tbuckley/cabot-search huggingface dataset:
WARFARIN FOR SUICIDE
Authors: J. Morgan Kellum
Journal: JAMA (1952)

<h3>To the Editor:—</h3> I read with interest the article "Suicide Attempt with Warfarin, a Bishydroxycoumarin-Like Rodenticide," which appeared in the March 15, 1952, issue ofThe Journal. The authors were Lt. Roy W. Holmes and Capt. Julian Lowe. I would like to report a somewhat similar experience that I had in February, 1952, as follows. I was called to the residence of J. L. H., a young white man. The story was that he had become despondent, because his young bride of a few weeks had left him, and he went to a drugstore and asked for "rat poison." He was sold a package of "warfarat," made by Dr. Hess &amp; Clark, Inc., Ashland, Ohio. The label on the package indicated that it contained bishydroxycoumarin (dicumarol®) and gave instructions as to the antidote. The patient stated that he took a "heaping tablespoonful" in a glass of water about one hour
In Vivo Quantitative Tissue Characterization of Human Coronary Arterial Plaques by Use of Integrated Backscatter Intravascular Ultrasound and Comparison With Angioscopic Findings
Authors: Masanori Kawasaki, Hisato Takatsu, Toshiyuki Noda, Keiji Sano, Yoko Ito, Kenji Hayakawa, Kunihiko Tsuchiya, Masazumi Arai, Kazuhiko Nishigaki, Genzou Takemura, Shinya Minatoguchi, Takako Fujiwara, Hisayoshi Fujiwara
Journal: Circulation (2002)

Background — The purpose of the present study was to define whether integrated backscatter (IB) combined with conventional intravascular ultrasound (IVUS) makes tissue characterization of coronary arterial plaques possible. Methods and Results — IB-IVUS was performed in coronary arteries (total 18 segments) of 9 patients at autopsy, and the findings were compared with the histology. RF signals, which were digitized at 2 GHz in 8-bit resolution, were obtained with an IVUS system with a 40-MHz catheter. IB values of the RF signal from the region of interest (ROI) (100-μm depth, 1.4° per line) were calculated by use of a personal computer. IB values on the ROIs were divided into 5 categories, compared with each of the plaque histologies: category 1 (thrombus), −88 &lt; IB ≤ −80; category 2 (intimal hyperplasia or lipid core), −73 &lt; IB ≤ −63; category 3 (fibrous tissue), −63 &lt; IB ≤ −55; category 4 (mixed lesions), −55 &lt; IB ≤ −30; and category 5 (calcification), −30 &lt; IB ≤ −23. On the basis of these categories, we analyzed 5120 ROIs per segment in each ring-like arterial specimen. Color-coded maps of plaques were constructed by use of these IB data and conventional IVUS data, which reflected the plaque histology of autopsied coronary arteries well. Then, the same method was undertaken in 24 segments with plaque from 12 patients in vivo with angina pectoris. Comparisons between coronary angioscopy and IB-IVUS revealed that the surface color of plaques in angioscopy reflected the thickness of the fibrous cap rather than the size of the lipid core. Conclusions — IB-IVUS represents a new and useful tool for evaluating the tissue structure of human coronary arterial plaques.
Rectal temperature after marathon running.
Authors: R J Maughan, J B Leiper, J Thompson
Journal: British Journal of Sports Medicine (1985)

Rectal temperature was measured in 62 male runners who competed in the 1983 Dundee marathon race: all measurements were made immediately after the race. Competitors' times were noted at 5, 10, 15 and 20 miles (8.0, 16.1, 24.1, 32.2 km) and at the finish (26.2 miles, 42.2 km). Mean finishing time of the group was 3 hr 33 min +/- 48 min (mean +/- S.D.; range = 2 hr 17 min-5 hr 11 min). Mean running speed of the group decreased progressively as the distance covered increased. Mean post-race rectal temperature was 38.7 +/- 0.9 degrees C (range 35.6-40.3 degrees C). The post-race temperature was correlated (p less than 0.01) with the time taken to cover the last 6.2 miles (10 km) of the race, but not with the overall finishing time (p greater than 0.05). Only the fastest runners were able to maintain an approximately constant pace throughout the race, whereas the slower runners slowed down progressively. The runners with the highest post-race temperature, although not necessarily the fastest runners, also tended to maintain a steady pace throughout. The runners with the lowest post-race temperature slowed down markedly only over the last 6.2 mile section of the race. The results clearly indicate that runners forced by fatigue or injury to slow down in the latter stages of races held at low ambient temperatures may already be hypothermic or at serious risk of hypothermia.
LOCOMOTOR CIRCUITS IN THE MAMMALIAN SPINAL CORD
Authors: Ole Kiehn
Journal: Annual Review of Neuroscience (2006)

Intrinsic spinal networks, known as central pattern generators (CPGs), control the timing and pattern of the muscle activity underlying locomotion in mammals. This review discusses new advances in understanding the mammalian CPGs with a focus on experiments that address the overall network structure as well as the identification of CPG neurons. I address the identification of excitatory CPG neurons and their role in rhythm generation, the organization of flexor-extensor networks, and the diverse role of commissural interneurons in coordinating left-right movements. Molecular and genetic approaches that have the potential to elucidate the function of populations of CPG interneurons are also discussed.
A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors
Authors: Jian Zhang, Junning Cao, Jin Li, Yifan Zhang, Zhiyu Chen, Wei Peng, Si Sun, Naiqing Zhao, Jiachen Wang, Dafang Zhong, Xiaofang Zhang, Jing Zhang
Journal: Journal of Hematology & Oncology (2014)

AST1306 is an orally active irreversible small molecule inhibitor of EGFR (erbB1), HER2 (erbB2) and HER4 (erbB4) signaling. This is a phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306. In addition the effects of food on PK was tested.A modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.Seventy-one patients were enrolled, with breast (n = 22) and lung cancers (n = 14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n = 1), 1500 mg BID (n = 1), 800 mg TID (n = 1) and 1200 mg TID (n = 2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean T(max) was prolonged, C(max) was increased, and AUC(0-∞) was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for ≥ 6 months was achieved in 7 patients.Based on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.
Drug Treatment Effects on Disease Progression
Authors: PLS Chan, NHG Holford
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Degenerative diseases are characterized by a worsening of disease status over time. The rate of deterioration is determined by the natural rate of progression of the disease and by the effect of drug treatments. A goal of drug treatment is to slow disease progression. Drug treatments can be categorized as symptomatic or protective. Symptomatic treatments do not affect the rate of disease progression whereas protective treatments have the ability to slow disease progression down. Many current methods for describing disease progression have two common drawbacks: a linear relationship between time and disease status is assumed, and within- and between-subject variability is ignored. Disease progress models combined with pharmacokinetic pharmacodynamic models and hierarchical random effects statistical models provide insights into understanding the time course and management of degenerative disease.
A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity
Authors: Hui Cheng, Gabor Kari, Adam P. Dicker, Ulrich Rodeck, Walter J. Koch, Thomas Force
Journal: Circulation Research (2011)

Rationale: Despite intense interest in strategies to predict which kinase inhibitor (KI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. Sorafenib is a KI of concern because it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of extracellular signal-regulated kinases (ERKs) and signal cardiomyocyte survival in the setting of stress. Objectives: To explore the potential use of zebrafish as a preclinical model to predict cardiotoxicity and to determine whether sorafenib has associated cardiotoxicity, and, if so, define the mechanisms. Methods and Results: We find that the zebrafish model is readily able to discriminate a KI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, a reduction in total myocyte number per heart, contractile dysfunction, and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1, which restores ERK activity even in the presence of sorafenib. Whereas growth factor–induced activation of ERKs requires Raf, α-adrenergic agonist-induced activation of ERKs does not require it. Consequently, activation of α-adrenergic signaling markedly decreases sorafenib-induced cell death. Consistent with these in vitro data, inhibition of α-adrenergic signaling with the receptor antagonist prazosin worsens sorafenib-induced cardiomyopathy in zebrafish. Conclusions: Zebrafish may be a valuable preclinical tool to predict cardiotoxicity. The α-adrenergic signaling pathway is an important modulator of sorafenib cardiotoxicity in vitro and in vivo and appears to act through a here-to-fore unrecognized signaling pathway downstream of α-adrenergic activation that bypasses Raf to activate ERKs.
Endoscopic submucosal dissection (ESD) of early neoplastic gastric lesions using a new double-channel endoscope (the ”R-scope”)
Authors: H. Neuhaus, G. Costamagna, J. Devière, P. Fockens, T. Ponchon, T. Rösch
Journal: Endoscopy (2006)

Endoscopic submucosal dissection (ESD) allows en bloc resection of lesions > 2 cm in diameter. However the procedure is difficult because of limited visualization of the cutting area. The aim of this study was to evaluate a new endoscope (the "R-scope") for ESD; this provides a second flexible section for improved positioning capability and two instrumentation channels for vertical lifting of the targeted mucosal area and horizontal cutting of the submucosa.The R-scope was tested first for ESD of 17 predetermined gastric areas in eight anesthetized pigs. Clinical experience was then prospectively obtained in 10 patients with early gastric neoplasia. In both instances, dye-stained saline solution was used for repeated submucosal injection. Various types of knives were available for circumferential cutting of the mucosa to isolate the targeted lesion. The specimen was then lifted and the submucosal layer was dissected with the appropriate type of knife to achieve en bloc resection.ESD succeeded in 14/17 animal cases (82 %), remained incomplete in two cases and failed in one because of an intractable perforation; a further two small perforations were clipped. In 10 patients (with nine early carcinomas and one adenoma, with a median diameter of 22 mm), lesions were completely resected in six cases. Surgery was necessary in two patients due to early and delayed perforation. Three other patients with small amounts of free air were conservatively managed but elective surgery was performed in two of these patients because of incomplete resection or deep submucosal tumor infiltration.The R-scope facilitated ESD of large gastric areas in live animal testing and in a small series of patients However the procedure is technically demanding and time-consuming. It was also associated with a high risk of perforation; this may be related to an insufficient volume of solution being injected submucosally, excessively forceful lifting of the specimen, or the short learning period.
PWE-098 <i>Clostridium difficile</i>diarrhoea—the changing hospital epidemiology and clinical outcomes from a high prevalence area in North East England
Authors: J Ross, P Brown, C Aldridge, L Lim, D Nayar, J Sloss, D Allison, A Dhar
Journal: Gut (2012)

<h3>Introduction</h3> <i>Clostridium difficile</i> associated diarrhoea (CDAD) is an important hospital acquired infection. In 2008–2009 Co. Durham had one of the highest reported annual incidence of CDAD with 232 cases, 74.4 cases/100 000 bed days. Following strict antibiotic stewardship in 2009, we set out to examine the changes to the hospital based epidemiology of CDAD in our three hospitals over a 12-month period. <h3>Methods</h3> Between June 2010 and May 2011, 70 patients with positive stool <i>C difficile</i> toxin were identified from the Microbiology database, and 56 case notes reviewed. Patient demographics, clinical symptoms, risk factors, severity, treatment for CDAD, and multi-disciplinary team decisions were recorded. Clinical outcomes including length of stay, treatment, mortality, and relapses were analysed and compared to standard hospital episode statistics (HES). <h3>Results</h3> The annualised hospital incidence of CDAD was 70/20 000 admissions, age range 2–100 yrs (mean 75.5, M: F). 76.8% patients were older than 70 yrs. 43% had received antibiotics prior to admission and 35 (62%) patients were commenced on antibiotics in hospital. The top 5 were Amoxicillin, Co-amoxiclav, Flucloxacillin, Cephalexin and Trimethoprim. 62% of these had received one course of antibiotic, and 30% two or more courses. 39% patients had a previous admission to hospital in the preceding 12 weeks, 46.4% were taking a PPI and 35.7% a laxative. <i>C difficile</i> was confirmed by both toxin and GDH positivity in 80.4%, and by toxin positivity only in 19.6%. Total length of stay ranged from 51 days (16%). A positive diagnosis was made in 80% patients, but severity was not always recorded. Stool charts were completed in 70%, serum lactate checked in 10% and abdominal x-ray done in 30%. Only 25% patients were seen by an MDT member. 78.5% pts were treated, 30/44 (68%) with Metronidazole and 11/44 (25%) with Vancomycin as first line drugs. 3/44 patients received both drugs initially. 30.4% pts received ≤7 days, 50% upto 14 days and 19.6% ≥14 days treatment. All cause mortality was 25%, almost entirely in the elderly. 7% had a recurrence, all treated by Vancomycin and pulsed/tapered regimes and probiotics were used infrequently. <h3>Conclusion</h3> CDAD continues to be an important hospital acquired infection with a significant increase in hospital length of stay and high mortality rates, especially in the elderly. This study indicates that a significant proportion of CDAD may be acquired in the community. Adherence to national recommendations for management and involvement of the MDT needs to be encouraged to improve outcomes. <h3>Competing interests</h3> None declared.
Characteristics of inflammatory bowel diseases-associated interstitial lung diseases
Authors: Camille Bron, Marianne Kambouchner, Thomas Gille, Yurdagul Uzunhan, Jean-Marc Naccache, Pierre-Yves Brillet, Michel Brauner, Dominique Valeyre, Hilario Nunes
Journal: European Respiratory Journal (2011)

Introduction:  Various interstitial lung diseases (ILD) have been reported in inflammatory bowel diseases (IBD) but most publications are limited to small series or predate the 2002 ATS/ERS statement on idiopathic interstitial pneumonias.   Aims:  To describe the epidemiological, clinical, radiological and pathological characteristics of IBD-associated ILD.   Methods:  This is a monocentric retrospective study of 9 patients with IBD-associated ILD refered from 1990 to 2010. Patients were classified according to HRCT and pathological patterns of ILD as recommended by 2002 ATS/ERS statement.   Results:  There were 5 men and 4 women with a mean age of 49±7 years (Crohn9s disease: n=4, ulcerative colitis: n=3, undetermined colitis: n=2). ILD developped in the course of previously known IBD in 7 cases, with a median delay of 10 years, while IBD was diagnosed after ILD in 2 cases. Surgical lung biopsy was available in 4 patients. ILD final diagnoses were: “hypersensitivity pneumonitis” (“HSP”): n=4, nonspecific interstitial pneumonia (NSIP): n=2, NSIP secondary to “HSP”: n=1, combined pulmonary fibrosis and emphysema: n=1, bronchiolitis: n=1. No patient had overt environnemental exposure but 4 patients received mesalazine at the onset of ILD, of which only one with “HSP”. One patient with NSIP also had dermatomyositis. Baseline FVC was 65±19% and DLCO 34±8%. ILD worsened despite corticosteroids in 7 patients who required other immunosuppressive drugs. At the end of follow-up (4.3±2.6 years), 2 patients died and 1 was transplanted.   Conclusion:  Our study outlines the severity of IBD-associated ILD and the high frequency of “HSP”, raising the possible role of a particular unrecognised antigen in such a context.
Human Cytomegalovirus Glycoprotein UL16 Causes Intracellular Sequestration of NKG2D Ligands, Protecting Against Natural Killer Cell Cytotoxicity
Authors: Claire Dunn, N. Jan Chalupny, Claire L. Sutherland, Stephanie Dosch, P.V. Sivakumar, David C. Johnson, David Cosman
Journal: The Journal of Experimental Medicine (2003)

The activating receptor, NKG2D, is expressed on a variety of immune effector cells and recognizes divergent families of major histocompatibility complex (MHC) class I–related ligands, including the MIC and ULBP proteins. Infection, stress, or transformation can induce NKG2D ligand expression, resulting in effector cell activation and killing of the ligand-expressing target cell. The human cytomegalovirus (HCMV) membrane glycoprotein, UL16, binds to three of the five known ligands for human NKG2D. UL16 is retained in the endoplasmic reticulum and cis-Golgi apparatus of cells and causes MICB to be similarly retained and stabilized within cells. Coexpression of UL16 markedly reduces cell surface levels of MICB, ULBP1, and ULBP2, and decreases susceptibility to natural killer cell–mediated cytotoxicity. Domain swapping experiments demonstrate that the transmembrane and cytoplasmic domains of UL16 are important for intracellular retention of UL16, whereas the ectodomain of UL16 participates in down-regulation of NKG2D ligands. The intracellular sequestration of NKG2D ligands by UL16 represents a novel HCMV immune evasion mechanism to add to the well-documented viral strategies directed against antigen presentation by classical MHC molecules.
Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer
Authors: J. Jassem, P. Kosmidis, R. Ramlau, K. Zarogoulidis, L. Novakova, J. Breton, P.-L. Etienne, C. Seebacher, M. Grivaux, A. Ojala, D. Aubert, F. Lefresne
Journal: Annals of Oncology (2003)

A phase II trial of alternating i.v. and oral vinorelbine in combination with cisplatin was designed to determine the response rate, safety profile, progression-free survival, overall survival and quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC).Fifty-six chemotherapy-naïve patients received cisplatin 100 mg/m(2) and i.v. vinorelbine 25 mg/m(2) on day 1, followed by oral vinorelbine 60 mg/m(2) on days 8, 15 and 22, every 28 days.After an independent review, the response rate was 33% [95% confidence interval (CI) 20% to 46%]. Median progression-free and overall survival were 5.5 months (95% CI 3.7-6.4) and 8.9 months (95% CI 8.8-11.7), respectively. The most frequent hematological toxicities were neutropenia (grade 3-4 in 73% of patients) and anemia (grade 3-4 in 11% of patients). Grade 3-4 infections and non-hematological toxicities occurred occasionally. QoL for lung cancer related symptoms was stable or improved.The efficacy and safety of the alternating vinorelbine schedule (i.v. on day 1, oral on days 8, 15 and 22) in combination with cisplatin in advanced NSCLC are similar to those of the standard regimen using exclusively i.v. vinorelbine, whereas ease of administration and patient comfort may favor the novel approach.
Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells
Authors: Heming Li, Ling Xu, Ce Li, Lei Zhao, Yanju Ma, Huachuan Zheng, Zhi Li, Ye Zhang, Ruoyu Wang, Yunpeng Liu, Xiujuan Qu
Journal: Molecular Cancer (2014)

Insulin-like growth factor I (IGF-I) can induce epithelial mesenchymal transition (EMT) in many epithelial tumors; however, the molecular mechanism by which this occurs is not clearly understood. Additionally, little is known about the involvement of IGF-I in gastric cancer. Two gastric cancer cell lines were treated with IGF-I to induce EMT and levels of transcription factor ZEB2 and microRNA-200c (miR-200c) were measured. Cells were treated with Akt/ERK inhibitors to investigate the role of these pathways in IGF-I-mediated EMT. Transfection of shRNA plasmids was used to silence the ubiquitin ligase Cbl-b to assess its involvement in this process. The relationship between IGF-IR and Cbl-b expression, and the effect of IGF-IR and Cbl-b on metastasis were analyzed in primary gastric adenocarcinoma patients. IGF-I-induced gastric cancer cell EMT was accompanied by ZEB2 up-regulation. Furthermore, both Akt/ERK inhibitors and knockdown of Akt/ERK gene reversed IGF-I-induced ZEB2 up-regulation and EMT through up-regulation of miR-200c, suggesting the involvement of an Akt/ERK-miR-200c-ZEB2 axis in IGF-I-induced EMT. The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. There was a significant negative correlation between the expression of IGF-IR and Cbl-b in gastric cancer patient tissues (r = -0.265, p < 0.05). More of patients with IGF-IR-positive expression and Cbl-b-negative expression were with lymph node metastasis (p < 0.001). Together, these findings demonstrate that the ubiquitin ligase Cbl-b represses IGF-I-induced EMT, likely through targeting IGF-IR for degradation and further inhibiting the Akt/ERK-miR-200c-ZEB2 axis in gastric cancer cells.
Medical electives: a chance for international health
Authors: Amitava Banerjee
Journal: Journal of the Royal Society of Medicine (2010)

Despite globalization, global health inequity has increased. The World Health Report 2006 stated, ‘A shortage of human resources has replaced financial issues as the most serious obstacle to implementing national HIV treatment plans’. New initiatives must tackle diverse system problems such as ‘brain drain’, training and recruitment. The Crisp report recognized the need for global health partnerships to tackle current and future international health (IH) challenges.