tbuckley/cabot-search huggingface dataset:
Relationships between symptoms, menstrual cycle and orocaecal transit in normal and constipated women.
Authors: G K Turnbull, D G Thompson, S Day, J Martin, E Walker, J E Lennard-Jones
Journal: Gut (1989)

Because severe constipation is a disorder largely confined to young women, the possibility that menstrually related factors contribute to disturbed gastrointestinal motor function has been raised. It has also been reported that normal menstruating women show changes in upper gut transit between the follicular and luteal phases of the menstrual cycle and that patients with constipation show prolonged transit. We therefore studied relationships between symptom severity and orocaecal transit during the menstrual cycle in a group of 14 constipated women and a series of control groups comprising seven normal menstruating women, five postmenopausal women, and eight normal men, to determine whether phases of the menstrual cycle were associated with alteration in symptoms or transit. A regular menstrual cycle was reported by 13 of the 14 patients (range 26-30 days) and by all the menstruating female volunteers. Seven patients noted variation in constipation during the menstrual cycle, in all cases this comprised an improvement in symptoms just before or during menstruation. No consistent relationship between symptom severity and follicular or luteal phase was noted. Repeated orocaecal transit measurements in the four study groups showed no consistent differences (greater than 0.05) between groups or during the menstrual cycle (mean change weeks 1-4, -10 +/- 20 min). These findings are inconsistent with the hypothesis of a progesterone related effect upon orocaecal transit in either normal or constipated women.
Trends in Short- and Long-Term Survival Among Out-of-Hospital Cardiac Arrest Patients Alive at Hospital Arrival
Authors: Michael K.Y. Wong, Laurie J. Morrison, Feng Qiu, Peter C. Austin, Sheldon Cheskes, Paul Dorian, Damon C. Scales, Jack V. Tu, P. Richard Verbeek, Harindra C. Wijeysundera, Dennis T. Ko
Journal: Circulation (2014)

Background— Out-of-hospital cardiac arrest (OHCA) is associated with a poor prognosis and poses a significant burden to the healthcare system, but few studies have evaluated whether OHCA incidence and survival have changed over time. Methods and Results— A population-based cohort study was conducted, including 34 291 OHCA patients &gt;20 years of age who were transported alive to the emergency department of an acute-care hospital from April 1, 2002, to March 31, 2012, in Ontario, Canada. Patients with life-threatening trauma and those who died before hospital arrival were excluded. The overall age- and sex-standardized incidence of OHCA patients who were transported alive was 36 cases per 100 000 persons and did not significantly change over the study period. Cardiac risk factor prevalence increased significantly, whereas the rate of most cardiovascular conditions decreased significantly. The 30-day survival improved from 9.4% in 2002 to 13.6% in 2011; 1-year survival improved from 7.7% to 11.8% ( P &lt;0.001). Patients hospitalized in 2011 were significantly more likely to survive 30 days (adjusted odds ratio, 1.47 [95% CI, 1.22–1.77]) and 1 year (adjusted odds ratio, 1.55 [95% CI, 1.27–1.91]) compared with 2002. A significant interaction between temporal trends in survival improvement and age group was observed in which the improvement in survival was largest in the youngest age groups. Conclusions— OHCA patients who were transported alive are increasingly likely to have cardiovascular risk factors but less likely to have previous cardiovascular conditions. The overall incidence of OHCA patients transported to hospital alive did not change over the past decade. Short- and longer-term survival after OHCA has substantially improved, with younger patients experiencing the greatest improvement.
Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice
Authors: Maurizio D’Antonio, Nicolò Musner, Cristina Scapin, Daniela Ungaro, Ubaldo Del Carro, David Ron, M. Laura Feltri, Lawrence Wrabetz
Journal: The Journal of Experimental Medicine (2013)

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.
Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study
Authors: Julio SG Montaner, Viviane D Lima, Rolando Barrios, Benita Yip, Evan Wood, Thomas Kerr, Kate Shannon, P Richard Harrigan, Robert S Hogg, Patricia Daly, Perry Kendall
Journal: The Lancet (2010)
Fluorescence <i>In situ</i> Hybridization Subgroup Analysis of TRIBUTE, a Phase III Trial of Erlotinib Plus Carboplatin and Paclitaxel in Non–Small Cell Lung Cancer
Authors: Fred R. Hirsch, Marileila Varella-Garcia, Rafal Dziadziuszko, Yun Xiao, Sujatha Gajapathy, Margaret Skokan, Ming Lin, Vincent O'Neill, Paul A. Bunn
Journal: Clinical Cancer Research (2008)

Abstract Purpose: TRIBUTE was a phase III trial evaluating the addition of erlotinib to carboplatin and paclitaxel as a first-line treatment for advanced non–small cell lung cancer that did not meet its primary end point of improving overall survival. Here, we assess the value of using epidermal growth factor receptor (EGFR) gene copy number in tumor biopsy samples, as determined by fluorescence in situ hybridization (FISH), as a predictor of treatment outcome. Methods: EGFR FISH analysis was done using LSI EGFR SpectrumOrange/CEP7 SpectrumGreen probe. Results: Of 275 samples, 245 (89.1%) were successfully analyzed by FISH. One hundred (40.8%) of patients were EGFR FISH(+). Median overall survival was not different between FISH(+) and FISH(−) patients in either the chemotherapy+erlotinib arm or the chemotherapy+placebo arm. In FISH(+) patients, median time to progression (TTP) was 6.3 months in the erlotinib arm versus 5.8 months in the placebo arm (hazard ratio, 0.59; 95% confidence interval, 0.35-0.99; P = 0.0430); in FISH(−) patients, median TTP was 4.6 months versus 6.0 months (hazard ratio, 1.42; 95% confidence interval, 0.95-2.14; P = 0.0895; treatment interaction test, P = 0.007). After 6 months of treatment, a notable separation of the TTP curves in favor of erlotinib emerged. Objective response rates were 11.6% versus 29.8% in FISH(+) patients (chemotherapy+erlotinib arm versus chemotherapy+placebo arm; P = 0.0495) and 21.8% versus 25.4%, respectively, for FISH(−) patients (P = 0.6954). Conclusions: EGFR gene copy number by FISH did not predict survival benefit. However, among EGFR FISH(+) patients, TTP was longer in patients who received erlotinib and continued to receive it after completing first-line therapy.
Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS)
Authors: Tiziana Bachetti, Sabrina Chiesa, Patrizio Castagnola, Daniele Bani, Eleonora Di Zanni, Alessia Omenetti, Andrea D'Osualdo, Alessandro Fraldi, Andrea Ballabio, Roberto Ravazzolo, Alberto Martini, Marco Gattorno, Isabella Ceccherini
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. Methods The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. Results We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. Conclusions Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.
Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study.
Authors: T L Bush, E Barrett-Connor, L D Cowan, M H Criqui, R B Wallace, C M Suchindran, H A Tyroler, B M Rifkind
Journal: Circulation (1987)

A cohort of 2270 white women, aged 40-69 years at baseline, were followed for an average of 8.5 years in the Lipid Research Clinics Program Follow-up Study. There were 44 deaths due to cardiovascular disease among the 1677 nonusers of estrogens and six cardiovascular disease deaths among the 593 estrogen users. The age-adjusted relative risk (RR) of cardiovascular disease deaths in users compared with nonusers was 0.34 (95% confidence limits 0.12 to 0.81). After multivariable adjustment for potential confounding factors (age, blood pressure, and smoking), the estimated RR for estrogen use was 0.37 (95% confidence limits 0.16 to 0.88). Analyses were done to explore whether these results could be due to selection bias for estrogen use. However, the prevalence of cardiovascular disease at baseline was slightly higher in estrogen users (12%) than in nonusers (10%); furthermore, the exclusion of all women with prevalent cardiovascular disease at baseline did not alter the apparent protective effect of estrogen use on cardiovascular disease mortality (RR = 0.42, 95% confidence limits 0.13 to 1.10). Additional analyses examining the complex association between estrogen use, lipoprotein levels, and cardiovascular disease mortality suggest that the protective effect of estrogen is substantially mediated through increased high-density lipoprotein levels.
Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma
Authors: M.D. Galsky, G.J. Chen, W.K. Oh, J. Bellmunt, B.J. Roth, R. Petrioli, L. Dogliotti, R. Dreicer, G. Sonpavde
Journal: Annals of Oncology (2011)
Indications for liver transplantation in hepatobiliary malignancy
Authors: Rudolf Pichlmayr, Arved Weimann, Burckhardt Ringe
Journal: Hepatology (1994)

Our personal experience with 172 patients, the results from the European Liver Transplant Registry and a review of the recent literature are summarized and discussed to define present indications for liver transplantation in hepatobiliary malignancy. The following conditions should be considered contraindications: advanced primary liver tumors with any extrahepatic spread, cholangiocellular carcinoma, hemangiosarcoma and liver metastases from nonendocrine primary tumor. Currently, “favorable” indications include uncommon tumors such as fibrolamellar carcinoma, epithelioid hemangioendothelioma, hepatoblastoma and metastases from endocrine tumors. Further indications may be nonresectable hepatocellular and proximal bile duct carcinoma in tumor stage II. Borderline indications are hepatocellular and proximal bile duct carcinoma in tumor stage III. In advanced tumors confined to the liver, transplantation should be restricted to multimodality treatment protocols. Although there are strong arguments for transplantation in early resectable hepatocellular carcinoma with underlying cirrhosis, it remains an open issue requiring further investigation in a controlled study using the same tumor classification. With regard to limited resources of donor organs, split-liver transplantation permits transplantation in tumor patients without neglecting those with benign diseases. (Hepatology 1994;20:33S–40S.)
Renal distal tubular handling of sodium in central fluid volume homoeostasis in preascitic cirrhosis
Authors: G Sansoe, A Ferrari, E Baraldi, C N Castellana, M C De Santis, F Manenti
Journal: Gut (1999)

<h3>BACKGROUND/AIMS</h3> Patients with preascitic liver cirrhosis have an increased central plasma volume, and, for any given plasma aldosterone concentration, they excrete less sodium than healthy controls. A detailed study of the distribution of sodium reabsorption along the segments of the renal tubule, especially the distal one, is still lacking in preascitic cirrhosis. <h3>METHODS</h3> Twelve patients with Child-Pugh class A cirrhosis and nine control subjects (both groups on a normosodic diet) were submitted to the following investigations: (<i>a</i>) plasma levels of active renin and aldosterone; (<i>b</i>) four hour renal clearance of lithium (an index of fluid delivery to the loop of Henle), creatinine, sodium, and potassium; (<i>c</i>) dopaminergic activity, as measured by incremental aldosterone response to intravenous metoclopramide. <h3>RESULTS</h3> Metoclopramide induced higher incremental aldosterone responses, indicating increased dopaminergic activity in patients than controls, which is evidence of an increased central plasma volume (+30 min: 160.2 (68.8)<i>v</i> 83.6 (35.2) pg/ml, p&lt;0.01; +60 min: 140.5 (80.3) <i>v</i> 36.8 (36.1) pg/ml, p&lt;0.01). Patients had increased distal fractional sodium reabsorption compared with controls (26.9 (6.7)% <i>v</i> 12.5 (3.4)% of the filtered sodium load, p&lt;0.05). In the patient group there was an inverse correlation between: (<i>a</i>) absolute distal sodium reabsorption and active renin (<i>r</i> −0.59, p&lt;0.05); (<i>b</i>) fractional distal sodium reabsorption and sodium excretion (<i>r</i> −0.66, p&lt;0.03). <h3>CONCLUSIONS</h3> These data suggest that in preascitic cirrhosis the distal fractional tubular reabsorption of sodium is increased and critical in regulating both central fluid volume and sodium excretion.
Transient complete remission of metastasized Merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation
Authors: V. Waldmann, H. Goldschmidt, A. Jäckel, M. Deichmann, U. Hegenbart, W. Hartschuh, A. Ho, H. Näher
Journal: British Journal of Dermatology (2000)

Merkel cell carcinoma (MCC) is a rare cutaneous tumour with neuroendocrine differentiation. Metastasis occurs preferentially to regional lymph nodes but distant and multiple visceral metastases may occur. Chemotherapy has been performed with a variety of protocols based largely on agents active in small-cell lung cancer. Owing to the rarity of MCC, there is no standard protocol for the treatment of metastatic disease. We report a 59-year-old patient with systemic metastatic MCC. After diagnosis of distant metastases, first-line polychemotherapy (cisplatin 80 mg m(-2), doxorubicin 50 mg m(-2), etoposide 300 mg m(-2) and bleomycin 30 mg) was administered four times at 3-weekly intervals and resulted in partial remission of metastases. Subsequently, high-dose chemotherapy according to the PEI regimen (ifosfamide 12 g m(-2), carboplatin 900 mg m(-2) and etoposide 1500 mg m(-2)) was applied, followed by autologous blood stem cell transplantation (ABSCT). This protocol resulted in a complete remission that lasted for 6 months. This is the first report on a complete remission of metastatic MCC after high-dose polychemotherapy and ABSCT. High-dose chemotherapy might be a therapeutic option in chemosensitive metastatic MCC, and further evaluation is warranted.
Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla
Authors: Tom M. McCaughtry, Troy A. Baldwin, Matthew S. Wilken, Kristin A. Hogquist
Journal: The Journal of Experimental Medicine (2008)

The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion.
Biological Sequence Simulation for Testing Complex Evolutionary Hypotheses: indel-Seq-Gen Version 2.0
Authors: Cory L. Strope, Kevin Abel, Stephen D. Scott, Etsuko N. Moriyama
Journal: Molecular Biology and Evolution (2009)

Sequence simulation is an important tool in validating biological hypotheses as well as testing various bioinformatics and molecular evolutionary methods. Hypothesis testing relies on the representational ability of the sequence simulation method. Simple hypotheses are testable through simulation of random, homogeneously evolving sequence sets. However, testing complex hypotheses, for example, local similarities, requires simulation of sequence evolution under heterogeneous models. To this end, we previously introduced indel-Seq-Gen version 1.0 (iSGv1.0; indel, insertion/deletion). iSGv1.0 allowed heterogeneous protein evolution and motif conservation as well as insertion and deletion constraints in subsequences. Despite these advances, for complex hypothesis testing, neither iSGv1.0 nor other currently available sequence simulation methods is sufficient. indel-Seq-Gen version 2.0 (iSGv2.0) aims at simulating evolution of highly divergent DNA sequences and protein superfamilies. iSGv2.0 improves upon iSGv1.0 through the addition of lineage-specific evolution, motif conservation using PROSITE-like regular expressions, indel tracking, subsequence-length constraints, as well as coding and noncoding DNA evolution. Furthermore, we formalize the sequence representation used for iSGv2.0 and uncover a flaw in the modeling of indels used in current state of the art methods, which biases simulation results for hypotheses involving indels. We fix this flaw in iSGv2.0 by using a novel discrete stepping procedure. Finally, we present an example simulation of the calycin-superfamily sequences and compare the performance of iSGv2.0 with iSGv1.0 and random model of sequence evolution.
Meta-analysis of individual participant data: rationale, conduct, and reporting
Authors: R. D. Riley, P. C. Lambert, G. Abo-Zaid
Journal: BMJ (2010)

The use of individual participant data instead of aggregate data in meta-analyses has many potential advantages, both statistically and clinically. <b>Richard D Riley and colleagues</b> describe the rationale for an individual participant data meta-analysis and outline how to conduct this type of study
Bronchial reactivity to cigarette smoke in smokers: repeatability, relationship to methacholine reactivity, smoking and atopy
Authors: EJ Jensen, R Dahl, F Steffensen
Journal: European Respiratory Journal (1998)

Bronchial reactivity to cigarette smoke (CBR) in a cross-section of 98 smokers has been investigated. All participants were subjects to skin-prick tests to common allergens, lung function measurements and bronchial challenges with methacholine and cigarette smoke. In 38 participants a rechallenge with cigarettes was performed 1 h after the first cigarette challenge. Lung function indices analysed were: forced expiratory volume in one second (FEV1); maximal expiratory flow at 75% of the forced vital capacity (MEF75%); and forced mid-expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75%)). All participants were tested for asthma and allergy, and were required to provide information regarding respiratory symptoms, first degree relatives with asthma and allergy and smoking habits. A substantial decrease was seen in all lung function indices after 12 cigarette-smoke inhalations, but only FEV1 was related to other variables. The maximal mean percentage fall in FEV1 was 10%, which was directly related to the number of inhalations (p<0.05). In multiple regression analyses the percentage fall in FEV1 was directly related to: FEV1/vital capacity (VC) (p<0.01); to the asthmatic/bronchitic status (p<0.05); and to the accumulated and standardized cigarette consumption (p<0.05). The percentage fall in FEV1 bore no relationship to methacholine bronchial reactivity, sex or age and had a continuous distribution. The repeat challenge showed a smaller fall in FEV1 compared to the first challenge after 12 cigarette smoke inhalations (p<0.05). The percentage fall in FEV1 correlated after the first and the repeat challenge (p<0.05). Repeatability of the challenge could not be determined in this study because of tachyphylaxis. Bronchial reactivity to cigarette smoke is a tobacco smoke-specific bronchial response. All participants responded and the response showed a continuous distribution. Bronchial reactivity to cigarette smoke may be of importance for symptoms and prognosis in chronic bronchitis and chronic obstructive pulmonary disease and should be studied in relation to the degree of accelerated lung function loss in smokers and other cigarette induced lung abnormalities.
Therapeutic Approaches to Hemoglobin Switching in Treatment of Hemoglobinopathies
Authors: J. A. Stamatoyannopoulos, A. W. Nienhuis
Journal: Annual Review of Medicine (1992)

The past decade has witnessed profound increases in knowledge of the structure, function, and developmental regulation of the human globin genes. This information has deepened our understanding of the molecular and cellular mechanisms underlying inherited disorders affecting hemoglobin, and it has provided a new perspective for attaining meaningful increases in fetal hemoglobin synthesis in the management of sickle cell anemia and beta thalassemia. Efforts to provide therapy for these disorders are based on three factors: an understanding of their pathophysiology; the potential for fetal hemoglobitno alter its manifestation; and the concept that developmental changes in globin gene expression might be reversed by manipulating cellular and molecular regulatory mechanisms. In this review we discuss these topics and examine critically recent efforts to apply various pharmacological agents to in vitro, animal, and human models with the goal of increasing HbF synthesis. Several agents have demonstrated activity in patients with hemoglobin disorders. One such agent, hydroxyurea, has been shown to be potentially efficacious in phase II clinical trials in patients with sickle cell anemia and awaits testing in a placebo-controlled phase III study.