tbuckley/cabot-search huggingface dataset:
The Timing of Discharge from the Intensive Care Unit and Subsequent Mortality. A Prospective, Multicenter Study
Authors: John D. Santamaria, Graeme J. Duke, David V. Pilcher, D. James Cooper, John Moran, Rinaldo Bellomo
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Previous studies suggested an association between after-hours intensive care unit (ICU) discharge and increased hospital mortality. Their retrospective design and lack of correction for patient factors present at the time of discharge make this association problematic.To determine factors independently associated with mortality after ICU discharge.This was a prospective, multicenter, binational observational study involving 40 ICUs in Australia and New Zealand. Participants were consecutive adult patients discharged alive from the ICU between September 2009 and February 2010.We studied 10,211 patients discharged alive from the ICU. Median age was 63 years (interquartile range, 49-74), 6,224 (61%) were male, 5,707 (56%) required mechanical ventilation, and their median Acute Physiology and Chronic Health Evaluation III risk of death was 9% (interquartile range, 3-25%). A total of 8,539 (83.6%) patients were discharged in-hours (06:00-18:00) and 1,672 (16.4%) after-hours (18:00-06:00). Of these, 408 (4.8%) and 124 (7.4%), respectively, subsequently died in hospital (P < 0.001). After risk adjustment for markers of illness severity at time of ICU discharge including limitations of medical therapy (LOMT) orders, the time of discharge was no longer a significant predictor of mortality. The presence of a LOMT order was the strongest predictor of death (odds ratio, 35.4; 95% confidence interval, 27.5-45.6).In this large, prospective, multicenter, binational observational study, we found that patient status at ICU discharge, particularly the presence of LOMT orders, was the chief predictor of hospital survival. In contrast to previous studies, the timing of discharge did not have an independent association with mortality.
External detection of pulmonary accumulation of indium-113m labelled transferrin in the guinea pig.
Authors: U Hultkvist-Bengtsson, L Martensson
Journal: Thorax (1990)

Accumulation of radioisotope labelled transferrin in the lungs of guinea pigs was determined with an external detection system. The method is based on the intravascular and extravascular distribution of indium-113m labelled transferrin compared with the intravascular distribution of technetium-99m labelled red blood cells. Guinea pigs were given iloprost, a prostacyclin analogue and potent pulmonary vasodilator, and noradrenaline, a pulmonary vasoconstrictor, in an attempt to increase and decrease respectively the blood volume in the lungs. Neither agent altered transferrin accumulation in the lung by comparison with a saline infusion. Iloprost infused before and after oleic acid infusion reduced macro-molecular leakage when compared with oleic acid alone. These data suggest that the double isotope method can distinguish between hydrostatic and injury induced pulmonary oedema.
Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression
Authors: Ramona Schulz, Natalia D. Marchenko, Lena Holembowski, Günter Fingerle-Rowson, Marina Pesic, Lars Zender, Matthias Dobbelstein, Ute M. Moll
Journal: The Journal of Experimental Medicine (2012)

Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF-HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF.
A phase 1 trial of GMX1777: An inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT)
Authors: M. J. Pishvaian, J. L. Marshall, J. H. Hwang, S. M. Malik, A. R. He, J. F. Deeken, C. B. Kelso, K. Dorsch-Vogel, M. S. Berger
Journal: Journal of Clinical Oncology (2008)

14568 Background: GMX1777 is a soluble pro-drug which rapidly converts in serum to GMX1778, recently established to be a small molecule inhibitor of NAMPRT, the rate-limiting enzyme in the NAD+ salvage pathway. NAMPRT activity is increased in tumor cells dependent on the glycolytic pathway. The aims of this first-in-man study were to define a dose of GMX1777 for Phase II studies, characterize the safety of 24-hour infusions of GMX1777, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour infusion every 21 days to successive cohorts of patients with advanced malignancies with no additional standard therapy options. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle 1; then a standard 3+3 dose escalation schema was utilized to enroll patients in subsequent cohorts. During Cycle 1, PK samples were drawn at regular intervals before, during and after the 24 hour infusion. Results: Nine patients received doses of 60, 120, 160 or 200 mg/m2 over 24 hours. Twenty-seven doses have been administered. There were no toxicities >Gr 1 in the single patient enrolled at 60 mg/m2 during cycle 1; however Gr 2 toxicities were observed at 120 mg/m2 and the cohort was expanded to 3. Preliminary data indicate that adverse events of all grades with > 25% incidence overall were diarrhea (89%), nausea (67%), vomiting (66%), fatigue (56%) anemia (44%), insomnia (44%), pruritis (44%), rash (44%), thrombocytopenia (33%), myalgia (33%), and neuropathy (33%). Gr 3 and 4 events were single events of Gr 3 diarrhea at 60 mg/m2; Gr 3 infusion site infection and dehydration at 120 mg/m2; Gr 3 pruritis and purpura at 160 mg/m2; Gr 4 GI hemorrhage and Gr 4 thrombocytopenia at 200 mg/m2. The Gr 4 thrombocytopenia was a DLT. Three patients have had stable disease for > 3 months. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels tested to date, and that exposure increases in a more than dose- proportional manner. Conclusions: GMX1777 can be administered as a 24 hour infusion with a tolerable safety profile. Identification of the mechanism of action of GMX1777 and its principal target organs for toxicity will allow more efficient optimization of its schedule of administration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GeminX
Prescribing of EpiPen to Patients Presenting to an Inner-City Hospital Emergency Room (ER) with Acute Allergic Reactions
Authors: S. Amara, T. Tavartkiladze, Y. Persaud, B. Silverman, P. Hemmers, N. Gupta, A.T. Schneider
Journal: Journal of Allergy and Clinical Immunology (2006)
Expression of the IL-2 receptor on human renal proximal tubular epithelial cells.
Authors: J S Gerritsma, A F Gerritsen, C van Kooten, L A van Es, M R Daha
Journal: Journal of the American Society of Nephrology (1997)

The high-affinity receptor for interleukin (IL)-2, IL-2R, is composed of three chains, i.e., the alpha, beta, and gamma chains. Previous studies have shown that human proximal tubular epithelial cells (PTEC) express IL-2R alpha during inflammation, such as in the kidneys after renal transplantation or in crescentic glomerulonephritis. Furthermore, in this study it is shown that PTEC in culture produce more complement C3 after stimulation with IL-2, suggesting the presence of a functional IL-2R on PTEC. In these experiments, the binding of IL-2 to PTEC was analyzed. PTEC stimulated with IL-2 exhibited very low binding of digoxigenin-labeled IL-2; however, stimulation of PTEC with IL-2, in combination with interferon (IFN)-gamma, resulted in increased binding of the digoxigenin-labeled IL-2. In addition, it was found that IL-2, together with IFN-gamma, enhanced the production of C3 by PTEC from baseline levels of 69.6 +/- 3.4 to 198.6 +/- 3.3 ng of C3 per 10(6) cells. The surface expression of IL-2R alpha and IL-2Rbeta was analyzed using monoclonal antibodies. Although unstimulated PTEC hardly showed detectable expression of these chains, stimulation of PTEC with the combination of IL-2 and IFN-gamma resulted in increases of the index of mean fluorescence for the alpha- and beta-chains of 5.5 +/- 0.5 and 9.7 +/- 0.7, respectively. Reverse transcription-PCR analysis revealed mRNA expression not only for the alpha- and beta-chains, but also for the gamma-chain, after stimulation with the combination of IL-2 and IFN-gamma. This study demonstrates that PTEC express the high-affinity IL-2R and that the IL-2R might be involved in the regulation of production of complement component C3 found during renal inflammation.
Lurasidone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Antony Loebel, Josephine Cucchiaro, Robert Silva, Hans Kroger, Jay Hsu, Kaushik Sarma, Gary Sachs
Journal: American Journal of Psychiatry (2013)

The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder.Patients were randomly assigned to receive double-blind treatment with lurasidone (20-60 mg/day [N=166] or 80-120 mg/day [N=169]) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively.Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone.Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.
Use of psychiatric services by patients in a general hospital.
Authors: R Mayou, V Seagroatt, M Goldacre
Journal: BMJ (1991)

To identify physical disorders associated with increased rate of use of psychiatric services.Retrospective analysis of routine abstracts of general hospital inpatient records linked with those of psychiatric care, for inpatients with physical disorders with possible psychiatric associations and for controls.Oxfordshire health district.Inpatients aged 15-64 years discharged from general hospitals during 1975-85 with a diagnosis among 14 selected diagnostic groups (including potentially life threatening conditions, chronic disabling diseases, and non-specific symptomatic conditions) and control inpatients with acute conditions.Observed and expected numbers of patients receiving psychiatric care.Observed use of psychiatric services before and after index admission was close to that expected for controls. For most other diagnoses the observed use was significantly increased in the year preceding and that subsequent to the admission. For four diagnostic groups it was significantly greater in the year after admission than in that before (acute myocardial infarction (ratio before to after 2.17, 95% confidence interval 1.5 to 3.3), cancer (2.05, 1.7 to 2.5), diabetes mellitus (1.89, 1.4 to 2.9), and chest pain (1.78, 1.3 to 2.4)). During four years after the admission the use of psychiatric services was significantly higher than in the general population for nonspecific symptomatic conditions (observed/expected: abdominal pain 1.7, chest pain 2.0, and headache 4.2), cirrhosis of the liver (10.4), and fractures in road accidents and other fractures (1.3, 1.6).More patients with certain physical conditions used psychiatric services. Alternative methods of service delivery may be needed, especially for disabling chronic physical illness, alcohol related disorders, and non-specific symptomatic conditions.
Sex hormones and the immune response in humans
Authors: Annechien Bouman, Maas Jan Heineman, Marijke M. Faas
Journal: Human Reproduction Update (2005)

In addition to their effects on sexual differentiation and reproduction, sex hormones appear to influence the immune system. This results in a sexual dimorphism in the immune response in humans: for instance, females produce more vigorous cellular and more vigorous humoral immune reactions, are more resistant to certain infections, and suffer a higher incidence of autoimmune diseases. Disease expression is also affected by the reproductive status of the female. As sex steroids—estrogens, progesterone and testosterone—differ between gender and within different reproductive stages, a lot of research has focussed on the effects of sex hormones on immune responses. Although there is also a vast literature on the effects of sex hormones on immune responses in animals, in this review we will focus on the most intriguing effects and mechanisms by which sex hormones affect different components of the immune system in humans.
Endothelin&lt;SUB&gt;A&lt;/SUB&gt;-receptor antagonism attenuates pulmonary hypertension in porcine endotoxin shock
Authors: M. Wanecek, A. Oldner, A. Rudehill, A. Sollevi, K. Alving, E. Weitzberg
Journal: European Respiratory Journal (1999)

Porcine endotoxin shock is characterized by pulmonary hypertension, decreased mean arterial pressure and deteriorated cardiac performance. These pathophysiological findings are accompanied by increased plasma endothelin-1 levels. Previous studies have shown that both the pulmonary and systemic circulation are improved by combined endothelinA- and endothelinB-receptor antagonism. This study was designed to evaluate further the specific involvement of the endothelinA-receptor in cardiopulmonary pathophysiology during endotoxin shock. In a porcine endotoxin shock model, the endothelinA-receptor antagonist PD 155080 was administered after the onset of endotoxaemia. Cardiopulmonary vascular changes, dynamic lung compliance, oxygen-related variables and plasma levels of endothelin-1-like immunoreactivity were compared with a control group receiving only endotoxin. PD 155080 counteracted the increase in pulmonary artery pressure seen in control animals. In contrast, cardiac performance was not improved. Dynamic lung compliance was not affected by PD 155080. Plasma levels of endothelin-1-like immunoreactivity increased to a similar degree in both groups. These findings indicate that the endothelin system is involved in the pathophysiology of endotoxin shock. Furthermore, the change in pulmonary circulation seen in the present shock model is to a large extent mediated by the endothelinA-receptor mechanism. In view of previous findings, the deterioration of cardiac performance may involve the endothelinB-receptor, either alone or in combination with the endothelinA-receptor.
Panic Disorder, Phobias, and Generalized Anxiety Disorder
Authors: Michelle G. Craske, Allison M. Waters
Journal: Annual Review of Clinical Psychology (2005)

This chapter provides a review of recent empirical developments, current controversies, and areas in need of further research in relation to factors that are common as well as specific to the etiology and maintenance of panic disorder, phobias, and generalized anxiety disorder. The relative contribution of broad risk factors to these disorders is discussed, including temperament, genetics, biological influences, cognition, and familial variables. In addition, the role that specific learning experiences play in relation to each disorder is reviewed. In an overarching hierarchical model, it is proposed that generalized anxiety disorder, and to some extent panic disorder, loads most heavily on broad underlying factors, whereas specific life history contributes most strongly to circumscribed phobias.
The Endothelin System and Its Antagonism in Chronic Kidney Disease
Authors: Neeraj Dhaun, Jane Goddard, DavidJ. Webb
Journal: Journal of the American Society of Nephrology (2006)

The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease (CVD) is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Treatments that slow the progression of CKD and improve the cardiovascular risk profile of patients with CKD are needed. The endothelins (ET) are a family of related peptides, of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both CVD and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness and more novel cardiovascular risk factors such as oxidative stress and inflammation. Through these, ET also contributes to endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In particular relation to the kidney, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET likely also is involved in progression of renal disease, and data are emerging to suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.
Role of nitric oxide released from iNANC neurons in airway responsiveness in cats
Authors: H. Aizawa, S. Takata, H. Inoue, K. Matsumoto, H. Koto, N. Hara
Journal: European Respiratory Journal (1999)

The precise role of inhibitory nonadrenergic noncholinergic (iNANC) neurons and nitric oxide in airway hyperresponsiveness remains uncertain. The role of NO in the regulation of airway responsiveness was studied in anaesthetized and mechanically ventilated cats. To assess airway responsiveness, the changes in total pulmonary resistance (RL) produced by delivering serotonin aerosol to the airways were measured before and after N(omega)-nitro-L-arginine methyl ester (L-NAME), or a ganglionic blocker, hexamethonium, which has been reported to block iNANC. Serotonin was chosen because it causes bronchoconstriction in part by neural reflex. To further clarify the mechanism(s) involved, the effect of inhaled capsaicin was also determined in animals with sustained bronchoconstriction induced by serotonin after treatment with atropine and propranolol. Inhibition of NO synthase by L-NAME or blockade of iNANC neurons by hexamethonium significantly increased airway responsiveness. However, addition of L-NAME did not further increase airway responsiveness in animals treated with hexamethonium. In the presence of atropine and propranolol, inhaled capsaicin caused a marked bronchodilation during serotonin-induced sustained bronchoconstriction. The bronchodilation induced by capsaicin was significantly suppressed by hexamethonium and by L-NAME. These results suggest that the nitric oxide released from inhibitory nonadrenergic noncholinergic neurons is important in modulating the airway responsiveness of cats in vivo.
G Protein–Dependent and G Protein–Independent Signaling Pathways and Their Impact on Cardiac Function
Authors: Douglas G. Tilley
Journal: Circulation Research (2011)

G protein-coupled receptors signal through a variety of mechanisms that impact cardiac function, including contractility and hypertrophy. G protein–dependent and G protein–independent pathways each have the capacity to initiate numerous intracellular signaling cascades to mediate these effects. G protein–dependent signaling has been studied for decades and great strides continue to be made in defining the intricate pathways and effectors regulated by G proteins and their impact on cardiac function. G protein–independent signaling is a relatively newer concept that is being explored more frequently in the cardiovascular system. Recent studies have begun to reveal how cardiac function may be regulated via G protein–independent signaling, especially with respect to the ever-expanding cohort of β-arrestin–mediated processes. This review primarily focuses on the impact of both G protein–dependent and β-arrestin–dependent signaling pathways on cardiac function, highlighting the most recent data that illustrate the comprehensive nature of these mechanisms of G protein-coupled receptor signaling.
High resolution computed tomography in patients referred for intraluminal bronchoscopic therapy with curative intent
Authors: G Sutedja, RP Golding, PE Postmus
Journal: European Respiratory Journal (1996)

In patients with so-called roentgenologically occult intraluminal lung tumours, an accurate assessment of tumour size, its location and peribronchial tumour extent is important prior to any intraluminal bronchoscopic therapy (IBT) with curative intent. In twenty patients with so-called occult early-stage lung cancers, clinical outcome was compared to high resolution computed tomography (HRCT) findings prior to IBT. HRCT showed peribronchial tumour extension or nodal enlargement in 7 of the 20 patients (35%), and consequently treatment policy was changed. Five of the seven died 1.5-6 months after diagnosis, one patient underwent a radical pneumonectomy after induction chemotherapy, and the remaining patient is alive with pleural metastasis. HRCT showed intraluminal tumours in 11 of the 20 patients and IBT with curative intent was given. Complete response (CR) was achieved in 10 of the 11 patients, follow-up has been 4-26 months. One patient underwent a radical lobectomy, pathological stage T1NO, after 3 months because of tumour recurrence. HRCT was inconclusive in 2 of the 20 patients with postobstructive infiltrates. IBT was unsuccessful in both these cases. High resolution computed tomography may provide supportive evidence of intra-and extraluminal tumour; thereby, helping in the assessment of patients who were judged to be suitable for intra-luminal bronchoscopic therapy with curative intent. This may lead to a change in the treatment policy. High resolution computed tomography findings are complementary to bronchoscopic, histological and cytological examinations for the proper evaluation of treatment indications in patients with occult lung cancer.