tbuckley/cabot-search huggingface dataset:
Models of Hepatic Elimination
Authors: Richard A. Weisiger, Denis J. Morgan, Brian D. Jones, Michael S. Ching, Richard A. Smallwood
Journal: Hepatology (1986)

A recent study by Jones and coworkers on the role of protein binding in hepatic drug elimination (1) warrants a second look.These authors found that increased extracellular binding due to addition of al-acid glycoprotein did not diminish the extraction of propranolol by the perfused rat liver.From this central finding, they reach a number of conclusions regarding the validity of various models of hepatic drug elimination.However, the authors do not address the possibility that their results may reflect Type I1 error: failure to confirm a valid hypothesis because of the insensitivity of the methods used.
SPOTTED FEVER
Authors: George M. Hass, Henry Pinkerton
Journal: The Journal of Experimental Medicine (1936)

Several methods for the experimental study of the rickettsial diseases have been applied to fièvre boutonneuse. An analysis of the results has indicated that fièvre boutonneuse is a variety of spotted fever and that the etiologic agent is a rickettsia which belongs to the genus Dermacentroxenus and to the species rickettsi (Wolbach (6)). The distinctive morphology of the organism and its characteristic intranuclear clustering in ticks and in tissue cultures are the important criteria upon which this conclusion is based. Immunological, histological, and cytological observations of a confirmatory nature are also reported.
Epigenetic changes wipe out protective mechanisms in Barrett's oesophagus
Authors: R. C Fitzgerald
Journal: Gut (2008)

Reactive oxygen and nitrogen species play important roles in the regulation of cell survival. The effects are dose dependent and consist of two stages: reversible redox regulation and irreversible oxidative molecular damage. The Barrett’s oesophageal epithelium is bathed in a hostile luminal environment comprising reflux and dietary components. Increasing evidence suggests that these factors lead to abnormal levels of oxidative stress in the metaplastic epithelium, thus setting the stage for dysplasia and adenocarcinoma1–4 Cancer might seem inevitable in the face of such insults but, due to a plethora of defence mechanisms, this outcome is usually avoided. Although the mechanisms by which higher organisms respond to elevated oxygen and nitrogen species in vivo is poorly understood, the endogenous antioxidases are a key mechanism through which our cells combat oxidative stress. Key enzyme families include the glutathione S -transferases and peroxidases, and the loci encoding these enzymes comprise large supergene families. The principle role of glutathione S -transferases is detoxification of endogenous and exogenous electrophiles by glutathione conjugation,5 whereas the glutathione peroxidases catalyse the reduction …
Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans
Authors: Hidenori Koyama, Takaaki Maeno, Shinya Fukumoto, Takuhito Shoji, Takahisa Yamane, Hisayo Yokoyama, Masanori Emoto, Tetsuo Shoji, Hideki Tahara, Masaaki Inaba, Masayuki Hino, Atsushi Shioi, Takami Miki, Yoshiki Nishizawa
Journal: Circulation (2003)

Background— Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. Methods and Results— Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index β) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index β. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectin–positive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol. Conclusions— Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.
Long-Term Effects of Caffeine Therapy for Apnea of Prematurity
Authors: Barbara Schmidt, Robin S. Roberts, Peter Davis, Lex W. Doyle, Keith J. Barrington, Arne Ohlsson, Alfonso Solimano, Win Tin
Journal: New England Journal of Medicine (2007)

Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth.We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months.Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups.Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).
Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes
Authors: Dirk Kienle, Axel Benner, Alexander Kröber, Dirk Winkler, Daniel Mertens, Andreas Bühler, Till Seiler, Ulrich Jäger, Peter Lichter, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2005)
Late Incomplete Stent Apposition After Sirolimus-Eluting Stent Implantation
Authors: Junya Ako, Yoshihiro Morino, Yasuhiro Honda, Ali Hassan, Shinjo Sonoda, Paul G. Yock, Martin B. Leon, Jeffrey W. Moses, Heidi N. Bonneau, Peter J. Fitzgerald
Journal: Journal of the American College of Cardiology (2005)
Erythroderma and erythroblastosis feralis
Authors: J. E. Schanberger
Journal: JAMA (1970)

To the Editor.—  The appearance of a rash during the course of therapy for neonatal hyperbilirubinemia has been recognized. 1,2 The first report associated a macular erythematous rash to the use of phototherapy for the reduction of serum bilirubin. The second report noted the occurrence of a macular erythematous rash as a possible complication following intensive transfusion therapy for severe hemolytic disease of the newborn. No other references relating hyperbilirubinemia and a macular erythroderma could be found in the available literature. This communication further documents our clinical observations of this peculiar skin reaction in four severely affected erythroblastolic infants, none of which were exposed to bilirubin reduction lamps.  Report of Cases.—Case 1.—  A 1.9-kg (4 lb 2 oz) male infant was delivered spontaneously at 33 weeks gestation. He had received three intrauterine transfusions beginning at 28 weeks gestation. The total cord bilirubin value was 4.6 mg/100 ml, and the
Effects of Conventional and New Peritoneal Dialysis Fluids on Leukocyte Recruitment in the Rat Peritoneal Membrane
Authors: Siska Mortier, An S. de Vriese, Rachel M. McLoughlin, Nicholas Topley, Thomas P. Schaub, Jutta Passlick-Deetjen, Norbert H. Lameire
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Peritonitis remains an important cause of morbidity and technique failure in peritoneal dialysis (PD). Conventional peritoneal dialysate fluids (PDF) inhibit peritoneal leukocyte function <i>in vitro</i> and may thus adversely affect the immune response to peritonitis. New PDF have been designed with neutral pH, low glucose degradation product (GDP) contents, and bicarbonate as buffer. The present intravital microscopy study examined the effects of conventional and new PDF on leukocyte behavior in the peritoneal microcirculation of Wistar rats. The visceral peritoneum was superfused by a control solution (EBSS), a conventional (CAPD), or a new bicarbonate-buffered PDF with neutral pH and low GDP content (CAPD BicaVera). In addition, spent conventional and new PDF were tested. The number of rolling, adhering, and extravasated leukocytes and leukocyte rolling velocity were assessed at different time intervals after exposure to lipopolysaccharide (LPS) or cell-free supernatants of coagulase-negative staphylococci (CNS-CFS). Exposure to LPS or CNS-CFS dissolved in EBSS dramatically increased the number of rolling, adhering and extravasated leukocytes and decreased leukocyte rolling velocity. Superfusion by CAPD abolished the LPS- or CNS-CFS-induced leukocyte recruitment, whereas CAPD BicaVera had significantly fewer depressant effect. Spent PDF affected the leukocyte response in a similar way as fresh PDF. High lactate concentrations, GDP, and hypertonicity appeared to be mainly responsible for the inhibition of leukocyte recruitment. In conclusion, conventional PDF abolish <i>in vivo</i> leukocyte recruitment in reponse to potent inflammatory stimuli. Bicarbonate-buffered pH-neutral PDF with low GDP contents have fewer depressant effects and may therefore contribute to a better preservation of peritoneal host defense. E-mail: siska.mortier@rug.ac.be
Oral Clodronate and Reduction in Loss of Bone Mineral Density in Women With Operable Primary Breast Cancer
Authors: Trevor J. Powles, Susan Ashley, V. Alwynne Tidy, Auli Nevantaus, Eugene McCloskey, John Kanis, Alexander H. G. Paterson, Kirsi Rosenqvist
Journal: JNCI Journal of the National Cancer Institute (1998)

Women with primary breast cancer who receive systemic therapy may experience ovarian failure or early menopause, leading to a loss of bone mineral density (BMD). Loss of BMD may be reduced by use of bisphosphonates, compounds that inhibit the action of osteoclasts (cells that absorb or remove bone tissue). We have conducted a double-blind, randomized, two-center trial to evaluate BMD in women with primary breast cancer who were given the bisphosphonate clodronate (1600 mg/day orally) or placebo for 2 years.From August 31, 1990, through March 31, 1996, more than 300 eligible patients had been accrued, randomly assigned to study treatment, given the appropriate primary surgical care and systemic (chemotherapy and/or tamoxifen) therapy, and had completed follow-up for at least 1 year. BMD in the lumbar spine and in the hip, including the trochanteric area, was measured by use of dual-energy x-ray absorptiometry at the beginning of treatment and after 1 and 2 years of treatment. Changes in BMD were calculated as percent changes from the initial readings. Treatment effects for clodronate versus placebo (i.e., mean percent changes in BMD with clodronate minus mean percent changes in BMD with placebo) at 1 and 2 years for individual sites were calculated.After 1 year, the treatment effects for clodronate versus placebo in the lumbar spine, the total hip, and the trochanter, respectively, were as follows: +2.38% (95% confidence interval [CI] = 1.36-3.41), +0.74% (95% CI = -0.13 - 1.60), and +1.29% (95% CI = 0.24-2.34). After 2 years, the corresponding treatment effects were +1.72% (95% CI = 0.12-3.34), +1.85% (95% CI = 0.51-3.20), and +2.30% (95% CI = 0.66-3.94), respectively.Oral clodronate appears to reduce the loss of BMD in patients who receive treatment for primary breast cancer.
Response to influenza virus vaccination during chemotherapy in patients with breast cancer
Authors: A. Meerveld-Eggink, O. de Weerdt, A.M.T. van der Velden, M. Los, A.W.G. van der Velden, J.M.L. Stouthard, M.R. Nijziel, M. Westerman, A. Beeker, R. van Beek, G.F. Rimmelzwaan, G.T. Rijkers, D.H. Biesma
Journal: Annals of Oncology (2011)
Cdc42-interacting protein–4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse
Authors: Pinaki P. Banerjee, Rahul Pandey, Rena Zheng, Megan M. Suhoski, Linda Monaco-Shawver, Jordan S. Orange
Journal: The Journal of Experimental Medicine (2007)

An essential function of the immunological synapse (IS) is directed secretion. NK cells are especially adept at this activity, as they direct lytic granules to the synapse for secretion, which enables cytotoxicity and facilitates host defense. This initially requires rearrangement of the actin cytoskeleton and, subsequently, microtubule-dependent trafficking of the lytic granules. As these two steps are sequential, specific linkages between them are likely to serve as critical regulators of cytotoxicity. We studied Cdc42-interacting protein-4 (CIP4), which constitutively interacts with tubulin and microtubules but focuses to the microtubule organizing center (MTOC) after NK cell activation, when it is able to associate with Wiskott-Aldrich syndrome protein (WASp) and the actin filament-rich IS. WASp deficiency, overexpression of CIP4, or parts of CIP4 interfere with this union and block normal CIP4 localization, MTOC polarization to the IS, and cytotoxicity. Reduction of endogenous CIP4 expression using small interfering RNA similarly inhibits MTOC polarization and cytotoxic activity but does not impair actin filament accumulation at the IS, or Cdc42 activation. Thus, CIP4 is an important cytoskeletal adaptor that functions after filamentous actin accumulation and Cdc42 activation to enable MTOC polarization and NK cell cytotoxicity.
<i>Campylobacter fetus</i>infection in three rheumatoid arthritis patients treated with rituximab: Table 1
Authors: Alain Meyer, Arnaud Theulin, Emmanuel Chatelus, Xavier Argemi, Christelle Sordet, Rose Marie Javier, Yves Hansmann, Jean Sibilia, Jacques-Eric Gottenberg
Journal: Annals of the Rheumatic Diseases (2012)

Campylobacter fetus osteoarticular or prosthetic material infection or cellulitis has been rarely described, mainly in immunocompromised patients. Among these cases, only two patients had inflammatory systemic diseases treated with rituximab (RTX).1 We report three patients with rheumatoid arthritis (RA) treated with RTX who developed osteoarticular or cutaneous infection due to C fetus .

The patients were aged 71, 53 and 80 years with disease durations of 24, 13 and 19 years, respectively. All patients had a history of diabetes. Patients 1 and 3 had hypertensive cardiomyopathy, while patient 2 suffered from chronic obstructive pulmonary disease (COPD) and patient 3 from bronchiolitis obliterans organising pneumonia. All patients were co-treated with corticosteroids (10 mg/day) and disease-modifying antirheumatic …
Sustained Inhibition of Receptor Tyrosine Kinases and Macrophage Depletion by PLX3397 and Rapamycin as a Potential New Approach for the Treatment of MPNSTs
Authors: Parag P. Patwardhan, Oliver Surriga, Michael J. Beckman, Elisa de Stanchina, Ronald P. Dematteo, William D. Tap, Gary K. Schwartz
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tumor type that is resistant to chemotherapy and there are no effective therapies. MPNSTs have been shown to have gene amplification for receptor tyrosine kinases (RTK), PDGFR and c-Kit. We tested the c-Kit inhibitor, imatinib, and PLX3397, a selective c-Fms and c-Kit inhibitor, to evaluate their efficacy against MPNST cells in vitro and in vivo. Experimental Design: We tested the efficacy of imatinib or PLX3397 either alone or in combination with TORC1 inhibitor rapamycin in a cell proliferation assay in vitro and by immunoblotting to determine target inhibition. Immunoblotting and immunohistochemical analysis was further carried out using xenograft samples in vivo. Results: Our in vitro studies show that imatinib and PLX3397 similarly inhibit cell growth and this can be enhanced with rapamycin with comparable target specificity. However, in vivo studies clearly demonstrate that compared with imatinib, PLX3397 results in sustained blockade of c-Kit, c-Fms, and PDGFRβ, resulting in significant suppression of tumor growth. Moreover, staining for Iba-1, a marker for macrophages, indicates that PLX3397 results in significant depletion of macrophages in the growing tumors. The combination of PLX3397 and rapamycin results in even greater macrophage depletion with continued growth suppression, even when the drug treatment is discontinued. Conclusions: Taken together, our data strongly suggest that PLX3397 is superior to imatinib in the treatment of MPNSTs, and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease. Clin Cancer Res; 20(12); 3146–58. ©2014 AACR.
Testing significance testing: A flawed defense
Authors: John E. Hunter
Journal: Behavioral and Brain Sciences (1998)

Most psychometricians believe that the significance test is counterproductive. I have read Chow's book to see whether it addresses or rebuts any of the key facts brought out by the psychometricians. The book is empty on this score; it is entirely irrelevant to the current debate. It presents nothing new and is riddled with errors.
Specific <i>EGFR</i> Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy
Authors: Chih-Hsin Yang, Chong-Jen Yu, Jin-Yuan Shih, Yeun-Chung Chang, Fu-Chang Hu, Meng-Chin Tsai, Kuan-Yu Chen, Zhong-Zhe Lin, Ching-Ju Huang, Chia-Tung Shun, Chin-Lun Huang, James Bean, Ann-Lii Cheng, William Pao, Pan-Chyr Yang
Journal: Journal of Clinical Oncology (2008)

To explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non-small-cell lung cancer (NSCLC) patients receiving gefitinib treatment.We designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis.One hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations.In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.
Signal peptide peptidase (SPP) dimer formation as assessed by fluorescence lifetime imaging microscopy (FLIM) in intact cells
Authors: Andrew C Nyborg, Lauren Herl, Oksana Berezovska, Anne V Thomas, Thomas B Ladd, Karen Jansen, Bradley T Hyman, Todd E Golde
Journal: Molecular Neurodegeneration (2006)

Signal peptide peptidase (SPP) is an intramembrane cleaving protease identified by its cleavage of several type II membrane signal peptides. Conservation of intramembrane active site residues demonstrates that SPP, SPP family members, and presenilins (PSs) make up a family of intramembrane cleaving proteases. Because SPP appears to function without additional protein cofactors, the study of SPP may provide structural insights into the mechanism of intramembrane proteolysis by this biomedically important family of proteins. Previous studies have shown that SPP isolated from cells appears to be a homodimer, but some evidence exists that in vitro SPP may be active as a monomer. We have conducted additional experiments to determine if SPP exists as a monomer or dimer in vivo.Fluorescence lifetime imaging microscopy (FLIM) can be is used to determine intra- or intermolecular interactions by fluorescently labeling epitopes on one or two different molecules. If the donor and acceptor fluorophores are less than 10 nm apart, the donor fluorophore lifetime shortens proportionally to the distance between the fluorophores. In this study, we used two types of fluorescence energy transfer (FRET) pairs; cyan fluorescent protein (CFP) with yellow fluorescent protein (YFP) or Alexa 488 with Cy3 to differentially label the NH2- or COOH-termini of SPP molecules. A cell based SPP activity assay was used to show that all tagged SPP proteins are proteolytically active. Using FLIM we were able to show that the donor fluorophore lifetime of the CFP tagged SPP construct in living cells significantly decreases when either a NH2- or COOH-terminally YFP tagged SPP construct is co-transfected, indicating close proximity between two different SPP molecules. These data were then confirmed in cell lines stably co-expressing V5- and FLAG-tagged SPP constructs.Our FLIM data strongly suggest dimer formation between two separate SPP proteins. Although the tagged SPP constructs are expressed throughout the cell, SPP dimer detection by FLIM is seen predominantly at or near the plasma membrane.
Risk factors for sports concussion: an evidence-based systematic review
Authors: Shameemah Abrahams, Sarah Mc Fie, Jon Patricios, Michael Posthumus, Alison V September
Journal: British Journal of Sports Medicine (2013)

Concussion is a common sports injury with approximately 1.6–3.8 million sport-related concussions reported in the USA annually. Identifying risk factors may help in preventing these injuries. This systematic review aims to identify such risk factors. Three electronic databases; ScienceDirect, PubMed and SpringerLink, were searched using the keywords ‘RISK FACTORS’ or ‘PREDISPOSITION’ in conjunction with ‘SPORT’ and ‘CONCUSSION’. Based on the inclusion and exclusion criteria, 13 628 identified titles were independently analysed by two of the authors to a final list of 86 articles. Only articles with a level of evidence of I, II and III were included according to robust study design and data analysis. The level of certainty for each risk factor was determined. A high level of certainty for increased risk of a subsequent concussion in athletes sustaining more than one previous concussion was reported in 10 of 13 studies. Further, a high level of certainty was assigned to match play with all 29 studies reporting an increased concussion risk during matches. All other risk factors were evaluated as having a low level of certainty. Although several risk factors were identified from the appraised studies, prospective cohort studies, larger sample sizes, consistent and robust measures of risk should be employed in future research.