tbuckley/cabot-search huggingface dataset:
Effects of Estrogen or Estrogen/ Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women
Authors: Valery T. Miller
Journal: JAMA (1995)

Objective.  —To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.  Design.  —A 3-year, multicenter, randomized, double-blind, placebo-controlled trial.  Participants.  —A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy.  Intervention.  —Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo.  Primary Endpoints.  —Four endpoints were chosen to represent four biological systems related to the risk of cardiovascular disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood pressure, (3) serum insulin, and (4) fibrinogen.  Analysis.  —Analyses presented are by intention to treat. P values for primary endpoints are adjusted for multiple comparisons; 95% confidence intervals around estimated effects were calculated without this adjustment.  Results.  —Mean changes in HDL-C segregated treatment regimens into three statistically distinct groups: (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]). Active treatments decreased mean low-density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean fibrinogen than any active treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active treatments were not significant. Systolic blood pressure increased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with other active treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status.  Conclusions.  —Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure. Unopposed estrogen is the optimal regimen for elevation of HDL-C, but the high rate of endometrial hyperplasia restricts use to women without a uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.  ( JAMA . 1995;273:199-208)
Opportunities for improving medication use and monitoring in gout
Authors: J A Singh, J S Hodges, S M Asch
Journal: Annals of the Rheumatic Diseases (2008)

To study patterns and predictors of medication use and laboratory monitoring in gout.In a cohort of veterans with a diagnosis of gout prescribed allopurinol, colchicine or probenecid, quality of care was assessed by examining adherence to the following evidence-based recommendations: (1) whether patients starting a new allopurinol prescription (a) received continuous allopurinol, (b) received colchicine prophylaxis, (c) achieved the target uric acid level of <or=6 mg/dl; and (2) whether doses were adjusted for renal insufficiency. The association of sociodemographic characteristics, healthcare utilisation and comorbidity with the recommendations was examined by logistic/Poisson regression.Of the 643 patients with gout receiving a new allopurinol prescription, 297 (46%) received continuous allopurinol, 66 (10%) received colchicine prophylaxis and 126 (20%) reached the target uric acid level of <or=6 mg/dl. During episodes of renal insufficiency, appropriate dose reduction/discontinuation of probenecid was done in 24/31 episodes (77%) and of colchicine in 36/52 episodes (69%). Multivariable regression showed that higher outpatient utilisation, more rheumatology care and lower comorbidity were associated with better quality of care; more rheumatology clinic or primary care visits were associated with less frequent allopurinol discontinuation; more total outpatient visit days or most frequent visits to a rheumatology clinic were associated with a higher likelihood of receiving colchicine prophylaxis; and a lower Charlson Comorbidity Index or more outpatient visit days were associated with higher odds of reaching the target uric acid level of <or=6 mg/dl.Important variations were found in patterns of medication use and monitoring in patients with gout with suboptimal care. A concerted effort is needed to improve the overall care of gout.
Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study
Authors: Chandra P Belani, Thomas Brodowicz, Tudor E Ciuleanu, Maciej Krzakowski, Sung Hyun Yang, Fábio Franke, Branka Cucevic, Jayaprakash Madhavan, Armando Santoro, Rodryg Ramlau, Astra M Liepa, Carla Visseren-Grul, Patrick Peterson, William J John, Christoph C Zielinski
Journal: The Lancet Oncology (2012)
Purification and Characterization of Human Kallikrein 11, a Candidate Prostate and Ovarian Cancer Biomarker, from Seminal Plasma
Authors: Liu-Ying Luo, Shannon J.C. Shan, Marc B. Elliott, Antoninus Soosaipillai, Eleftherios P. Diamandis
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Preliminary data suggest that hK11 is a novel serum biomarker for prostate and ovarian cancer. To examine the enzymatic characteristics of hK11, we purified and functionally characterized native hK11 from seminal plasma. Experimental Design: hK11 was purified from seminal plasma by immunoaffinity chromatography and characterized by kinetic analysis, electrophoresis, Western blots, and mass spectrometry. Results: hK11 is present in seminal plasma at concentrations ranging from 2 to 37 μg/mL. Using immunoaffinity chromatography and reverse-phase high-performance liquid chromatography, we purified hK11 to homogeneity. In seminal plasma, hK11 is present as a free enzyme of ∼40 kDa. About 40% of hK11 is enzymatically active, whereas the rest is inactivated by internal cleavage after Arg156 (Genbank accession no. AF164623), which generates two peptides of ∼20 kDa, connected by internal disulfide bonds. Purified hK11 possesses trypsin-like activity and cleaves synthetic peptides after arginine but not lysine residues. It does not cleave chymotrypsin substrates. Antithrombin, α1-antichymotrypsin, α2-antiplasmin, and α1-antitrypsin have no effect on hK11 activity and do not form complexes with hK11 in vitro. The strongest inhibitor, APMSF, completely inhibited hK11 activity at a concentration of 2.5 mmol/L. Aprotinin and an hK11-specific monoclonal antibody inhibited hK11 activity up to 40%. Plasmin is a strong candidate for cleaving hK11 at Arg156. Conclusion: This is the first report on purification and characterization of native hK11. We speculate that hK11, along with other kallikreins, proteases, and inhibitors, participates in a cascade enzymatic pathway responsible for semen liquefaction after ejaculation.
Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences
Authors: R Kessler, A Chaouat, E Weitzenblum, M Oswald, M Ehrhart, M Apprill, J Krieger
Journal: European Respiratory Journal (1996)

"Cor pulmonale" is a classic feature of the "Pickwickian syndrome". Earlier studies have reported a high prevalence of pulmonary hypertension (PH) in obstructive sleep apnoea (OSA) patients, but this has not been confirmed by recent studies with a more adequate methodology, including larger groups of patients. The first part of this review is devoted to the prevalence of PH in OSA; most recent studies agree on prevalence of 15-20%. The second (and major) part of the study deals with the causes and mechanisms of PH in OSA. Pulmonary hypertension is rarely observed in the absence of day-time hypoxaemia, and the severity of nocturnal events (apnoea index (AI), apnoea+ hypopnoea index (AHI) does not appear to be the determining factor of PH. Diurnal arterial blood gas disturbances and PH are most often explained by the presence of severe obesity (obesity-hypoventilation syndrome) and, principally, by association of OSA with chronic obstructive pulmonary disease (the so called "overlap syndrome"). Bronchial obstruction is generally of mild-to-moderate degree and may be asymptomatic. The final part of the review analyses the therapeutic consequences of the presence of PH in OSA patients. Pulmonary hypertension, which is generally mild-to-moderate, does not need a specific treatment. When nasal continuous positive airway pressure (CPAP) fails to correct sleep-related hypoxaemia, supplementary oxygen must be administered. In patients with marked daytime hypoxaemia (arterial oxygen tension (Pa,O2), &lt; or = 7.3 kPa (55 mmHg) conventional O2 therapy (nocturnal + diurnal) is required.
Alterations in DMBA-Induced Rat Mammary Tumors by Actinomycin D2
Authors: H. Allen Gardner, J. A. Kellen, K. M. Anderson
Journal: JNCI Journal of the National Cancer Institute (1973)

Actinomycin D not only protected against the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene, but also influenced the nature of those tumors that developed. Fewer glandular neoplasms, and more secretory adenomas and fibroadenomas were formed. Histologic distinctions among the various mammary nodules are described, and it is stressed that evaluation of experimental data without consideration of the histologic nature of the nodules may be invalid.
Interpreting the Right to Bear Arms — Gun Regulation and Constitutional Law
Authors: Mark Tushnet
Journal: New England Journal of Medicine (2008)

In D.C. v. Heller, the question before the Court is whether the District's prohibition of further registration of handguns, its ban on the carrying of concealed guns, and its mandate that guns kept in homes remain unloaded and either locked or disassembled violate citizens' rights that are guaranteed by the Second Amendment. Mark Tushnet writes that the Supreme Court's upcoming decision dramatizes the tension between public policy and the Constitution. David Hemenway discusses gun violence in the United States and the likely effects of the Supreme Court case D.C. v. Heller. He is a professor of health policy at the Harvard School of Public Health, Boston.
Ebola: will enlightened self interest spur us to act?
Authors: F. Godlee
Journal: BMJ (2014)

More than 4400 people are now reported to have died in the Ebola epidemic in west Africa (doi:10.1136/bmj.g6255), and the US Centers for Disease Control has estimated that as many as 1.4 million people may be infected by the end of January. Fatality rates are reported to be around 50%. Health infrastructure in the three worst affected countries was already struggling but is now close to total collapse. The limited ranks of trained healthcare workers have been decimated by disease, exhaustion, and fear. Almost 200 healthcare workers are known to have died. 

The head of the charity Medecins Sans Frontieres, Joanne Liu, describes the desperate situation in an interview with The BMJ published this week: “Local doctors have been extremely brave, but we are running out of staff” (doi:10.1136/bmj.g6151). And she herself is “running out of words to convey the sense of …
Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms
Authors: Antoinette R. Tan, Donna Headlee, Richard Messmann, Edward A. Sausville, Susan G. Arbuck, Anthony J. Murgo, Giovanni Melillo, Suoping Zhai, William D. Figg, Sandra M. Swain, Adrian M. Senderowicz
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m 2 /d for 5 days; doses of 50 and 62.5 mg/m 2 /d for 3 days; and doses of 62.5 and 78 mg/m 2 /d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses ≥ 52.5 mg/m 2 /d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 μmol/L (range, 1.3 to 4.2 μmol/L), 3.2 μmol/L (range, 1.7 to 4.8 μmol/L), and 3.9 μmol/L (1.8 to 5.1 μmol/L), respectively. Twelve patients had stable disease for ≥ 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m 2 /d for 5 days, 50 mg/m 2 /d for 3 days, and 62.5 mg/m 2 /d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.
Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics
Authors: Antoine Italiano, Pauline Lagarde, Céline Brulard, Philippe Terrier, Marick Laë, Bernard Marques, Dominique Ranchere-Vince, Jean-Jacques Michels, Martine Trassard, Angela Cioffi, Sophie Piperno-Neumann, Christine Chevreau, Jean-Yves Blay, Corinne Delcambre, Nicolas Isambert, Nicolas Penel, Jacques-Olivier Bay, Sylvie Bonvalot, Axel Le Cesne, Jean-Michel Coindre, Frédéric Chibon
Journal: Clinical Cancer Research (2013)

Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.Median age was 59 years (range, 21-98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59-67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients.
A Highly Selective Cc Chemokine Receptor (Ccr)8 Antagonist Encoded by the Poxvirus Molluscum Contagiosum
Authors: Hans R. Lüttichau, Johnny Stine, Thomas P. Boesen, Anders H. Johnsen, David Chantry, Jan Gerstoft, Thue W. Schwartz
Journal: The Journal of Experimental Medicine (2000)

The MC148 CC chemokine from the human poxvirus molluscum contagiosum (MCV) was probed in parallel with viral macrophage inflammatory protein (vMIP)-II encoded by human herpesvirus 8 (HHV8) in 16 classified human chemokine receptors. In competition binding using radiolabeled endogenous chemokines as well as radiolabeled MC148, MC148 bound with high affinity only to CCR8. In calcium mobilization assays, MC148 had no effect on its own on any of the chemokine receptors, but in a dose-dependent manner blocked the stimulatory effect of the endogenous I-309 chemokine on CCR8 without affecting chemokine-induced signaling of any other receptor. In contrast, vMIP-II acted as an antagonist on 10 of the 16 chemokine receptors, covering all four classes: XCR, CCR, CXCR, and CX(3)CR. In chemotaxis assays, MC148 specifically blocked the I-309-induced response but, for example, not stromal cell-derived factor 1alpha, monocyte chemoattractant protein 1, or interleukin 8-induced chemotaxis. We thus concluded that the two viruses choose two different ways to block the chemokine system: HHV8 encodes the broad-spectrum chemokine antagonist vMIP-II, whereas MCV encodes a highly selective CCR8 antagonist, MC148, conceivably to interfere with monocyte invasion and dendritic cell function. Because of its pharmacological selectivity, the MC148 protein could be a useful tool in the delineation of the role played by CCR8 and its endogenous ligand, I-309.
Rats Injected with Syngenic Rat Apoptotic Neutrophils Develop Antineutrophil Cytoplasmic Antibodies
Authors: YAE[Combining Diaeresis]L C. PATRY, DAVID C. TREWICK, MARC GREGOIRE, MARIE A. P. AUDRAIN, ANNE M. N. MOREAU, JEAN-YVES MULLER, KHALED MEFLAH, VINCENT L. M. ESNAULT
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Antineutrophil cytoplasmic antibodies (ANCA) are present in sera from patients with various forms of vasculitis-associated glomerulonephritis. Because autoantibodies may be directed against antigens presented by apoptotic cells, generation of ANCA using apoptotic neutrophils (PMN) in syngenic Brown Norway (BN) rats was attempted. These rats are T-helper type 2-prone animals, already used successfully in other ANCA-positive animal models. BN rats received repeated injections of buffer or of nonapoptotic or apoptotic PMN aged in cultures, in the footpad and once intravenously. Four of five rats that received injections of PMN aged for 48 h developed ANCA, which cross-reacted with human leukocyte elastase in three cases. None of the rats that received injections of freshly isolated neutrophils developed ANCA. One rat that received buffer injection and that exhibited chronic skin infection developed delayed ANCA. None of the rats showed signs of disease: no weight loss and no proteinuria. Then a subnephritogenic dose of antibody directed against rat glomerular basement membrane was injected. Rats then were killed, and different organs were frozen and studied. No significant lesions were found in kidneys or lungs. It is concluded that injections of apoptotic but not freshly isolated PMN can generate ANCA in BN rats. Additional studies are needed to elucidate the immunization mechanism and the ability of these autoantibodies to initiate vasculitis in these experimental animals.
Detection of bacterial DNA in lymph nodes of Crohn's disease patients using high throughput sequencing
Authors: Claire L O'Brien, Paul Pavli, David M Gordon, Gwen E Allison
Journal: Gut (2014)

<h3>Objective</h3> Our aim was to determine whether or not specific microorganisms were transported selectively to lymph nodes in Crohn9s disease (CD) by comparing node and mucosal microbial communities in patients and controls. We also sought evidence of dysbiosis and bacterial translocation. <h3>Design</h3> Lymph nodes, and involved and uninvolved mucosal samples were obtained from resections of 58 patients (29 CD, eight 'other inflammatory bowel disease' (IBD) and 21 non-IBD). Universal primers targeting V1–V3 regions of bacterial 16S rRNA genes were used to amplify bacterial DNA and amplicons sequenced using high throughput sequencing. 20 patients (eight CD (28%), two other IBD (25%) and 10 non-IBD (48%)) had PCR positive nodes. <h3>Results</h3> All samples from an individual were similar: there was no evidence of selective concentration of any microorganism in nodes. No specific microorganism was present in the nodes of all CD samples. <i>Escherichia/Shigella</i> were common in all patient groups but patients with ileal CD had a greater proportion of <i>Escherichia coli</i> reads in their nodes than other CD patients (p=0.0475). <i>Campylobacter</i>, <i>Helicobacter</i> and <i>Yersinia</i> were uncommon; <i>Mycobacterium</i> and <i>Listeria</i> were not detected. Dysbiosis was present in all groups but shifts were specific and no common pattern emerged. <h3>Conclusions</h3> It is unlikely that a single bacterium perpetuates inflammation in late stage CD; dysbiosis was common and we found no evidence of increased bacterial translocation. We believe that future studies should focus on early disease and viable bacteria in nodes, aphthous ulcers and granulomas, as they may be more relevant in the initiation of inflammation in CD.
Studies of Human Adipose Tissue ADIPOSE CELL SIZE AND NUMBER IN NONOBESE AND OBESE PATIENTS
Authors: Lester B. Salans, Samuel W. Cushman, Rodger E. Weismann
Journal: Journal of Clinical Investigation (1973)

The cellular character of the adipose tissue of 21 nonobese and 78 obese patients has been examined. Adipose cell size (lipid per cell) was determined in three different subcutaneous and deep fat depots in each patient and the total number of adipose cells in the body estimated by division of total body fat by various combinations of the adipose cell sizes at six different sites. Cell number has also been estimated on the basis of various assumed distribution of total fat between the subcutaneous and deep fat depots. Obese patients, as a group, have larger adipose cells than do nonobese patients; cell size, however, varies considerably among the fat depots of individuals of either group. The variation in cell size exists not only between, but also within subcutaneous and deep sites. Estimates of total adipose cell number for a given individual based upon cell size can, therefore, vary by as much as 85%. On the basis of these studies it is suggested that the total adipose number of an individual is best and most practically estimated, at this time, by division of total body fat by the mean of the adipose cell sizes of at least three subcutaneous sites. IRRESPECTIVE OF THE METHOD BY WHICH TOTAL ADIPOSE CELL NUMBER IS ESTIMATED, TWO PATTERNS OF OBESITY EMERGE WITH RESPECT TO THE CELLULAR CHARACTER OF THE ADIPOSE TISSUE MASS OF THESE PATIENTS: hyperplastic, with increased adipose cell number and normal or increased size, and hypertrophic, with increased cell size alone. These two cellular patterns of obesity are independent of a variety of assumed distributions of fat among the subcutaneous and deep depots. When these different cellular patterns are examined in terms of various aspects of body size, body composition, and the degree, duration, and age of onset of obesity, only the latter uniquely distinguishes the hyperplastic from the hypertrophic: hyperplastic obesity is characterized by an early age of onset, hypertrophic, by a late age of onset. These studies indicate that there are two distinct periods early in life during which hypercellularity of the adipose tissue are most likely to occur: very early within the first few years, and again from age 9 to 13 yr.