 and ERα with CYP2C9 and CYP2C19 gene promoter. In conclusion, we have established novel mechanisms of CYP2C9 and CYP2C19 transcriptional regulation that involve transcription factors from the GATA family and estrogen receptor ?. The estrogen mediated regulation may explain the clinically observed inhibitory effects of oral contraceptives on CYP2C19 and CYP2C9 activity.
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  • Olivo, Gaia, MD, 1989- (författare)
  • Brain Structure and Function in Adolescents with Atypical Anorexia Nervosa
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Atypical anorexia nervosa (AAN) has a high incidence in adolescents, resulting in significant morbidity and mortality. The weight loss is generally less pronounced than that experienced in full-syndrome anorexia nervosa (AN), but the medical consequences can be as severe. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders, however research on adolescents is limited, and no neuroimaging studies have been conducted in AAN. In paper I, we investigated brain structure through a voxel-based morphometry analysis in 22 drug-naïve adolescent females newly-diagnosed with AAN, and 38 age- and sex-matched healthy controls. In Paper II, we investigated white matter microstructural integrity on 25 drug-naïve adolescent patients with AAN and 25 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. No differences in brain structure could be detected, indicating preserved regional grey matter volumes and white matter diffusivity in patients with AAN compared to controls. These findings suggest that previous observations of brain structure alterations in full syndrome AN may constitute state-related consequences of severe underweight. Alternatively, the preservation of brain structure might indeed differentiate AAN from AN. In paper III, we investigated resting-state functional connectivity in 22 drug-naïve adolescent patients with AAN, and 24 healthy controls. We report reduced connectivity in patients in brain areas involved in face-processing and social cognition, while an increased connectivity, correlating with depressive symptoms, was found in areas involved in the multimodal integration of sensory stimuli, aesthetic judgment, and social rejection anxiety. These findings point toward a core role for an altered development of socio-emotional skills in the pathogenesis of AAN. In Paper IV, we investigated neural connectivity underlying visual processing of foods with different caloric content in a sample of 28 adolescent females diagnosed with AAN, and 33 age- and sex-matched healthy controls. Our results showed higher connectivity in patients in pathways related to the integration of sensory input and memory retrieval, in response to food with high caloric content. This, however, was coupled to lower connectivity in salience and attentional networks, and lower connectivity between areas involved in visual food cues processing and appetite regulatory regions. Thus, despite food with high caloric content is associated to greater processing of somatosensory information in patients, it is attributed less salience and engages patients’ attention less than food with low caloric content.
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  • Welander, Nike (författare)
  • Migraine comorbidities : Associations with psychiatric and gastrointestinal disorders
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Migraine is a prevalent neurological disorder with a complex pathophysiology. One factor that potentially complicates migraine treatment is comorbidity between migraine and other disorders, including psychiatric and gastrointestinal disorders.In Paper I, associations between migraine and symptoms of peripartum depression and anxiety were explored, including assessments in early/mid-pregnancy, late pregnancy and in the postpartum period. A history of migraine was found to be associated with symptoms of anxiety in early/mid-pregnancy and with symptoms of both depression and anxiety in late pregnancy, after adjusting for confounding factors.In Paper II, cross-sectional associations between migraine and several gastrointestinal disorders were investigated. Migraine was associated with irritable bowel syndrome and peptic ulcers in the fully adjusted model. While Helicobacter pylori infection and coeliac disease were associated with migraine in unadjusted analyses, there were no significant associations between migraine and Crohn’s disease or ulcerative colitis.In Paper III, associations between use of proton-pump inhibitors (PPIs) and migraine were investigated. As PPIs are largely metabolised by the enzyme CYP2C19, participants were categorised according to their CYP2C19 phenotypes. PPI use was associated with a greater prevalence and incidence of migraine in both cross-sectional and prospective analyses. Metaboliser phenotype affected some of the outcomes in stratified analyses.In Paper IV, summary statistics from genome-wide association studies were used to assess genetic correlations and causal associations between migraine and both inflammatory bowel disese (IBD) and coeliac disease. There was no evidence of genetic correlations between any of the disorders, and there was no indication of causality. Nominally significant results were obtained in subtype analyses. Together, these results indicate that migraine is associated with symptoms of depression and anxiety in the peripartum period as well as with irritable bowel syndrom, peptic ulcers and use of PPIs in adults, thus adding to the literature on comorbidity in migraine. The previously observed associations between migraine and both IBD and coeliac disease were not corroborated in these studies, and the basis of these associations, if present, does not appear to be accounted for by shared genetics.
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  • Resultat 1-9 av 9

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