3,4-Dehydrodebrisoquine, a novel debrisoquine metabolite formed from 4-hydroxydebrisoquine that affects the CYP2D6 metabolic ratio

Considerable unexplained intersubject variability in the debrisoquine metabolic ratio (urinary debrisoquine/4-hydroxydebrisoquine) exists within individual CYP2D6 genotypes. We speculated that debrisoquine was converted to as yet undisclosed metabolites. Thirteen healthy young volunteers, nine CYP2D6*1 homozygotes [extensive metabolizers (EMs)] and four CYP2D6*4 homozygotes [poor metabolizers (PMs)] took 12.8 mg of debrisoquine hemisulfate by mouth and collected 0- to 8- and 8- to 24-h urines, which were analyzed by gas chromatography-mass spectrometry (GCMS) before and after treatment with beta-glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, liquid chromatography-tandem mass spectrometry, and (1)H NMR. 3,4-Dehydrodebrisoquine is a novel metabolite of debrisoquine excreted variably in 0- to 24-h urine, both in EMs (3.1-27.6% of dose) and PMs (0-2.1% of dose). This metabolite is produced from 4-hydroxydebrisoquine in vitro by human and rat liver microsomes. A previously unstudied CYP2D6*1 homozygote was administered 10.2 mg of 4-hydroxydebrisoquine orally and also excreted 3,4-dehydrodebrisoquine. EMs excreted 6-hydroxydebrisoquine (0-4.8%) and 8-hydroxydebrisoquine (0-1.3%), but these phenolic metabolites were not detected in PM urine. Debrisoquine and 4-hydroxydebrisoquine glucuronides were excreted in a highly genotype-dependent manner. A microsomal activity that probably does not involve cytochrome P450 participates in the further metabolism of 4-hydroxydebrisoquine, which we speculate may also lead to the formation of 1- and 3-hydroxydebrisoquine and their ring-opened products. In conclusion, this study suggests that the traditional metabolic ratio is not a true measure of the debrisoquine 4-hydroxylation capacity of an individual and thus may, in part, explain the wide intragenotype variation in metabolic ratio.

Female-biased dispersal and patrilocal kin groups in a mammal with resource-defence polygyny

In most mammals, dispersal rates are higher in males than in females. Using behavioural and genetic data of individually marked bats, we show that this general pattern is reversed in the greater sac-winged bat (Saccopteryx bilineata). Dispersal is significantly female biased and male philopatry in combination with rare male immigration causes a patrilineal colony structure. Female dispersal helps avoid father-daughter inbreeding, as male tenure exceeds female age at first breeding in this bat species. Furthermore, our data suggest that females may engage in extra-harem copulations to mate with genetically dissimilar males, and thus avoid their male descendants as mating partners. Acquaintance with the natal colony might facilitate territory takeover since male sac-winged bats queue for harem access. Given the virtual absence of male immigration and the possible lower reproductive success of dispersing males, we argue that enhancing the likelihood of settlement of male descendants could be adaptive despite local mate competition. We conclude that resource defence by males is important in promoting male philopatry, and argue that the potential overlap of male tenure and female first conception is the driving force for females to disperse.

Losses of chromosome arms 4q, 8p, 13q and gain of 8q are correlated with increasing chromosomal instability in hepatocellular carcinoma

OBJECTIVE: Chromosomal instability is a key feature in hepatocellular carcinoma (HCC). Array comparative genomic hybridization (aCGH) revealed recurring structural aberrations, whereas fluorescence in situ hybridization (FISH) indicated an increasing number of numerical aberrations in dedifferentiating HCC. Therefore, we examined whether there was a correlation between structural and numerical aberrations of chromosomal instability in HCC. METHODS AND RESULTS: 27 HCC (5 well, 10 moderately, 12 lower differentiated) already cytogenetically characterized by aCGH were analyzed. FISH analysis using probes for chromosomes 1, 3, 7, 8 and 17 revealed 1.46-4.24 signals/nucleus, which correlated with the histological grade (well vs. moderately,p < 0.0003; moderately vs. lower, p < 0.004). The number of chromosomes to each other was stable with exceptions only seen for chromosome 8. Loss of 4q and 13q, respectively, were correlated with the number of aberrations detected by aCGH (p < 0.001, p < 0.005; Mann-Whitney test). Loss of 4q and gain of 8q were correlated with an increasing number of numerical aberrations detected by FISH (p < 0.020, p < 0.031). Loss of 8p was correlated with the number of structural imbalances seen in aCGH (p < 0.048), but not with the number of numerical changes seen in FISH. CONCLUSION: We found that losses of 4q, 8p and 13q were closely correlated with an increasing number of aberrations detected by aCGH, whereas a loss of 4q and a gain of 8q were also observed in the context of polyploidization, the cytogenetic correlate of morphological dedifferentiation.

Synthesis of computations and experiments for obtaining pulsatile gas flow rates from dynamic pressure difference measurements across an orifice-plate meter

The use of conventional orifice-plate meter is typically restricted to measurements of steady flows. This study proposes a new and effective computational-experimental approach for measuring the time-varying (but steady-in-the-mean) nature of turbulent pulsatile gas flows. Low Mach number (effectively constant density) steady-in-the-mean gas flows with large amplitude fluctuations (whose highest significant frequency is characterized by the value fF) are termed pulsatile if the fluctuations have a direct correlation with the time-varying signature of the imposed dynamic pressure difference and, furthermore, they have fluctuation amplitudes that are significantly larger than those associated with turbulence or random acoustic wave signatures. The experimental aspect of the proposed calibration approach is based on use of Coriolis-meters (whose oscillating arm frequency fcoriolis >> fF) which are capable of effectively measuring the mean flow rate of the pulsatile flows. Together with the experimental measurements of the mean mass flow rate of these pulsatile flows, the computational approach presented here is shown to be effective in converting the dynamic pressure difference signal into the desired dynamic flow rate signal. The proposed approach is reliable because the time-varying flow rate predictions obtained for two different orifice-plate meters exhibit the approximately same qualitative, dominant features of the pulsatile flow.

Same-day administration of verteporfin and ranibizumab 0.5 mg in patients with choroidal neovascularisation due to age-related macular degeneration

OBJECTIVE: To evaluate safety of same-day administration of verteporfin and ranibizumab. METHODS: Prospective, open-label, multicentre study; patients with predominantly classic (n = 13) or occult (n = 19) choroidal neovascularisation secondary to age-related macular degeneration received standard-fluence verteporfin at baseline and months 3, 6 and 9, based on fluorescein angiography (FA). Ranibizumab 0.5 mg was administered at baseline and months 1, 2 and 3. MAIN OUTCOME MEASURE: The incidence of severe vision loss (best-corrected visual acuity (BCVA) loss > or = 30 letters; primary safety assessment). RESULTS: No severe vision loss due to ocular inflammation or uveitis occurred. One patient had moderate vision loss (BCVA loss > or = 15 letters). Three patients had mild/moderate uveitis. Two serious ocular adverse events occurred (retinal pigment epithelial tear and moderate BCVA decrease). No systemic adverse events occurred. At 9 months, all lesions were inactive with no recurrent leakage on FA and optical coherence tomography; macular oedema and subretinal fluid resolved. The mean BCVA measured at 2 m improved by 6.9 letters at 4 months and 2.4 letters at 9 months. CONCLUSIONS/APPLICATION TO CLINICAL PRACTICE: Same-day verteporfin and ranibizumab was safe and not associated with severe vision loss or severe ocular inflammation. Lesions stabilized, with minimal treatment required after month 3.

Aktuelle Fragen aus dem Erbrecht: Weiterbildungstagung des Verbandes bernischer Notare und des Instituts für Notariatsrecht und Notarielle Praxis an der Universität Bern vom 19./20. August 2009

Gegenstand des Werks bilden «Aktuelle Fragen aus dem Erbrecht». Das Erbrecht ist ein eigentliches Kerngebiet notarieller Tätigkeit, und Fragen aus dem Erbrecht stellen sich den Notarinnen und Notaren in mannigfacher Hinsicht und in immer wieder neuer Art und Weise. Prof. Dr. Jolanta Kren Kostkiewicz behandelt das im Zeitalter zunehmender Mobilität bedeutender werdende Internationale Erbrecht. Der Beitrag von Prof. Dr. Stephan Wolf gilt dem Thema Erbrecht in besonderen Situationen; er geht ein auf das Konkubinat, die Ehekrise und das neue Erwachsenenschutzrecht.Rechtsanwalt Dr. Philipp Studhalter befasst sich mit praktischen Aspekten der Nutzniessung gemäss Art. 473 ZGB, einem Klassiker der Rechtsgeschäftsgestaltung unter Ehegatten. Notar und Rechtsanwalt Peter Muntwyler und Notar/Grundbuchverwalter Dr. Roland Pfäffli, beide Mitglieder der Musterurkundensammlungs-Kommission des Verbandes bernischer Notare, widmen sich dem Erbenschein in der Praxis.