Inhibitors of COP-mediated Transport and Cholera Toxin Action Inhibit Simian Virus 40 Infection

Simian virus 40 (SV40) is a nonenveloped virus that has been shown to pass from surface caveolae to the endoplasmic reticulum in an apparently novel infectious entry pathway. We now show that the initial entry step is blocked by brefeldin A and by incubation at 20degreesC. Subsequent to the entry step, the virus reaches a domain of the rough endoplasmic reticulum by an unknown pathway. This intracellular trafficking pathway is also brefeldin A sensitive. Infection is strongly inhibited by expression of GTP-restricted ADP-ribosylation factor 1 (Arf1) and Sar1 mutants and by microinjection of antibodies to betaCOP. In addition, we demonstrate a potent inhibition of SV40 infection by the dipeptide N-benzoyl-oxycarbonyl-Gly-Phe-amide, which also inhibits late events in cholera toxin action. Our results identify novel inhibitors of SV40 infection and show that SV40 requires COPI- and COPII-dependent transport steps for successful infection.

Complete mitochondrial genomes confirm the distinctiveness of the horse-dog and sheep-dog strains of Echinococcus granulosus

Unlike other members of the genus, Echinococcus granulosus is known to exhibit considerable levels of variation in biology, physiology and molecular genetics. Indeed, some of the taxa regarded as 'genotypes' within E. granulosus might be sufficiently distinct as to merit specific status. Here, complete mitochondrial genomes are presented of 2 genotypes of E. granulosus (G1-sheep-dog strain: G4-horse-dog strain) and of another taeniid cestode, Taenia crassiceps. These genomes are characterized and compared with those of Echinococcus multilocularis and Hymenolepis diminuta. Genomes of all the species are very similar in structure, length and base-composition. Pairwise comparisons of concatenated protein-coding genes indicate that the G1 and G4 genotypes of E. granulosus are almost as distant from each other as each is from a distinct species, E. multilocularis. Sequences for the variable genes atp6 and nad3 were obtained from additional genotypes of E. granulosus, from E. vogeli and E. oligarthrus. Again, pairwise comparisons showed the distinctiveness of the G1 and G4 genotypes. Phylogenetic analyses of concatenated atp6, nad1 (partial) and cox1 (partial) genes from E. multilocularis, E. vogeli, E. oligarthrus, 5 genotypes of E. granulosus, and using T. crassiceps as an outgroup, yielded the same results. We conclude that the sheep-dog and horse-dog strains of E. granulosus should be regarded as distinct at the specific level.

Colony-stimulating factor-1 suppresses responses to CpG DNA and expression of toll-like receptor 9 but enhances responses to lipopolysaccharide in murine macrophages

During bacterial infections, the balance between resolution of infection and development of sepsis is dependent upon the macrophage response to bacterial products. We show that priming of murine bone marrow-derived macrophages (BMMs) with CSF-1 differentially regulates the response to two such stimuli, LPS and immunostimulatory (CpG) DNA. CSF-1 pretreatment enhanced IL-6, IL-12, and TNF-alpha production in response to LPS but suppressed the same response to CpG DNA. CSF-1 also regulated cytokine gene expression in response to CpG DNA and LPS; CpG DNA-induced IL-12 p40, IL-12 p35, and TNF-alpha mRNAs were all suppressed by CSF-1 pretreatment. CSF-1 pretreatment enhanced LPS-induced IL-12 p40 mRNA but not TNF-alpha and IL-12 p35 mRNAs, suggesting that part of the priming effect is posttranscriptional. CSF-1 pretreatment also suppressed CpG DNA-induced nuclear translocation of NF-kappaB and phosphorylation of the mitogen-activated protein kinases p38 and extracellular signal-related kinases-1/2 in BMMs, indicating that early events in CpG DNA signaling were regulated by CSF-1. Expression of Toll-like receptor (TLR)9, which is necessary for responses to CpG DNA, was markedly suppressed by CSF-1 in both BMMs and thioglycolate-elicited peritoneal macrophages. CSF-1 also down-regulated expression of TLR1, TLR2, and TLR6, but not the LPS receptor, TLR4, or TLR5. Hence, CSF-1 may regulate host responses to pathogens through modulation of TLR expression. Furthermore, these results suggest that CSF-1 and CSF-1R antagonists may enhance the efficacy of CpG DNA in vivo.

Cost comparison of hospital- and home-based treatment models for acute chronic obstructive pulmonary disease

This trial compared the cost of an integrated home-based care model with traditional inpatient care for acute chronic obstructive pulmonary disease (COPD). 25 patients with acute COPD were randomised to either home or hospital management following request for hospital admission. The acute care at home group costs per separation ($745, CI95% $595-$895, n = 13) were significantly lower (p < 0.01) than the hospital group ($2543, CI95% $1766-$3321, n = 12). There was an improvement in lung function in the hospital-managed group at the Outpatient Department review, decreased anxiety in the Emergency Department in the home-managed group and equal patient satisfaction with care delivery. Acute care at home schemes can substitute for usual hospital care for some patients without adverse effects, and potentially release resources. A funding model that allows adequate resource delivery to the community will be needed if there is a move to devolve acute care to community providers.

Health and demographic characteristics of respondents in an Australian national sexuality survey: comparison with population norms

Study objective: To assess the representativeness of survey participants by systematically comparing volunteers in a national health and sexuality survey with the Australian population in terms of self reported health status (including the SF-36) and a wide range of demographic characteristics. Design: A cross sectional sample of Australian residents were compared with demographic data from the 1996 Australian census and health data from the 1995 National Health Survey. Setting: The Australian population. Participants: A stratified random sample of adults aged 18-59 years drawn from the Australian electoral roll, a compulsory register of voters. Interviews were completed with 1784 people, representing 40% of those initially selected (58% of those for whom a valid telephone number could be located). Main results: Participants were of similar age and sex to the national population. Consistent with prior research, respondents had higher socioeconomic status, more education, were more likely to be employed, and less likely to be immigrants. The prevalence estimates, means, and variances of self reported mental and physical health measures (for example, SF-36 subscales, women's health indicators, current smoking status) were similar to population norms. Conclusions: These findings considerably strengthen inferences about the representativeness of data on health status from volunteer samples used in health and sexuality surveys.

Estimates of global and regional potential health gains from reducing multiple major risk factors

Background Estimates of the disease burden due to multiple risk factors can show the potential gain from combined preventive measures. But few such investigations have been attempted, and none on a global scale. Our aim was to estimate the potential health benefits from removal of multiple major risk factors. Methods We assessed the burden of disease and injury attributable to the joint effects of 20 selected leading risk factors in 14 epidemiological subregions of the world. We estimated population attributable fractions, defined as the proportional reduction in disease or mortality that would occur if exposure to a risk factor were reduced to an alternative level, from data for risk factor prevalence and hazard size. For every disease, we estimated joint population attributable fractions, for multiple risk factors, by age and sex, from the direct contributions of individual risk factors. To obtain the direct hazards, we reviewed publications and re-analysed cohort data to account for that part of hazard that is mediated through other risks. Results Globally, an estimated 47% of premature deaths and 39% of total disease burden in 2000 resulted from the joint effects of the risk factors considered. These risks caused a substantial proportion of important diseases, including diarrhoea (92%-94%), lower respiratory infections (55-62%), lung cancer (72%), chronic obstructive pulmonary disease (60%), ischaemic heart disease (83-89%), and stroke (70-76%). Removal of these risks would have increased global healthy life expectancy by 9.3 years (17%) ranging from 4.4 years (6%) in the developed countries of the western Pacific to 16.1 years (43%) in parts of sub-Saharan Africa. Interpretation Removal of major risk factors would not only increase healthy life expectancy in every region, but also reduce some of the differences between regions, The potential for disease prevention and health gain from tackling major known risks simultaneously would be substantial.

Numerical study of hydrogenic effective mass theory for an impurity P donor in Si in the presence of an electric field and interfaces

In this paper we examine the effects of varying several experimental parameters in the Kane quantum computer architecture: A-gate voltage, the qubit depth below the silicon oxide barrier, and the back gate depth to explore how these variables affect the electron density of the donor electron. In particular, we calculate the resonance frequency of the donor nuclei as a function of these parameters. To do this we calculated the donor electron wave function variationally using an effective-mass Hamiltonian approach, using a basis of deformed hydrogenic orbitals. This approach was then extended to include the electric-field Hamiltonian and the silicon host geometry. We found that the phosphorous donor electron wave function was very sensitive to all the experimental variables studied in our work, and thus to optimize the operation of these devices it is necessary to control all parameters varied in this paper.

Novel sesquiterpenes from the fungus lactarius piperatus

Four novel sesquiterpenes, namely 7alpha,8beta,13-trihydroxy-5,13-marasmanolide (2), isoplorantinone (5), 4,8,14-trihydroxyilludala-2,6,8-triene (6), and 8-hydroxy-8,9-secolactara-1,6-dien-5,13-olide (10), together with six known ones, 7alpha,8beta-dihydroxy-5,13-marasmanolide (1), 7alpha,8alpha-dihydroxy-5,13-marasmanolide (3), isolactarorufin (4), blennin A (7), blennin D (8), and lactarorufin (9), were isolated from the ethanolic extract of Lactarius piperatus. The structures of these sesquiterpenes, representing diversified structural types, were determined mainly by spectroscopic methods, especially 2D-NMR techniques. The structure of 6 was further confirmed by a single-crystal X-ray-diffraction determination.

Telehealth responses to bio-terrorism and emerging infections

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS), are of huge economic importance. They are difficult to predict. The World Health Organization has a Global Outbreak Alert and Response Network, which was involved at an early stage in the SARS outbreak in 2003. Three major lessons were learned as a result of the SARS epidemic in 2003, involving communication, evidence-based action and global partnerships. It is proposed that a series of broadband global response networks should be developed. At a technical level the networks are essentially in place, such as the Internet2 global network. Suitable peripheral devices also exist. What has not yet been created is the appropriate software to allow the use of these networks, although a number of commercial products are in the process of development.