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891.
892.
Christine N. Kay Renee C. Ryals George V. Aslanidi Seok Hong Min Qing Ruan Jingfen Sun Frank M. Dyka Daniel Kasuga Andrea E. Ayala Kim Van Vliet Mavis Agbandje-McKenna William W. Hauswirth Sanford L. Boye Shannon E. Boye 《PloS one》2013,8(4)
Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self-complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY−F+T−V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY−F+T−V) −hGRK1−GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors. 相似文献
893.
Jeremy Howick Felicity L. Bishop Carl Heneghan Jane Wolstenholme Sarah Stevens F. D. Richard Hobbs George Lewith 《PloS one》2013,8(3)
Objectives
Surveys in various countries suggest 17% to 80% of doctors prescribe ‘placebos’ in routine practice, but prevalence of placebo use in UK primary care is unknown.Methods
We administered a web-based questionnaire to a representative sample of UK general practitioners. Following surveys conducted in other countries we divided placebos into ‘pure’ and ‘impure’. ‘Impure’ placebos are interventions with clear efficacy for certain conditions but are prescribed for ailments where their efficacy is unknown, such as antibiotics for suspected viral infections. ‘Pure’ placebos are interventions such as sugar pills or saline injections without direct pharmacologically active ingredients for the condition being treated. We initiated the survey in April 2012. Two reminders were sent and electronic data collection closed after 4 weeks.Results
We surveyed 1715 general practitioners and 783 (46%) completed our questionnaire. Our respondents were similar to those of all registered UK doctors suggesting our results are generalizable. 12% (95% CI 10 to 15) of respondents used pure placebos while 97% (95% CI 96 to 98) used impure placebos at least once in their career. 1% of respondents used pure placebos, and 77% (95% CI 74 to 79) used impure placebos at least once per week. Most (66% for pure, 84% for impure) respondents stated placebos were ethical in some circumstances.Conclusion and implications
Placebo use is common in primary care but questions remain about their benefits, harms, costs, and whether they can be delivered ethically. Further research is required to investigate ethically acceptable and cost-effective placebo interventions. 相似文献894.
Alexandra V. Stavropoulou Florentia Fostira Maroulio Pertesi Marianthi Tsitlaidou Gerassimos E. Voutsinas Olga Triantafyllidou Aristotelis Bamias Meletios A. Dimopoulos Eleni Timotheadou Dimitrios Pectasides Christos Christodoulou George Klouvas Christos Papadimitriou Thomas Makatsoris George Pentheroudakis Gerasimos Aravantinos Vassilis Karydakis Drakoulis Yannoukakos George Fountzilas Irene Konstantopoulou 《PloS one》2013,8(3)
Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23–24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer. 相似文献
895.
896.
Rachel B. Slayton George Turabelidze Sarah D. Bennett Colin A. Schwensohn Anna Q. Yaffee Faisal Khan Cindy Butler Eija Trees Tracy L. Ayers Marjorie L. Davis Alison S. Laufer Stephen Gladbach Ian Williams Laura B. Gieraltowski 《PloS one》2013,8(2)
Background
Shiga toxin-producing Escherichia coli (STEC) O157:H7 is the causal agent for more than 96,000 cases of diarrheal illness and 3,200 infection-attributable hospitalizations annually in the United States.Materials and Methods
We defined a confirmed case as a compatible illness in a person with the outbreak strain during 10/07/2011-11/30/2011. Investigation included hypothesis generation, a case-control study utilizing geographically-matched controls, and a case series investigation. Environmental inspections and tracebacks were conducted.Results
We identified 58 cases in 10 states; 67% were hospitalized and 6.4% developed hemolytic uremic syndrome. Any romaine consumption was significantly associated with illness (matched Odds Ratio (mOR) = 10.0, 95% Confidence Interval (CI) = 2.1–97.0). Grocery Store Chain A salad bar was significantly associated with illness (mOR = 18.9, 95% CI = 4.5–176.8). Two separate traceback investigations for romaine lettuce converged on Farm A. Case series results indicate that cases (64.9%) were more likely than the FoodNet population (47%) to eat romaine lettuce (p-value = 0.013); 61.3% of cases reported consuming romaine lettuce from the Grocery Store Chain A salad bar.Conclusions
This multistate outbreak of STEC O157:H7 infections was associated with consumption of romaine lettuce. Traceback analysis determined that a single common lot of romaine lettuce harvested from Farm A was used to supply Grocery Store Chain A and a university campus linked to a case with the outbreak strain. An investigation at Farm A did not identify the source of contamination. Improved ability to trace produce from the growing fields to the point of consumption will allow more timely prevention and control measures to be implemented. 相似文献897.
George A. Bray 《Obesity (Silver Spring, Md.)》2013,21(5):893-899
Objective:
Obesity is a public health problem, which increases the risk of chronic diseases and mortality. Weight loss can reduce mortality and improve most of the detrimental health consequences of obesity.Design and Methods:
This paper was developed from two presentations to the US Food and Drug Administration (FDA), which has responsibility for reviewing and approving drugs to treat obesity.Results:
A weight loss of 5% or more is sufficient to significantly reduce health risks in individuals with impaired glucose tolerance, hypertension, or nonalcoholic fatty liver disease. Slightly more weight loss (16% on average, achieved by surgery) reduces mortality. The goal of medicating for obesity is to help more patients achieve more weight loss. A barrier to drug approval has been the concern that weight loss medications might be used by individuals with little or no health risks, thus mandating a low side effect profile for approval of any drug. This limits the options for patients who have obesity‐related health problems that could improve with weight loss. Recently the FDA signaled interest in identifying health benefits in higher risk patients that might justify medications with higher risk; however, the potential impact on a large segment of the population has led the FDA to consider requiring a cardiovascular outcome trial for all obesity medications, either prior to or after approval.Conclusion:
This review argues that drugs are needed for obesity because they enhance behaviorally induced weight loss and that new medications for obesity are needed in the approval process. 相似文献898.
Alexandra D. Ogorodnikova Unab I. Khan Aileen P. McGinn Irfan Zeb Matthew J. Budoff S.M. Harman Virginia M. Miller Eliot A. Brinton JoAnn E. Manson Howard N. Hodis George R. Merriam Marcelle I. Cedars Hugh S. Taylor Frederick Naftolin Rogerio A. Lobo Nanette Santoro Rachel P. Wildman 《Obesity (Silver Spring, Md.)》2013,21(8):1726-1733
899.
Djesika D. Amendah George Mukamah Albert Komba Carolyne Ndila Thomas N. Williams 《PloS one》2013,8(4)
Background
More than 70% of children with sickle cell disease (SCD) are born in sub-Saharan Africa where the prevalence at birth of this disease reaches 2% or higher in some selected areas. There is a dearth of knowledge on comprehensive care received by children with SCD in sub-Saharan Africa and its associated cost. Such knowledge is important for setting prevention and treatment priorities at national and international levels. This study focuses on routine care for children with SCD in an outpatient clinic of the Kilifi District Hospital, located in a rural area on the coast of Kenya.Objective
To estimate the per-patient costs for routine SCD outpatient care at a rural Kenyan hospital.Methods
We collected routine administrative and primary cost data from the SCD outpatient clinic and supporting departments at Kilifi District Hospital, Kenya. Costs were estimated by evaluating inputs - equipment, medication, supplies, building use, utility, and personnel - to reflect the cost of offering this service within an existing healthcare facility. Annual economic costs were similarly calculated based on input costs, prorated lifetime of equipment and appropriate discount rate. Sensitivity analyses evaluated these costs under different pay scales and different discount rate.Results
We estimated that the annual economic cost per patient attending the SCD clinic was USD 138 in 2010 with a range of USD 94 to USD 229.Conclusion
This study supplies the first published estimate of the cost of routine outpatient care for children born with SCD in sub-Saharan Africa. Our study provides policy makers with an indication of the potential future costs of maintaining specialist outpatient clinics for children living with SCD in similar contexts. 相似文献900.
Anastasios Kollias Isidoros Psilopatis Eirini Karagiaouri Maria Glaraki Evangelos Grammatikos Emmanouel E. Grammatikos Anastasia Garoufi George S. Stergiou 《Obesity (Silver Spring, Md.)》2013,21(5):1013-1017