tbuckley/cabot-search huggingface dataset:
"MODEL PSYCHOSIS" PRODUCED BY INHALATION OF GASOLINE FUMES
Authors: ELIERE J. TOLAN, FRIEDRICH A. LINGL
Journal: American Journal of Psychiatry (1964)

Two teen-age cases of toxic psychosis associated with gasoline inhalation are described and compared with the so-called "model psychoses" evoked by mescaline, LSD =25 and psilocybin. The symptoms were predominantly autonomic, perceptual and affective. The perceptual experiences included much personnally significant symbolic content. The inhaling of gasoline quickly became a tempting recurrent activity in the case of these two boys with maladjusted and impulsive personalities.
Adverse Hemodynamic Effects of Interrupting Chest Compressions for Rescue Breathing During Cardiopulmonary Resuscitation for Ventricular Fibrillation Cardiac Arrest
Authors: Robert A. Berg, Arthur B. Sanders, Karl B. Kern, Ronald W. Hilwig, Joseph W. Heidenreich, Matthew E. Porter, Gordon A. Ewy
Journal: Circulation (2001)

Background Despite improving arterial oxygen saturation and pH, bystander cardiopulmonary resuscitation (CPR) with chest compressions plus rescue breathing (CC+RB) has not improved survival from ventricular fibrillation (VF) compared with chest compressions alone (CC) in numerous animal models and 2 clinical investigations. Methods and Results After 3 minutes of untreated VF, 14 swine (32±1 kg) were randomly assigned to receive CC+RB or CC for 12 minutes, followed by advanced cardiac life support. All 14 animals survived 24 hours, 13 with good neurological outcome. For the CC+RB group, the aortic relaxation pressures routinely decreased during the 2 rescue breaths. Therefore, the mean coronary perfusion pressure of the first 2 compressions in each compression cycle was lower than those of the final 2 compressions (14±1 versus 21±2 mm Hg, P &lt;0.001). During each minute of CPR, the number of chest compressions was also lower in the CC+RB group (62±1 versus 92±1 compressions, P &lt;0.001). Consequently, the integrated coronary perfusion pressure was lower with CC+RB during each minute of CPR ( P &lt;0.05 for the first 8 minutes). Moreover, at 2 to 5 minutes of CPR, the median left ventricular blood flow by fluorescent microsphere technique was 60 mL · 100 g −1 · min −1 with CC+RB versus 96 mL · 100 g −1 · min −1 with CC, P &lt;0.05. Because the arterial oxygen saturation was higher with CC+RB, the left ventricular myocardial oxygen delivery did not differ. Conclusions Interrupting chest compressions for rescue breathing can adversely affect hemodynamics during CPR for VF.
Plasma surfactant protein D (SP-D) and nutritive status in patients with COPD
Authors: Kateryna Gashynova
Journal: European Respiratory Journal (2013)

Nutritional abnormalities are frequently occurring systemic complication of COPD. They often determinate functional capacity, health status and mortality of patients. However, causes and mechanisms of weight loss are still under investigation.

The aim of study was to reveal influence of SP-D on the nutritive status in patients (pts) with COPD.

Study population and methods . 44 men with stable COPD (Stage II-IV) were surveyed.

Plasma SP-D evaluation, spirometry, measurement of body mass index (BMI) by means of bioelectrical impedance analysis were performed for all pts.

Results . In accordance with SP-D level all pts were divided on two groups: Group I – pts with SP-D   600 ng/ml.

Results of nutritive status examination present in table 1.

View this table:



Conclusion. 

High level of SPD did not associate with significant BMI changes in patient with COPD.
Validation of Analytic Methods for Biomarkers Used in Drug Development
Authors: Cindy H. Chau, Olivier Rixe, Howard McLeod, William D. Figg
Journal: Clinical Cancer Research (2008)

Abstract The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and, in particular, assay validation become essential with the need to establish standardized guidelines for analytic methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics but are contingent on the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development.
Collagenase production by human mononuclear cells in culture: inhibition by gold containing compounds and other antirheumatic agents.
Authors: A Ohta, J S Louie, J Uitto
Journal: Annals of the Rheumatic Diseases (1986)

Human peripheral blood mononuclear cells in adherent cultures have been shown to synthesise and secrete collagenase. In the present study we have examined the modulation of collagenase production in these cultures by several antirheumatic agents. Incubation of monocytes in serum free medium with sodium aurothiomalate in concentrations varying from 7.7 X 10(-7) to 7.7 X 10(-3) mol/l resulted in marked dose dependent inhibition of the collagenase production. This inhibition was apparently selective in that total protein synthesis or the viability of the cells were not affected. Similar inhibition of the collagenase production was also noted with auranofin, aurothioglucose, and chloroauric acid. The inhibition with auranofin was achieved with a concentration as low as 7.4 X 10(-8) mol/l. To examine the mechanisms of the inhibition of the collagenase activity induced by sodium aurothiomalate the production of prostaglandin E2 was also measured in the same cell cultures. Sodium aurothiomalate in concentrations greater than 7.7 X 10(-4) mol/l significantly inhibited the prostaglandin E2 production; the prostaglandin E2 production was not inhibited, however, in 7.7 X 10(-5) mol/l concentration, while the collagenase production was reduced by 51.0%. Also, exogenous prostaglandin E2 added to the cultures only slightly reversed the inhibition of the collagenase production by sodium aurothiomalate. Thus the inhibition of collagenase production by sodium aurothiomalate in human adherent mononuclear cell cultures appears to be independent of the inhibition of prostaglandin E2 production. The inhibition of collagenase produced by monocyte-macrophages, as shown here in vitro, may contribute to the clinical efficacy of the compounds tested in the treatment of rheumatoid arthritis.
Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer
Authors: José Baselga, Joan Albanell, Amparo Ruiz, Ana Lluch, Pere Gascón, Vicente Guillém, Sonia González, Silvia Sauleda, Irene Marimón, Josep M. Tabernero, Maria T. Koehler, Federico Rojo
Journal: Journal of Clinical Oncology (2005)

To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer.In this phase II multicenter trial, the primary objective was assessment of the tumor response rate with gefitinib; secondary objectives included analysis of the pharmacodynamic and biologic profiles in healthy and tumor tissue.while phosphorylation of mitogen-activated protein kinase was inhibited in both tissues, gefitinib treatment induced p27 and a decrease in Ki67 in skin but not in tumors. Furthermore, gefitinib did not inhibit the activated form of Akt in the tumors.This study demonstrates a good correlation between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant clinical activity of gefitinib in our study population is not due to lack of receptor inhibition in these tumors but rather to lack of EGFR dependence in the tested population.
Hypoxia-Induced Activation of p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3′-Kinase Signaling Pathways Contributes to Expression of Interleukin 8 in Human Ovarian Carcinoma Cells
Authors: Lei Xu, Pooja S. Pathak, Dai Fukumura
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Overexpression of interleukin 8 (IL-8) is associated with disease progression in human ovarian cancer. Hypoxia, a common feature in solid tumors, induces IL-8 expression in human ovarian carcinoma cells through activation of nuclear factor-kappa B and activating protein-1. Here we show the upstream components of these signal transduction pathways that lead to IL-8 expression under hypoxia. Experimental Design: We incubated Hey-A8 human ovarian carcinoma cells under hypoxic condition (1% O2) and determined hypoxia regulation of phosphatidylinositol 3′-kinase (PI3K)/Akt pathway, mitogen-activated protein kinases (MAPKs), and effects of ras and vascular endothelial growth factor by Western and Northern blots, the use of specific inhibitors, in vitro kinase assays, luciferase reporter genes, and ELISA. Results: While investigating the upstream signaling pathways, we found that Akt kinase and p38 MAPK are activated by hypoxia. Both hypoxia-induced Akt and p38 MAPK functional activity, and IL-8 mRNA and protein expression were reduced with the inhibition of PI3K and p38 MAPK. Oncogenic ras overexpression resulted in an increase in the hypoxia-induced IL-8 expression, whereas the inhibition of ras by transfection of dominant-negative ras inhibited the hypoxia-induced IL-8 expression. Conclusions: These results show that hypoxia activates ras, PI3K/Akt pathway, and p38 MAPK pathway to enhance IL-8 gene transcription under hypoxia, and suggest these signaling pathways as potential targets for controling IL-8 expression and angiogenesis by human ovarian carcinoma cells.
French journal calls for domperidone to be withdrawn
Authors: P. Benkimoun
Journal: BMJ (2014)

The independent French medical journal Prescrire has called for the drug domperidone to be withdrawn after a study it conducted estimated that the drug caused about 25 to 120 premature deaths in 2012 in France alone.

The European Medicines Agency (EMA) is due to issue an opinion on domperidone in March, but the journal believes the agency will recommend lower dosages and shorter treatment. This is not enough, believes Prescrire . “It is high time the European health authorities withdrew this drug from the market,” it said in a statement.

It added: “These measures [proposed by the …
Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies
Authors: Q. Shi
Journal: Journal of Clinical Investigation (2006)

Inhibitory immune response to exogenously infused factor VIII (FVIII) is a major complication in the treatment of hemophilia A. Generation of such inhibitors has the potential to disrupt gene therapy for hemophilia A. We explore what we believe to be a novel approach to overcome this shortcoming. Human B-domain–deleted FVIII (hBDDFVIII) was expressed under the control of the platelet-specific αIIb promoter in platelets of hemophilic (FVIIInull) mice to create 2bF8trans mice. The FVIII transgene product was stored in platelets and released at the site of platelet activation. In spite of the lack of FVIII in the plasma of 2bF8trans mice, the bleeding phenotype of FVIIInull mice was corrected. More importantly, the bleeding phenotype was corrected in the presence of high inhibitory antibody titers introduced into the mice by infusion or by spleen cell transfer from recombinant hBDDFVIII–immunized mice. Our results demonstrate that this approach to the targeted expression of FVIII in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune responses to infused FVIII.
Distal cT2N0 Rectal Cancer: Is There an Alternative to Abdominoperineal Resection?
Authors: Ramesh Rengan, Philip Paty, W. Douglas Wong, Jose Guillem, Martin Weiser, Larissa Temple, Leonard Saltz, Bruce D. Minsky
Journal: Journal of Clinical Oncology (2005)

Patients with cT2N0 distal rectal cancer do not require adjuvant therapy. However, when a patient refuses an abdominoperineal resection (APR), is there an alternative? The purpose of this trial is to determine whether preoperative external-beam radiation therapy can increase the rate of sphincter preservation for patients with distal cT2N0 adenocarcinoma of the rectum.Between April 1988 and October 2003, 27 patients with distal rectal adenocarcinoma staged T2 by clinical and/or endorectal ultrasound who were judged by the operating surgeon to require an APR were treated with preoperative pelvic radiation alone (50.4 Gy). Surgery was performed 4 to 7 weeks later. If pathologic positive pelvic nodes were identified, postoperative adjuvant chemotherapy was recommended. The median follow-up was 55 months (range, 9 to 140 months).The pathologic complete response rate was 15% and 78% of patients underwent a sphincter-sparing procedure. The crude incidence of local failure for patients undergoing a sphincter sparing procedure was 10% and the 5-year actuarial incidence was 13%. The actuarial 5-year survival for patients undergoing sphincter preservation was as follows: disease-free, 77%; colostomy-free, 100%; and overall, 85%. Using the Memorial Sloan-Kettering Cancer Center sphincter function score, 54% of those undergoing a sphincter-sparing procedure had good/excellent bowel function at 12 to 24 months after surgery, and 77% had good/excellent function at 24 to 36 months after surgery.Our data suggest that for patients with cT2N0 distal rectal cancer who require an APR, preoperative pelvic radiation improves sphincter preservation without an apparent compromise in local control or survival.
Proliferation of Human Neuroblastomas Mediated by the Epidermal Growth Factor Receptor
Authors: Ruth Ho, Jane E. Minturn, Tomoro Hishiki, Huaqing Zhao, Qun Wang, Avital Cnaan, John Maris, Audrey E. Evans, Garrett M. Brodeur
Journal: Cancer Research (2005)

Neuroblastoma is a common solid tumor of childhood that is derived from the neural crest. Expression of epidermal growth factor (EGF) receptors (EGFRs) has been associated with enhanced cell growth and aggressive behavior in other tumors. Here, we examined the expression profile of EGFRs in neuroblastoma cell lines and primary tumors. We found that all 13 neuroblastoma cell lines examined expressed EGFR1 (HER1), most at readily detectable levels. Low levels of other human EGFR family receptors were also detected in almost all cell lines. All primary tumors examined expressed readily detectable levels of HER1 and HER3 and lower levels of HER2 and HER4. EGF had a significant effect on the proliferation of neuroblastoma cell lines in vitro. EGF treatment (100 ng/mL) of the cell lines SY5Y and NLF significantly increased cell number (P < 0.01). EGF stimulated more cells to enter S and G2-M phase, as suggested by flow cytometry, indicating that EGF increases cell number by increasing proliferation, with no appreciable change in apoptosis. EGF exposure resulted in receptor autophosphorylation and activation of both the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. Exposure to 0.5 micromol/L ZD1839, a HER1-specific inhibitor, caused a 40% to 50% reduction in the number of SY5Y and NLF cells grown in medium containing 10% fetal bovine serum (P < 0.01). Even at 0.01 micromol/L, ZD1839 inhibited autophosphorylation of HER1 by EGF. At 0.1 micromol/L, it also blocked phosphorylation of AKT, but not MAPK, in NLF cells. Additional studies showed that the PI3K/AKT-specific inhibitor LY294002 had a more profound effect than the MAPK-specific inhibitor U0126 in blocking EGF-induced cell proliferation. This suggests that the PI3K/AKT pathway is the main signaling pathway responsible for the proliferation effects of EGF in neuroblastomas. Our results also indicate that ZD1839 is a potent inhibitor of neuroblastoma cell proliferation; therefore, it may be a useful, biologically based therapeutic agent for these tumors.
New Molecular Classifications of Breast Cancer
Authors: M. Cianfrocca, W. Gradishar
Journal: CA A Cancer Journal for Clinicians (2009)

Traditionally, pathologic determinations of tumor size, lymph node status, endocrine receptor status, and human epidermal growth factor receptor 2 (HER2) status have driven prognostic predictions and adjuvant therapy recommendations for patients with early stage breast cancer. However, these prognostic and predictive factors are relatively crude measures, resulting in many patients being overtreated or undertreated. As a result of gene expression assays, there is growing recognition that breast cancer is a molecularly heterogeneous disease. Evidence from gene expression microarrays suggests the presence of multiple molecular subtypes of breast cancer. The recent commercial availability of gene expression profiling techniques that predict risk of disease recurrence as well as potential chemotherapy benefit have shown promise in refining clinical decision making. These techniques will be reviewed in this article.
Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer
Authors: Bjørn H. Grønberg, Roy M. Bremnes, Øystein Fløtten, Tore Amundsen, Paal Fr. Brunsvig, Harald H. Hjelde, Stein Kaasa, Christian von Plessen, Frøydis Stornes, Terje Tollåli, Finn Wammer, Ulf Aasebø, Stein Sundstrøm
Journal: Journal of Clinical Oncology (2009)

PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin area under the curve (AUC) = 5 (Calvert's formula) on day 1 or gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received > or = one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms. CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.
Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer
Authors: Taly R. Spivak-Kroizman, Galen Hostetter, Richard Posner, Meraj Aziz, Chengcheng Hu, Michael J. Demeure, Daniel Von Hoff, Sunil R. Hingorani, Timothy B. Palculict, Julie Izzo, Galina M. Kiriakova, Mena Abdelmelek, Geoffrey Bartholomeusz, Brian P. James, Garth Powis
Journal: Cancer Research (2013)

Abstract Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor–stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer. Cancer Res; 73(11); 3235–47. ©2013 AACR.
Vulnerable people are being oppressed because of failures of Mental Capacity Act, say peers
Authors: A. O'Dowd
Journal: BMJ (2014)

Tens of thousands of people are being deprived of their liberty unlawfully in care settings because of failures of the Mental Capacity Act, peers have said.

Misunderstanding and ignorance concerning the 2005 Mental Capacity Act are widespread among healthcare professionals and social care staff, says a highly critical report published on 13 March by a House of Lords select committee.1 The committee was set up to scrutinise …
Development of New Peripheral Arterial Occlusive Disease in Patients With Type 2 Diabetes During a Mean Follow-Up of 11 Years
Authors: Milla Kallio, Carol Forsblom, Per-Henrik Groop, Leif Groop, Mauri Lepäntalo
Journal: Diabetes Care (2003)

OBJECTIVE— To assess the occurrence and development of new peripheral arterial occlusive disease (PAOD), its risk factors, and the outcome in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS— A total of 130 type 2 diabetic patients (mean age 58 years) were examined at baseline and after a mean follow-up of 11 years (range 7–14). The ankle-brachial index (ABI) and toe-brachial index were used to detect PAOD. Blood and urine samples were taken at baseline, and a history of cardiovascular events was recorded during follow-up. RESULTS— PAOD was diagnosed in 21 (16%) patients at baseline. During follow-up, 21 of 89 (24%) patients developed new PAOD. There were 29 patients who died, 21 (72%) of them from cardiovascular disease. Patients with PAOD suffered an excess mortality compared with patients without PAOD (58 vs. 16%; P &amp;lt; 0.001). Logistic regression analysis showed that PAOD at baseline was associated with age, duration of diabetes, smoking, and urinary albumin excretion rate. Patients who developed new PAOD during follow-up had higher serum LDL cholesterol concentrations and lower HDL cholesterol concentrations and were older than the patients who remained free of PAOD. CONCLUSIONS— Objectively measured PAOD is frequent in type 2 diabetic patients. It presents the early clinical signs of atherosclerosis and is strongly associated with cardiovascular death. The risk factor pattern for PAOD was different at baseline and after a mean follow-up of 11 years. We consider routine ABI measurements and modification of risk factors necessary also in patients with asymptomatic PAOD.