tbuckley/cabot-search huggingface dataset:
Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study
Authors: M. Pierce, J. J. Kurinczuk, P. Spark, P. Brocklehurst, M. Knight
Journal: BMJ (2011)

<b>Objectives</b> To follow up a UK national cohort of women admitted to hospital with confirmed 2009/H1N1 influenza in pregnancy in order to obtain a complete picture of pregnancy outcomes and estimate the risks of adverse fetal and infant outcomes. <b>Design</b> National cohort study. <b>Setting</b> 221 hospitals with obstetrician led maternity units in the UK. <b>Participants</b> 256 women admitted to hospital with confirmed 2009/H1N1 in pregnancy during the second wave of pandemic infection between September 2009 and January 2010; 1220 pregnant women for comparison. <b>Main outcome measures</b> Rates of stillbirth, perinatal mortality, and neonatal mortality; odds ratios for infected versus comparison women. <b>Results</b> Perinatal mortality was higher in infants born to infected women (10 deaths among 256 infants; rate 39 (95% confidence interval 19 to 71) per 1000 total births) than in infants of uninfected women (9 deaths among 1233 infants; rate 7 (3 to 13) per 1000 total births) (P&lt;0.001). This was principally explained by an increase in the rate of stillbirth (27 per 1000 total births <i>v</i> 6 per 1000 total births; P=0.001). Infants of infected women were also more likely to be born prematurely than were infants of comparison women (adjusted odds ratio 4.0, 95% confidence interval 2.7 to 5.9). Infected women who delivered preterm were more likely to be infected in their third trimester (P=0.046), to have been admitted to an intensive care unit (P&lt;0.001), and to have a secondary pneumonia (P=0.001) than were those who delivered at term. <b>Conclusions</b> This study suggests an increase in the risk of poor outcomes of pregnancy in women infected with 2009/H1N1, which reinforces the message from studies of maternal risk alone. The health of pregnant women is an important public health priority in future waves of this and other influenza pandemics.
Gastroparesis: separate entity or just a part of dyspepsia?
Authors: Vincenzo Stanghellini, Jan Tack
Journal: Gut (2014)

Gastroparesis is defined by the presence of delayed gastric emptying (GE) in the absence of mechanical obstruction. Symptoms that have been attributed to gastroparesis include postprandial fullness, early satiation nausea and vomiting. Gastroprokinetic drugs are the preferred treatment option. A number of problems with the concept of gastroparesis have been identified recently. Major overlap exists with the symptom complex of the functional dyspepsia subtype of postprandial distress syndrome. The distinguishing feature of gastroparesis is delayed GE, but the correlation between delayed emptying and symptom pattern or severity in gastroparesis is modest and the stability of delayed emptying over time is poor. Other pathophysiological mechanisms such as hypersensitivity or impaired accommodation may also underlie symptoms in patients with gastroparesis. Moreover, symptomatic response to prokinetic therapy is variable and cannot be predicted based on the degree of enhancing GE. A number of approaches have been proposed to increase clinical usefulness of a diagnosis of gastroparesis, including a higher threshold of abnormal emptying and selection of patients with a specific symptom pattern more likely to be associated with delayed emptying.
AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor
Authors: J.-L. Liu, Z. Mao, G. E. Gallick, W. K. A. Yung
Journal: Neuro-Oncology (2010)

The regulation of the subcellular localization of phosphatase and tensin homologue (PTEN) is critical to its tumor-suppressing functions. Previously, we found that the activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR/S6 protein kinase (S6K) cascade triggers the nuclear export of PTEN during the G1/S transition. Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5′ adenosine monophosphate-activated protein kinase (AMPK), we proposed that the activation of AMPK α1/2 by LKB1 and/or by calmodulin-dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K. We found that in LKB1-null A549 lung adenocarcinoma cells, an AMPK activator, metformin, failed to block the nuclear export of PTEN, and the reintroduction of functional LKB1 into these cells restored the metformin-mediated inhibition of the nuclear export of PTEN. In addition, the nuclear export of PTEN was blocked in cells treated with the CaMKK activator ATP, and this inhibition was reversed by the addition of inhibitors of either AMPK (compound C) or CaMKK (STO-609). Although the nuclear export of PTEN is blocked by metformin in MCF-7 breast cancer cells carrying wild-type LKB1, this inhibition could not be reversed by an AMPK inhibitor, suggesting that LKB1 could regulate the nuclear export of PTEN by bypassing AMPK α1/2. Moreover, ATP could not block the nuclear export of PTEN in AMPK α1/2−/− or TSC2−/− mouse embryonic fibroblasts. However, metformin was still able to induce the LKB1-mediated inhibition of the nuclear export of PTEN in these cells. Taken together, these findings strongly suggest that although CaMKK mediates the nuclear retention of PTEN mainly through the activation of AMPK, LKB1 can regulate the nuclear-cytoplasmic trafficking of PTEN, with or without the AMPK/TSC2/mTOR/S6K-signaling intermediates.
Therapeutic Role of TGF-β–Neutralizing Antibody in Mouse Cyclosporin A Nephropathy
Authors: Hong Ling, Xuemei Li, Sharda Jha, Wei Wang, Lina Karetskaya, Bruce Pratt, Steven Ledbetter
Journal: Journal of the American Society of Nephrology (2003)

TGF-beta is believed to play a central role in the development of Cyclosporin A (CsA)-induced nephropathy. This study investigated the effects of 1D11, a murine pan-specific TGF-beta-neutralizing monoclonal antibody, in an ICR mouse model of chronic CsA nephropathy. Mice were administered a low-salt diet (0.01% sodium) for 1 wk followed by CsA treatment (30 mg/kg, subcutaneously, daily) for 4 wk. 1D11 was administered (2.5 mg/kg, intraperitoneally, 3 times/wk) beginning immediately after the termination of CsA dosing and continued through 8 wk. CsA caused extensive renal histopathologic alterations, including tubular damage, interstitial infiltrates and fibrosis, deposition of collagen III, and apoptosis of tubular epithelial cells. 1D11 ameliorated the CsA-induced histopathologic alterations, with significant reduction in collagen III expression and deposition. Additionally, elevated levels of mRNA encoding TGF-beta1 and TGF-beta2 were significantly reduced. 1D11 also protected tubular epithelial cells from apoptosis by 48% (P < 0.05). In contrast, 13C4 (a control antibody) had no significant effect on any of the endpoints described above. Importantly, the effects of 1D11 on the CsA-induced morphologic alterations were followed by a reduction in serum creatinine level when compared with CsA mice treated with 13C4 (13C4, 0.45 +/- 0.09; 1D11, 0.30 +/- 0.08; P < 0.05) after 8 wk of treatment. Endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), nitrotyrosine, and tissue hypoxia were examined by immunostaining using specific antibodies. eNOS was significantly reduced in the endothelium of arterioles in the kidneys of mice treated with CsA, whereas iNOS was induced in the cortical tubules. Tissue hypoxia was found in both the arterioles and tubules, whereas nitrotyrosine was localized in the tubules. Administration of 1D11 improved tissue hypoxia and reduced nitrotyrosine formation. Moreover, the reciprocal changes in iNOS and eNOS expression were normalized by 1D11. This study demonstrates that 1D11 administration ameliorated morphologic alterations and preserved renal function in the context of existing chronic CsA nephropathy.
NHS safety agency issues guidance on nasogastric tubes
Authors: Rebecca Coombes
Journal: BMJ (2005)

New NHS safety advice has been issued on reducing the harm caused by nasogastric feeding tubes that have been wrongly inserted. The alert, from the National Patient Safety Agency, follows 11 deaths of patients in the past two years, including that of one child.

A further 13 incidents have also been reported, one of which caused serious harm to the patient. The agency said this week that it was concerned that unreliable tests were being used by health professionals and carers to check whether a tube had been …
Effect of E. coli antigens, tuberculin, and phytohaemagglutinin upon ulcerative colitis lymphocytes.
Authors: S Stefani, S Fink
Journal: Gut (1967)

EDITORIAL COMMENT Some very interesting observations showing that lymphocytes from the peripheral blood in patients with active ulcerative colitis differed from other lymphocytes tested in their response to E. coli extracts.Human peripheral blood lymphocytes respond in vitro to a wide range of agents by undergoing blastoid transformation and mitosis (Pearmain, Lycette, and Fitzgerald, 1963; Elves, Roath, and Israels, 1963).It is believed that specific antigen- antibody reactions within the growing cells are responsible for these changes (Hashem, 1965).As a result of these observations, Hirschhorn, Back, Kolodny, Firschein, and Hashem (1963), among others, have stated that the human peripheral lymphocyte provides a readily available system representative in vitro of the donor's immune status.
Disruption of Autosomal Recessive Hypercholesterolemia Gene Shows Different Phenotype In Vitro and In Vivo
Authors: Mariko Harada-Shiba, Atsuko Takagi, Kousuke Marutsuka, Sayaka Moriguchi, Hiroaki Yagyu, Shun Ishibashi, Yujiro Asada, Shinji Yokoyama
Journal: Circulation Research (2004)

We previously characterized the patients with autosomal recessive hypercholesterolemia (ARH) as having severe hypercholesterolemia and retarded plasma low-density lipoprotein (LDL) clearance despite normal LDL receptor (LDLR) function in their cultured fibroblasts, and we identified a mutation in the ARH locus in these patients. ARH protein is an adaptor protein of the LDL and reportedly modulates its internalization. We developed ARH knockout mice (ARH-/-) to study the function of this protein. Plasma total cholesterol level was higher in ARH-/- mice than that in wild-type mice (ARH+/+), being attributed to a 6-fold increase of LDL, whereas plasma lipoprotein was normal in the heterozygotes (ARH+/-). Clearance of 125I-LDL from plasma was retarded in ARH-/- mice, as much as that found in LDLR-/- mice. Fluorescence activity of the intravenously injected 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-LDL was recovered in the cytosol of the hepatocytes of ARH+/+ mice, but not in those of ARH-/- or LDLR-/- mice. Also, less radioactivity was recovered in the liver of ARH-/- or LDLR-/- mice when [3H]cholesteryl oleyl ether (CE)-labeled LDL was injected. In contrast, uptakes of [3H]CE-labeled LDL, 125I-LDL, and DiI-LDL were all normal or slightly subnormal when the ARH-/- hepatocytes were cultured. We thus concluded that the function of the hepatic LDLR is impaired in the ARH-/- mice in vivo, despite its normal function in vitro. These findings were consistent with the observations with the ARH homozygous patients and suggested that certain cellular environmental factors modulate the requirement of ARH for the LDLR function.
Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori
Authors: S Nakamura
Journal: Gut (2001)

<h3>BACKGROUND</h3> While a close association between gastric mucosa associated lymphoid tissue (MALT) lymphoma and <i>Helicobacter pylori</i>infection has been established, there are still cases which do not respond to <i>H pylori </i>eradication. <h3>AIMS</h3> To investigate the clinicopathological factors which may help predict the therapeutic efficacy of <i>H pylori</i> eradication in gastric MALT lymphoma. <h3>PATIENTS</h3> Forty one patients with gastric MALT lymphoma, including low and high grade lesions. <h3>METHODS</h3> After endosonographic staging was determined, <i>H pylori</i> was eradicated in all patients, and the subsequent gastric pathological course was then investigated. <h3>RESULTS</h3> Complete regression of MALT lymphoma was observed in 29(71%) patients, partial regression in five (12%), and no regression in seven (17%). Twenty six (93%) of 28 MALT lymphomas restricted to the mucosa but only three (23%) of 13 lymphomas which invaded the deep portion of the submucosa or beyond completely regressed. Kaplan-Meier analysis for the probability of complete regression of MALT lymphoma revealed a significant difference between tumours restricted to the mucosa and those invading the submucosa deeply or beyond (p&lt;0.05). Neither the presence of a high grade component, perigastric lymphadenopathy, nor clinical staging prior to eradication correlated with the probability of lymphoma regression. <h3>CONCLUSIONS</h3> Assessment of deep submucosal invasion by endosonography is valuable for predicting the efficacy of <i>H pylori</i>eradication in gastric MALT lymphoma.
Type 1 Helper T Cells and FoxP3-positive T Cells in HIV–Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome
Authors: Graeme Meintjes, Katalin Andrea Wilkinson, Molebogeng Xheeda Rangaka, Keira Skolimowska, Kerryn van Veen, Musaed Abrahams, Ronnett Seldon, Dominique J. Pepper, Kevin Rebe, Priscilla Mouton, Gilles van Cutsem, Mark Patrick Nicol, Gary Maartens, Robert John Wilkinson
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-gamma-secreting CD4(+) T cells.To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS.Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-gamma enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART.In cross-sectional analysis the frequency of IFN-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P <or= 0.03). The biggest difference was in the recognition of alpha-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4(+) and CD8(+) cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4(+) cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 +/- 4.5; non-IRIS, 2.46 +/- 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-gamma-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P = 0.041).There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.
369 EGFR SIGNALING IMPAIRS THE ANTIVIRAL ACTIVITY OF INTERFERON-ALPHA
Authors: J. Lupberger, F.H.T. Duong, I. Fofana, L. Zona, F. Xiao, S.C. Durand, M.B. Zeisel, M.H. Heim, T.F. Baumert
Journal: Journal of Hepatology (2013)
Surgical Factors Influence Bladder Cancer Outcomes: A Cooperative Group Report
Authors: Harry W. Herr, James R. Faulkner, H. Barton Grossman, Ronald B. Natale, Ralph deVere White, Michael F. Sarosdy, E. David Crawford
Journal: Journal of Clinical Oncology (2004)

Purpose A randomized, cooperative group trial (Southwest Oncology Group 8710, Intergroup 0080) reported that neoadjuvant chemotherapy improved the survival of patients with locally advanced bladder cancer who were treated with radical cystectomy. We evaluated whether surgical factors from patients enrolled onto the study predicted bladder cancer outcomes. Patients and Methods Surgical and tumor factors were recorded from surgical and pathologic reports from 268 patients with muscle-invasive bladder cancer who received radical cystectomy. Cystectomies were performed by 106 surgeons in 109 institutions. Half of the patients received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. Variables were tested in univariate and multivariate analyses for associations with postcystectomy survival (PCS) and local recurrence (LR) in all patients receiving cystectomy. Results Five-year PCS and LR rates were 54% and 15%, respectively. A multivariate model adjusted for MVAC (P = .97), age (P = .03), pathologic stage (P = .0002), and node status (P = .04) showed that surgical variables associated with longer PCS were negative margins (v positive; hazard ratio [HR], 0.37; P = .0007), and ≥ 10 nodes removed (v &lt; 10; HR, 0.51; P = .0001). These associations did not differ by treatment arms (P &gt; .21 for all tests of interactions between treatment and surgical variables). Predictors of LR in a multivariate model adjusted for MVAC (P = .16), pathologic stage (P = .02), and node status (P = .37) were positive margins (v negative; odds ratio [OR], 11.2; P = .0001) and fewer than 10 nodes removed (v ≥ 10; OR, 5.1; P = .002). Conclusion Surgical factors influence bladder cancer outcomes after cystectomy, after adjustment for pathologic factors and neoadjuvant chemotherapy usage.
The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study
Authors: S. Vermeire, S. Ghosh, J. Panes, J. F. Dahlerup, A. Luegering, J. Sirotiakova, U. Strauch, G. Burgess, J. Spanton, S. W. Martin, W. Niezychowski
Journal: Gut (2011)

<h3>Background and aims</h3> Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. <h3>Methods</h3> In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03–10 mg/kg IV<i>/</i>SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α<sub>4</sub>β<sub>7</sub><sup>+</sup> lymphocytes was measured to demonstrate drug activity. <h3>Results</h3> No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α<sub>4</sub>β<sub>7</sub><sup>+</sup> lymphocytes in patients receiving PF-00547,659. <h3>Conclusions</h3> The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. <h3>Trial Register No:</h3> NCT00928681.
Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature
Authors: Gabriel G. Malouf, Sylvie Job, Valérie Paradis, Monique Fabre, Laurence Brugières, Pierre Saintigny, Laure Vescovo, Jacques Belghiti, Sophie Branchereau, Sandrine Faivre, Aurélien de Reyniès, Eric Raymond
Journal: Hepatology (2014)

Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p-FLC) and mixed-FLC (m-FLC), differing in clinical presentation and course. We show that p-FLCs have a distinct gene expression signature different from that of m-FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p-FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p-FLCs with different outcomes. Pathway analysis of p-FLCs revealed ERBB2 overexpression and an up-regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p-FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch-like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase. p-FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p-FLC.
Biochemical Pharmacology of the Intestinal Flora
Authors: P Goldman
Journal: The Annual Review of Pharmacology and Toxicology (1978)

Animal and bacteriological techniques have been developed for clarifying the role of the flora in the metabolism of drugs and other exogenous compounds. In general the flora tends to catalyze reductive and hydrolytic reactions, some of which reverse the detoxification reactions normally occurring in the liver. These reactions and others have been implicated in the pharamacological or toxicological action of exogenous compounds. Only in a few instances, however, have practical consequences of these reactions been documented. The major challenge at present is to develop methods capable of further defining the implications of reactions due to the flora.