tbuckley/cabot-search huggingface dataset:
Adrenergic responsiveness after abrupt propranolol withdrawal in normal subjects and in patients with angina pectoris.
Authors: J Lindenfeld, M H Crawford, R A O'Rourke, S P Levine, M M Montiel, L D Horwitz
Journal: Circulation (1980)

Adrenergic responsiveness after abrupt propranolol withdrawas during exogenous and esdogenous catecholamine stimulation was assessed in 10 normal subjects and 10 patients with angina pectoris. Propranolol, 160 mg/day, was administered for 2 weeks and then stopped. During an epinephrine infusion, period (p < 0.005). There were no differences from control 96 hours after the drug had been stopped in both groups or at 144 hours in the angina patients who were studied for a longer time. At 48 hours of heart rate and the pressure-rate product were significantly less than control level in the angina patient, but not in the normal subjects. Similar results were observed during exercise in both groups. The epinephrine-induced increase in free fatty acids was blocked by propranolol (p < 0.005), was still attenuated at 48 hours of withdrawals (p < 0.05), but returned to control levels thereafter in both groups. Resting serum triiodothyromine levels decreased with propranolol ( < 0.005) and remaind low throughout the withdrawal period. Measurements of dopamine beta-hydroxylase, plasma platelet factor 4, and platelet aggregation at rest and after exercise did not change significantly during or after propranolol administration. Plasma norepinephrine and epinephrine values were not changed from control during the withdrawal period at rest or after exerise. We conclude that there is no evidence of hypersensitivity to beta-adrenergically mediated responses after abrupt propranolol withdrawal.
Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer
Authors: Fei Huang, Li-an Xu, Shirin Khambata-Ford
Journal: Clinical Cancer Research (2012)

This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC).Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate.Higher IGF-1R, higher GRB(7), and lower INSIG(2) expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P = 0.01), 122 versus 57 days (P = 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB(7), and lower INSIG(2) expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP(3) and INSR expression levels showed trends for a PFS benefit. Lower INSIG(2) expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P = 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG(2) expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P = 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001).These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings.
679 ACTIVATION OF WNT/β-CATENIN SIGNALING PATHWAY IN THE LIVER OF TRANSGENIC MICE OVEREXPRESSING GROWTH HORMONE
Authors: J.G. Miquet, C.S. Martinez, L. González, M.E. Díaz, E. Zotta, A. Bartke, D. Turyn, A.I. Sotelo
Journal: Journal of Hepatology (2011)
Survival effect of first- and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010
Authors: F. Nava, I. Tramacere, A. Fittipaldo, M. G. Bruzzone, F. DiMeco, L. Fariselli, G. Finocchiaro, B. Pollo, A. Salmaggi, A. Silvani, M. Farinotti, G. Filippini
Journal: Neuro-Oncology (2014)

Prospective follow-up studies of large cohorts of patients with glioblastoma (GBM) are needed to assess the effectiveness of conventional treatments in clinical practice. We report GBM survival data from the Brain Cancer Register of the Fondazione Istituto Neurologico Carlo Besta (INCB) in Milan, Italy, which collected longitudinal data for all consecutive patients with GBM from 1997 to 2010.Survival data were obtained from 764 patients (aged>16 years) with histologically confirmed primary GBM who were diagnosed and treated over a 7-year period (2004-2010) with follow-up to April 2012 (cohort II). Equivalent data from 490 GBM patients diagnosed and treated over the preceding 7 years (1997-2003) with follow-up to April 2005 (cohort I) were available for comparison. Progression-free survival (PFS) was available from 361 and 219 patients actively followed up at INCB in cohorts II and I, respectively.Survival probabilities were 54% at 1 year, 21% at 2 years, and 11% at 3 years, respectively, in cohort II compared with 47%, 11%, and 5%, respectively, in cohort I. PFS was 22% and 12% at 1 year in cohorts II and I. Better survival and PFS in cohort II was significantly associated with introduction of the Stupp protocol into clinical practice, with adjusted hazard ratios (HRs) of 0.78 for survival and 0.73 for PFS, or a 22% relative decrease in the risk of death and a 27% relative decrease in the risk of recurrence. After recurrence, reoperation was performed in one-fifth of cohort I and in one-third of cohort II but was not effective (HR, 1.05 in cohort I and 1.02 in cohort II). Second-line chemotherapy, mainly consisting of nitrosourea-based chemotherapy, temozolomide, mitoxantrone, fotemustine, and bevacizumab, improved survival in both cohorts (HR, 0.57 in cohort I and 0.74 in cohort II). Radiosurgery was also effective (HR, 0.52 in cohort II).We found a significant increase in overall survival, PFS, and survival after recurrence after 2004, likely due to improvements in surgical techniques, introduction of the Stupp protocol as a first-line treatment, and new standard protocols for second-line chemotherapy and radiosurgery after tumor recurrence. In both cohorts, reoperation after tumor recurrence did not improve survival.
Multidrug-resistant pathogens in hospitalised patients coming from the community with pneumonia: a European perspective: Table 1
Authors: Stefano Aliberti, Catia Cilloniz, James D Chalmers, Anna Maria Zanaboni, Roberto Cosentini, Paolo Tarsia, Alberto Pesci, Francesco Blasi, Antoni Torres
Journal: Thorax (2013)

<h3>Background</h3> Probabilistic scores have been recently suggested to identify pneumonia caused by multidrug-resistant (MDR) bacteria. The aim of the study was to validate both Aliberti and Shorr scores in predicting MDR pneumonia, comparing them with healthcare associated pneumonia (HCAP) classification. <h3>Methods</h3> Two independent European cohorts of consecutive patients hospitalised with pneumonia were prospectively evaluated in Barcelona, Spain (BC) and Edinburgh, UK (EC). Data on admission and during hospitalisation were collected. The predictive value of the three scores was explored for correctly indicating the presence of MDR pneumonia via a receiver-operating characteristic (ROC) curve. <h3>Results</h3> A total of 1591 patients in the BC and 1883 patients in the EC were enrolled. The prevalence of patients with MDR pathogen among those with isolated bacteria was 7.6% in the BC and 3.3% in the EC. The most common MDR pathogen found in both cohorts was MRSA, followed by MDR <i>P aeruginosa</i>. A significantly higher prevalence of MDR bacteria was found among patients in the intensive care unit (ICU). The two probabilistic scores, and particularly the Aliberti one, showed an area under the ROC curve higher than the HCAP classification in predicting MDR pneumonia, especially in the ICU. <h3>Conclusions</h3> Risk scores able to identify MDR pneumonia could help in developing strategies for antimicrobial stewardship.
Quality of life after restorative proctocolectomy in Muslim patients
Authors: Fareed Iqbal, Shafquat Zaman, Douglas M Bowley, Carolynne J Vaizey
Journal: Gut (2013)

Dear Editor,

Current guidelines from the British Society of Gastroenterology concerning the management of IBD in adults1 highlight that surgery remains necessary in up to 30% of patients with UC. First described by Parks and Nicholls,2 restorative proctocolectomy with ileal pouch–anal anastomosis (RPC) has become the established operation for patients with therapy-resistant UC, indeterminate colitis, familial adenomatous polyposis and for some patients with UC-related neoplasia.3 ,4

Ethnic variations in the incidence and prevalence of IBD in the UK are diminishing.5 IBD has increased dramatically in British South Asians,6 the majority of whom are Muslim. Intestinal surgery impacts on the lives of all patients, but we wish to highlight some issues specific to the Muslim population.

Daily prayer constitutes one of the five pillars of Islam and is deemed the most important after the shahadah (declaration of faith). Muslims pray up to five times a day and hold strict hygiene requirements for their prayer. This includes washing the perianal skin (called istinjāh) after every bowel movement. Faecal seepage invalidates istinjāh , and this must be repeated in order to resume prayers. Some Muslims with a stoma avoid …
The active and passive components of extravascular coronary resistance
Authors: R. SNYDER, J. M. DOWNEY, E. S. KIRK
Journal: Cardiovascular Research (1975)

Intramyocardial stresses compress the coronary arteries raising their resistance to flow. The present study measures the relative contribution of ventricular pressure and the contractile state of the myocardium to this extravascular component of the coronary resistance. The extravascular resistance, which was found to be as much as one third of the total coronary resistance at normal ventricular and perfusion pressures, consists of two components. The major component, which persists when myocardial tension development is prevented, is attributed to passive stresses which are in equilibrium with the ventricular pressure. It accounts for 75% of the extravascular resistance. The remaining 25% is due to a modification of these passive stresses by active contraction of the myocardium. Massive increases in contractility resulted in only an additional 19% increase in the extravascular resistance. It is concluded that changes in contractility per se have only a slight effect on the amount of compression experienced by the coronary arteries and that ventricular pressure is the major determinant of the extravascular resistance.
Proteasome Inhibition Up-regulates p53 and Apoptosis-Inducing Factor in Chondrocytes Causing Severe Growth Retardation in Mice
Authors: Farasat Zaman, Victoria Menendez-Benito, Emma Eriksson, Andrei S. Chagin, Masaharu Takigawa, Bengt Fadeel, Nico P. Dantuma, Dionisios Chrysis, Lars Sävendahl
Journal: Cancer Research (2007)

Proteasome inhibitors (PI), a novel class of anticancer drugs, are relatively well tolerated and have recently been introduced into the clinic for the treatment of multiple myeloma. The tumor selectivity and low toxicity of PIs are surprising, given the crucial role of the ubiquitin/proteasome system in a multitude of cellular processes. Here, we show that systemic administration of PIs specifically impairs the ubiquitin/proteasome system in growth plate chondrocytes. Importantly, young mice displayed severe growth retardation during treatment as well as 45 days after the cessation of treatment with clinically relevant amounts of MG262 (0.2 micromol/kg body weight/injection) or bortezomib (1.0 mg/kg body weight/injection). Dysfunction of the ubiquitin/proteasome system was accompanied by the induction of apoptosis of stem-like and proliferative chondrocytes in the growth plate. These results were recapitulated in cultured fetal rat metatarsal bones and chondrocytic cell lines (rat, human). Apoptosis was associated with up-regulation of the proapoptotic molecules, p53 and apoptosis-inducing factor (AIF), both in vitro and in vivo. In addition to the observation that AIF is expressed in the growth plate, we also provide evidence that AIF serves as a direct target protein for ubiquitin, thus explaining its prominent up-regulation upon proteasome inhibition. Suppression of p53 or AIF expression with small interfering RNAs partly rescued chondrocytes from proteasome inhibition-induced apoptosis (35% and 41%, respectively). Our observations show that proteasome inhibition may selectively target essential cell populations in the growth plate causing significant growth failure. These findings could have important implications for the use of proteasome inhibitors in the treatment of childhood cancer.
Integration of Chemical and RNAi Multiparametric Profiles Identifies Triggers of Intracellular Mycobacterial Killing
Authors: Varadharajan Sundaramurthy, Rico Barsacchi, Nikolay Samusik, Giovanni Marsico, Jerome Gilleron, Inna Kalaidzidis, Felix Meyenhofer, Marc Bickle, Yannis Kalaidzidis, Marino Zerial
Journal: Cell Host & Microbe (2013)
Impact of Electron Beam Tomography, With or Without Case Management, on Motivation, Behavioral Change, and Cardiovascular Risk Profile
Authors: Patrick G. O'Malley, Irwin M. Feuerstein, Allen J. Taylor
Journal: JAMA (2003)

Although the use of electron beam tomography (EBT) as a motivational tool to change behavior is practiced, its efficacy has not been studied.To assess the effects of incorporating EBT as a motivational factor into a cardiovascular screening program in the context of either intensive case management (ICM) or usual care by assessing its impact over 1 year on a composite measure of projected risk.Randomized controlled trial with a 2 x 2 factorial design and 1 year of follow-up.A consecutive sample of 450 asymptomatic active-duty US Army personnel aged 39 to 45 years stationed within the Washington, DC, area and scheduled to undergo a periodic Army-mandated physical examination were enrolled between January 1999 and March 2001 (mean age, 42 years; 79% male; 66 [15%] had coronary calcification; mean [SD] predicted 10-year coronary risk, 5.85% [3.85%]).Patients were randomly assigned to 1 of 4 intervention arms: EBT results provided in the setting of either ICM (n = 111) or usual care (n = 119) or EBT results withheld in the setting of either ICM (n = 124) or usual care (n = 96).The primary outcome measure was change in a composite measure of risk, the 10-year Framingham Risk Score (FRS).Comparing the groups who received EBT results with those who did not, the mean absolute risk change in 10-year FRS was +0.30 vs +0.36 (P =.81). Comparing the groups who received ICM with those who received usual care, the mean absolute risk change in 10-year FRS was -0.06 vs +0.74 (P =.003). Improvement or stabilization of cardiovascular risk was noted in 157 patients (40.2%). In multivariable analyses predicting change in FRS, after controlling for knowledge of coronary calcification, motivation for change, and multiple psychological variables, only the number of risk factors (odds ratio, 1.42; 95% confidence interval, 1.16-1.75 for each additional risk factor) and receipt of ICM (odds ratio, 1.62; 95% confidence interval, 1.04-2.52) were associated with improved or stabilized projected risk.Using coronary calcification screening to motivate patients to make evidence-based changes in risk factors was not associated with improvement in modifiable cardiovascular risk at 1 year. Case management was superior to usual care in the management of risk factors.
ANAPHYLAXIS IN CHOPPED GUINEA PIG LUNG
Authors: K. F. Austen, W. E. Brocklehurst
Journal: The Journal of Experimental Medicine (1961)

The quantitative release of histamine by specific antigen from perfused, chopped, sensitized guinea pig lung has been used to study the effect of peptidase substrates and inhibitors on the anaphylactic reaction. The anaphylactic release of histamine is prevented by chymotrypsin substrates and inhibitors but not by trypsin, carboxypeptidase, or leucine aminopeptidase substrates or the soybean trypsin inhibitor. The chymotrypsin substrates and inhibitors appear to be acting on an antigen-antibody-activated step because these substances fail to inhibit if the tissue is washed free of them prior to antigen addition, and because there is complete desensitization of the tissue without histamine release when the antigen is added in the presence of these inhibitors. The inhibitors work equally well in tissue from passively sensitized animals or in tissue from animals actively sensitized with either ovalbumin or bovine gamma globulin. These observations suggest that activation of a chymotrypsin-like enzyme is a necessary condition for the anaphylactic release of histamine in guinea pig lung. Diisopropylfluophosphate is inhibitory when present at the time of antigen addition but not when the tissue is washed free of unfixed diisopropylfluophosphate prior to adding antigen. This indicates that diisopropylfluophosphate must be acting exclusively on an enzyme which exists in lung tissue in a precursor form resistant to diisopropylfluophosphate until activated by the antigen-antibody interaction. Thiol alkylating or oxidizing agents also prevent the anaphylactic release of histamine, but in contrast to the situation with diisopropylfluophosphate and the other chymotrypsin inhibitors, the phase of the anaphylactic reaction inhibited by N-ethylmaleimide is available prior to the antigen-antibody interaction. The similarities and differences between immune hemolysis and anaphylaxis in chopped guinea pig lung are considered in detail.
Improved Visualization of Glaucomatous Retinal Damage Using High-speed Ultrahigh-Resolution Optical Coherence Tomography
Authors: Tarkan Mumcuoglu, Gadi Wollstein, Maciej Wojtkowski, Larry Kagemann, Hiroshi Ishikawa, Michelle L. Gabriele, Vivek Srinivasan, James G. Fujimoto, Jay S. Duker, Joel S. Schuman
Journal: Ophthalmology (2007)
The Risk of Intraocular Pressure Elevation in Pediatric Noninfectious Uveitis
Authors: Srishti Kothari, C. Stephen Foster, Maxwell Pistilli, Teresa L. Liesegang, Ebenezer Daniel, H. Nida Sen, Eric B. Suhler, Jennifer E. Thorne, Douglas A. Jabs, Grace A. Levy-Clarke, Robert B. Nussenblatt, James T. Rosenbaum, Scott D. Lawrence, John H. Kempen
Journal: Ophthalmology (2015)
Quantitative Studies of Testicular Atrophy Following Portacaval Shunt in Rats
Authors: Abd M. Zaitoun, Gustav Apelqvist, Cecilia Wikell, Hanan Al-mardini, Finn Bengtsson, Christopher O. Record
Journal: Hepatology (1998)

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal–systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin–eosin (HE)-stained sections at 5–μm thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end–labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high–power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats ( P &lt; .00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 μm) compared with sham (126 μm) and control groups (108 μm). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats ( P &lt; .00001). There was a 112–fold increase in apoptosis in PCS rats (112) in comparison with the control and sham–operation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group ( P = .0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans.
Sex: a major predictor of remission in early rheumatoid arthritis?
Authors: K Forslind, I Hafstrom, M Ahlmen, B Svensson
Journal: Annals of the Rheumatic Diseases (2006)

The treatment goal of early rheumatoid arthritis is remission. This study reports remission rates in clinical practice using a cohort of patients with early rheumatoid arthritis.698 patients with early rheumatoid arthritis were included. Mean age at inclusion was 58 years and mean disease duration was 6.4 months; 64% of the patients were women, 56% were positive for antibodies to cyclic citrullinated peptide and 60% were positive for rheumatoid factor. Remission was defined as a disease activity score <2.6, with or without ongoing treatment with drugs for rheumatoid arthritis.After 2 years, 261 of 689 patients were in remission (37.9%), and after 5 years, the remission rate was 38.5%. However, only 26.1% were in remission at both these time points. Multiple logistic regression analyses found sex to be a main predictor for remission. Thus, significantly fewer women were in remission after 2 years (32.1% v 48%, p = 0.001) after 5 years (30.8% v 52.4%, p = 0.001) and at both these time points (19.1% v 39.3%, p = 0.001). Although disease activity was not with certainty more pronounced in women at onset of disease, the disease course became markedly worse in women. The disparity in remission frequency between women and men could not be explained by differences in disease duration, age or treatment with disease modifying antirheumatic drugs or glucocorticoids.Early remission of rheumatoid arthritis by 28-joint Disease Activity Score<2.6 was as frequent or more frequent in this study than in most previous reports. Importantly, women had more severe disease with a considerably lower remission rate than men, although the disease activity before treatment seemed similar.
Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2
Authors: Shasha Tao, Shue Wang, Seyed Javad Moghaddam, Aikseng Ooi, Eli Chapman, Pak K. Wong, Donna D. Zhang
Journal: Cancer Research (2014)

Oncogenic KRAS mutations found in 20% to 30% of all non-small cell lung cancers (NSCLC) are associated with chemoresistance and poor prognosis. Here we demonstrate that activation of the cell protective stress response gene NRF2 by KRAS is responsible for its ability to promote drug resistance. RNAi-mediated silencing of NRF2 was sufficient to reverse resistance to cisplatin elicited by ectopic expression of oncogenic KRAS in NSCLC cells. Mechanistically, KRAS increased NRF2 gene transcription through a TPA response element (TRE) located in a regulatory region in exon 1 of NRF2. In a mouse model of mutant KrasG12D-induced lung cancer, we found that suppressing the NRF2 pathway with the chemical inhibitor brusatol enhanced the antitumor efficacy of cisplatin. Cotreatment reduced tumor burden and improved survival. Our findings illuminate the mechanistic details of KRAS-mediated drug resistance and provide a preclinical rationale to improve the management of lung tumors harboring KRAS mutations with NRF2 pathway inhibitors.