tbuckley/cabot-search huggingface dataset:
Biological Function and Prognostic Significance of Peroxisome Proliferator-Activated Receptor δ in Rectal Cancer
Authors: Lie Yang, Hong Zhang, Zong-Guang Zhou, Hui Yan, G Adell, Xiao-Feng Sun
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To investigate the expression significance of PPAR β/δ in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients. Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR δ antibody. Survival probability was computed by the Kaplan–Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR δ knockdown. Results: PPAR δ was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR δ was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR δ was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR δ knockdown. Conclusions: RT decreases the PPAR δ expression in primary rectal cancers and lymph node metastases. PPAR δ is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR δ predicts favorable survival in the rectal cancer patients either with or without preoperative RT. Clin Cancer Res; 17(11); 3760–70. ©2011 AACR.
ROLE OF NUTRITION IN PREVENTION OF THE PROGRESSION OF RENAL DISEASE
Authors: Bradley J. Maroni, William E. Mitch
Journal: Annual Review of Nutrition (1997)

▪ Abstract In rats with renal disease, low-protein diets slow the decline in renal function, histologic damage, and mortality. Low-protein (and phosphorus) diets can also ameliorate uremic symptoms, secondary hyperparathyroidism, and metabolic acidosis in patients with chronic renal failure. Albeit controversial, evidence also suggests that dietary protein restriction can slow the rate of progression of renal failure and the time until end-stage renal failure. These dietary regimens appear to be safe and patients with chronic renal failure are able to activate normal compensatory mechanisms designed to conserve lean body mass when dietary protein intake is restricted. When low-protein diets are prescribed, patients should be closely monitored to assess dietary compliance and to ensure nutritional adequacy. Evidence that the spontaneous intake of dietary protein decreases in patients with progressive chronic renal failure who consume unrestricted diets should not be construed as an argument against the use of low-protein diets. Rather, it is a persuasive argument to restrict dietary protein intake in order to minimize complications of renal failure while preserving nutritional status.
Contents of Endometriotic Cysts, Especially the High Concentration of Free Iron, Are a Possible Cause of Carcinogenesis in the Cysts through the Iron-Induced Persistent Oxidative Stress
Authors: Ken Yamaguchi, Masaki Mandai, Shinya Toyokuni, Junzo Hamanishi, Toshihiro Higuchi, Kenji Takakura, Shingo Fujii
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Experimental Design: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free “catalytic” iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro. Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P &amp;lt; 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-OHdG were also significantly higher in endometriotic cysts (P &amp;lt; 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P &amp;lt; 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P &amp;lt; 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P &amp;lt; 0.05). In vitro analyses showed that the contents of endometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts. Conclusions: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.
Tests to predict imminent delivery in threatened preterm labour
Authors: N. L. Hezelgrave, A. H. Shennan, A. L. David
Journal: BMJ (2015)

#### The bottom line

#### How patients were involved in the creation of this article

This article was reviewed by Susan Harper-Clarke, a member of the St Thomas’ Hospital/King’s College London Premature Birth Patient, Carer, Public Involvement and Engagement (PCPIE) group. She suggested that healthcare professionals should consider patient anxiety associated with unnecessary interventions in the absence of predictive testing.

A 30 year old gravida 2 para 0 woman presented to her local hospital at 25 weeks’ gestation with a four hour history of worsening “contraction-like” abdominal pain every 5-10 minutes. She had had a miscarriage at 23 weeks’ after similar symptoms a year earlier; no cause had been identified. Mild uterine tightenings were confirmed on abdominal palpation. She had no fever or symptoms of urinary tract infection and the fetal heart rate was normal. A vaginal speculum examination showed a long closed cervix with normal vaginal discharge. No neonatal cots were available in the event of delivery.

Because of her symptoms and history of late miscarriage, this woman should be considered at high risk of spontaneous preterm birth. However, regardless of history, women who present with symptoms and signs of threatened preterm labour rarely deliver early; most (75%) deliver at term.1 Even women with one previous spontaneous preterm birth or late miscarriage have only a 15% chance of spontaneous preterm birth in …
Improved delivery of fenoterol plus ipratropium bromide using Respimat® compared with a conventional metered dose inhaler
Authors: J. Goldberg, E. Freund, B. Beckers, R. Hinzmann
Journal: European Respiratory Journal (2001)

Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat®, a soft mist inhaler, and to establish the Respimat® dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 µg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV 1 ) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 µg delivered via Respimat®; F/I 50/20 or 100/40 µg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV 1 than placebo. A log-linear dose-response was obtained for the average increase in FEV 1 up to 6 h (AUC 0–6 h ) and peak FEV 1 across the dose range administered by Respimat®. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat® compared with the MDI. However 12.5/5 and 25/10 µg F/I administered via Respimat® were closest (slightly superior) to the F/I dose of 100/40 µg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat® compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat®, is as effective and as safe as higher doses given via a metered dose inhaler.
Molecular, cellular, and functional properties of bone marrow T lymphocyte progenitor clones.
Authors: R Palacios, M Kiefer, M Brockhaus, K Karjalainen, Z Dembić, P Kisielow, H von Boehmer
Journal: The Journal of Experimental Medicine (1987)

The continuous proliferating bone marrow clones C4-77, C4-86, and C4-95 express low levels of Thy-1 and Ly-1 surface antigens, but no detectable surface antigens normally present on thymocytes, peripheral mature T lymphocytes, cells of the B lymphocyte or myeloid lineages. They contain the T cell antigen receptor genes alpha, beta, and the T cell-specific gene gamma in the germline configuration, and they express functional receptors for IL-3 and nonfunctional receptors for IL-2. The C4 clones are able to home and undergo differentiation in the thymus of sublethally irradiated mice and give rise in vivo to phenotypically and functionally mature peripheral T lymphocytes displaying several antigen specificities. In vitro 5-Azacytidine induces the C4 clones to express Lyt-2 and L3T4 T cell differentiation antigens, and renders them amenable to be switched from IL-3 to IL-2 dependence. However, the C4 clones seem incapable of giving rise to B lymphocytes either in vivo or in vitro. They self-renew in vitro in the presence of IL-3 every 12-14 h. We conclude that the C4 clones represent cells at the earliest stage of T cell development, i.e., Pro-T lymphocytes.
Perception of direction is not compensated for neural latency
Authors: Bart Krekelberg
Journal: Behavioral and Brain Sciences (2008)

Abstract Neural activity in the middle temporal area (MT) is strongly correlated with motion perception. I analyzed the temporal relationship between the representation of direction in MT and the actual direction of a stimulus that continuously changed direction. The representation in MT lagged the stimulus by 45 msec. Hence, as far as the perception of direction is concerned, the hypothesis of lag compensation can be rejected.
ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction: Executive Summary and Recommendations
Authors: Eugene Braunwald, Elliott M. Antman, John W. Beasley, Robert M. Califf, Melvin D. Cheitlin, Judith S. Hochman, Robert H. Jones, Dean Kereiakes, Joel Kupersmith, Thomas N. Levin, Carl J. Pepine, John W. Schaeffer, Earl E. Smith, David E. Steward, Pierre Theroux, Raymond J. Gibbons, Joseph S. Alpert, Kim A. Eagle, David P. Faxon, Valentin Fuster, Timothy J. Gardner, Gabriel Gregoratos, Richard O. Russell, Sidney C. Smith
Journal: Circulation (2000)

HomeCirculationVol. 102, No. 10ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction: Executive Summary and Recommendations
Activation of DNA Synthesis and AP-1 by Profilin, an Actin-Binding Protein, via Binding to a Cell Surface Receptor in Cultured Rat Mesangial Cells
Authors: MASAHITO TAMURA, NOBUYUKI YANAGIHARA, HIROSHI TANAKA, AKIHIKO OSAJIMA, TAKESHI HIRANO, KEN HIGASHI, KENNETH M. YAMADA, YASUHIDE NAKASHIMA, HIDEYASU HIRANO
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Profilin is known to bind to actin monomers (to regulate actin polymerization) and to phosphatidylinositol-4,5-bisphosphate (to inhibit hydrolysis by unphosphorylated phospholipase C-γl). It was recently reported that profilin is overexpressed in glomerular mesangial cells (MC) of rats with anti-Thy-1.1-induced glomerulonephritis and is accumulated in the extracellular space around MC. In this study, the biologic activities of extracellular profilin were examined. Scatchard analysis indicated the existence of a single class of cell surface binding sites, with similar equilibrium dissociation constants for purified splenic profilin and recombinant profilin, in cultured rat MC. Profilin increased [ 3 H]thymidine incorporation in a dose-dependent manner and produced additive effects on platelet-derived growth factor-induced [ 3 H]thymidine incorporation. Profilin increased AP-1 DNA-binding activity in a concentration-dependent (ED 50 = 30 nM) and time-dependent manner after transient c- jun gene expression, as measured using gel-shift assays and competitive reverse transcription-PCR. Pretreatment of profilin with an anti-profilin inhibitory antibody suppressed profilin-induced AP-1 activation and [ 3 H]thymidine incorporation. Furthermore, profilin induced rapid transient activation of protein kinase C, and staurosporine and H-7 reduced the profilin-induced activation of AP-1, suggesting protein kinase C-dependent activation of AP-1. These findings indicate that profilin in the extracellular space can bind to cell surface receptors of MC and act as an inducer of signal transduction. These results suggest that extracellular profilin may be involved in the progression of glomerular diseases, by affecting cell growth.
Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: Role of endothelium-derived nitric oxide
Authors: Stuart D. Katz, Henry Krum, Tehreen Khan, Mathius Knecht
Journal: Journal of the American College of Cardiology (1996)

Objectives. This study was undertaken to investigate the role of endothelium-derived nitric oxide in the regulation of forearm blood flow during exercise in normal subjects and patients with congestive heart failure. Background. Nitric oxide-mediated vasodilation in response to muscarinic stimulation is impaired in the peripheral circulation of patients with congestive heart failure. Whether nitric oxide-mediated vasodilation during exercise is also impaired in patients with congestive heart failure is unknown. Methods. Forearm blood flows (ml/min per 100 ml) were determined during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction by venous occlusion plethysmography before and after regional inhibition of nitric oxide synthesis with administration of L-NG-monomethylarginine (L-NMMA) in the brachial artery of 17 patients with congestive heart failure (mean age 49 years, mean left ventricular ejection fraction 0.22) and 10 age-matched normal subjects. Results. Before administration of L-NMMA in the brachial artery, forearm blood flows in patients with congestive heart failure during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction were slightly but not significantly lower than that of normal subjects ([mean ± SE] 6.8 ± 1.0, 8.5 ± 1.0 and 12.9 ± 1.7 ml/min per 100 ml, respectively, in patients with congestive heart failure vs. 6.6 ± 1.2, 11.6 ± 1.9 and 16.2 ± 1.9 ml/min per 100 ml, respectively, in normal subjects, p = NS). After administration of L-NMMA in the brachial artery, forearm blood flows in normal subjects significantly decreased by 10% to 21% during hand grip exercise but did not change during exercise in patients with congestive heart failure. Conclusions. Regional inhibition of nitric oxide synthase with administration of L-NMMA in the brachial artery significantly decreased forearm blood flows during rhythmic hand grip exercise in normal subjects but not in patients with congestive heart failure. These findings suggest that nitric oxide-mediated vasodilation during submaximal exercise is impaired in the forearm circulation of patients with congestive heart failure.
Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data
Authors: Natalie Thurtle, Jane Greig, Lauren Cooney, Yona Amitai, Cono Ariti, Mary Jean Brown, Michael J. Kosnett, Krystel Moussally, Nasir Sani-Gwarzo, Henry Akpan, Leslie Shanks, Paul I. Dargan
Journal: PLoS Medicine (2014)

Background In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children ≤5 y of age with severe paediatric lead intoxication reported to date to our knowledge. Methods and Findings In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children ≤5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL ≥ 45 µg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL ≥ 80 µg/dl and ≥ 120 µg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%–79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%–57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged ≤5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for. Conclusions Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment. Please see later in the article for the Editors' Summary
Regulation of cytokine secretion by cystic fibrosis airway epithelial cells
Authors: C Ruef, DM Jefferson, SE Schlegel-Haueter, S Suter
Journal: European Respiratory Journal (1993)

Chronic airway inflammation is an important feature of cystic fibrosis (CF), markedly influencing morbidity and mortality. We wanted to assess the contribution of the respiratory epithelium in the mediation of local inflammatory events, and, more particularly, its regulating role through cytokine secretion. We have studied the regulation of interleukin-6 and 8 (IL-6 and IL-8) production by the SV40 transformed airway epithelial cell line JME/CF15 (homozygous for the deletion of Phe 508). We show that unstimulated JME/CF15 cells secrete IL-6 and IL-8. Neutrophil chemotactic activity (NCA) is detected in supernatants. The secretion of IL-6 and IL-8 is increased following stimulation of the JME/CF15 cells by IL-1 beta and neutrophil elastase. Lipopolysaccharide and granulocyte macrophage colony stimulating factor (GM-CSF) have no effect on secretion of IL-6 or IL-8. Neutrophil elastase inactivates recombinant human IL-6 at 37 degrees C in vitro, but has no effect at 4 degrees C, suggesting a proteolytic effect of elastase on IL-6. IL-8 activity remains preserved, even after prolonged exposure to elastase. Our data suggest that the airway epithelium may play an active role in the mediation of neutrophil chemotaxis. Local production of IL-8 in response to elastase and IL-1 beta, together with the inactivation of the anti-inflammatory protein IL-6, may result in a significant upregulation of airway inflammation in cystic fibrosis.
Detection of spread of malignant lymphoma to the liver by low field strength magnetic resonance imaging.
Authors: M A Richards, J A Webb, R H Reznek, G Davies, S E Jewell, W S Shand, P F Wrigley, T A Lister
Journal: BMJ (1986)

The accuracy of spin lattice relaxation time (T1) measurement obtained with a low field strength magnetic resonance imager for the detection of spread of malignant lymphoma to the liver was assessed. The results of histological examination obtained at open liver biopsy were compared with liver T1 values in 27 patients with lymphoma. The normal range for T1 was established by scanning 61 healthy volunteers. Magnetic resonance imaging was highly sensitive in detecting hepatic lymphoma, all seven patients with liver lymphoma proved by biopsy having considerably higher T1 values. Specificity was less good. Five out of 20 patients with no histological evidence of hepatic lymphoma had abnormal T1 values. this level of sensitivity is considerably better than that reported for other imaging methods and contrasts with the results of one previous study using a different magnetic resonance system. Low field strength magnetic resonance imaging may prove to be a useful screening test in patients with lymphoma. The presence of a normal liver T1 seems to be a reliable guide to the absence of hepatic disease.