Ecto-5′-nucleotidase and intestinal ion secretion by enteropathogenic Escherichia coli

Enteropathogenic Escherichia coli (EPEC) triggers a large release of adenosine triphosphate (ATP) from host intestinal cells and the extracellular ATP is broken down to adenosine diphosphate (ADP), AMP, and adenosine. Adenosine is a potent secretagogue in the small and large intestine. We suspected that ecto-5′-nucleotidase (CD73, an intestinal enzyme) was a critical enzyme involved in the conversion of AMP to adenosine and in the pathogenesis of EPEC diarrhea. We developed a nonradioactive method for measuring ecto-5′-nucleotidase in cultured T84 cell monolayers based on the detection of phosphate release from 5′-AMP. EPEC infection triggered a release of ecto-5′-nucleotidase from the cell surface into the supernatant medium. EPEC-induced 5′-nucleotidase release was not correlated with host cell death but instead with activation of phosphatidylinositol-specific phospholipase C (PI-PLC). Ecto-5′-nucleotidase was susceptible to inhibition by zinc acetate and by α,β-methylene-adenosine diphosphate (α,β-methylene-ADP). In the Ussing chamber, these inhibitors could reverse the chloride secretory responses triggered by 5′-AMP. In addition, α,β-methylene-ADP and zinc blocked the ability of 5′-AMP to stimulate EPEC growth under nutrient-limited conditions in vitro. Ecto-5′-nucleotidase appears to be the major enzyme responsible for generation of adenosine from adenine nucleotides in the T84 cell line, and inhibitors of ecto-5′-nucleotidase, such as α,β-methylene-ADP and zinc, might be useful for treatment of the watery diarrhea produced by EPEC infection

Mammography stages of change in middle-aged women with schizophrenia: An exploratory analysis

BACKGROUND: Health care providers and educators who seek to create health promotion programs and individualized comprehensive care plans for women with schizophrenia are hindered by the lack of data to guide their efforts. PURPOSE: This study tested the hypothesis that women with schizophrenia adhere to mammography screening guidelines at the same rate as other same-age women. The study also investigated the validity of the Health Belief (HB) and Stages of Change (SOC) models for breast cancer screening among women with schizophrenia. METHODS: Socio-demographic and clinical variables, as well as knowledge, attitudes, and barriers were assessed as a function of stage of change related to breast cancer screening in 46 women with schizophrenia. RESULTS: Women with schizophrenia were statistically less likely to be adherent to the screening recommendations than those without schizophrenia. Some support was found for the validity of the HB and SOC models for breast cancer screening in women with schizophrenia. Women in the Precontemplation stage had significantly higher negative attitude scores compared to Contemplation and Action/Maintenance stages (59.7, 45.7, and 43.2, respectively), and there was a trend for more barriers in the Precontemplation group (4.6, 2.6, 2.7 respectively). CONCLUSION: Given the small sample size, further research on the rates of breast cancer screening in women with schizophrenia is warranted. Nonetheless, these data suggest that providers who care for women with schizophrenia may need to make take additional measures to ensure that this population receives appropriate screening so as to not put them at greater risk for a late-stage diagnosis of breast cancer. Furthermore, these pilot data suggest that HB and SOC theory-based interventions may be valid for increasing mammography rates in women with schizophrenia

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study

BACKGROUND: Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals. METHODS: In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3–6 months (when below the threshold) or every 9–12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count. FINDINGS: 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86–1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95–1·22) for threshold 200 and 1·03 (0·96–1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17–3·43) for threshold 200 and 1·24 (0·89–1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (−25·5 to 26·3) cells per μL for threshold 200 and −3·5 (−16·0 to 8·9) cells per μL for threshold 350. INTERPRETATION: Decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies. FUNDING National Institutes of Health

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease

TESS Reveals a Short-period Sub-Neptune Sibling (HD 86226c) to a Known Long-period Giant Planet

The Transiting Exoplanet Survey Satellite mission was designed to find transiting planets around bright, nearby stars. Here, we present the detection and mass measurement of a small, short-period (≈4 days) transiting planet around the bright (V = 7.9), solar-type star HD 86226 (TOI-652, TIC 22221375), previously known to host a long-period (~1600 days) giant planet. HD 86226c (TOI-652.01) has a radius of 2.16 ± 0.08 R⊕ and a mass of ${7.25}_{-1.12}^{+1.19}$ M⊕, based on archival and new radial velocity data. We also update the parameters of the longer-period, not-known-to-transit planet, and find it to be less eccentric and less massive than previously reported. The density of the transiting planet is 3.97 g cm−3, which is low enough to suggest that the planet has at least a small volatile envelope, but the mass fractions of rock, iron, and water are not well-constrained. Given the host star brightness, planet period, and location of the planet near both the "radius gap" and the "hot Neptune desert," HD 86226c is an interesting candidate for transmission spectroscopy to further refine its composition

HATS-47b, HATS-48Ab, HATS-49b and HATS-72b: Four Warm Giant Planets Transiting K Dwarfs

We report the discovery of four transiting giant planets around K dwarfs. The planets HATS-47b, HATS-48Ab, HATS49b, and HATS-72b have masses of 0.369+ 0.0210.031MJ, 0.243+ 0.0300.022 MJ, 0.353+ 0.0270.038 MJ, and 0.1254. 0.0039 MJ, respectively, and radii of 1.117. 0.014 RJ, 0.800. 0.015 RJ, 0.765. 0.013 RJ, and 0.7224. 0.0032 RJ, respectively. The planets orbit close to their host stars with orbital periods of 3.9228 days, 3.1317 days, 4.1480 days, and 7.3279 days, respectively. The hosts are main-sequence K dwarfs with masses of 0.674+ 0.0120.016.M, 0.7279. 0.0066.M, 0.7133. 0.0075.M, and 0.7311. 0.0028, and with V-band magnitudes of V = 14.829. 0.010, 14.35. 0.11, 14.998. 0.040 and 12.469. 0.010. The super-Neptune HATS-72b (a.k.a. WASP-191b and TOI 294.01) was independently identified as a transiting planet candidate by the HATSouth, WASP, and TESS surveys, and we present a combined analysis of all of the data gathered by each of these projects (and their follow-up programs). An exceptionally precise mass is measured for HATS-72b thanks to high-precision radial velocity (RV) measurements obtained with VLT/ESPRESSO, FEROS, HARPS, and Magellan/PFS. We also incorporate TESS observations of the warm Saturn-hosting systems HATS-47 (a.k.a. TOI.1073.01), HATS-48A, and HATS-49. HATS-47 was independently identified as a candidate by the TESS team, while the other two systems were not previously identified from the TESS data. The RV orbital variations are measured for these systems using Magellan/PFS. HATS-48A has a resolved 5.. 4 neighbor in Gaia.DR2, which is a common-proper-motion binary star companion to HATS-48A with a mass of 0.22.M and a current projected physical separation of similar to 1400 au

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

Medical school faculty discontent: prevalence and predictors of intent to leave academic careers

<p>Abstract</p> <p>Background</p> <p>Medical school faculty are less enthusiastic about their academic careers than ever before. In this study, we measured the prevalence and determinants of intent to leave academic medicine.</p> <p>Methods</p> <p>A 75-question survey was administered to faculty at a School of Medicine. Questions addressed quality of life, faculty responsibilities, support for teaching, clinical work and scholarship, mentoring and participation in governance.</p> <p>Results</p> <p>Of 1,408 eligible faculty members, 532 (38%) participated. Among respondents, 224 (40%; CI95: 0.35, 0.44) reported that their careers were not progressing satisfactorily; 236 (42%; CI95: 0.38, 0.46) were "seriously considering leaving academic medicine in the next five years." Members of clinical departments (OR = 1.71; CI95: 1.01, 2.91) were more likely to consider leaving; members of inter-disciplinary centers were less likely (OR = 0.68; CI95: 0.47, 0.98). The predictors of "serious intent to leave" included: Difficulties balancing work and family (OR = 3.52; CI95: 2.34, 5.30); inability to comment on performance of institutional leaders (OR = 3.08; CI95: 2.07, 4.72); absence of faculty development programs (OR = 3.03; CI95: 2.00, 4.60); lack of recognition of clinical work (OR = 2.73; CI95: 1.60, 4.68) and teaching (OR = 2.47; CI95: 1.59, 3.83) in promotion evaluations; absence of "academic community" (OR = 2.67; CI95: 1.86, 3.83); and failure of chairs to evaluate academic progress regularly (OR = 2.60; CI95: 1.80, 3.74).</p> <p>Conclusion</p> <p>Faculty are a medical school's key resource, but 42 percent are seriously considering leaving. Medical schools should refocus faculty retention efforts on professional development programs, regular performance feedback, balancing career and family, tangible recognition of teaching and clinical service and meaningful faculty participation in institutional governance.</p

Serum CA 19-9 as a Marker of Resectability and Survival in Patients with Potentially Resectable Pancreatic Cancer Treated with Neoadjuvant Chemoradiation

Purpose The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials. Patients and Methods We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level. Results We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74). Conclusions Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.PublishedN/