Over enkele enzoötieën veroorzaakt door S. typhi-murium

Zusammenfassung Verf. weist aus das Vorkommen von Endemien und Enzo?zien, die durchS. typhimurium von verschiedenem Kulturtyp verursacht werden. Der Kulturtyp gibt wichtige Hinweise für das Feststellen der Infektionsquelle. Dies ist besonders wichtig bei Nahrungsmittelvergiftungen des Menschen und für die Beziehungen zwischen die Tiersalmonellosen untereinander. Der Rhamnosenegative Typ, der bisher beim Menschen und bei der Ente(Anas Boschas) bekannt war, wurde weiter gefunden bei Ratte(Mus norvegicus), Sturmm?we(Larus canus), Silberm?we(Larus argentatus), Star(Sturnus vulgaris), Wendehals(Jynx torquilla), Kanarienvogel(Serinus canarius L.) und Affe(Macacus rhesus).

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Ingezonden: November 1937.     

Overexpression of Rad51 inhibits double-strand break-induced homologous recombination but does not affect gene conversion tract lengths

DNA double-strand breaks (DSBs) in yeast are repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). Rad51 forms nucleoprotein filaments at processed broken ends that effect strand exchange, forming heteroduplex DNA (hDNA) that gives rise to a gene conversion tract. We hypothesized that excess Rad51 would increase gene conversion tract lengths. We found that excess Rad51 reduced DSB-induced HR but did not alter tract lengths or other outcomes including rates of crossovers, break-induced replication, or chromosome loss. Thus, excess Rad51 appears to influence DSB-induced HR at an early stage. MAT heterozygosity largely mitigated the inhibitory effect of excess Rad51 on allelic HR, but not direct repeat HR. Excess Rad52 had no effect on DSB-induced HR efficiency or outcome, nor did it mitigate the dominant negative effects of excess Rad51. Excess Rad51 had little effect on DSB-induced lethality in wild-type cells, but it did enhance lethality in yku70Delta mutants. Interestingly, dnl4Delta showed marked DSB-induced lethality but this was not further enhanced by excess Rad51. The differential effects of yku70Delta and dnl4Delta indicate that the enhanced killing with excess Rad51 in yku70Delta is not due to its NHEJ defect, but may reflect its defect in end-protection and/or its inability to escape from checkpoint arrest. Srs2 displaces Rad51 from nucleoprotein filaments in vitro, suggesting that excess Rad51 might antagonize Srs2. We show that excess Rad51 does not reduce survival of wild-type cells treated with methylmethane sulfonate (MMS), or cells suffering a single DSB. In contrast, excess Rad51 sensitized srs2Delta cells to both MMS and a single DSB. These results support the idea that excess Rad51 antagonizes Srs2, and underscores the importance of displacing Rad51 from nucleoprotein filaments to achieve optimum repair efficiency.     

Differential induction of electrophile-responsive element-regulated genes by n-3 and n-6 polyunsaturated fatty acids

In this study the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid appear to be effective inducers of electrophile-responsive element (EpRE) regulated genes, whereas the n-6 PUFA arachidonic acid is not. These n-3 PUFAs need to be oxidized to induce EpRE-regulated gene expression, as the antioxidant vitamin E can partially inhibit the PUFA induced dose-dependent effect. Results were obtained using a reporter gene assay, real-time RT-PCR and enzyme activity assays. The induction of EpRE-regulated phase II genes by n-3 PUFAs may be a major pathway by which n-3 PUFAs, in contrast to n-6 PUFAs, are chemopreventive and anticarcinogenic.     

Imidazolylpyrimidine based CXCR2 chemokine receptor antagonists

An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.     

The role of epoxidation and electrophile-responsive element-regulated gene transcription in the potentially beneficial and harmful effects of the coffee components cafestol and kahweol

Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds.     

Economic Evaluation of a Problem Solving Intervention to Prevent Recurrent Sickness Absence in Workers with Common Mental Disorders

Objectives

Workers with common mental disorders (CMDs) frequently experience recurrent sickness absence but scientifically evaluated interventions to prevent recurrences are lacking. The objectives of this study are to evaluate the cost-effectiveness and cost-benefit of a problem solving intervention aimed at preventing recurrent sickness absence in workers with CMDs compared to care as usual.

Methods

An economic evaluation was conducted alongside a cluster-randomised controlled trial with 12 months follow-up. Treatment providers were randomised to either a 2-day training in the SHARP-at work intervention, i.e. a problem solving intervention, or care as usual. Effect outcomes were the incidence of recurrent sickness absence and time to recurrent sickness absence. Self-reported health care utilisation was measured by questionnaires. A cost-effectiveness analysis (CEA) from the societal perspective and a cost-benefit analysis (CBA) from the employer’s perspective were conducted.

Results

The CEA showed that the SHARP-at work intervention was more effective but also more expensive than care as usual. The CBA revealed that employer’s occupational health care costs were significantly higher in the intervention group compared to care as usual. Overall, the SHARP-at work intervention showed no economic benefit compared to care as usual.

Conclusions

As implementation of the SHARP-at work intervention might require additional investments, health care policy makers need to decide if these investments are worthwhile considering the results that can be accomplished in reducing recurrent sickness absence.     

Neural processing of imminent collision in humans

Detecting a looming object and its imminent collision is imperative to survival. For most humans, it is a fundamental aspect of daily activities such as driving, road crossing and participating in sport, yet little is known about how the brain both detects and responds to such stimuli. Here we use functional magnetic resonance imaging to assess neural response to looming stimuli in comparison with receding stimuli and motion-controlled static stimuli. We demonstrate for the first time that, in the human, the superior colliculus and the pulvinar nucleus of the thalamus respond to looming in addition to cortical regions associated with motor preparation. We also implicate the anterior insula in making timing computations for collision events.     

Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island

Migraine is a common neurovascular disorder with a complex envirogenomic aetiology. In an effort to identify migraine susceptibility genes, we conducted a study of the isolated population of Norfolk Island, Australia. A large portion of the permanent inhabitants of Norfolk Island are descended from 18th Century English sailors involved in the infamous mutiny on the Bounty and their Polynesian consorts.In total, 600 subjects were recruited including a large pedigree of 377 individuals with lineage to the founders. All individuals were phenotyped for migraine using International Classification of Headache Disorders-II criterion. All subjects were genotyped for a genome-wide panel of microsatellite markers. Genotype and phenotype data for the pedigree were analysed using heritability and linkage methods implemented in the programme SOLAR. Follow-up association analysis was performed using the CLUMP programme.A total of 154 migraine cases (25%) were identified indicating the Norfolk Island population is high-risk for migraine. Heritability estimation of the 377-member pedigree indicated a significant genetic component for migraine (h² = 0.53, P = 0.016). Linkage analysis showed peaks on chromosome 13q33.1 (P = 0.003) and chromosome 9q22.32 (P = 0.008). Association analysis of the key microsatellites in the remaining 223 unrelated Norfolk Island individuals showed evidence of association, which strengthen support for the linkage findings (P ≤ 0.05).In conclusion, a genome-wide linkage analysis and follow-up association analysis of migraine in the genetic isolate of Norfolk Island provided evidence for migraine susceptibility loci on chromosomes 9q22.22 and 13q33.1.