Quality of life in patients with various Barrett's esophagus associated health states

BACKGROUND: The management of Barrett's esophagus (BE), particularly high grade dysplasia (HGD), is an area of much debate and controversy. Surgical esophagectomy, intensive endoscopic surveillance and mucosal ablative techniques, especially photodynamic therapy (PDT), have been proposed as possible management strategies. The purpose of this study was to determine the health related quality of life associated with Barrett's esophagus and many of the pivotal health states associated with Barrett's HGD management. METHODS: 20 patients with Barrett's esophagus were enrolled in a pilot survey study at a large urban hospital. The utility of Barrett's esophagus without dysplasia (current health state) as well as various health states associated with HGD management (hypothetical states as the subject did not have HGD) were measured using a validated health utility instrument (Paper Standard Gamble). These specific health states were chosen for the study because they are considered pivotal in Barrett's HGD decision making. Information regarding Barrett's HGD was presented to the subject in a standardized format that was designed to be easily comprehendible. RESULTS: The average utility scores (0–1 with 0 = death and 1 = perfect health) for the various Barrett's esophagus associated states were: BE without dysplasia-0.95; Post-esophagectomy for HGD with dysphagia-0.92; Post-PDT for HGD with recurrence uncertainty-0.93; Post-PDT for HGD with recurrence uncertainty and dysphagia-0.91; Intensive endoscopic surveillance for HGD-0.90. CONCLUSION: We present the scores for utilities associated with Barrett's esophagus as well as various states associated with the management of HGD. The results of our study may be useful in advising patients and providers regarding expected outcomes of the various HGD management strategies as well as providing utility scores for future cost-effectiveness analyses

CYP17 5'-UTR MspA1 polymorphism and the risk of premenopausal breast cancer in a German population-based case–control study

INTRODUCTION: Studies on the association between the cytochrome P450c17α gene (CYP17) 5'-untranslated region MspA1 genetic polymorphism and breast cancer risk have yielded inconsistent results. Higher levels of estrogen have been reported among young nulliparous women with the A2 allele. Therefore we assessed the impact of CYP17 genotypes on the risk of premenopausal breast cancer, with emphasis on parity. METHODS: We used data from a population-based case–control study of women aged below 51 years conducted from 1992 to 1995 in Germany. Analyses were restricted to clearly premenopausal women with complete information on CYP17 and encompassed 527 case subjects and 904 controls, 99.5% of whom were of European descent. The MspA1 polymorphism was analyzed using PCR-RFLP (PCR–restriction fragment length polymorphism) assay. RESULTS: The frequencies of the variant allele among the cases and controls were 43% and 41%, respectively. Overall, CYP17 A1/A2 and A2/A2 genotypes compared with the A1/A1 genotype were not associated with breast cancer, with adjusted odds ratios (ORs) of 1.04 and 1.23, respectively. Among nulliparous women, however, breast cancer risk was elevated for the A1/A2 (OR = 1.31; 95% confidence interval (CI) 0.74 to 2.32) and the A2/A2 genotype (OR = 2.12; 95% CI 1.04 to 4.32) compared with the A1/A1 genotype, with a trend towards increasing risk associated with number of A2 alleles (P = 0.04). Otherwise, the CYP17 polymorphism was found neither to be an effect modifier of breast cancer risks nor to be associated with stage of disease. CONCLUSION: Our results do not indicate a major influence of CYP17 MspA1 polymorphism on the risk of premenopausal breast cancer, but suggest that it may have an impact on breast cancer risk among nulliparous women. The finding, however, needs to be confirmed in further studies

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Ion mobility spectrometry for the rapid analysis of over-the-counter drugs and beverages

In the pharmaceutical industry, there are increasing requirements for analytical methods in quality assessment for the production of drugs. In this investigation, ion mobility spectrometry (IMS) was used for the rapid qualitative separation and identification of active ingredients in generic over-the-counter drugs and food additives in beverages. The active ingredients determined in drugs were acetaminophen, aspartame, bisacodyl, caffeine, dextromethorphan, diphenhydramine, famotidine, glucosamine, guaifenesin, loratadine, niacin, phenylephrine, pyridoxine, thiamin, and tetrahydrozoline. Aspartame and caffeine were determined in beverages. Fourteen over-the-counter drugs and beverages were analyzed. Analysis times below 10 s were obtained for IMS, and reduced mobilities were reported for the first time for 12 compounds. A quadrupole mass spectrometer coupled to a mobility spectrometer was used to assure a correct peak assignation. The combination of fast analysis, low cost, and inexpensive maintenance of IMS instruments makes IMS an attractive technique for the qualitative determination of the active ingredients in over-the-counter drugs and food additives in manufacture quality control and cleaning verification for the drug and food industries

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study

INTRODUCTION: Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T→C polymorphism. METHODS: Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A(2)/A(2 )genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A(1)/A(1 )(wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions. CONCLUSION: We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene–environment interactions

Diet-Induced Obesity Impairs Endothelium-Derived Hyperpolarization via Altered Potassium Channel Signaling Mechanisms

BACKGROUND: The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO)-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH) mechanism; which predominates in smaller resistance vessels and is characterized in this study. METHODOLOGY/PRINCIPAL FINDINGS: Membrane potential, vessel diameter and luminal pressure were recorded in 4(th) order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (∼30 kJ, fat) over 16-20 weeks. Age and sexed matched controls received standard chow (∼12 kJ, fat). Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK(Ca)/IK(Ca)) inhibition; with such activity being impaired in obesity. SK(Ca)-IK(Ca) activation with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) and 1-ethyl-2-benzimidazolinone (1-EBIO), respectively, hyperpolarized and relaxed vessels from control and obese rats. IK(Ca)-mediated EDH contribution was increased in obesity, and associated with altered IK(Ca) distribution and elevated expression. In contrast, the SK(Ca)-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K(ir)) and Na(+)/K(+)-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K(ir) expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density. CONCLUSION/SIGNIFICANCE: In obese rats, vasodilation to EDH is impaired due to changes in the underlying potassium channel signaling mechanisms. Whilst myoendothelial gap junction density is unchanged in arteries of obese compared to control, increased IK(Ca) and Na(+)/K(+)-ATPase, and decreased K(ir) underlie changes in the EDH mechanism

Update of complications and functional outcome of the ileo-pouch anal anastomosis: overview of evidence and meta-analysis of 96 observational studies

Item does not contain fulltextOBJECTIVE: The objective of this study is to provide a comprehensive update of the outcome of the ileo-pouch anal anastomosis (IPAA). DATA SOURCES: An extensive search in PubMed, EMBASE, and The Cochrane Library was conducted. STUDY SELECTION AND DATA EXTRACTION: All studies published after 2000 reporting on complications or functional outcome after a primary open IPAA procedure for UC or FAP were selected. Study characteristics, functional outcome, and complications were extracted. DATA SYNTHESIS: A review with similar methodology conducted 10 years earlier was used to evaluate developments in outcome over time. Pooled estimates were compared using a random-effects logistic meta-analyzing technique. Analyses focusing on the effect of time of study conductance, centralization, and variation in surgical techniques were performed. RESULTS: Fifty-three studies including 14,966 patients were included. Pooled rates of pouch failure and pelvic sepsis were 4.3% (95% CI, 3.5-6.3) and 7.5% (95% CI 6.1-9.1), respectively. Compared to studies published before 2000, a reduction of 2.5% was observed in the pouch failure rate (p = 0.0038). Analysis on the effect of the time of study conductance confirmed a decline in pouch failure. Functional outcome remained stable over time, with a 24-h defecation frequency of 5.9 (95% CI, 5.0-6.9). Technical surgery aspects did not have an important effect on outcome. CONCLUSION: This review provides up to date outcome estimates of the IPAA procedure that can be useful as reference values for practice and research. It is also shows a reduction in pouch failure over time.1 juli 201

Duox, Flotillin-2, and Src42A Are Required to Activate or Delimit the Spread of the Transcriptional Response to Epidermal Wounds in Drosophila

The epidermis is the largest organ of the body for most animals, and the first line of defense against invading pathogens. A breach in the epidermal cell layer triggers a variety of localized responses that in favorable circumstances result in the repair of the wound. Many cellular and genetic responses must be limited to epidermal cells that are close to wounds, but how this is regulated is still poorly understood. The order and hierarchy of epidermal wound signaling factors are also still obscure. The Drosophila embryonic epidermis provides an excellent system to study genes that regulate wound healing processes. We have developed a variety of fluorescent reporters that provide a visible readout of wound-dependent transcriptional activation near epidermal wound sites. A large screen for mutants that alter the activity of these wound reporters has identified seven new genes required to activate or delimit wound-induced transcriptional responses to a narrow zone of cells surrounding wound sites. Among the genes required to delimit the spread of wound responses are Drosophila Flotillin-2 and Src42A, both of which are transcriptionally activated around wound sites. Flotillin-2 and constitutively active Src42A are also sufficient, when overexpressed at high levels, to inhibit wound-induced transcription in epidermal cells. One gene required to activate epidermal wound reporters encodes Dual oxidase, an enzyme that produces hydrogen peroxide. We also find that four biochemical treatments (a serine protease, a Src kinase inhibitor, methyl-ß-cyclodextrin, and hydrogen peroxide) are sufficient to globally activate epidermal wound response genes in Drosophila embryos. We explore the epistatic relationships among the factors that induce or delimit the spread of epidermal wound signals. Our results define new genetic functions that interact to instruct only a limited number of cells around puncture wounds to mount a transcriptional response, mediating local repair and regeneration