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Articles by N Scherbaum
Total Records ( 3 ) for N Scherbaum
  J Treutlein , S Cichon , M Ridinger , N Wodarz , M Soyka , P Zill , W Maier , R Moessner , W Gaebel , N Dahmen , C Fehr , N Scherbaum , M Steffens , K. U Ludwig , J Frank , H. E Wichmann , S Schreiber , N Dragano , W. H Sommer , F Leonardi Essmann , A Lourdusamy , P Gebicke Haerter , T. F Wienker , P. F Sullivan , M. M Nothen , F Kiefer , R Spanagel , K Mann and M. Rietschel

Context  Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.

Objective  To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.

Design  The GWAS tested 524 396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10–4 were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.

Setting  Five university hospitals in southern and central Germany.

Participants  The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.

Main Outcome Measures  Significant association findings in the GWAS and follow-up study with the same alleles.

Results  The GWAS produced 121 SNPs with nominal P < 10–4. These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10–9; rs1344694, P = 1.69 x 10–8). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.

Conclusions  This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.

  N Ansermot , O Albayrak , J Schlapfer , S Crettol , M Croquette Krokar , M Bourquin , J. J Deglon , M Faouzi , N Scherbaum and C. B. Eap

Background  Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go–related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias.

Methods  To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken.

Results  The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of –3.9 ms (95% confidence interval [CI], –7.7 to –0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006).

Conclusions  Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

  B Schiffer , B. W Muller , N Scherbaum , M Forsting , J Wiltfang , N Leygraf and E. R. Gizewski

Despite a high prevalence of schizophrenia patients with comorbid substance abuse, little is known about possible impacts on the brain. Hence, our goal was to determine whether addicted and non-addicted schizophrenic patients suffer from different brain deficits. We were especially interested to determine if grey matter volumes were affected by impulsivity. We hypothesized that (comorbid) substance abuse would be associated with enhanced impulsivity and that this enhanced impulsivity would be related to grey matter volume deficits in prefrontal areas. We employed a voxel-based morphometry approach as well as neuropsychological assessment of executive functions and trait impulsivity in 51 participants (age range 23–55). The schizophrenia group comprised 24 patients (12 patients with paranoid schizophrenia and 12 with additional comorbid substance use disorders). The comparison group comprised 27 non-schizophrenic individuals, matched by age and education (14 healthy individuals and 13 patients with substance use disorders). Total grey matter volume deficits were found in all patient groups as compared with healthy controls but were largest (~8%) in both addicted groups. While grey matter volume losses in lateral orbitofrontal and temporal regions were affected by schizophrenia, volume decreases of the medial orbitofrontal, anterior cingulate and frontopolar cortex were associated with addiction. Compared with non-addicted schizophrenics, comorbid patients showed significant volume decreases in anterior cingulate, frontopolar and superior parietal regions. Additionally, they showed an increased non-planning impulsivity that was negatively related to grey matter volumes in the same regions, except for parietal ones. The present study indicates severe grey matter volume and functional executive deficits in schizophrenia, which were only partially exacerbated by comorbid addiction. However, the relationship between non-planning impulsivity and anterior cingulate and frontopolar grey matter volumes points to a specific structure–function relationship that seems to be impaired in schizophrenia-addiction comorbidity.

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