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Notes: The suprachiasmatic nuclei (SCN) of the hypothalamus house the main circadian pacemaker in mammals. Vasoactive intestinal polypeptide (VIP) is the most abundant neuropeptide in the SCN and has been shown to phase-shift the electrical activity rhythm of SCN cells in vitro. However, the effects of VIP on the cellular activity of rat SCN neurones are unknown. In this study, we examined the acute effects of VIP on the extracellularly recorded spontaneous firing rate of SCN neurones in an in-vitro hypothalamic slice preparation. Furthermore, with the use of receptor-selective agonists and antagonists, we determined which receptors might mediate the effects of VIP in the SCN. Approximately 50% of cells responded to VIP; the main type of response was suppression in firing rate, although a few cells were activated. Suppression responses to VIP were mimicked by the VPAC2 receptor agonist Ro 25-1553 and blocked by the selective VPAC2 receptor antagonist PG 99-465. The PAC1 receptor agonist maxadilan evoked responses from 40% of SCN cells, and activations to this agonist were not altered by PG 99-465. Responses to VIP were not blocked by antagonists to ionotropic glutamate receptors, but the duration of suppression was modulated by the GABAA receptor antagonist bicuculline. Our data indicate that VIP alters the electrical activity of rat SCN neurones in vitro, via both VPAC2 and PAC1 receptors.

Notes: Mucosal mast cells (MMC) play a central role in gut hypersensitivities and inflammation. They are morphologically, biochemically and functionally distinct from their connective tissue counterparts. Massive hyperplasia of MMC occurs 7–10 days after intestinal infection with nematodes but it has never been possible to replicate this phenomenon in vitro.〈section xml:id="abs1-2"〉〈title type="main"〉Objective(1) To determine whether mouse bone marrow-derived mast cells (mBMMC) grown in the presence of transforming growth factor (TGF)-β1 could develop over the same time frame (7–10 days) as MMC in parasitized mice. (2) To compare the early expression of surface receptors (integrins αE and β7, c-kit and FcεR) with that of the MMC-specific granule chymase mouse mast cell protease-1 (mMCP-1).〈section xml:id="abs1-3"〉〈title type="main"〉MethodsMouse bone marrow cells were cultured in the presence of IL-9, IL-3 and Stem Cell Factor (SCF) with or without TGF-β1. mBMMC were quantified after toluidine blue or Leishmans' staining. Expression of MMC-specific mouse mast cell proteases was analysed by ELISA, immunohistochemistry and RT-PCR. Surface antigen expression was characterized by flow cytometry and confocal microscopy.〈section xml:id="abs1-4"〉〈title type="main"〉ResultsTGF-β1 promotes the development of abundant MMC-like mBMMC from bone marrow progenitor cells with kinetics, which closely parallel that seen in vivo. mRNA transcripts encoding mMCP-1 and -2 are readily detectable by day 4 ex vivo in cultures grown in the presence of TGF-β1. Between 30 and 40% and 75–90% of the cells in these cultures on days 4 and 7, respectively, have typical mast cell morphology, are c-kit+, FcεR+, integrin αEβ7+, and express and secrete abundant mMCP-1. The integrin αE subunit is coexpressed with mMCP-1.〈section xml:id="abs1-5"〉〈title type="main"〉ConclusionThe kinetics of mMCP-1+/αE+ mBMMC development, regulated by TGF-β1, are consistent with that seen in vivo in the parasitized intestine. The normally down-regulatory functions of TGF-β1 in haematopoiesis are superseded in this culture system by its ability to promote the early expression of αE and mMCP-1.

Notes: The biotrophic fungus Puccinia striiformis f.sp. tritici, a basidiomycete that causes yellow rust on wheat, is spread by wind-dispersed spores. Analysis of amplified fragment length polymorphism (AFLP) variation showed that the fungus frequently migrates between the UK, Germany, France and Denmark. There is no biological evidence for sexual or parasexual reproduction under natural conditions, and this was supported by the lack of recombination, as revealed by AFLP, over the time and area represented by the samples in this study. A phylogeographic analysis revealed that there was effectively a single, clonal population in the four countries, up to 1700 km apart, consistent with a ‘continent-island’ model in which Denmark is the recipient of migrants from other countries. In five cases, specific pathogen clones were dispersed between the UK and Denmark, and on at least two recent occasions clones were also spread from the UK to Germany and France, causing outbreaks of yellow rust on wheat cultivars that were previously resistant to the disease in these countries. The agronomic consequences of migration were enhanced because of the limited genetic diversity for yellow rust resistance in wheat cultivars in the area. These results demonstrate that long-distance migration of pathogen clones, coupled with low diversity in the host species, may cause previously useful resistance genes to become ineffective for disease control on a continental scale.

Notes: Economic models have suggested that population Helicobacter pylori screening and treatment may be a cost-effective method of reducing mortality from gastric cancer. These models are conservative as they do not consider that the programme may reduce health service peptic ulcer and other dyspepsia costs. We have evaluated the economic impact of population H. pylori screening and treatment over 2 years in a randomized controlled trial and have incorporated the results into an economic model exploring the impact of H. pylori eradication on peptic ulcer disease and gastric cancer.〈section xml:id="abs1-2"〉〈title type="main"〉Methods:Subjects between the ages of 40 and 49 years were randomly invited to attend their local primary care centre. H. pylori status was evaluated by 13C-urea breath test and infected individuals were randomized to receive omeprazole, 20 mg b.d., clarithromycin, 250 mg b.d., and tinidazole, 500 mg b.d., for 7 days or identical placebos. Economic data on health service costs for dyspepsia were obtained from a primary care note review for the 2 years following randomization. These data were incorporated into a Markov model comparing population H. pylori screening and treatment with no intervention.〈section xml:id="abs1-3"〉〈title type="main"〉Results:A total of 2329 of 8407 subjects were H. pylori positive: 1161 were randomized to receive eradication therapy and 1163 to receive placebo. The cost difference favoured the intervention group 2 years after randomization, but this did not reach statistical significance (£11.42 per subject cost saving; 95% confidence interval, £30.04 to – £7.19; P=0.23). Analysis by gender suggested a statistically significant dyspepsia cost saving in men (£27.17 per subject; 95% confidence interval, £50.01 to £4.32; P=0.02), with no benefit in women (– £4.46 per subject; 95% confidence interval, – £33.85 to £24.93). Modelling of these data suggested that population H. pylori screening and treatment for 1 000 000 45-year-olds would save over £6 000 000 and 1300 years of life. The programme would cost £14 200 per life year saved if the health service dyspepsia cost savings were the lower limit of the 95% confidence intervals and H. pylori eradication had only a 10% efficacy in reducing mortality from distal gastric cancer and peptic ulcer disease.〈section xml:id="abs1-4"〉〈title type="main"〉Conclusions:Modelling suggests that population H. pylori screening and treatment are likely to be cost-effective and could be the first cost-neutral screening programme. This provides a further mandate for clinical trials to evaluate the efficacy of population H. pylori screening and treatment in preventing mortality from gastric cancer and peptic ulcer disease.