The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses.

Previously we derived independent estimates of the effect of the dopamine D2 receptor (DRD2) Ser311Cys polymorphism on risk for schizophrenia using fixed- and random-effects meta-analyses. Both analyses identified a significant association between the Cys allele and schizophrenia, but neither included all available data. Furthermore, genotype data were not evaluated in either analysis, thus precluding any determination of the mode of inheritance. The present study was conducted to resolve discrepancies between the existing meta-analyses, and provide more comprehensive and accurate estimates of the nature and magnitude of the influence of the Ser311Cys polymorphism on risk for schizophrenia. All discrepancies between the two sets of previously meta-analyzed studies were identified and resolved to the mutual satisfaction of the authors, and the final dataset was analyzed independently by fixed- and random-effects meta-analyses. A total of 27 samples, comprising 3,707 schizophrenia patients and 5,363 control subjects, were included in the analyses of allelic association, while smaller numbers of studies and subjects were included in each of the genotypic association analyses. A significant effect of the Cys allele was observed under both fixed-effects (odds ratio [OR] = 1.4; P = 0.002) and random-effects (OR = 1.4; P = 0.007) models. Cys/Ser heterozygotes were at elevated risk for schizophrenia when compared to Ser/Ser homozygotes (fixed- and random-effects OR = 1.4, p(s) or= 0.948). There was no evidence of heterogeneity, excessive influence of any single study, or publication bias in any of the analyses, suggesting that the effect of this DRD2 polymorphism on schizophrenia risk is reliable and uniform across populations, and our estimates of its magnitude are robust and accurate.     

Induction of chromosomal aberrations and spindle disturbances in Chinese hamster epithelial liver cells in culture by pyrene and benzo[a]pyrene quinones

Regioisomers of pyrene and benzo[a]pyrene quinones were testedfor their ability to induce structural and numerical aberrationsand spindle disturbance in Chinese hamster epithelial liver(CHEL) cells in culture. All quinones tested were clastogenicPyrene-1,8-quinone (P-1,8-Q) and benzo[a]pyrene–3,6–quinone(BP-3,6-Q) induced strikingly high levels of triradials. Inaddition, dicentrics and ring chromosomes were very common inBP-3,6-Q-treated cultures. Isomers of these compounds, pyrene-1,6-quinone(P-1,6-Q) and benzo[a]pyrene-1,6-quinone (BP-1,6-Q), inducedunobtrusive patterns of chromosomal aberrations. We suspectthat the P-1,8-Q and BP-3,6-Q moieties bound to the DNA werestill reactive, and formed crosslinks and/or underwent redoxcycling leading to high local concentrations of reactive oxygenspecies. In addition, P-1,8-Q and BP-3,6-Q induced c-mitoses,hyperdiploidies and polyploidies, in particular endoreduplications.These effects were not seen with the other two test compounds,or they were only detected at the highest concentrations used,which were strongly cytotoxic (c-mitoses with P-1,6-Q, polyploidieswith BP-1,6-Q). ⁶To whom correspondence should be addressed at: European Centre for the Validation of Alternative Methods (ECVAM), Joint Research Centre (JRC), TP58O, 1–21020 Ispra, Italy     

Dacryocystorhinostomy in Wegener's granulomatosis

Dacryocystorhinostomy was performed on two patients with Wegener's granulomatosis that had been quiescent for many years. Excellent results were attained, with elimination of dacryocystitis, complete relief from epiphora, and maintenance of a patent outflow tract. No wound necrosis occurred postoperatively, in contrast to a previous report in the literature. Our experience suggests that nasolacrimal duct obstruction in the setting of quiescent Wegener's granulomatosis can be treated safely and effectively with dacryocystorhinostomy.     

Metabolism of the bay-region diol-epoxide of chrysene to a triol-epoxide and the enzyme-catalysed conjugation of these epoxides with glutathione

Metabolic activation of chrysene in mouse skin appears to involver-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene (anti-chrysene-1,2-diol 3, 4-oxide) and 9-hydroxy-r-1,t-2-dihydroxy-t-3, 4-oxy-1,2, 3, 4-tetrahydrochrysene (anti-9-OH-chrysene-1, 2-diol 3,4-oxide). The enzyme-catalysed conjugation of these epoxideswith [³⁵S]glutathione has been studied in experiments in whichthe glutathione conjugates were separated by h.p.l.c. and examinedby fluorescence spectrophotometry. Both anti-chrysene-1, 2-diol3, 4-oxide and anti-9-OH-chrysene-1, 2-diol 3, 4-oxide formedconjugates nonenzymically and both were shown to be substratesfor rat liver glutathione transferases. When anti-chrysene-1,2-diol 3, 4-oxide was incubated with [³⁵S]glutathione and arat liver microsomal metabolizing system, glutathione conjugateswith h.p.l.c. and fluorescence spectral characteristics identicalto those of conjugates formed from both anti-chrysene-1, 2-diol3,4-oxide and anti-9-OH-chrysene-1, 2-diol 3, 4-oxide were detected.This finding provides evidence that anti-chrysene-1, 2-diol3, 4-oxide can be further metabolized to the triolepoxide, anti-9-OH-chrysene-1,2-diol 3, 4-oxide by rat liver microsomal systems.     

Metabolic activation to a mutagen of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, a secondary metabolite of benzo[a]pyrene

3-Hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol)wag isolated from arylsulfatase/ß-glucuronidase-treatedbile of rats to which 3-hydroxybenzo[a]pyrene (3-OH-BP) hasbeen administered. This triol was investigated for mutagenicityin Salmonella typhimurium (reversion to histidine prototrophyof strains TA 97, TA 98, TA 100 and TA 1537) and in V79 Chinesehamster cells (acquisition of resistance to 6-thioguanine).When no exogenous metabolizing system was added the triol wasinactive, while 3-OH-BP showed weak mutagenic effects with allfour bacterial strains. In the presence of NADPH-fortified postmitochondrialsupernatant fraction (S9 mix) of liver homogenate from Aroclor1254-treated rats, the mutagenicity of 3-OH-BP was potentiated,and the triol was activated to a mutagen(s). In the presenceof S9 mix, the triol was 5—18 times more mutagenic than3-OH-BP in strains TA 97, TA 100 and TA 1537, but both compoundsshowed similar mutagenic potencies with strain TA 98. Thesestrain differences strongly suggest that the mutagenicity of3-OH-BP in the S9 mix-mediated test was not exclusively dueto metabolites of 3-OH-BP-7, 8-diol. Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene(BP-7,8-diol), like the triol, showed mutagenic effects onlyin the presence of S9 mix. Strain TA 1537 was reverted by thetriol but not by the diol. In the other bacterial strains thediol was more mutagenic than the triol, the difference in potencybeing largest in strain TA 100 (2.5-to 10-fold, depending onthe experimental conditions). In V79 cells, the diol was a potentmutagen, while the triol showed only very weak mutagenic effects.However the triol was more cytotoxic than the diol. High cytotoxicityof the triol was observed even in the absence of S9 mix. Theresults of the present study demonstrate that metabolites of3-OH-BP-7, 8-diol) are biologically-active derivatives of benzo[a]pyrene.Comparison of the mutagenic effectiveness in different bacterialstrains also reveals that metabolites of 3-OH-BP-7, 8-diol andof BP-7, 8-diol substantially differ in the kind of geneticalterations they evoke.     

Studies on the induction of gene mutations in bacterial and mammalian cells by the ring-opened benzene metabolites trans,trans-muconaldehyde and trans,trans-muconic acid

t,t-Muconaldehyde and t,t-muconic acid have been investigated for the induction of gene mutations in Salmonella typhimurium (reversion of the his- strains TA97, TA98, TA100, TA102, TA104 and TA1535), Escherichia coli (reversion of the trp- strain WP2 uvrA) and Chinese hamster V79 cells (acquisition of resistance toward 6-thioguanine). t,t-Muconaldehyde proved weakly mutagenic in strain TA104 in the presence and absence of NADPH-fortified postmitochondrial fraction from rat liver homogenate (S9 mix). In strains TA97, TA100 and TA102, weak positive responses were observed only in the presence of S9 mix. In strains TA98, TA1535 and WP2 uvrA, the result was negative. In V79 cells, the mutation frequency was increased from approximately 7 X 10(-6) to 90 X 10(-6) in cultures exposed to t,t-muconaldehyde at optimal concentration (1.7-3 microM in separate experiments). The concentration-response curve showed pronounced hyperlinearity, with no mutagenic effect being observed at a third of the optimal concentration. t,t-Muconic acid was greater than 100 times less toxic than t,t-muconaldehyde in both bacteria and mammalian cells, and it did not show any mutagenic effect. These results complete a previous mutagenicity study, carried out on benzene and 13 metabolites. It is concluded that the newly investigated metabolites cannot account for the bacterial mutagenicity of bioactivated benzene and benzene-trans-1,2-dihydrodiol, since these compounds exhibited their strongest response in strain TA1535. t,t-Muconaldehyde showed similarities in its mutagenicity to p-benzoquinone and hydroquinone. All three compounds showed, at most, weak effects in bacteria, but were strongly mutagenic in V79 cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced slow-wave activity within NREM sleep in the cortical and subcortical EEG of the cat after sleep deprivation.

Electroencephalograms (EEGs) of the cortex and of seven subcortical structures were recorded during two baseline days and during a recovery day following a 12-hour period of sleep deprivation (SD) in eight cats. The EEGs were analyzed by visual scoring and by spectral analysis. The following subcortical structures were studied: hippocampus, amygdala, hypothalamus, nucleus centralis lateralis of the thalamus, septum, nucleus caudatus and substantia nigra. The EEGs of all brain structures exhibited sleep state-dependent changes. In general, slow-wave activity (SWA, 0.5-4.0 Hz) during nonrapid eye movement (NREM) sleep exceeded that of REM sleep. The power spectra (0.5-24.5 Hz) in NREM, as well as the relationship between the power spectra of NREM and REM sleep, differed between the recording sites. Moreover, the rate of increase of SWA in the course of an NREM episode and the rate of decrease of SWA at the transition from NREM to REM sleep differed between the brain structures. During the first 12 hours following SD, the duration of NREM increased due to a prolongation of the NREM episodes. REM increased by a rise in the number of REM episodes. During the same period, the NREM EEG power density in the delta and theta frequencies was enhanced in all brain structures. Furthermore, in all structures the enhancement of SWA was most pronounced at the beginning of the recovery period and gradually declined thereafter. SD also induced a rise in the rate of increase of SWA in the NREM episodes in all recording sites. This indicates that the enhancement of EEG power density was not only due to prolongation of the NREM episodes. The EEG activity during REM was barely affected by the SD. It is concluded that, in all brain structures studied, the EEG during NREM is characterized by high levels of SWA. Furthermore, in each brain structure, SWA within NREM sleep is enhanced after a prolonged vigil. These data may indicate that SWA reflects a recovery process in cortical and subcortical structures.     

Activation of benzylic alcohols to mutagens by human hepatic sulphotransferases

Four primary and five secondary benzylic alcohols derived frompolycyclic aromatic hydrocarbons were tested for mutagenicityin Salmonella typhimurium TA98 in the presence of 3'-phosphoadenosine-5'-phosphosulphate,the cofactor for sulphotransferases, and varying amounts ofhepatic cytosol from three or four different human subjects,a 3-year-old child, an adult female, an adult male and one unknown.All compounds except one, 4H-cyclopenta[def] phenanthren-4-ol,were activated to mutagens. The interindividual variation inthe activities was at most 3-fold and the individual activitiestowards the different substrates were correlated with each other.The same compounds had previously been tested in the presenceof hepatic cytosol from rats and all compounds activated inone species were also activated in the other species. However,there were marked quantitative differences, which were furthercomplicated by the observation of a substantial sex differencein the rat. Male and female rat liver cytosol showed highersulphotransferase activities towards 1-hydroxymethylpyrene,9-hydroxymethylanthracene, 7-hydroxymethyl-12-methylbenz[a]anthraceneand 4H-cyclopenta[def]chrysen-4-ol than human liver cytosol.The largest difference in activity was seen with 7-hydroxymethyl-12-methylbenz[a]anthracene,reaching a factor of     

Long-term follow-up of a sponge breast implant and review of the literature

A case of a woman who underwent removal of a breast implant consistent with a polyvinyl sponge contained within a polyethylene bag is described. The use of the polyvinyl alcohol sponge as a breast implant virtually ceased in the mid 1960s with the introduction of silicone gel breast prostheses. However, it is still possible that the plastic surgeon may encounter a patient with one of these sponge implants in place. Thus, it is important for the plastic surgeon to be aware of their existence, natural history, and potential late complications. In addition, since the removal of silicone from general use for augmentation mammaplasty, there have been intense efforts to identify new filler materials for use in breast implants. Polyvinyl alcohol has been considered a possible material. There is a paucity of information in the recent literature pertaining to the characteristics and use of polyvinyl alcohol sponge implants. Therefore, this report describes a patient treated 38 years following placement of this type of implant and reviews the literature.