tbuckley/cabot-search huggingface dataset:
Noninvasive ventilation for prevention of post-extubation respiratory failure in obese patients
Authors: A. A. El Solh, A. Aquilina, L. Pineda, V. Dhanvantri, B. Grant, P. Bouquin
Journal: European Respiratory Journal (2006)

Current recommendations for management of obese patients post-extubation are based on clinical experience and expert opinions. It was hypothesised that the application of noninvasive ventilation (NIV) during the first 48 h after extubation in severely obese patients would reduce post-extubation failure and avert the need for reintubation. Following protocol-driven weaning trials, 62 consecutive severely obese patients (body mass index > or =35 kg x m(-2)) were assigned to NIV via nasal mask immediately post-extubation and compared with 62 historically matched controls who were treated with conventional therapy. The primary end-point was the incidence of respiratory failure in the first 48 h post-extubation. Compared with conventional therapy, the institution of NIV resulted in 16% (95% confidence interval 2.9-29.3%) absolute risk reduction in the rate of respiratory failure. There was a significant difference in the intensive care unit and lengths of hospital stay between the two groups. Subgroup analysis of hypercapnic patients showed reduced hospital mortality in the NIV group compared with the control group. In conclusion, noninvasive ventilation may be effective in averting respiratory failure in severely obese patients when applied during the first 48 h post-extubation. In selected patients with chronic hypercarbia, early application of noninvasive ventilation may confer a survival benefit.
Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice
Authors: J Thulesen
Journal: Gut (2004)

<b>Background:</b> Glucagon-like peptide 2 (GLP-2) is an intestinotrophic mediator with therapeutic potential in conditions with compromised intestinal capacity. However, growth stimulation of the intestinal system may accelerate the growth of existing neoplasms in the intestine. <b>Aims:</b> In the present study, the effects of GLP-2 treatment on the growth of chemically induced colonic neoplasms were investigated. <b>Methods:</b> In 210 female C57bl mice, colonic tumours were initially induced with the methylating carcinogen 1,2-dimethylhydrazine (DMH) and mice were then treated with GLP-2. Two months after discontinuation of the carcinogen treatment, 135 of the mice were allocated to one of six groups which were treated twice daily with 25 μg GLP-2, 25 μg Gly2-GLP-2 (stable analogue), or phosphate buffered saline for a short (10 days) or long (one month) period. The remaining 75 mice had a treatment free period of three months and were then allocated to groups subjected to long term treatment, as above. <b>Results:</b> Colonic polyps developed in 100% of the mice, regardless of treatment. Survival data revealed no statistical significant differences among the different groups but histopathological analysis demonstrated a clear and significant increase in tumour load of mice treated with Gly2-GLP-2. The tumour promoting effect of native GLP-2 was less pronounced but the number of small sized polyps increased following long term treatment. <b>Conclusions:</b> The present results clearly indicate that GLP-2 promotes the growth of mucosal neoplasms. Our findings highlight the need for future investigations on the effects of GLP-2 in conditions needing long time treatment or with increased gastrointestinal cancer susceptibility.
Inhibition of TGF-? signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction
Authors: M IKEUCHI, H TSUTSUI, T SHIOMI, H MATSUSAKA, S MATSUSHIMA, J WEN, T KUBOTA, A TAKESHITA
Journal: Cardiovascular Research (2004)

Objective:: Transforming growth factor (TGF)-β promotes the deposition of extracellular matrix protein and also acts as an anti-inflammatory cytokine. These biological effects might be involved in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). However, its pathophysiological significance remains obscure in post-MI hearts.
Multidrug resistance in cancer
Authors: D R Ferry, D J Kerr
Journal: BMJ (1994)

many of the questions to be answered will have been predefined, together with the clinical core datasets.The Royal College of Radiologists will own the summary data and control access to them.Clinical oncologists will be able to study the outcome of comparative analyses before publication and to determine measures to complete the audit cycle.Education and the achievement of quality, rather than coercion and censure, are the goals ofthe network.
Complete heart block and sudden death in mice overexpressing calreticulin
Authors: Kimitoshi Nakamura, Murray Robertson, Gang Liu, Peter Dickie, Kyoko Nakamura, Ji Qing Guo, Henry J. Duff, Michal Opas, Katherine Kavanagh, Marek Michalak
Journal: Journal of Clinical Investigation (2001)

The expression of calreticulin, a Ca(2+)-binding chaperone of the endoplasmic reticulum, is elevated in the embryonic heart, and because of impaired cardiac development, knockout of the Calreticulin gene is lethal during embryogenesis. The elevated expression is downregulated after birth. Here we have investigated the physiological consequences of continued high expression of calreticulin in the postnatal heart, by producing transgenic mice that overexpress the protein in the heart. These transgenic animals exhibit decreased systolic function and inward I(Ca,L), low levels of connexin43 and connexin40, sinus bradycardia, and prolonged atrioventricular (AV) node conduction followed by complete heart block and sudden death. We conclude that postnatal downregulation of calreticulin is essential in the development of the cardiac conductive system, in particular in the sinus and AV nodes, when an inward Ca(2+) current is required for activation. This work identifies a novel pathway of events, leading to complete heart block and sudden cardiac death, which involves high expression of calreticulin in the heart.
Gemcitabine Plus Paclitaxel Versus Paclitaxel Monotherapy in Patients With Metastatic Breast Cancer and Prior Anthracycline Treatment
Authors: Kathy S. Albain, Shona M. Nag, German Calderillo-Ruiz, Johann P. Jordaan, Antonio C. Llombart, Anna Pluzanska, Janusz Rolski, Allen S. Melemed, Jose M. Reyes-Vidal, Jagdev S. Sekhon, Lorinda Simms, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2008)

The objective of this phase III global study was to compare the efficacy of gemcitabine plus paclitaxel (GT) versus paclitaxel in patients with advanced breast cancer. It was designed as a pivotal study for the approval of G for a breast cancer treatment indication.Patients who relapsed after adjuvant anthracyclines were randomly assigned to gemcitabine,1,250 mg/m(2) days 1 and 8 plus paclitaxel, 175 mg/m(2) on day 1; or, to paclitaxel at same dose on day 1 (both arms administered every 21 days, unblinded). The primary end point was overall survival (OS) and secondary end points were time to progression (TTP), response rate (RR), progression-free survival, response duration, and toxicity. This final OS analysis was planned at 380 deaths.A total of 266 patients were randomly assigned to GT and 263 to paclitaxel. Median survival on GT was 18.6 months versus 15.8 months on paclitaxel (log-rank P = . 0489), with an adjusted Cox hazard ratio of 0.78 (95% CI, 0.64 to 0.96; P = .0187). The TTP was longer (6.14 v 3.98 months; log-rank P = .0002) and the RR was better (41.4% v 26.2%; P = .0002) on GT. There was more grade 3 to 4 neutropenia on GT and grade 2 to 4 fatigue and neuropathy were slightly more prevalent on GT.This phase III study documents a role for gemcitabine in advanced breast cancer after anthracycline-based adjuvant therapy. The results establish GT as a reasonable choice for women who require cytoreduction with manageable toxicities and validate ongoing testing of GT in the adjuvant setting.
Real-time kinetics of sarcomere relaxation by laser diffraction.
Authors: Y Lecarpentier, J L Martin, V Claes, J P Chambaret, A Migus, A Antonetti, P Y Hatt
Journal: Circulation Research (1985)

Kinetics of sarcomere movement were studied in real-time by laser diffraction. Instantaneous sarcomere shortening was measured during afterloaded twitches simultaneously with instantaneous shortening and tension of the whole trabecula excised from rat right ventricle. Resting sarcomere length at optimal length was 2.20 +/- 0.02 micron (mean +/- SEM). Maximum amplitude of sarcomere shortening was 0.30 +/- 0.01 and 0.16 +/- 0.01 micron, respectively, in twitches loaded with preload only, and in "isometric" twitches. When the isotonic load (expressed as a percentage of maximum isometric force TF) increased, the maximum velocity of sarcomere relaxation max Vr (micron/sec) decreased: max Vr = -4 exp (-2.5 X 10(-2) % TF); r = 0.95. The time course of sarcomere relaxation appeared to be progressively delayed when the total load increased from preload only up to "isometric" load. Sarcomere relaxation occurred in two successive exponential phases, a rapid phase [time constant (msec): tau 1] followed by a slower one (time constant: tau 2). When the total load increased, tau 1 increased and tau 2 decreased according to the linear relations: % TF = 0.2 tau 1 + 4.8 (r = 0.83) and % TF = -0.1 tau 2 + 157 (r = 0.95). The relative predominance of both the time course and the amplitude of these two phases depended upon the level of total load. The rapid process predominated at low load, the slow one at high load. The role of load and/or shortening in the time course of these two phases is discussed.
Left ventricular hypertrophy in emphysema
Authors: C. W. Edwards
Journal: Thorax (1974)

<b>Edwards, C. W. (1973)</b>. <i>Thorax</i>, <b>29</b>, 75-80. <b>Left ventricular hypertrophy in emphysema</b>. The role of systemic hypertension in 10 emphysematous subjects with left ventricular hypertrophy was investigated. The medial thickness of the internal mammary artery was used as a parameter of raised systemic blood pressure during life. The pulmonary vasculature, ventricular weights, and the type and severity of emphysema in these patients were also studied. A group of 10 normotensive subjects and a group of 10 subjects with systemic hypertension were used as controls. The medial thickness of the internal mammary artery was significantly greater in the group of patients with systemic hypertension. Using this criterion it was found that four of the 10 patients with emphysema and left ventricular hypertrophy showed evidence of systemic hypertension. In these patients the pulmonary arterioles and arteries were normal. Three of the remaining six patients with emphysema and left ventricular hypertrophy showed the changes of hypoxic pulmonary vascular disease. In the other three the pulmonary vasculature showed no abnormality. The left ventricular weights and total ventricular weights in the patients with emphysema and left ventricular hypertrophy were significantly higher than in the group of patients with systemic hypertension only. There was no correlation between ventricular weights and the type or severity of emphysema. There appears to be a definite syndrome characterized by emphysema, normal systemic blood pressure, and enlargement of the left as well as the right ventricle. Hypoxic pulmonary vascular disease is not always present.
Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results
Authors: D van der Heijde
Journal: Annals of the Rheumatic Diseases (2005)

Objective: To assess methods to calculate achieving and sustaining remission in a double blind randomised trial in patients with RA who received etanercept, methotrexate, or an etanercept/methotrexate combination. Methods: Remission was defined as DAS <1.6, DAS28 <2.6, and ACR70 response. Sustaining remission was analysed in three ways: ( a ) analysis of sustained DAS remission, DAS28 remission, or ACR70 response continuously for 6 months; ( b ) analysis of sustained remission appraised through a continuity rewarded scoring system, which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission; or ( c ) longitudinal modelling of remission odds using generalised estimating equations. Results: Significantly more patients treated with the etanercept/methotrexate combination reached DAS remission (37%) than those treated with either methotrexate (14%) or etanercept (18%) alone (p<0.01). Results for DAS28 and for the ACR70 response were similar. Agreement between DAS remission and DAS28 remission was good, but agreement between either of these and the ACR70 response was less. Patients in DAS or DAS28 remission had a lower level of disease activity (fewer active joints, lower ESR) than those achieving ACR70 response; the converse was seen using pain VAS. The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy, which increased the number and durability of remission periods. Conclusions: DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA, frequently differing from patients classified as ACR70 responders. The three methods of examining duration of remission produced comparable results.
A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma
Authors: M. R. Gilbert, J. Gonzalez, K. Hunter, K. Hess, P. Giglio, E. Chang, V. Puduvalli, M. D. Groves, H. Colman, C. Conrad, V. Levin, S. Woo, A. Mahajan, J. de Groot, W. K. A. Yung
Journal: Neuro-Oncology (2010)

External beam radiation therapy (XRT) with concomitant temozolomide and 6 cycles of adjuvant temozolomide (5/28-day schedule) improves survival in patients with newly diagnosed glioblastoma compared with XRT alone. Studies suggest that dose-dense temozolomide schedules and addition of cytostatic agents may further improve efficacy. This factorial design phase I/II protocol tested dose-dense temozolomide alone and combined with cytostatic agents. Patients with newly diagnosed glioblastoma received fractionated XRT to 60 Gy concomitant with temozolomide (75 mg/m2/day for 42 days). In the phase I portion, patients with stable disease or radiologic response 1 month after chemoradiation were randomized to adjuvant temozolomide alone (150 mg/m2/day, 7/14-day schedule) or with doublet combinations of thalidomide (400 mg/day), isotretinoin (100 mg/m2/day), and/or celecoxib (400 mg twice daily), or all 3 agents. Toxicity was assessed after 4 weeks. Among 54 patients enrolled (median age, 52 years; median Karnofsky performance status, 90), adjuvant treatment was not administered to 12 (22%), primarily because of disease progression (n = 10). All combinations were well tolerated. Grade 3/4 lymphopenia developed in 63% of patients, but no related infections occurred. One patient treated with temozolomide plus isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1 patient receiving all 4 agents had dose-limiting grade 4 neutropenia. Venous thrombosis occurred in 7 patients, 4 of whom received thalidomide. From study entry, median survival was 20 months and the 2-year survival rate was 40%. Multiple cytostatic agents can be safely combined with dose-dense temozolomide. The factorial-based phase II portion of this study is currently ongoing.
Quantitative Imaging of Lymphatic Function with Liposomal Indocyanine Green
Authors: Steven T. Proulx, Paola Luciani, Stefanie Derzsi, Matthias Rinderknecht, Viviane Mumprecht, Jean-Christophe Leroux, Michael Detmar
Journal: Cancer Research (2010)

Lymphatic vessels play a major role in cancer progression and in postsurgical lymphedema, and several new therapeutic approaches targeting lymphatics are currently being developed. Thus, there is a critical need for quantitative imaging methods to measure lymphatic flow. Indocyanine green (ICG) has been used for optical imaging of the lymphatic system, but it is unstable in solution and may rapidly enter venous capillaries after local injection. We developed a novel liposomal formulation of ICG (LP-ICG), resulting in vastly improved stability in solution and an increased fluorescence signal with a shift toward longer wavelength absorption and emission. When injected intradermally to mice, LP-ICG was specifically taken up by lymphatic vessels and allowed improved visualization of deep lymph nodes. In a genetic mouse model of lymphatic dysfunction, injection of LP-ICG showed no enhancement of draining lymph nodes and slower clearance from the injection site. In mice bearing B16 luciferase-expressing melanomas expressing vascular endothelial growth factor-C (VEGF-C), sequential near-IR imaging of intradermally injected LP-ICG enabled quantification of lymphatic flow. Increased flow through draining lymph nodes was observed in mice bearing VEGF-C-expressing tumors without metastases, whereas a decreased flow pattern was seen in mice with a higher lymph node tumor burden. This new method will likely facilitate quantitative studies of lymphatic function in preclinical investigations and may also have potential for imaging of lymphedema or improved sentinel lymph detection in cancer.
International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels
Authors: William A. Catterall, Alan L. Goldin, Stephen G. Waxman
Journal: Pharmacological Reviews (2005)

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.
Dilated Cardiomyopathy and Sensorineural Hearing Loss
Authors: Jost Schönberger, Hara Levy, Ekkehard Grünig, Somkiat Sangwatanaroj, Diane Fatkin, Calum MacRae, Hinrich Stäcker, Christopher Halpin, Roland Eavey, Edward F. Philbin, Hugo Katus, J. G. Seidman, Christine E. Seidman
Journal: Circulation (2000)

Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized.Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified.A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.
Discovering the Truth About Tamoxifen: Problems of Multiplicity in Statistical Evaluation of Biomedical Data
Authors: R. Simon
Journal: JNCI Journal of the National Cancer Institute (1995)

In this issue of the Journal, Rutqvist et al. (7) report on a retrospective analysis of second cancers in women in three adjuvant-treatment breast cancer clinical trials. One unexpected finding is of sufficient statistical weight to warrant further scrutiny: the association of tamoxifen use with an increased risk of colorectal cancer. Rutqvist et al. (7) initially noted the association during the course of multiple testing to compare the incidence of numerous second cancers in a group of patients randomly assigned to receive 40 mg per day of tamoxifen versus a control group receiving no tamoxifen. Multiple testing is a widely used and valuable tool for the generation of new hypotheses. However, chance can play a substantial role in these evaluations; consequently, the special features of multiple testing should be considered in the statistical analysis, or the results must be viewed as scientifically interesting but preliminary until tested and confirmed independently. To understand why this is so—and why, statistically speaking, the tamoxifen-colorectal cancer hypothesis warrants further examination—requires some knowledge of hypothesis testing. The traditional statistical significance test is a quantitative method for evaluating the strength of evidence against a specific null hypothesis, in this case the null hypothesis that tamoxifen has no effect on the risk of developing colorectal cancer. A significance level of 5% means that the chance of falsely rejecting the specific null hypothesis is 5%. If we independently test five true null hypotheses, the chance of falsely rejecting at least one of them at the 5% significance level is 1 - (.95) 5 or 22.6%. Consequently, the finding of some statistical significance in the context of performing multiple tests is difficult to interpret.
Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat
Authors: Julia H. Hayes, Carol J. Soroka, Laura Rios-Velez, James L. Boyer
Journal: Hepatology (1999)

In contrast to organic anions, substrates for the canalicular mdr1a and b are usually organic cations and are often sequestered in high concentrations in intracellular acidic compartments. Because many of these compounds are therapeutic agents, we investigated if their sequestration could be regulated. We used isolated perfused rat liver (IPRL), isolated rat hepatocyte couplets (IRHC), and WIF-B cells to study the cellular localization and biliary excretion of the fluorescent cation, daunorubicin (DNR). Despite rapid (within 15 minutes) and efficient (>90%) cellular uptake in the IPRL, only approximately 10% of the dose administered (0.2-20 micromol) was excreted in bile after 85 minutes. Confocal microscopy revealed fluorescence predominantly in vesicles in the pericanalicular region in IPRL, IRHC, and WIF-B cells. Treatment of these cells with chloroquine and bafilomycin A, agents that disrupt the pH gradient across the vesicular membrane, resulted in a loss of vesicular fluorescence, reversible in the case of bafilomycin A. Taurocholate (TC) and dibutyryl cAMP (DBcAMP), stimulators of transcytotic vesicular transport, increased the biliary recovery of DNR significantly above controls, by 70% and 35%, respectively. The microtubule destabilizer, nocodazole, decreased biliary excretion of DNR. No effect on secretion was noted in TR- mutant rats deficient in mrp2. Coadministration of verapamil, an inhibitor of mdr1, also decreased DNR excretion. While TC and DBcAMP did not affect the fluorescent intensity or pattern of distribution in IRHC, nocodazole resulted in redistribution of DNR to peripheral punctuate structures. These findings suggest that the organic cation, DNR, is largely sequestered in cells such as hepatocytes, yet its excretion can still be modulated.