tbuckley/cabot-search huggingface dataset:
Celiac Disease and Risk of Subsequent Type 1 Diabetes
Authors: Jonas F. Ludvigsson, Johnny Ludvigsson, Anders Ekbom, Scott M. Montgomery
Journal: Diabetes Care (2006)

OBJECTIVE—Earlier studies suggest that children with type 1 diabetes are more likely to have a subsequent diagnosis of celiac disease. However, research is sparse on the risk of subsequent type 1 diabetes in individuals with celiac disease. We sought to determine the risk of subsequent type 1 diabetes diagnosed before the age of 20 years in children and adolescents with celiac disease in a national, general population–based cohort. RESEARCH DESIGN AND METHODS—We identified 9,243 children with a diagnosis of celiac disease in the Swedish national inpatient register between 1964 and 2003. We then identified five reference individuals matched at time of diagnosis for age, calendar year, sex, and county (n = 45,680). Only individuals with &amp;gt;1 year of follow-up after study entry (diagnosis of celiac disease) were included in the analyses. RESULTS—Celiac disease was associated with a statistically significantly increased risk of subsequent type 1 diabetes before age 20 years (hazard ratio 2.4 [95% CI 1.9–3.0], P &amp;lt; 0.001). This risk increase was seen regardless of whether celiac disease was first diagnosed between 0 and 2 (2.2 [1.7–2.9], P &amp;lt; 0.001) or 3 and 20 (3.4 [1.9–6.1], P &amp;lt; 0.001) years of age. Individuals with prior celiac disease were also at increased risk of ketoacidosis or diabetic coma before the age of 20 years (2.3 [1.4–3.9], P = 0.001). CONCLUSIONS—Children with celiac disease are at increased risk of subsequent type 1 diabetes. This risk increase is low considering that 95% of individuals with celiac disease are HLA-DQ2 positive.
Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs
Authors: Anne Estrup Olesen, Trine Andresen, Camilla Staahl, Asbjørn Mohr Drewes
Journal: Pharmacological Reviews (2012)

Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.
Tuberculous Otitis Media
Authors: Ming K. Jeang
Journal: JAMA (1983)

SINCE the introduction of effective antibiotics, tuberculosis of the middle ear has become a rare entity in the United States and other western countries. Only 11 of 23,000 cases of suppurative otitis media reported from Great Britain during 1950 to 1959 were attributable to<i>Mycobacterium tuberculosis</i>.<sup>1</sup>This represented a substantial change from an early report<sup>2</sup>in which chronic suppurative otitis media was described as being of tuberculous origin in 50% of infants younger than 1 year, 27% of infants younger than 2 years, and 2% of children younger than 15 years. Primarily a disease of children, it has occasionally been reported in adults.<sup>1,3,4</sup> Although it is rare, tuberculous otitis media remains a serious disease. The often painless nature of the infection and low diagnostic suspicion by clinicians serve to delay diagnosis. This may result in severe complications, including deafness, ataxia, cranial nerve palsy, and intracranial abscesses or
Tetrahydroaminoacridine-induced ribosomal changes and inhibition of protein synthesis in rat hepatocyte suspensions
Authors: Marc W. Fariss, Sharon A. Johnsen, Lloyd P. Walton, Virgil R. Mumaw, Sidhartha D. Ray
Journal: Hepatology (1994)

Tacrine (tetrahydroaminoacridine) is currently the only drug approved for the treatment of Alzheimer's disease. Unfortunately, tetrahydroaminoacridine therapy is often limited by this drug's propensity to induce reversible hepatotoxicity. Using suspensions of freshly isolated rat hepatocytes, we investigated the mechanism of tetrahydroaminoacridine cytotoxicity by examining the effect of tetrahydroaminoacridine on hepatocyte viability, protein synthesis, protein, DNA and RNA levels and ultrastructure. Our experimental findings support the explanation that tetrahydroaminoacridine-induced hepatotoxicity results from tetrahydroaminoacridine's adverse effect on protein synthesis and ribosomal structure and function. We found that viable, tetrahydroaminoacridine-treated hepatocytes (1.0 to 2.0 mmol/L or 118 to 235 μg/106 cells) demonstrated a dose-dependent and dramatic aggregation of ribosomes on endoplasmic reticulum as well as the aggregation of other nucleic acids found in the nucleus (chromatin) and in mitochondria. These electron microscopy data suggest that tetrahydroaminoacridine treatment results in severe ribosomal dysfunction. This was confirmed by the observed rapid loss of cellular RNA content (but not DNA or protein) and the rapid and complete inhibition of protein synthesis in tetrahydroaminoacridine-treated cells (lowest concentration tested was 0.5 mmol/L or 58 μg/106 cells). Thus tetrahydroaminoacridine treatment appears to aggregate hepatocellular nucleic acids, and in doing so adversely affects ribosomal function and protein synthesis. We propose that these adverse effects of exposure to tetrahydroaminoacridine are responsible for tetrahydroaminoacridine-induced hepatotoxicity. (Hepatology 1994;20:•••.)
Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology
Authors: Pawel K Mazur, Jens T Siveke
Journal: Gut (2011)

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease despite tremendous scientific efforts. Numerous trials have failed to improve the outcome on this deadliest of all major cancers. Potential causes include a still insufficient understanding of key features of this cancer and imperfect preclinical models for identification of active agents and mechanisms of therapeutic responses and resistance. Modern genetically engineered mouse models of PDAC faithfully recapitulate the genetic and biological evolution of human PDAC, thereby providing a potentially powerful tool for addressing tumour biological issues as well as strategies for early detection and assessment of responses to therapeutic interventions. Here, the authors will discuss opportunities and challenges in the application of genetically engineered mouse models for translational approaches in pancreatic cancer and provide a non-exhaustive list of examples with already existing or future clinical relevance.
Human Rhinovirus C Specific IgE Is Detectable in High Risk Children
Authors: Jared I. Darveaux, Yury Bochkov, Christopher J. Tisler, Michael D. Evans, James E. Gern, Robert F. Lemanske, Daniel J. Jackson
Journal: Journal of Allergy and Clinical Immunology (2015)

Viral respiratory infections and allergic sensitization play important roles in asthma inception and exacerbations. Children who are atopic have increased susceptibility to human rhinovirus (RV) infections. One potential mechanism involves impairment of antiviral responses by high affinity IgE receptor (FcεRI) cross-linking. If RV-specific IgE is produced in atopic individuals, it could function like an allergen, which may have important implications in the development of asthma and severity of exacerbations. Peripheral blood samples were obtained from 134 nine year-old children enrolled in the Childhood Origins of Asthma (COAST) cohort. Biotinylated RV-C15 was bound to streptavidin on the Phadia ImmunoCap. The presence of RV-C15 specific IgE was detected using standard Immunocap methods. Levels ≥ 0.10 kUA/l were considered positive. Relationships among RV-C specific IgE, asthma, and other atopic phenotypes were assessed. 7.5% (n=10) had detectable RV-C specific IgE, with a range of 0.13 – 1.11 kUA/l. Children with RV-C specific IgE had higher total serum IgE [median: 841 vs. 58 kUA/l in the positive and negative groups, respectively (p=0.0002)], and were more likely to be sensitized to aeroallergens (p=0.04). There were non-significant trends toward higher peripheral blood eosinophils, rhinitis, and asthma in children with RV-C specific IgE. RV-C specific IgE was detected in 7.5% of high risk children, and was associated with elevated total IgE and aeroallergen sensitization. It is unclear whether the IgE produced is specific to RV-C or common to all RV species. The biological activity of RV-C specific IgE is unknown and warrants further investigation.
Potential of Computer-Aided Diagnosis to Improve CT Lung Cancer Screening
Authors: Noah Lee, Andrew F. Laine, Guillermo Mrquez, Jeffrey M. Levsky, John K. Gohagan
Journal: IEEE Reviews in Biomedical Engineering (2009)

The development of low-dose spiral computed tomography (CT) has rekindled hope that effective lung cancer screening might yet be found. Screening is justified when there is evidence that it will extend lives at reasonable cost and acceptable levels of risk. A screening test should detect all extant cancers while avoiding unnecessary workups. Thus optimal screening modalities have both high sensitivity and specificity. Due to the present state of technology, radiologists must opt to increase sensitivity and rely on follow-up diagnostic procedures to rule out the incurred false positives. There is evidence in published reports that computer-aided diagnosis technology may help radiologists alter the benefit-cost calculus of CT sensitivity and specificity in lung cancer screening protocols. This review will provide insight into the current discussion of the effectiveness of lung cancer screening and assesses the potential of state-of-the-art computer-aided design developments.
Fibroblast chemotactic response elicited by native bronchoalveolar lavage fluid from patients with fibrosing alveolitis.
Authors: J Behr, B C Adelmann-Grill, F Krombach, T Beinert, M Schwaiblmair, G Fruhmann
Journal: Thorax (1993)

BACKGROUND--In fibrosing alveolitis activation of lung fibroblasts is the decisive event in the pathogenetic sequence leading to pulmonary fibrosis. Fibroblast stimulating activity was measured in bronchoalveolar lavage (BAL) fluid to assess its relationship to the activity of fibrosing alveolitis. METHODS--Nine control subjects and 40 patients with fibrosing alveolitis caused by idiopathic pulmonary fibrosis (n = 22) or pulmonary involvement in systemic sclerosis (n = 18) were studied. All patients were followed up by lung function testing for a minimum of six months (mean (SE) 13.3 (1.4) months). Twenty five patients received immunosuppressive therapy and 15 refused. At the beginning of follow up BAL was performed and, as a possible indicator of fibroblast stimulating mediators within the lungs, chemotactic migration of cultured human fibroblasts elicited by native BAL fluid was measured in Boyden-type chambers and expressed as a percentage of the chemoattractant effect of 25 ng/ml platelet derived growth factor. The procollagen III peptide level in BAL fluid served as a marker for collagen synthesis. RESULTS--Chemoattractant activity was elevated in the patients with idiopathic pulmonary fibrosis and systemic sclerosis compared with the control group, (mean (SE) 56.4% (8.5%)) and 72.3% (16.3%) v 12.6% (4.0%). Chemoattractant activity was inversely correlated with total lung capacity (TLC) (r = -0.45) and with vital capacity (VC) (r = -0.33). Procollagen III peptide concentrations in BAL fluid and chemoattractant activity were not significantly correlated. For further evaluation chemoattractant activity of 36% (mean value of controls +2 SD) was used to separate normal (&lt; 36%) from elevated (&gt; or = 36%) activity. At the end of follow up, untreated patients with high chemoattractant activity (&gt; or = 36%) showed a significant reduction of VC, TLC, and exercise arterial oxygen tension (PaO2) and a small decrease in carbon monoxide transfer factor (TLCO), whereas a significant improvement in VC, TLC, and TLCO and a small increase of exercise PaO2 occurred in treated patients with high chemoattractant activity. Patients with low chemoattractant activity (&lt; 36%) showed no consistent change in lung function measurements, irrespective of treatment. In contrast, lung function results and differential cell counts in BAL fluid failed to identify progressive disease. CONCLUSIONS--In patients with fibrosing alveolitis the chemoattractant activity of BAL fluid seems to be an independent indicator of lung fibroblast stimulating activity providing relevant information about disease activity, and may help to improve the clinical management of these patients.
Ryanodine and the left ventricular force–interval and relaxation–interval relations in closed-chest dogs: insights on calcium handling
Authors: S Prabhu
Journal: Cardiovascular Research (1998)

Objective: Although the myocardial force–interval and relaxation–interval relations are considered to be mechanical expressions of myocardial Ca2+ handling, correlation of these phenomena with altered Ca2+ kinetics in the intact state is limited. Thus, I sought to determine the impact of selective impairment of physiologic sarcoplasmic reticulum Ca2+ release, achieved by the use of the drug ryanodine, on these relations in the intact animal. Methods: Twelve dogs instrumented with left ventricular manometers and piezoelectric dimension crystals were studied before and after ryanodine (4 μg/kg intravenously). End-systolic elastance was measured at paced heart rates of 120–180 bpm to determine the force-frequency response. Mechanical restitution and relaxation restitution were determined by measuring contractile (single beat elastance) and relaxation (peak negative dP/dt) responses for beats delivered at graded extrasystolic intervals, with normalized responses expressed as a function of extrasystolic interval. Results: Ryanodine accelerated mechanical restitution (time constant 60.3±3.9 versus 81.7±10.1 ms, p<0.05) and reduced maximal contractile response (107.5±2.1 versus 122.1±5.7%, p<0.05), slowed early relaxation restitution (time constant 65.5±13.8 versus 36.8±3.8 ms, p<0.05) without changing late relaxation restitution kinetics, and amplified the force-frequency response (end-systolic elastance, 180 bpm, 19.4±4.3 versus 11.4±1.2 mm Hg/ml, p<0.05). Conclusions: These findings suggest that in the intact animal, Ca2+ handling by the sarcoplasmic reticulum is a primary determinant of mechanical restitution and early relaxation restitution, but not late relaxation restitution. Conversely, ryanodine induced augmentation of the force-frequency response indicates a central role for sarcolemmal Ca2+ influx in producing frequency potentiation.
Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation
Authors: H Spencer
Journal: Thorax (2004)

<b>Background:</b> Recent reports have shown evidence of host derived parenchymal engraftment in several human allografts including the lung, leading to speculation that stem cell therapy may be useful for lung repair in diseases such as cystic fibrosis (CF). To date, previous studies have looked at single surgical or autopsy specimens and no longitudinal studies have been reported. The aim of this study was to assess whether transbronchial biopsies could be used to study the time course of chimerism following lung transplantation. <b>Methods:</b> Specimens of archived transbronchial lung biopsies from five time points taken for clinical purposes from two boys who had received a sex mismatched heart-lung transplant for end stage CF were examined. Sections were dual stained for cytokeratin (epithelium) and a mixture of leucocyte common antigen and CD68 for inflammatory cells. Co-localisation of cells containing a Y chromosome was confirmed by fluorescent in situ hybridisation. <b>Results:</b> Evidence of chimerism was found in up to 6.6% of epithelial cells in bronchial (median 1.4% (range 0–6.6)) and alveolar (median 3.6% (range 2.3–5.5) tissue without apparent evidence of fusion. This engraftment was seen as early as 3 weeks and remained relatively constant up to 37 months. <b>Conclusions:</b> This study has demonstrated proof of principle for long term chimerism in lung epithelium. Transbronchial biopsies may provide a new method for studying the kinetics of stem cell engraftment in the lung.
STAT3 Inhibition Is a Therapeutic Strategy for ABC-like Diffuse Large B-Cell Lymphoma
Authors: Anna Scuto, Maciej Kujawski, Claudia Kowolik, Ludmila Krymskaya, Lin Wang, Lawrence M. Weiss, David DiGiusto, Hua Yu, Stephen Forman, Richard Jove
Journal: Cancer Research (2011)

Abstract Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)–like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy. Cancer Res; 71(9); 3182–8. ©2011 AACR.
IGF-Binding Protein-1 Levels Are Related to Insulin-Mediated Glucose Disposal and Are a Potential Serum Marker of Insulin Resistance
Authors: Betty A. Maddux, Adeline Chan, Elena A. De Filippis, Lawrence J. Mandarino, Ira D. Goldfine
Journal: Diabetes Care (2007)

We appreciate the interest of van Haeflen et al. (1) in our article (2) concerning IGF-binding protein (IGFBP)-1 as a maker of insulin resistance in healthy nondiabetic subjects. In contrast to our study, they did not find a strong a correlation between insulin action as determined …
Nonplatinum Topotecan Combinations Versus Topotecan Alone for Recurrent Ovarian Cancer: Results of a Phase III Study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group
Authors: Jalid Sehouli, Dirk Stengel, Guelten Oskay-Oezcelik, Alain G. Zeimet, Harald Sommer, Peter Klare, Martina Stauch, Axel Paulenz, Oumar Camara, Elke Keil, Werner Lichtenegger
Journal: Journal of Clinical Oncology (2008)

The management of recurrent ovarian cancer remains controversial. Single-agent topotecan is an established treatment option, and preliminary evidence suggests improved tumor control by combining topotecan with etoposide or gemcitabine.Women with relapsed ovarian cancer after primary surgery and platinum-based chemotherapy were randomly assigned to topotecan monotherapy 1.25 mg/m(2)/d, topotecan 1.0 mg/m(2) plus oral etoposide 50 mg/d, or topotecan 0.5 mg/m(2)/d plus gemcitabine 800 mg/m(2) on day 1 and 600 mg/m(2) on day 8 every 3 weeks. Patients were stratified for platinum-refractory and platinum-sensitive disease according to a recurrence-free interval of less or more than 12 months, respectively. The primary end point was overall survival. Secondary end points included progression-free survival, objective response rates, toxicity, and quality of life (as measured by the European Organisation for Research and Treatment of Cancer [EORTC] 30-item Quality-of-Life Questionnaire).The trial enrolled 502 patients with a mean age of 60.5 years (+/- 10.2 years), 208 of whom were platinum resistant. Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344). Platinum-sensitive patients lived significantly longer than platinum-refractory patients (21.9 v 10.6 months). The median progression-free survival was 7.0, 7.8, and 6.3 months, respectively. Objective response rates were 27.8%, 36.1%, and 31.6%, respectively. Patients under combined treatment were at higher risk of severe thrombocytopenia.Nonplatinum topotecan combinations do not provide a survival advantage over topotecan alone in women with relapsed ovarian cancer.
Ubiquitousness of<i>Legionella pneumophila</i>in the Water Supply of a Hospital with Endemic Legionnaires' Disease
Authors: Janet Stout, Victor L. Yu, R. M. Vickers, Jeffrey Zuravleff, Michele Best, Arnold Brown, Robert B. Yee, Robert Wadowsky
Journal: New England Journal of Medicine (1982)

SINCE 1977 there have been numerous outbreaks of nosocomial Legionnaires' disease; however, in only one was a reservoir established for Legionella pneumophila. Dondero and his colleagues have suggested that the organisms were spread from a contaminated cooling tower adjacent to a hospital with 39 cases of Legionnaires' disease.1 L. pneumophila has also been isolated from showerheads and mixing valves of hospitals in the United States and England.2 , 3 The two largest sustained outbreaks of nosocomial Legionnaires' disease have been at the Wadsworth Veterans Administration Hospital in Los Angeles and here at the Pittsburgh Veterans Administration Medical Center.4 , 5 Although a definitive epidemiologic . . .
New medical contracts hamper trusts' financial performance
Authors: Adrian O'Dowd
Journal: BMJ (2005)

The new contracts for GPs and consultants may be contributing to a rise in the number of trusts that are failing crucial financial performance targets set out in the latest star ratings for the NHS, according to Anna Walker, head of the Healthcare Commission. The commission published its performance ratings for all English trusts for 2004-5 this week.

She issued the annual ratings with a warning that patient care would be threatened if financial management did not improve at poorly performing trusts.

The overall performance of trusts is improving, according to the ratings. 28% of all the 590 trusts in England have three stars (compared with 25% in …
Laboratory-confirmed case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in Malaysia: preparedness and response, April 2014
Authors: J Premila Devi, W Noraini, R Norhayati, C Chee Kheong, A S Badrul, S Zainah, K Fadzilah, I Hirman, S Lokman Hakim, A Noor Hisham
Journal: Eurosurveillance (2014)

On 14 April 2014, the first laboratory-confirmed case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection was reported in Malaysia in a man in his mid-fifties, who developed pneumonia with respiratory distress, after returning from a pilgrimage to Saudi Arabia. The case succumbed to his illness three days after admission at a local hospital. The follow-up of 199 close contacts identified through contact tracing and vigilant surveillance did not result in detecting any other confirmed cases of MERS-CoV infection.