tbuckley/cabot-search huggingface dataset:
PWE-247 Slow transit constipation is associated with altered colonic ph and increased motility: novel findings from studies using the wireless motility capsule
Authors: SD Mohammed, YT Wang, A Farmer, S Christodoulides, J Semler, P Hellström, A Hobson, P Dinning, SM Scott
Journal: Gut (2015)

<h3>Introduction</h3> The wireless motility capsule (WMC) allows investigation of regional gut transit times, intraluminal pH and pressure changes as it traverses the gastrointestinal tract. It is a useful diagnostic tool to confirm slow transit constipation (STC), which recent studies suggest is allied to dysregulated rather than impaired colonic motility (Dinning <i><i>et al</i></i>. NGM 2010). Whether luminal pH differs in STC is unknown. AIM: to compare colonic pressure and pH profiles between healthy volunteers (HV) and STC. Method data from 18 WMC studies in STC (15 female, median age 37; colon transit time (CTT) &gt;72h) were compared to those of 112 HV (48 female; median age 43). Pressure and pH profiles were analysed for: (1) the whole colon; (2) within the caecum and proximal colon (first 60 min following passage of WMC through the ICJ); and (3) within the distal colon (last 60 min prior to WMC expulsion). Results overall frequency of colonic contractions was similar between STC and HV (STC: 3.0 ± 1.3/min vs. HV: 2.8 ± 1.2/min; <i>P</i>=NS). However, the colonic motility index (CMI) was significantly higher in STC than HV (STC: 330 ± 166 vs. HV: 184 ± 104; <i>P &lt; 0</i>.0001). CMI and CTT were positively correlated (<i>r = 0</i>.38; <i>P = 0</i>.003). The proximal and distal colonic pressure profiles were similar between groups. For colonic pH profile, STC had a significantly more alkaline pH, both overall (STC: 7.7 ± 1.0 vs. HV: 6.8 ± 0.7; <i>P &lt; 0</i>.0001), and in the distal colon (STC: 8.1 ± 1 vs. HV: 7.2 ± 0.9; <i>P = 0</i>.0004). Using linear regression modelling, alkaline pH was associated with an increase in the CMI when controlling for age and gender between groups (beta=62.1; <i>P = 0</i>.023). Conversely, proximal colonic pH was more acidic in STC, manifest as a greater difference in pH across the ICJ than in HV (STC delta ICJ: 1.8 ± 0.6 vs. HV: 1.3 ± 0.8; P &lt; 0.005). Conclusion the CMI was found to be higher in STC than HV, supporting a more contemporary acceptance of underlying dysregulation of colonic contractility rather than “inertia”. Differences in colonic pH in STC may reflect alterations in regional gut microbiota (i.e. dysbiosis), resulting in excessive production of acidic metabolites in the proximal colon (e.g. short-chain fatty acids) of STC patients, and more alkaline metabolites in the distal colon (perhaps related to methanogenic activity). The observed associations between colonic pH, CMI and CCT warrants further investigation; conceivably, this may represent a biomarker to sub-classify constipated patients, and identify those who may benefit from antibiotic and/or dietary interventions <h3>Disclosure of interest</h3> None Declared.
P40 Ex vivo treatment of neutrophils with a p38-MAPK agonist in patients with liver failure improves their bacteriocidal capacity
Authors: D Shawcross, A Nishtala, N J Taylor, J A Wendon
Journal: Gut (2010)

Introduction  Ammonia reduces neutrophil phagocytic and bacteriocidal capacity. Neutrophils swell in response to ammonia exposure and activation of the p38-MAPK pathway has been implicated in protecting the neutrophil against osmotic shock and in normalising neutrophil phagocytic dysfunction. (Shawcross  et al. ,  Hepatology  2008) In patients with acute and chronic liver failure with elevated arterial ammonia, we hypothesised that treating neutrophils ex vivo with isoproterenol, a β adrenergic receptor and p38-MAPK agonist would improve neutrophil phagocytic capacity.  Aim  Within the context of an ongoing longitudinal study of neutrophil function in 100 patients with acute (ALF) and chronic liver failure we investigated the role of ex vivo incubation of neutrophils with an exogenous ammonia load, a p38-MAPK agonist (isoproterenol) and the specific p38-MAPK antagonist SB203580 (Calbiochem) on neutrophil function in a cohort of 10 patients (5 ALF and 5 chronic) all with elevated arterial ammonia concentration.  Method  Phagocytic capacity in heparinised whole blood was quantitatively determined by flow cytometry using FITC-labelled opsonised  E. coli  at baseline, and following incubation for 90 min with ammonium chloride (200 μmol/l), isoproterenol (2 μmol/l) or SB203580 (40 μmol/l) at 37°C.  Results  The ALF patients (drug-induced n=3 and seronegative n=2) had a median SOFA score of 17 (IQR 16–18) and APACHE II score of 24 (22–28). The patients with cirrhosis (alcohol n=3; HCV; NASH) had a median MELD score of 10 (7–27). The median arterial ammonia level in the ALF group was 96 (49–158) and in the chronic group was 97 (63–122) μmol/l. Baseline bactericidal capacity was 49% (36–57) in the ALF group and 75% (67–84) in the chronic group compared to >85% in healthy controls and a median of 82% in a septic control group without liver disease. The exogenous ammonia load further reduced neutrophil phagocytic capacity by a median of 8% (3–16). The p38-MAPK agonist significantly abrogated the ammonia-induced phagocytic impairment and improved bacteriocidal capacity (p=0.003). The p38-MAPK antagonist however, exacerbated the ammonia-induced reduction in neutrophil phagocytic capacity by a median of 15% (4–24); p=0.0015.  Conclusion  These data show that in patients with acute and chronic liver failure and elevated arterial ammonia that neutrophil bacteriocidal capacity is disabled. Activation of the p38-MAPK pathway serves as an important cellular protective mechanism against ammonia-induced impairment and further trials of p38-MAPK agonists in patients with liver failure are warranted.
David Oliver: Grill the politicians live on TV
Authors: David Oliver
Journal: BMJ (2015)

BerkshireThe US television debates for the Republican presidential candidacy have been strangely compelling, with Donald Trump and Ben Carson's bizarre pronouncements and a long line-up of egos.Claims and counterclaims are made about candidates' records in politics or business.Moderators struggle to challenge assertions or aspirations.More heat than light ensues.UK television election debates are blander, but the party leaders do face some glare.The mass media's scrutiny of UK
Neoadjuvant chemotherapy AC-D in breast cancer patients.
Authors: O. Pribylova, L. B. Petruzelka, P. Tesarova, A. Svobodnik
Journal: Journal of Clinical Oncology (2010)

e11009 Background: To compare the efficacy of neoadjuvant (NA) chemotherapy with adriamycine, cyclophosphamide, and docetaxel (AC-D) in the group of breast cancer patients according to estrogen receptor (ER), HER2 expression, grade, and KI-67. Methods: 137 patients with large or locally advanced breast cancer received four cycles of adriamycine 60 mg/m2 and cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 100 mg/m2. Age of patients was 25-76 years, median 50 years, 63 of them (46%) were premenopausal, 59 (43%) postmenopausal, and 15 (11%) perimenopausal. Majority of them were N1-2-92 (71%) or T4 57 (45%) or both. 79 tumors (58%) were ER +, HER2 2+ was found in 12 (9%), HER2 3+ in 28 (20%). KI 67 value were in ranges 1-90%. Tumor response was assessed clinically, by mammography and microscopically. Statistical evaluation was done by chi-square test and Kruskal-Wallis method. Results: See Table. Patients' ER negative achieved statistically significant better response (p=0.005) than ER+. HER2 positivity was not statistically signifficant, but remarkably better were efficacy in HER-negative patients. We did not see any difference according to tumor grade. Patients with CR had statistically signifficantly higher KI-67 (p=0.028). Conclusions: Efficacy of chemotherapy in breast cancer patients is clearly dependent on ER status and KI-67. Response Clinical Mammography Pathological CR 28/17 ER-/10 HER+ 23/15 ER-/6 HER + 20/13 ER-/5 HER+ PR 93/61 ER-/46 HER+ 95/63 ER-/47 HER+ 95/63 ER-/47 HER+ SD 14 14 PD 2 137 No significant financial relationships to disclose.
Clinical and Laboratory Investigations on Man: Systemic Administration of Potent Interferon to Man234
Authors: Hans Strander, Kari Cantell, Gun Carlström, Per Å. Jakobsson
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Clinical and Laboratory Investigations on Man: Systemic Administration of Potent Interferon to Man Get access Hans Strander, Hans Strander Search for other works by this author on: Oxford Academic PubMed Google Scholar Kari Cantell, Kari Cantell Search for other works by this author on: Oxford Academic PubMed Google Scholar Gun Carlström, Gun Carlström Search for other works by this author on: Oxford Academic PubMed Google Scholar Per Å. Jakobsson Per Å. Jakobsson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 3, September 1973, Pages 733–742, https://doi.org/10.1093/jnci/51.3.733 Published: 01 September 1973 Article history Received: 29 December 1972 Accepted: 01 May 1973 Published: 01 September 1973
Peroxisome Proliferator-lnduced Hepatocarcinogenesis: Histochemical Analysis of Ciprofibrate-lnduced Preneoplastic and Neoplastic Lesions for γ-Glutamyl Transpeptidase Activity&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M S Rao, V Subbarao, J K Reddy
Journal: JNCI Journal of the National Cancer Institute (1986)

Previous studies revealed that putative preneoplastic and neoplastic lesions induced in the liver by Wy-14,643, a peroxisome proliferator, were gamma-glutamyl transpeptidase (GGT) negative. For ascertainment as to whether phenotypes of foci and carcinomas induced by all peroxisome proliferators are similarly GGT negative, altered areas (AAs), neoplastic nodules (NNs), and hepatocellular carcinomas (HCCs) induced in the livers of male F344 rats by chronic dietary administration of ciprofibrate (0.025% wt/wt in chow; CAS: 52214-84-3) were analyzed histochemically for GGT activity. Eighty-nine percent of AAs, 91% of NNs, and 91% of HCCs were GGT negative. The GGT-negative property of these various hepatic preneoplastic and neoplastic lesions persisted at 8 weeks after the withdrawal of ciprofibrate treatment. The results of this study indicate that the absence of GGT activity is a common feature in hepatic lesions induced by structurally unrelated peroxisome proliferators and is not related to the drug toxicity. The proposal was made that peroxisome proliferators do not derepress the activity of the GGT gene during hepatocarcinogenesis in the rat.
SP0019 Estrogens Effects on B Cells and Implications for Sex Bias in Development of Autoimmunity
Authors: D. Choubey
Journal: Annals of the Rheumatic Diseases (2015)

The female sex hormone 17β-estradiol (E2) increases the risk of developing certain autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren syndrome (SS), in genetically susceptible women and certain mouse strains. E2 signals through two nuclear receptors, namely estrogen receptor ERα and ERβ. These receptors are expressed in most immune cell types, including B cells. Both ERα and ERβ receptors differentially regulate the maturation and selection of B cells. Accordingly, studies have noted that steady-state levels of the ERα mRNA and protein are significantly higher in PBMCs from SLE patients when compared with gender- and age-matched normal individuals. Further, studies on lupus in mouse models indicated a prominent role of ERα, but not ERβ, in the development of disease. ERs are ligand-activated nuclear receptors that can either directly bind to estrogen responsive elements (EREs) that are present in gene promoters or serve as cofactors with other transcription factors (such as AP-1 and NF-κB) to activate the transcription of the target genes. The E2 target genes that influence B cell development and functions include: BCL2 (survival of autoreactive cells), BAFF (survival and differentiation of autoreactive cells), AID (production of pathogenic autoantibodies), and IRF5 (B cell differentiation). E2-mediated increased expression of these (and other) genes results in an increased production of pathogenic autoantibodies. Several clinical manifestations of autoimmune diseases are thought to be the result of autoantibody and immune complex deposition in tissues and organs; thus, leading to secondary inflammatory responses and organ damage. Evidence indicates that activation of toll-like receptors (TLR)-dependent and independent innate immune responses, which result in increased production of type I interferon-α/β (IFN-α/β) and an increased expression of the IFN-inducible genes ("IFN-signature"), contribute to the development of disease phenotype in certain autoimmune diseases (e.g., SLE and SS). We have identified a feedforward loop between IFN-α/β and ERα in B cells. Further, our studies revealed that the expression of certain E2-responsive genes such as BAFF, IRF5, and UNC93b (encodes for a transporter of certain TLRs) is also induced by type I IFNs in immune cells, including B cells. Notably, activation of IFN-signaling in murine B cells (CD19+) induced inflammasome activity, thus increasing the production of proinflammatory cytokines (e.g., IL-1β and IL-18). Although recent advancement in the field have provided new insights into the role of E2/ERα-signaling in B cells and implicated its role in sex bias in the development of certain autoimmune diseases, further work is needed to fully understand the molecular mechanisms. These studies are integral to identifying new approaches to effectively treat autoimmune diseases. <h3>Disclosure of Interest</h3> None declared
Evaluating the Impact of Provincial Implementation of Screening for Distress on Quality of Life, Symptom Reports, and Psychosocial Well-Being in Patients With Cancer
Authors: Linda Watson, Shannon Groff, Rie Tamagawa, Jennifer Looyis, Sydney Farkas, Brent Schaitel, Andrea DeIure, Peter Faris, Barry D Bultz
Journal: Journal of the National Comprehensive Cancer Network (2016)

Although a number of accreditation agencies and professional societies recommend routine screening for distress (SFD) for patients with cancer, it has been integrated very slowly into clinical practice.This evaluation investigated the impact of a large-scale SFD intervention on patients' quality of life, symptom reports, and psychosocial well-being. The SFD intervention involved (1) completion of the SFD tool by patients, (2) discussion between patient and provider about the concerns indicated, and (3) provision of appropriate assessments/interventions based on priority concerns.This quality improvement work included a pre-evaluation and postevaluation of the impact of implementation on patients' well-being. Patients in cohort 1 (N=740) were surveyed before implementation, whereas patients in cohort 2 (N=534) were surveyed 10 months after the implementation at 17 clinics province-wide. As part of the implementation, providers received training on assessing and responding to patient priority concerns with the standardized tool.No differences were seen in total score of quality of life between the cohorts. Fewer patients in cohort 2 than in cohort 1 reported health problems, including tiredness, drowsiness, poor appetite, nausea, anxiety, and poor well-being. Similarly, significantly fewer patients in cohort 2 endorsed problems relating to emotional, practical, informational, spiritual, social, and physical aspects of well-being.Results showed significantly improved psychological and physical symptoms and psychosocial well-being after routine SFD was implemented, suggesting that a large-scale SFD intervention is beneficial for patients when it is integrated into existing clinical practice and community resources.
Phase Ii Study Evaluating Oral Vinorelbine As a Single-Agent As First-Line Chemotherapy for Metastatic Breast Cancer Patients with Bone Metastases (Norbreast-228 Trial): First Efficacy Results
Authors: G.G. Steger, A. Dominguez, O. Switsers, N. Dobrovolskaya, F. Giotta, I. Glogowska, N. Tubiana-Mathieu, M. Pecherstorfer, A. Ardizzoia, P. Bougnoux, M. Blasinska-Morawiec, C. Veyret, S. Garcia, J. Dorca, C. Marth, A. Manikhas, M. Benasso, S. Protsenko, G.R. Villanova, E. Espinosa
Journal: Annals of Oncology (2014)
Additive cardioprotection by pharmacological postconditioning with hydrogen sulfide and nitric oxide donors in mouse heart: S-sulfhydration vs. S-nitrosylation
Authors: Junhui Sun, Angel M. Aponte, Sara Menazza, Marjan Gucek, Charles Steenbergen, Elizabeth Murphy
Journal: Cardiovascular Research (2016)

Hydrogen sulfide (H2S), as a gaseous signalling molecule, has been found to play important roles in postconditioning (PostC)-induced cardioprotection. Similar to nitric oxide (NO)-mediated protein S-nitrosylation (SNO), recent studies suggest that H2S could regulate protein function through another redox-based post-translational modification on protein cysteine residue(s), i.e. S-sulfhydration (SSH). In this study, we examined whether there are changes in protein SSH associated with cardioprotection induced by treatment with H2S on reperfusion. In addition, we also examined whether there is cross talk between H2S and NO. Compared with control, treatment on reperfusion with NaHS (H2S donor, 100 µmol/L) significantly reduced post-ischaemic contractile dysfunction and infarct size. A comparable cardioprotective effect could be also achieved by reperfusion treatment with SNAP (NO donor, 10 µmol/L). Interestingly, simultaneous reperfusion with both donors had an additive protective effect. In addition, C-PTIO (NO scavenger, 20 µmol/L) eliminated the protection induced by NaHS and also the additive protection by SNAP + NaHS together. Using a modified biotin switch method, we observed a small increase in SSH following NaHS treatment on reperfusion. We also found that NaHS treatment on reperfusion increases SNO to a level comparable to that with SNAP treatment. In addition, there was an additive increase in SNO but not SSH when SNAP and NaHS were added together at reperfusion. Thus, part of the benefit of NaHS is an increase in SNO, and the magnitude of the protective effect is related to the magnitude of the increase in SNO.
A major difference between the divergence patterns within the lines-1 families in mice and voles.
Authors: F Vanlerberghe, F Bonhomme, C A Hutchison, M H Edgell
Journal: Molecular Biology and Evolution (1993)

L1 retroposons are represented in mice by subfamilies of interspersed sequences of varied abundance. Previous analyses have indicated that subfamilies are generated by duplicative transposition of a small number of members of the L1 family, the progeny of which then become a major component of the murine L1 population, and are not due to any active processes generating homology within preexisting groups of elements in a particular species. In mice, more than a third of the L1 elements belong to a clade that became active approximately 5 Mya and whose elements are > or = 95% identical. We have collected sequence information from 13 L1 elements isolated from two species of voles (Rodentia: Microtinae: Microtus and Arvicola) and have found that divergence within the vole L1 population is quite different from that in mice, in that there is no abundant subfamily of homologous elements. Individual L1 elements from voles are very divergent from one another and belong to a clade that began a period of elevated duplicative transposition approximately 13 Mya. Sequence analyses of portions of these divergent L1 elements (approximately 250 bp each) gave no evidence for concerted evolution having acted on the vole L1 elements since the split of the two vole lineages approximately 3.5 Mya; that is, the observed interspecific divergence (6.7%-24.7%) is not larger than the intraspecific divergence (7.9%-27.2%), and phylogenetic analyses showed no clustering into Arvicola and Microtus clades.
Perceived statutory applicability versus clinical desirability of emergency involuntary hospitalization
Authors: M A Peszke, G G Affleck, R M Wintrob
Journal: American Journal of Psychiatry (1980)

The authors used a questionnaire survey conducted by mail in 1975 to assess psychiatrists' perceptions of the applicability of two jurisdictions' statutes for emergency involuntary hospitalization and the desirability of such hospitalization in four case vignettes. The great majority of the 287 respondents agreed that the statutes were applicable and hospitalization was desirable for individuals who were at risk for suicide and who were psychotic. Most of them also agreed that such hospitalization was neither legally applicable nor desirable for nonpsychotic, nonsuicidal people. Their perceptions of applicability versus desirability differed, however, regarding people who were nonsuicidal but psychotic or nonpsychotic but suicidal.
<i>ERBB2 (HER2)</i>Testing in Breast Cancer
Authors: Talal Hilal, Edward H. Romond
Journal: JAMA (2016)

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High autonomic arousal and electrodermal orienting at age 15 years as protective factors against criminal behavior at age 29 years
Authors: A Raine, P H Venables, M Williams
Journal: American Journal of Psychiatry (1995)

Nothing is known about biological factors that protect a predisposed individual from becoming criminal. This 14-year prospective study tested the hypothesis that antisocial adolescents who desist from crime by age 29 have greater physiological arousal and orienting than antisocial adolescents who become adult criminals.Physiological arousal and orienting were measured in 101 unselected 15-year-old male schoolchildren. Of these, 17 antisocial adolescents who desisted from adult crime (desistors) were matched on adolescent antisocial behavior and demographic variables with 17 antisocial adolescents who became criminal by age 29 (criminals), and 17 nonantisocial, noncriminal normal subjects.Desistors had significantly higher electrodermal and cardiovascular arousal and higher electrodermal orienting than the criminal group.This is the first study to report biological factors that protect against the development of criminal behavior. The findings suggest that individuals predisposed to adult crime by virtue of showing antisocial behavior in adolescence may be protected from committing crime by high levels of autonomic arousal and orienting.