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Helge Rootwelt

Publications and source records attributed to Helge Rootwelt.

7 recordsLinked to original sources
PubMed2006

Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4.

Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48-75 years. Fifty nine were APOE epsilon 4- (no epsilon 4 allele) and 37 were epsilon 4+ (1 or 2 epsilon 4 alleles). The genotype groups had similar age, sex and IQ. Two T(1)-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. epsilon 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the epsilon 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer's disease (AD), we conclude that APOE epsilon 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-beta aggregation (occipitotemporal and basal temporal cortex).

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PubMed2006

The G protein beta3 subunit 825C allele is associated with sudden infant death due to infection.

AIM: To investigate the Gbeta3 subunit C825T polymorphism with regard to sudden unexpected infant death. The reported association between the Gbeta3s protein and increased immune cell function in humans makes this polymorphism highly interesting both with regard to sudden infant death syndrome (SIDS) and deleterious infectious disease. METHODS: The cases investigated in the present study consist of 250 SIDS cases, 38 cases of sudden unexpected infant death due to infection and 99 living infant controls. Typing of the C825T polymorphism was performed by real-time PCR with allele-specific probes and melting curve analyses. RESULTS: The cases of infectious death have a higher percentage of both the C allele (p=0.037 compared to the SIDS cases, p=0.022 compared to the controls) and the CC genotype (p=0.05 compared to the SIDS cases, p=0.016 compared to the controls). There were no differences between SIDS cases and controls. CONCLUSION: The observed association between the 825C allele and infectious death may indicate that the presence of the 825T allele exerts a protective effect towards serious infection, possibly through enhanced G protein signalling. The C allele, on the other hand, appears to represent a disadvantage in this regard.

Alleles↗
PubMed2006

Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults.

In the present study, we investigated age-related changes in interactions between efficiency of neuronal repair mechanisms and efficiency of cholinergic neurotransmission in the context of attentional orienting. In addition, we explored white matter volume changes as possible neuronal underpinnings. A sample of 230 healthy middle-aged (53-64 years) and older (65-75 years) adults was genotyped for polymorphisms of APOE and CHRNA4, a nicotinic receptor subunit gene. Participants were administered a visuospatial attention task involving letter discrimination with location cues of varying validity. Genotype effects on white matter volume were also investigated in a subset of participants who received MRI scans. APOE interacted with CHRNA4, such that APOE-epsilon4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues. The interaction was stronger in the middle-aged participants than in the older participants. There was also a trend for individuals with combined APOE-epsilon4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task The interaction of a neurotransmission gene (CHRNA4) and a susceptibility gene (APOE) suggests that the efficiency of neuronal repair mechanisms may modulate the cholinergic system to influence attentional function.

Aged↗
PubMed2003

Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl-coenzyme A (CoA) desaturase 1, and stearoyl-CoA desaturase 2 in rat testis.

In mammalian cells, essential polyunsaturated fatty acids (PUFAs) are converted to longer PUFAs by alternating steps of elongation and desaturation. In contrast to other PUFA-rich tissues, the testis is continuously drained of these fatty acids as spermatozoa are transported to the epididymis. Alteration of the germ cell lipid profile from spermatogonia to condensing spermatids and mature spermatozoa has been described, but the male gonadal gene expression of the desaturases, responsible for the PUFA-metabolism, is still not established. The focus of this study was to characterize the expression and regulation of stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), and Delta5- and Delta6-desaturase in rat testis. Desaturase gene expression was detected in testis, epididymis, and separated cells from seminiferous tubulus using Northern blot analysis. For the first time, SCD1 and SCD2 expression is demonstrated in rat testis and epididymis, both SCDs are expressed in epididymis, while testis mainly contains SCD2. Examination of the testicular distribution of Delta5- and Delta6-desaturase and SCD1 and SCD2 shows that all four desaturases seem to be localized in the Sertoli cells, with far lower expression in germ cells. In light of earlier published results showing that germ cells are richer in PUFAs than Sertoli cells, this strengthens the hypothesis of a lipid transport from the Sertoli cells to the germ cells. As opposed to what is shown in liver, Delta5- and Delta6-desaturase mRNA levels in Sertoli cells are up-regulated by dexamethasone. Furthermore, dexamethasone induces SCD2 mRNA. Insulin also up-regulates these three genes in the Sertoli cell, while SCD1 mRNA is down-regulated by both insulin and dexamethasone. Delta5- and Delta6-desaturase, SCD1, and SCD2 are all up-regulated by FSH. A similar up-regulation of the desaturases is observed when treating Sertoli cells with (Bu)2cAMP, indicating that the desaturase up-regulation observed with FSH treatment results from elevated levels of cAMP. Finally, testosterone has no influence on the desaturase gene expression. Thus, FSH seems to be a key regulator of the desaturase expression in the Sertoli cell.

Animals↗
PubMed2002

[Individualized pharmacotherapy based on cytochrome P-450 (CYP) genotyping].

BACKGROUND: Genetic polymorphisms of the drug-metabolising cytochrome P-450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6 have been characterized, and several of these variants lead to reduced or absent activity. This is of clinical importance mainly in patients having two non-functional alleles, phenotypically characterised as "poor metabolisers" (1-10% of Caucasians). Since most drugs are transformed into inactive or less active metabolites, "poor metabolisers" are at increased risk of developing drug induced adverse reactions. MATERIAL AND METHODS: Studies of relevant literature (MedLine search) in addition to our own experiences, show that CYP genotyping can predict the phenotype and thereby explain some abnormal drug responses and may be used to individualize pharmacotherapy. RESULTS: At present, CYP genotyping (CYP2C9/2C19/2D6) is most frequently requested in psychiatry and anticoagulant therapy, but the field is expanding. Important factors for implementation of pharmacogenetic methods are accuracy of diagnosis, quality of reports, response time, and cost. INTERPRETATION: Pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The expenses of full genotyping (CYP2C9/2C19/2D6) are equivalent to one day of sick leave. One might ask: Are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness?

Cytochrome P-450 Enzyme System↗
PubMed2002

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.

OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.

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