tbuckley/cabot-search huggingface dataset:
Pulmonary vascular effects of prostaglandin D2, but not its systemic vascular or airway effects, are mediated through thromboxane receptor activation.
Authors: L S King, M Fukushima, M Banerjee, K H Kang, J H Newman, I Biaggioni
Journal: Circulation Research (1991)

Prostaglandin D2 (PGD2) can cause pulmonary vasoconstriction or vasodilation depending on animal species and age. Because the constrictor effects of PGD2 in some vascular beds may be mediated through thromboxane receptors, the purpose of this study was to determine whether the vascular or bronchial effects of PGD2 are mediated through thromboxane/endoperoxide (TX/E) receptor activation. In chronically instrumented awake sheep, PGD2 (5-25 micrograms/kg i.v.) produced a dose-dependent increase in pulmonary arterial pressure and in systemic arterial blood pressure. These changes were due to increases in resistance, because cardiac output remained unchanged. PGD2 also decreased dynamic compliance at lower doses (0.1-5 micrograms/kg i.v.) than those required to produce pulmonary vasoconstriction, confirming that PGD2 is a potent bronchoconstrictor. The airway and systemic vascular effects of PGD2 were not altered by TX/E receptor antagonism. In contrast, PGD2-induced pulmonary vasoconstriction was blocked by two TX/E receptor antagonists, SQ-29,548 and AH-23848, implying that this effect is mediated through activation of TX/E receptors. The pulmonary vasoconstrictor effects of PGD2 could not be explained by thromboxane generation, because neither cyclooxygenase inhibition with ibuprofen nor thromboxane synthase inhibition with OKY-046 had any effect on PGD2 actions. In contrast, a mild but consistent pulmonary vasodilation produced by PGD2 could be uncovered if the pulmonary vascular bed was preconstricted by hypoxia with simultaneous TX/E receptor blockade. These results indicate that TX/E receptor antagonists, although still useful pharmacological probes to determine the role of TX/E receptor activation in pathophysiological processes, should not be used to infer a role of endogenous thromboxane A2. It is possible that PGD2 participates in pulmonary processes previously ascribed uniquely to thromboxane A2.
What is the lowest threshold to make a diagnosis of concussion?
Authors: Paul McCrory, Willem H Meeuwisse, Ruben J Echemendia, Grant L Iverson, Jiří Dvořák, Jeffrey S Kutcher
Journal: British Journal of Sports Medicine (2013)

Objective The purpose of this review is to examine the evidence for determining the lowest threshold for diagnosing a sport-related concussion. Data Sources MEDLINE, CINAHL, EMBASE, Mosby's Index, PsycEXTRA, PsycINFO and Scopus. Key words included sports concussion, concussion assessment, diagnosis, concussion symptoms, onfield assessment and sports-related traumatic brain injury. Results The majority of concussions in sport occur without loss of consciousness or frank neurological signs. Some of the hallmark signs of acute concussion include mental confusion, memory and balance disturbance. Over the course of the first 24 h, the most common symptoms include headache, nausea, dizziness and balance problems, blurred vision or other visual disturbance, confusion, memory loss and ‘fatigue’. Symptoms such as tiredness, irritability, nervousness or anxiety, sleep disturbance and sensitivity to light or noise may be noticed in the days after injury. The pathophysiology of sports concussion remains poorly understood. There appears to be a period of vulnerability following concussion in which an overlapping injury might cause magnified pathophysiology. Conclusions Sport-related concussions can be difficult to diagnose. Concussion produces an evolving constellation of somatic, cognitive and neurobehavioral symptoms that are typically most severe during the earliest acute postinjury period (ie, within the first 24–48 h) and diminish over a matter of several days to weeks in the majority of athletes. Athletes suspected of concussion should be removed from play and evaluated thoroughly.
Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia
Authors: Niranjan Yanamandra, Nandita M. Colaco, Nancy A. Parquet, Robert W. Buzzeo, David Boulware, Gabriela Wright, Lia E. Perez, William S. Dalton, Darrin M. Beaupre
Journal: Clinical Cancer Research (2006)

Abstract It has been established in preclinical models of multiple myeloma and acute myeloid leukemia (AML) that the bone marrow microenvironment provides protection from chemotherapy- and death receptor–mediated apoptosis. This form of resistance, termed de novo drug resistance, occurs independent of chronic exposure to cancer-related therapies and likely promotes the development of multidrug resistance. Consequently, it is of major interest to identify compounds or drug combinations that can overcome environment-mediated resistance. In this study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of multiple myeloma and AML. The combination proved to be synergistic in multiple myeloma and AML cell lines treated in suspension culture. Even in tumor cells relatively resistant to tipifarnib, combined activity was maintained. Tipifarnib and bortezomib were also effective when multiple myeloma and AML cells were adhered to fibronectin, providing evidence that the combination overcomes cell adhesion–mediated drug resistance (CAM-DR). Of importance, activation of the endoplasmic reticulum stress response was enhanced and correlated with apoptosis and reversal of CAM-DR. Multiple myeloma and AML cells cocultured with bone marrow stromal cells also remained sensitive, although stromal-adhered tumor cells were partially protected (relative to cells in suspension or fibronectin adhered). Evaluation of the combination using a transwell apparatus revealed that stromal cells produce a protective soluble factor. Investigations are under way to identify the cytokines and/or growth factors involved. In summary, our study provides the preclinical rationale for trials testing the tipifarnib and bortezomib combination in patients with multiple myeloma and AML.
A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C
Authors: Jules L. Dienstag, Marc G. Ghany, Timothy R. Morgan, Adrian M. Di Bisceglie, Herbert L. Bonkovsky, Hae-Young Kim, Leonard B. Seeff, Gyongyi Szabo, Elizabeth C. Wright, Richard K. Sterling, Gregory T. Everson, Karen L. Lindsay, William M. Lee, Anna S. Lok, Chihiro Morishima, Anne M. Stoddard, James E. Everhart
Journal: Hepatology (2011)

The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) ( P &lt; 0.0001). Child-Turcotte-Pugh (CTP) score ≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score ≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. Conclusion: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7. (Hepatology 2011)
Chemokine Receptor CCR6 Expression Level and Liver Metastases in Colorectal Cancer
Authors: Pirus Ghadjar, Sarah Ellen Coupland, Il-Kang Na, Michel Noutsias, Anne Letsch, Andrea Stroux, Sandra Bauer, Heinz J. Buhr, Eckhard Thiel, Carmen Scheibenbogen, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2006)

Purpose The liver is the primary organ of metastasis in colorectal cancer (CRC). Chemokine receptor CCR6 is expressed on a subset of T cells and is associated with their migration into the liver. This study was performed to analyze a possible association between CCR6 expressed by primary CRC and liver metastases. Patients and Methods CCR6 expression levels were evaluated by immunohistology in 64 CRC primary tumor specimens. Twenty-four of 64 patients had synchronous liver metastases. Evaluation of immunostaining was performed semiquantitatively by visual assessment and quantitatively by digital image analysis (DIA). Multiple logistic regression analysis was performed to assess relevant parameters for liver metastases. Results CCR6 expression was verified in all 64 primary tumor specimens with considerable variations in intensity; 21 tumors (33%) demonstrated weak CCR6 staining, 32 (50%) demonstrated intermediate staining, and 11 (17%) demonstrated strong staining. Quantitative assessment by DIA showed an up to 5-log difference in CCR6 values. CCR6 staining was significantly stronger in tumor cells compared with adjacent colon epithelial cells (P &lt; .0005). Multiple logistic regression analysis, controlling for age, sex, tumor stage, nodal status, pathologic grade, and preoperative carcinoembryonic antigen levels, revealed that CCR6 staining in the primary tumor was independently associated with the presence of liver metastases (odds ratio = 2.1; P = .002). Conclusion The association between expression level of CCR6 in primary CRC and synchronous liver metastases suggests that CCR6 and its ligand may be involved in the metastatic spread to the liver. Therefore, CCR6 may be a potential target for specific therapeutic interventions.
High-dose topical calcipotriol in the treatment of extensive psoriasis vulgaris
Authors: J.F. BOURKE, J. BERTH-JONES, S.J. IQBAL, P.E. HUTCHINSON
Journal: British Journal of Dermatology (1993)

Ten patients with extensive plaque psoriasis were treated with calcipotriol ointment (50 micrograms/g) for 2 weeks (200 g for 1 week, followed by 300 g during the second week). Mean improvement in psoriasis area and severity index (PASI) was 71%. Mean 24 h urine calcium rose from 4.79 mmol/24 h to 7.27 mmol/24 h (P < 0.0001). Urine calcium returned towards baseline after stopping calcipotriol. Mean serum calcium also rose slightly, but significantly, from 2.26 mmol/l to 2.32 mmol/l (P < 0.005), and fell again in the washout phase. Individual serum calcium values remained within the normal range throughout the study. Topical calcipotriol is an effective, rapidly acting and safe in-patient treatment for extensive plaque psoriasis.
Concanavalin A-mediated binding and sphering of human red blood cells by homologous monocytes.
Authors: D Guerry, M A Kenna, A D Schrieber, R A Cooper
Journal: The Journal of Experimental Medicine (1976)

Human red blood cells sensitized with concanavalin A became bound to homologous peripheral blood monocytes. Binding occured at a concentration of 10(5) molecules of tetrameric Con A per red blood cell (RBC) and increased with additional Con A. RBC binding began within 5 min and was maximal at 90 min. Phagocytosis of sensitized RBCs was minimal. RBC attachment was prevented by 0.01 M alpha-methyl-D-mannopyranoside, and, once the RBC-monocyte rosette was established, bound RBCs were largely removed with this specific saccharide inhibitor of Con A. RBCs attached to monocytes became spherocytic and osmotically fragile. The recognition of concanavalin A (Con A)-coated RBCs was not mediated through the monocyte IgG-Fc receptor. These studies demonstrate that, like IgG and C3b, Con A is capable of mediating the binding of human RBCs to human monocytes. Red cells so bound are damaged at the monocyte surface.
A 51‐year‐old male CML patient with progressive hearing loss, confusion, ataxia, and aphasia during imatinib treatment
Authors: Jeroen J.W.M. Janssen, Henk W. Berendse, Gerrit‐Jan Schuurhuis, Pauline A. Merle, Gert J. Ossenkoppele
Journal: American Journal of Hematology (2009)

physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type).This is followed by a discussion/commentary.
General practice commissioning: in whose interests?
Authors: G. Iacobucci
Journal: BMJ (2015)

<h3>Objectives</h3> To evaluate the psychometric properties (and identify specific anomalies to be resolved) of urinary and sexual function scales of the Symptom Tracking and Reporting (STAR) instrument for use in clinical practice with individual men using Rasch analysis. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> 9 UK surgery centres in secondary care. <h3>Participants</h3> 403 men diagnosed with prostate cancer and completed at least one questionnaire immediately before and at 1 or 3 months after radical prostatectomy. <h3>Primary and secondary outcomes</h3> STAR instrument before surgery and 1 and 3 months afterwards. <h3>Results</h3> Neither scale fitted the Rasch model (both scales p&lt;0.001). Both urinary (seven items) and sexual function (six items) had disordered thresholds, suggesting response categories are not working as intended. Both scales (three urinary items; five sexual function items) showed problems with item fit (large fit residuals, significant χ<sup>2</sup>, an inspection of item characteristic curves). Both scales showed items that were unstable over time (differential item functioning (DIF) by time). Both scales (four pairs of items in each scale) showed local response dependency (residual correlations &gt;0.2 above the average). Internal consistency was acceptable at the group level for both scales. Targeting was poor for both scales, indicating an inadequate match between the location of items and the distribution of the patients, suggesting that the underlying constructs that the scales purport to measure are not clear. <h3>Conclusion</h3> Using Rasch analysis as a diagnostic tool, we identified that both the urinary and the sexual function scales have issues that need to be resolved before STAR can be used with confidence in clinical practice. The sexual function scale, in particular, is unlikely to provide precise estimates for the outcomes experienced by men after radical prostatectomy. These results demonstrate the need to evaluate the suitability of any patient-reported outcome measure before implementation in routine clinical practice, preferably using modern psychometric methods.
Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic Plaques
Authors: Jun-O Deguchi, Elena Aikawa, Peter Libby, Jeffrey R. Vachon, Masaki Inada, Stephen M. Krane, Peter Whittaker, Masanori Aikawa
Journal: Circulation (2005)

Interstitial collagen plays a crucial structural role in arteries. Matrix metalloproteinases (MMPs), including MMP-13/collagenase-3, likely contribute to collagen catabolism in atherosclerotic plaques.To test the hypothesis that a specific MMP-collagenase influences the development and structure of atherosclerotic plaques, this study used atherosclerosis-susceptible apolipoprotein E-deficient mice that lack MMP-13/collagenase-3 (Mmp-13(-/-)/apoE(-/-)) or express wild-type MMP-13/collagenase-3 (Mmp-13(+/+)/apoE(-/-)). Both groups consumed an atherogenic diet for 5 (n=8) or 10 weeks (n=9). Histological analyses of the aortic root of both groups revealed similar plaque size and accumulation of smooth muscle cells (a collagen-producing cell type) and macrophages (a major source of plaque collagenases) after 5 and 10 weeks of atherogenic diet. By 10 weeks, the plaques of Mmp-13(-/-)/apoE(-/-) mice contained significantly more interstitial collagen than those of Mmp-13(+/+)/apoE(-/-) mice (P<0.01). Furthermore, quantitative optical analyses revealed thinner and less aligned periluminal collagen fibers within the plaques of Mmp-13(+/+)/apoE(-/-) mice versus those from Mmp-13(-/-)/apoE(-/-) mice.These data support the hypothesis that MMP-13/collagenase-3 plays a vital role in the regulation and organization of collagen in atherosclerotic plaques.
New markers for murine memory B cells that define mutated and unmutated subsets
Authors: Shannon M. Anderson, Mary M. Tomayko, Anupama Ahuja, Ann M. Haberman, Mark J. Shlomchik
Journal: The Journal of Experimental Medicine (2007)

The study of murine memory B cells has been limited by small cell numbers and the lack of a definitive marker. We have addressed some of these difficulties with hapten-specific transgenic (Tg) mouse models that yield relatively large numbers of antigen-specific memory B cells upon immunization. Using these models, along with a 5-bromo-2'-deoxyuridine (BrdU) pulse-label strategy, we compared memory cells to their naive precursors in a comprehensive flow cytometric survey, thus revealing several new murine memory B cell markers. Most interestingly, memory cells were phenotypically heterogeneous. Particularly surprising was the finding of an unmutated memory B cell subset identified by the expression of CD80 and CD35. We confirmed these findings in an analogous V region knock-in mouse and/or in non-Tg mice. There also was anatomic heterogeneity, with BrdU(+) memory cells residing not just in the marginal zone, as had been thought, but also in splenic follicles. These studies impact the current understanding of murine memory B cells by identifying new phenotypes and by challenging assumptions about the location and V region mutation status of memory cells. The apparent heterogeneity in the memory compartment implies either different origins and/or different functions, which we discuss.
Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study
Authors: C.M. de Jongh, L. Khrenova, M.M. Verberk, F. Calkoen, F.J.H. van Dijk, H. Voss, S.M. John, S. Kezic
Journal: British Journal of Dermatology (2008)

Polymorphisms in the filaggrin (FLG) gene, which result in loss of filaggrin production, may alter the skin barrier and are a well-known predisposing factor for atopic dermatitis.As a compromised skin barrier and atopic dermatitis are risk factors for chronic irritant contact dermatitis (CICD), our objective was to determine whether polymorphisms in the FLG gene contribute towards susceptibility to occupational CICD.In a case-control study, the FLG polymorphisms R501X and 2282del4 were determined in 296 patients with CICD. Two hundred and seventeen apprentices in vocational training for high-risk occupations for CICD were chosen as controls. Data on skin diseases and conditions were collected by dermatologists from patients and by means of questionnaires from controls.Heterozygotes for R501X and 2282del4, FLG null alleles, were more frequent among patients with CICD (12.5%) compared with controls (6.9%), resulting in an odds ratio of 1.91 (95% confidence interval 1.02-3.59). Among patients who were carriers of a FLG null allele, we found a higher lifetime prevalence of flexural eczema (62% vs. 46%; P = 0.04) and a higher atopy score (13 vs. 10 points; P = 0.05) compared with noncarriers. In the apprentice group, signs of dermatitis before the start of the vocational training were four times more prevalent in carriers (43%) than in noncarriers (10%; P < 0.001).Our study shows that FLG null alleles are associated with increased susceptibility to CICD; whether or not the FLG null allele is an independent risk factor needs further study.
Obesity, Atherosclerosis, and Coronary Artery Disease
Authors: ELIZABETH L. BARRETT-CONNOR
Journal: Annals of Internal Medicine (1985)

Although several risk factors for heart disease including high blood pressure, diabetes mellitus, and lipid and lipoprotein abnormalities are associated with overweight, overweight is not consistently associated with coronary heart disease risk. Some prospective studies of white men (life insurance cohorts, airline pilots, cancer study volunteers, and the Framingham population) have shown a positive linear relationship of weight to coronary heart disease. Other epidemiologic studies show a negative association, no association, a U-shaped relationship, or a threshold effect. The inconsistencies do not appear to be explained by differences in the definition or distribution of obesity, duration of follow-up, or risk factor distribution. Neither misclassification bias nor confounding by cigarette smoking or chronic disease appears to explain the inconsistencies. No known protective effect of obesity could explain these divergent findings. Inconsistent results with regard to the nature, strength, and linearity of the association between obesity and atherosclerosis do not support the hypothesis that obesity causes atherosclerosis, despite its biological plausibility.
Severe bullous emphysema associated with cocaine smoking
Authors: J M VAN DER KLOOSTER
Journal: Thorax (2001)

Multidrug resistant tuberculosisWe read with interest the report by White and Moore-Gillon 1 on the resource implications of multidrug resistant tuberculosis (MDR-TB) in the UK.We studied the outcome of 44 HIV negative patients with MDR-TB admitted to two tertiary care tuberculosis units in the Netherlands between 1985 and 1998. 2 3 Most (38 patients) had pulmonary tuberculosis.The mean admission period was 164 days and all patients received an individually tailored combination of antituberculosis drugs for a mean period of 608 days.We estimated the cost of treatment per patient to be US$60 000 which included admission fee, costs for outpatient visits, and the costs of drug provision.Although we did not include cost of toxicity monitoring and additional procedures, our costs compare favourably with those of White et al 1 (mean £60 000) and Mahmoudi 4 (mean US$180 000).In the Netherlands the number of patients with tuberculosis resistant to any antituberculous drugs is limited to 11%, and only 0.6% of the bacilli are MDR.Between 1993 and 1997 only 43 cases of MDR-TB were identified, of which 28% had received previous treatment for tuberculosis (Index Tuberculosis 1998, Royal Netherlands Tuberculosis Association, The Hague, 2000).This suggests that transmission of MDR bacilli rather than inadequate treatment contributes to the resistance problem in the Netherlands.In poor resource countries, directly observed short course chemotherapy of tuberculosis is generally recommended to prevent the occurrence of MDR-TB.We feel that new rapid molecular methods for detecting resistance should be developed to limit the period of potential (nosocomial and community) transmission of MDR bacilli and thus prevent the emergence of MDR-TB.Such tests should then be made available to poor resource countries at an aVordable price.