Schizofreni og genetikk

Summary: Schizophrenia is a mental disorder which affects about 24 million people worldwide. It is caused by a complex interplay of genetic and environmental factors. It would be of value to find out which genes predispose to schizophrenia. For many years geneticists have attempted to figure out which genes are relevant, through linkage studies, association studies and genome wide association studies (GWAS). Several genes and loci have been identified to have a modest effect on schizophrenia, but no single gene or chromosomal locus has been proven to, on its own, be linked to schizophrenia. Through linkage studies, chromosomal regions have been found to possibly have consequences for the development of schizophrenia. Through candidate gene studies, some genes seem to be relevant in schizophrenia. Genome-wide association studies, among other findings, show genetic variation on MHC locus as a contributor to schizophrenia. A major problem has been the reproduction of positive results; typically one positive association study has been followed by negative analyses. A great challenge has been to clarify the reasons for this, and develop new study designs, also considering gene-gene and gene-environment interactions. In this paper I will present an overview of some of today’s genetic challenges in research on schizophrenia

Protective Role of Ramipril and Candesartan against Myocardial Ischemic Reperfusion Injury: A Biochemical and Transmission Electron Microscopical Study

The present study was designed to investigate the role of combined administration of Ramipril and Candesartan against in vitro myocardial ischemic reperfusion injury in rat. Male Wistar albino rats were divided into five groups (n=6) and treated with saline (10 mL/kg), Ramipril (2 mg/kg), Candesartan (1 mg/kg), and the combination of both drugs, respectively 24 h before induction of global ischemia (5 min of stabilization, 9 min of global ischemia, and 12 min of reflow). Combination of Ramipril and Candesartan when compared to the monotherapy significantly increased the levels of superoxide dismutase, reduced glutathione, catalase, and nitric oxide and decreased the levels of thiobarbituric acid reactive substances. In addition, the superior protective role of combination of Ramipril and Candesartan on ischemia induced myocardial damage was further confirmed by well preserved myocardial tissue architecture in light microscopy and transmission electron microscopy analysis studies. The combination was proved to be effective in salvaging the myocardial tissue against ischemic reperfusion injury when compared to the monotherapy of individual drugs and further investigations on protective mechanism of drugs by increasing the nitric oxide level at molecular levels are needed

Cerebrospinal fluid catecholamines in Alzheimer's disease patients with and without biological disease

Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer's disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A-T- cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A-T- cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease

Introduction: The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. Methods: In our longitudinal case–control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. Results: Patients with AD exhibited higher concentrations of KA (β = 0.18, P < 0.01) and picolinic acid (β = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (β = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. Discussion: The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment.publishedVersio

Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging

High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series

Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results

Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

BACKGROUND: The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. METHODS: We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). RESULTS: The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). CONCLUSION: These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine

Rapid Accumulation of CD14+CD11c+ Dendritic Cells in Gut Mucosa of Celiac Disease after in vivo Gluten Challenge

Of antigen-presenting cells (APCs) expressing HLA-DQ molecules in the celiac disease (CD) lesion, CD11c(+) dendritic cells (DCs) co-expressing the monocyte marker CD14 are increased, whereas other DC subsets (CD1c(+) or CD103(+)) and CD163(+)CD11c(-) macrophages are all decreased. It is unclear whether these changes result from chronic inflammation or whether they represent early events in the gluten response. We have addressed this in a model of in vivo gluten challenge.Treated HLA-DQ2(+) CD patients (n = 12) and HLA-DQ2(+) gluten-sensitive control subjects (n = 12) on a gluten-free diet (GFD) were orally challenged with gluten for three days. Duodenal biopsies obtained before and after gluten challenge were subjected to immunohistochemistry. Single cell digests of duodenal biopsies from healthy controls (n = 4), treated CD (n = 3) and untreated CD (n = 3) patients were analyzed by flow cytometry.In treated CD patients, the gluten challenge increased the density of CD14(+)CD11c(+) DCs, whereas the density of CD103(+)CD11c(+) DCs and CD163(+)CD11c(-) macrophages decreased, and the density of CD1c(+)CD11c(+) DCs remained unchanged. Most CD14(+)CD11c(+) DCs co-expressed CCR2. The density of neutrophils also increased in the challenged mucosa, but in most patients no architectural changes or increase of CD3(+) intraepithelial lymphocytes (IELs) were found. In control tissue no significant changes were observed.Rapid accumulation of CD14(+)CD11c(+) DCs is specific to CD and precedes changes in mucosal architecture, indicating that this DC subset may be directly involved in the immunopathology of the disease. The expression of CCR2 and CD14 on the accumulating CD11c(+) DCs indicates that these cells are newly recruited monocytes