tbuckley/cabot-search huggingface dataset:
Structural adaptations in the murine colon microcirculation associated with hapten-induced inflammation
Authors: D. J Ravnic, M. A Konerding, A. Tsuda, H. T Huss, T. Wolloscheck, J. P Pratt, S. J Mentzer
Journal: Gut (2006)

Blood flowing across the vascular endothelium creates wall shear stress, dependent on velocity of flow and vessel geometry, that tends to disrupt lymphocyte-endothelial cell adhesion.The microcirculation in a murine model of acute colitis was investigated to identify structural adaptations during acute colitis that may facilitate transmigration.In 2,4,6-trinitrobenzenesulphonic acid-induced acute colitis, the infiltrating cells and colonic microcirculation was investigated by cellular topographic mapping, corrosion casting and three-dimensional scanning electron microscopy (SEM). Colonic blood velocimetry was performed using intravital microscopy.Clinical and histological parameters suggested a peak inflammatory response at 96 h (p<0.001). The infiltrating cells were spatially related to the mucosal capillary plexus by three-dimensional topographic mapping (p<0.001). In normal mice, corrosion casting and three-dimensional SEM showed a polygonal mucosal plexus supplied by ascending arteries and descending veins. After 2,4,6-trinitrobenzenesulphonic acid stimulation, three-dimensional SEM showed preserved branch angles (p = 0.52) and nominal vessel lengths (p = 0.93), but a significantly dilated mucosal capillary plexus (p<0.001). Intravital microscopy of the mucosal plexus showed a greater than twofold decrease in the velocity of flow (p<0.001).The demonstrable slowing of the velocity of flow despite an increase in volumetric flow suggests that these microvascular adaptations create conditions suitable for leucocyte adhesion and transmigration.
Insulin Induces Upregulation of Vascular AT <sub>1</sub> Receptor Gene Expression by Posttranscriptional Mechanisms
Authors: Georg Nickenig, Jörg Röling, Kerstin Strehlow, Petra Schnabel, Michael Böhm
Journal: Circulation (1998)

Background —An interaction of insulin with angiotensin II effects could be pathophysiologically important for the pathogenesis of atherosclerosis and hypertension. Methods and Results —We examined the effect of insulin on AT 1 receptor gene expression in cultured vascular smooth muscle cells (VSMCs). A 24-hour incubation with insulin (100 nmol/L) produced a 2-fold increase in AT 1 receptor density on VSMCs, as assessed by radioligand binding assays. This enhanced AT 1 receptor expression was caused by a time- and concentration-dependent upregulation of the AT 1 receptor mRNA levels, as assessed by Northern analysis. The maximal effect was detected after a 24-hour incubation of cells with 100 nmol/L insulin (270±20%). AT 1 receptor upregulation was caused by a stabilization of the AT 1 receptor mRNA, because the AT 1 receptor mRNA half-life was prolonged from 5 hours under basal conditions to 10 hours after insulin stimulation. In contrast, insulin had no influence on AT 1 receptor gene transcription, as assessed by nuclear run-on assays. The insulin-induced AT 1 receptor upregulation was followed by an increased functional response, because angiotensin II evoked a significantly elevated intracellular release of calcium in cells that were preincubated with 100 nmol/L insulin for 24 hours. The insulin-induced AT 1 receptor upregulation was dependent on tyrosine kinases, as assessed by experiments with the tyrosine kinase inhibitor genistein. Furthermore, experiments using the intracellular calcium chelator bis(2-amino-5-methylphenoxy)ethane- N , N , N ′, N ′-tetraacetic acid tetraacetoxymethyl ester suggest that intracellular calcium release may be involved in AT 1 receptor regulation. Conclusions —Insulin-induced upregulation of the AT 1 receptor by posttranscriptional mechanisms may explain the association of hyperinsulinemia with hypertension and arteriosclerosis, because activation of the AT 1 receptor plays a key role in the regulation of blood pressure and fluid homeostasis.
Assessment Of Acute Urticaria In Pediatric Emergency Department
Authors: Raquel Reis Pitchon, Daniel Reis, Adriana Reis, André Chuster, Teresa Mohallen, José Ribeiro, Nívea Claret, Giane Chaves, Virgilio Aleixo, Maria do Socorro Fernandes, Fausto Pacheco
Journal: Journal of Allergy and Clinical Immunology (2014)
Prognostic Value of p16 in Locally Advanced Prostate Cancer: A Study Based on Radiation Therapy Oncology Group Protocol 9202
Authors: Arnab Chakravarti, Michelle DeSilvio, Min Zhang, David Grignon, Seth Rosenthal, Sucha O. Asbell, Gerald Hanks, Howard M. Sandler, Li-Yan Khor, Alan Pollack, William Shipley
Journal: Journal of Clinical Oncology (2007)

Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202.RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system.On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index < or = 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort.Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.
“Key to the Future”: British American Tobacco and Cigarette Smuggling in China
Authors: Kelley Lee, Jeff Collin
Journal: PLoS Medicine (2006)

Background Cigarette smuggling is a major public health issue, stimulating increased tobacco consumption and undermining tobacco control measures. China is the ultimate prize among tobacco's emerging markets, and is also believed to have the world's largest cigarette smuggling problem. Previous work has demonstrated the complicity of British American Tobacco (BAT) in this illicit trade within Asia and the former Soviet Union. Methods and Findings This paper analyses internal documents of BAT available on site from the Guildford Depository and online from the BAT Document Archive. Documents dating from the early 1900s to 2003 were searched and indexed on a specially designed project database to enable the construction of an historical narrative. Document analysis incorporated several validation techniques within a hermeneutic process. This paper describes the huge scale of this illicit trade in China, amounting to billions of (United States) dollars in sales, and the key supply routes by which it has been conducted. It examines BAT's efforts to optimise earnings by restructuring operations, and controlling the supply chain and pricing of smuggled cigarettes. Conclusions Our research shows that smuggling has been strategically critical to BAT's ongoing efforts to penetrate the Chinese market, and to its overall goal to become the leading company within an increasingly global industry. These findings support the need for concerted efforts to strengthen global collaboration to combat cigarette smuggling.
PET Study Examining Pharmacokinetics, Detection and Likeability, and Dopamine Transporter Receptor Occupancy of Short- and Long-Acting Oral Methylphenidate
Authors: Thomas J. Spencer, Joseph Biederman, Patrick E. Ciccone, Bertha K. Madras, Darin D. Dougherty, Ali A. Bonab, Elijahu Livni, Dolly A. Parasrampuria, Alan J. Fischman
Journal: American Journal of Psychiatry (2006)

The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate.Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography.Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate.The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.
Effects of Agents which Inhibit the Slow Channel on Sinus Node Automaticity and Atrioventricular Conduction in the Dog
Authors: DOUGLAS P. ZIPES, JOHN C. FISCHER
Journal: Circulation Research (1974)

A slow ionic current carried by calcium, sodium, or both constitutes transmembrane ionic flow through the slow channel; such a current may be involved in normal action potentials of sinus and atrioventricular (AV) nodal cells. In this study, we investigated the effects of the slow-channel inhibiting agents verapamil, D600, manganous chloride, and lanthanum chloride on sinus node automaticity and AV nodal conduction in open-chest dogs treated with atropine (0.5 mg/kg) and propranolol (1.0 mg/kg). The arteries to the sinus node and the AV node were cannulated and perfused with agents that inhibit the slow current. These agents slowed sinus node discharge rate, depressed AV nodal conduction, and lengthened the effective and the functional AV nodal refractory period. Effects were dose related and reversed with time. His-Purkinje conduction remained normal. Isoproterenol and epinephrine reversed the effects of slow-channel inhibiting agents, but calcium, sodium, glucagon, and phenylephrine did not. Concentrations of propranolol which produced beta-receptor blockade prevented Isoproterenol-induced reversal of the effects of slow-channel inhibitors. We concluded that (1) agents which inhibit the slow channel directly depress sinus node discharge rate and AV nodal conduction, (2) effects of slow-channel inhibiting agents are not mediated through the activation of cholinergic discharge or inhibition of adrenergic discharge, and (3) beta-receptor stimulation reverses these effects.
Impact of bronchiectasis and trapped air on quality of life and exacerbations in cystic fibrosis
Authors: Leonie A. Tepper, Elisabeth M.W.J. Utens, Daan Caudri, Aukje C. Bos, Karla Gonzalez-Graniel, Hugo J. Duivenvoorden, Els C.W. van der Wiel, Alexandra L. Quittner, Harm A.W.M. Tiddens
Journal: European Respiratory Journal (2013)

Cystic fibrosis (CF) is primarily characterised by bronchiectasis and trapped air on chest computed tomography (CT). The revised Cystic Fibrosis Questionnaire respiratory symptoms scale (CFQ-R RSS) measures health-related quality of life. To validate bronchiectasis, trapped air and CFQ-R RSS as outcome measures, we investigated correlations and predictive values for pulmonary exacerbations. CF patients (aged 6–20 years) underwent CT, CFQ-R RSS and 1-year follow-up. Bronchiectasis and trapped air were scored using the CF-CT scoring system. Correlation coefficients and backward multivariate modelling were used to identify predictors of pulmonary exacerbations. 40 children and 32 adolescents were included. CF-CT bronchiectasis (r = -0.38, p&lt;0.001) and CF-CT trapped air (r = -0.35, p = 0.003) correlated with CFQ-R RSS. Pulmonary exacerbations were associated with: bronchiectasis (rate ratio 1.10, 95% CI 1.02–1.19; p = 0.009), trapped air (rate ratio 1.02, 95% CI 1.00–1.05; p = 0.034) and CFQ-R RSS (rate ratio 0.95, 95% CI 0.91–0.98; p = 0.002). The CFQ-R RSS was an independent predictor of pulmonary exacerbations (rate ratio 0.96, 95% CI 0.94–0.97; p&lt;0.001). Bronchiectasis, trapped air and CFQ-R RSS were associated with pulmonary exacerbations. The CFQ-R RSS was an independent predictor. This study further validated bronchiectasis, trapped air and CFQ-R RSS as outcome measures in CF.
Comorbidities and Mortality in Persons With Schizophrenia: A Swedish National Cohort Study
Authors: Casey Crump, Marilyn A. Winkleby, Kristina Sundquist, Jan Sundquist
Journal: American Journal of Psychiatry (2013)

Schizophrenia is associated with premature mortality, but the specific causes and pathways are unclear. The authors used outpatient and inpatient data for a national population to examine the association between schizophrenia and mortality and comorbidities.This was a national cohort study of 6,097,834 Swedish adults, including 8,277 with schizophrenia, followed for 7 years (2003-2009) for mortality and comorbidities diagnosed in any outpatient or inpatient setting nationwide.On average, men with schizophrenia died 15 years earlier, and women 12 years earlier, than the rest of the population, and this was not accounted for by unnatural deaths. The leading causes were ischemic heart disease and cancer. Despite having twice as many health care system contacts, schizophrenia patients had no increased risk of nonfatal ischemic heart disease or cancer diagnoses, but they had an elevated mortality from ischemic heart disease (adjusted hazard ratio for women, 3.33 [95% CI=2.73-4.05]; for men, 2.20 [95% CI=1.83-2.65]) and cancer (adjusted hazard ratio for women, 1.71 [95% CI=1.38-2.10; for men, 1.44 [95% CI=1.15-1.80]). Among all people who died from ischemic heart disease or cancer, schizophrenia patients were less likely than others to have been diagnosed previously with these conditions (for ischemic heart disease, 26.3% compared with 43.7%; for cancer, 73.9% compared with 82.3%). The association between schizophrenia and mortality was stronger among women and the employed. Lack of antipsychotic treatment was also associated with elevated mortality.Schizophrenia patients had markedly premature mortality, and the leading causes were ischemic heart disease and cancer, which appeared to be underdiagnosed. Preventive interventions should prioritize primary health care tailored to this population, including more effective risk modification and screening for cardiovascular disease and cancer.
Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes <i>Bcr-Abl</i>T315I Mutant Cells to Imatinib
Authors: Wen-Hsin Chang, Ta-Chih Liu, Wen-Kuang Yang, Chien-Chih Lee, Yi-Hsiung Lin, Tsai-Yun Chen, Jan-Gowth Chang
Journal: Cancer Research (2011)

The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-xs and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib.
A new series in <i>Allergy</i>: rare immunological respiratory diseases
Authors: M. Humbert, J. Bousquet
Journal: Allergy (2005)

Allergic asthma and rhinitis account for millions of patients worldwide and represent an important burden for patients and health care systems (1–3). However, ‘all is not allergy that wheezes’, and, in daily practice, the allergist will be regularly confronted to either rare variants of asthma or to more uncommon respiratory conditions sometimes initially mislabelled as ‘asthma’. We therefore considered that it might be adequate to publish a series on rare immunological respiratory diseases in Allergy. After taking this decision, the next step was to identify which topics should be discussed in priority. This was a difficult choice and we decided to select six entities, namely allergic broncho-pulmonary aspergillosis (4), eosinophilic pneumonias (5), idiopathic pulmonary fibrosis (6), pulmonary sarcoidoisis (7), adult pulmonary Langerhans’ cell histiocytosis (8) and the respiratory system in connective tissue disorders (9). Many other chapters could have been selected and should be considered for the next series. Allergic broncho-pulmonary aspergillosis was clearly on the top of our list (4). Indeed, this relatively uncommon variant of asthma has been revisited extensively and the availability of novel treatments clearly labels this condition as a ‘hot topic in allergy’. Similarly, discussing the whole spectrum of eosinophilic pneumonias was regarded as another priority, as all allergists will certainly be confronted to these difficult clinical entities (5). The recent efforts to improve classification and management of idiopathic pulmonary fibrosis with several guidelines and therapeutic trials published in the last few years justified to select this subject in our shortlist (6). Pulmonary sarcoidosis is a Th1-driven granulomatous disease of unknown aetiology, mirroring the Th2 paradigm of allergic reactions. These patients often have a nonspecific and sometimes misleading clinical presentation and it is not rare to have them referred for ‘asthma’. However, a rapid evaluation easily rules out this diagnosis (7). In addition, asthma and pulmonary sarcoidosis may indeed coexist. Adult pulmonary Langerhans’ cell histiocytosis has been the subject of intense clinical research in the last years and we felt that this rare disease should be discussed in this series (8). Last, the respiratory system is often involved in autoimmune diseases and we all agreed that it would be relevant to have a comment on the involvement of the respiratory system in connective tissue disorders (9). The outstanding quality of the manuscripts submitted has been highlighted by the reviewers involved in the editing process of these chapters and we thank all the authors who spent so much time on these review articles. We hope that this new series on ‘Rare Immunological Respiratory Diseases’ will be a success and that a second series will follow shortly!
Report of the Organ Transplant Panel
Authors: George M. Bohigian
Journal: JAMA (1988)

Corneal transplantation is the most common form of organ transplantation practiced in the United States. Two procedures for transplantation are utilized. Penetrating keratoplasty is used in about 90% of the cases, with lamellar keratoplasty being utilized in the remaining situations. Demand for corneal transplantation exceeds the available supply of corneas. Advances in procurement and preservation must continue to meet this demand. Finally, these procedures are not without complications, and these are discussed to provide a clear risk-benefit analysis. (<i>JAMA</i>1988;259:719-722)
Antibiotic Usage in a Pediatric Medical Center
Authors: Shehlah H. Naqvi
Journal: JAMA (1979)

Antibiotic usage in a large pediatric teaching hospital was evaluated during a three-month period. A total of 1,067 patients received antibiotics and 295 patient records were reviewed. One hundred sixty-nine courses of antibiotics were administered to surgical patients, 77% for surgical prophylaxis. One hundred forty-seven antibiotic courses administered to medical patients were therapeutic in 61.2% and in 35.3% were given because of suspicion of infection. Ampicillin was the most commonly used antibiotic; cephalosporins were used for surgical prophylaxis. Aminoglycosides were used commonly for suspected infection in medical patients. Antibiotic management was inappropriate in 66% of surgical patients and in 21% of medical patients. Not obtaining appropriate studies prior to and during therapy were common infractions on all services. Surgical prophylaxis was frequently inappropriate by reason of no indication, wrong drug or dose, or inappropriate timing. (<i>JAMA</i>242:1981-1984, 1979)
Esophageal responses to distension and electrical stimulation
Authors: James Christensen, Gordon F. Lund
Journal: Journal of Clinical Investigation (1969)

The opossum esophagus contains only smooth muscle in the distal two-thirds; it can be used to study autonomic control of esophageal smooth muscle. Three different preparations of opossum esophagus were used; the esophagus in vivo, the isolated whole esophagus, and isolated strips of the three layers of esophageal smooth muscle. Responses were examined to localized distension and to electrical stimulation. Distension of the esophagus in vivo produced three separate responses: inflation of a distending balloon caused a brief contraction rostral to the point of distension, the on response; maintenance of distension produced shortening of the esophagus, sustained for the duration of the distension, the duration response; and deflation of the balloon caused a single brief caudal circumferential contraction, apparently propagated caudad, the off response. In the isolated whole esophagus distension produced the same three responses. Electrical stimulation in this preparation produced apparently identical responses. Electrical stimulation of isolated strips of the three muscle layers showed that the muscularis mucosae and the longitudinal layer of the muscularis propria always respond with a duration response only. The circular layer of the muscularis propria responds with on and off responses only. These observations suggest that both types of stimuli excite the same afferent nerve fibers in local reflex pathways. Peristalsis can be maintained by these reflexes in the smooth muscle part of the esophagus independent of central nervous connections.