| 1. |
- Chourbaji, Sabine, et al.
(författare)
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CREB-regulated diurnal activity patterns are not indicative for depression-like symptoms in mice and men.
- 2008
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Ingår i: Medical Hypotheses. - : Elsevier BV. - 0306-9877 .- 1532-2777. ; 70:1, s. 117-21
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREB(S142A) mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREB(S142A) mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREB(S142A) mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms.
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| 2. |
- Jensen, Karin B, et al.
(författare)
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Increased sensitivity to thermal pain following a single opiate dose is influenced by the COMT val(158)met polymorphism.
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Increased pain sensitivity after opioid administration (opioid-induced hyperalgesia) and/or repeated painful stimuli is an individually varying and clinically important phenomenon. The functional polymorphism (val(158)met) of the Catechol-O-methyltransferase (COMT) gene regulates the metabolism of dopamine/noradrenaline. Individuals homozygous for the met(158) allele have been reported to have increased pain sensitivity and there are findings of lower micro-opioid system activation during sustained pain. We hypothesized that met/met individuals would exhibit higher pain sensitization and opioid-induced hyperalgesia in response to repeated pain stimuli and an intravenous injection of an opioid drug. Participants were 43 healthy subjects who went through an experiment where five blocks of pain were induced to the hand using a heat probe. After each stimulus subjects rated the pain on a visual analogue scale (VAS) from 0 mm (no pain) to 100 mm (worst possible pain). Before the second stimulus there was an intravenous injection of a rapid and potent opioid drug. At baseline there was no difference in pain ratings between the COMTval(158)met genotypes, F(2, 39)<1. However, a repeated measures ANOVA for all five stimuli revealed a main effect for COMTval(158)met genotype, F(2, 36) = 4.17, p = 0.024. Met/met individuals reported significantly more pain compared to val/val, p = 0.010. A pairwise comparison of baseline and the opioid intervention demonstrated that analgesia was induced in all groups (p = 0.042) without a separating effect for genotype (n.s). We suggest that the initial response of the descending pain system is not influenced by the COMTval(158)met polymorphism but when the system is challenged the difference is revealed. An important clinical implication of this may be that the COMTval(158)met related differences may be more expressed in individuals where the inhibitory system is already challenged and sensitive, e.g. chronic pain patients. This has to be proven in future studies where the impact of the COMTval(158)met polymorphism on opioid treatment in patients is addressed.
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| 3. |
- Kosek, Eva, et al.
(författare)
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Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans.
- 2009
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders.RESULTS: At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression.CONCLUSION: This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.
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| 4. |
- Partonen, Timo, et al.
(författare)
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Three circadian clock genes Per2, Arnt1, and Npas2 contribute to winter depression
- 2007
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Ingår i: Annals of Medicine. - New York : Informa Healthcare. - 0785-3890 .- 1365-2060. ; 39:3, s. 229-238
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Tidskriftsartikel (refereegranskat)abstract
- Background. Multiple lines of evidence suggest that the circadian clock contributes to the pathogenesis of winter depression or seasonal affective disorder (SAD). We hypothesized that sequence variations in three genes, including Per2, Arntl, and Npas2, which form a functional unit at the core of the circadian clock, predispose to winter depression.Methods. In silico analysis of the biological effects of allelic differences suggested the target single-nucleotide polymorphisms (SNPs) to be analyzed in a sample of 189 patients and 189 matched controls. The most relevant SNP in each gene was identified for the interaction analysis and included in the multivariate assessment of the combined effects of all three SNPs on the disease risk.Results. SAD was associated with variations in each of the three genes in gene-wise logistic regression analysis. In combination analysis of variations of Per2, Arntl, and Npas2, we found additive effects and identified a genetic risk profile for the disorder. Carriers of the risk genotype combination had the odds ratio of 4.43 of developing SAD as compared with the remaining genotypes, and of 10.67 as compared with the most protective genotype combination.Conclusion. Variations in the three circadian clock genes Per2, Arntl, and Npas2 are associated with the disease, supporting the hypothesis that the circadian clock mechanisms contribute to winter depression.
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| 5. |
- Beleza-Meireles, Ana, et al.
(författare)
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Complex aetiology of an apparently Mendelian form of mental retardation
- 2008
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated. METHODS: After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree. RESULTS: No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status. CONCLUSION: These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons may underlie the phenotypic variation of intelligence and explain instances of intellectual impairment.
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| 8. |
- Lonsdorf, Tina B, et al.
(författare)
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The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism
- 2009
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Ingår i: Progress in Neuro-psychopharmacology and Biological Psychiatry. - : Elsevier BV. - 0278-5846 .- 1878-4216. ; 33:8, s. 1479-1483
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Forskningsöversikt (refereegranskat)abstract
- The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case-control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery-Asberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.
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| 9. |
- Oliynyk, Igor, et al.
(författare)
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Azithromycin increases chloride efflux from cystic fibrosis airway epithelial cells
- 2009
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Ingår i: Experimental Lung Research. - : Taylor & Francis. - 0190-2148 .- 1521-0499. ; 35:3, s. 210-221
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Tidskriftsartikel (refereegranskat)abstract
- It was investigated whether azithromycin (AZM) stimulates chloride (Cl−) efflux from cystic fibrosis (CF) and non-CF airway epithelial cells, possibly secondary to up-regulation of the multidrug resistance protein (MDR). CF and non-CF human airway epithelial cell lines (CFBE and 16HBE) were treated with 0.4, 4, and 40 μ g/mL AZM for 4 days. Cl− efflux was explored in the presence or absence of specific inhibitors of CFTR and alternative Cl− channels. Six CF patients received AZM (500 mg daily) for 6 months. The percentage of predicted forced vital capacity (FVC%), forced expiratory volume (FEV1%), and the number of acute exacerbations were compared before and after treatment. Nasal biopsies were taken before and after treatment, and mRNA expression of MDR and CFTR was determined by in situ hybridization. A significant dose-dependent increase of Cl− efflux from CFBE cells (but not from 16HBE cells) was observed after AZM treatment. A CFTR inhibitor significantly reduced AZM-stimulated Cl− efflux from CFBE cells. A significant improvement in FEV1%, and fewer exacerbations were observed. AZM treatment did not affect mRNA expression of MDR and CFTR. The stimulation of Cl− efflux could be part of the explanation for the clinical improvement seen among the patients.
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