tbuckley/cabot-search huggingface dataset:
The Accuracy of the Inferior&gt;Superior&gt;Nasal&gt;Temporal Neuroretinal Rim Area Rule for Diagnosing Glaucomatous Optic Disc Damage
Authors: James E. Morgan, Ioanna Bourtsoukli, Kadaba N. Rajkumar, Ejaz Ansari, Ian A. Cunliffe, Rachel V. North, John M. Wild
Journal: Ophthalmology (2012)
Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: population based retrospective cohort study
Authors: D. Prieto-Alhambra, M. K. Javaid, A. Judge, D. Murray, A. Carr, C. Cooper, N. K. Arden
Journal: BMJ (2011)

<b>Objectives </b>To test whether bisphosphonate use is related to improved implant survival after total arthroplasty of the knee or hip. <b>Design</b> Population based retrospective cohort study. <b>Setting</b> Primary care data from the United Kingdom. <b>Participants</b> All patients undergoing primary total arthroplasty of the knee (n=18 726) or hip (n=23 269) in 1986-2006 within the United Kingdom’s General Practice Research Database. We excluded patients with a history of hip fracture before surgery or rheumatoid arthritis, and individuals younger than 40 years at surgery. <b>Intervention</b> Bisphosphonate users were classified as patients with at least six prescriptions of bisphosphonates or at least six months of prescribed bisphosphonate treatment with more than 80% adherence before revision surgery. <b>Outcome measures</b> Revision arthroplasties occurring after surgery, identified by READ and OXMIS codes. Parametric survival models were used to determine effects on implant survival with propensity score adjustment to account for confounding by indication. <b>Results </b>Of 41 995 patients undergoing primary hip or knee arthroplasty, we identified 1912 bisphosphonate users, who had a lower rate of revision at five years than non-users (0.93% (95% confidence interval 0.52% to 1.68%) <i>v</i> 1.96% (1.80% to 2.14%)). Implant survival was significantly longer in bisphosphonate users than in non-users in propensity adjusted models (hazard ratio 0.54 (0.29 to 0.99); P=0.047) and had an almost twofold increase in time to revision after hip or knee arthroplasty (time ratio 1.96 (1.01 to 3.82)). Assuming 2% failure over five years, we estimated that the number to treat to avoid one revision was 107 for oral bisphosphonates. <b>Conclusions </b>In patients undergoing lower limb arthroplasty, bisphosphonate use was associated with an almost twofold increase in implant survival time. These findings require replication and testing in experimental studies for confirmation.
Proteasome functional insufficiency activates the calcineurin–NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts
Authors: Mingxin Tang, Jie Li, Wei Huang, Huabo Su, Qiangrong Liang, Zongwen Tian, Kathleen M. Horak, Jeffery D. Molkentin, Xuejun Wang
Journal: Cardiovascular Research (2010)

AimsProteasome functional insufficiency (PFI) may play an important role in the progression of congestive heart failure but the underlying molecular mechanism is poorly understood. Calcineurin and nuclear factor of activated T-cells (NFAT) are degraded by the proteasome, and the calcineurin–NFAT pathway mediates cardiac remodelling. The present study examined the hypothesis that PFI activates the calcineurin–NFAT pathway and promotes maladaptive remodelling of the heart.
Electroanatomic Mapping and Catheter Ablation of Breakthroughs From the Right Atrium to the Superior Vena Cava in Patients With Atrial Fibrillation
Authors: Masahiko Goya, Feifan Ouyang, Sabine Ernst, Marius Volkmer, Matthias Antz, Karl-Heinz Kuck
Journal: Circulation (2002)

Background— The superior vena cava (SVC) is one of the sources of ectopies that can initiate atrial fibrillation (AF). We investigated by radiofrequency ablation the electrophysiological characteristics of the junction of the right atrium (RA) and the SVC and the feasibility of electrical disconnection of the SVC from the RA. Methods and Results— Sixteen patients with paroxysmal AF after pulmonary vein isolation underwent electroanatomic mapping at the RA–SVC junction during sinus rhythm. Mapping showed sharp potentials (SVC potentials) inside the SVC. Activation spread from the earliest SVC potential (breakthrough) to the rest of the SVC. SVC potentials were found over a large amount of the circumference, suggesting widespread muscle coverage of the SVC. Breakthroughs from the RA to SVC were located anteriorly, laterally, posteriorly, and septally in 3, 4, 10, and 6 patients, respectively. The number of breakthroughs was 1.4±0.5 per patient. Radiofrequency energy was applied with the end point of electrical disconnection. All breakthroughs were eliminated with 3.1±1.7 applications per breakthrough without complications. Conclusions— SVC potentials can be recorded inside the SVC. There are specific breakthroughs from the RA to the SVC that can be identified by electroanatomic mapping. The electrical disconnection of the SVC from the RA is feasible.
Early and severe amyloidosis in a patient with concurrent familial Mediterranean fever and pseudoxanthoma elasticum
Authors: D. Cattan, B. Bouali, N. Chassaing, F. Martinez, J.M. Dupont, C. Dode, L. Martin
Journal: British Journal of Dermatology (2006)

A young woman patient had early and extensive familial Mediterranean fever (FMF)‐related amyloidosis and pseudoxanthoma elasticum (PXE). She had the novel G1042S mutation in the ATP‐binding cassette subfamily C member 6 (ABCC6) gene, responsible for PXE, and the mutation M694I in MEFV, the FMF gene. Both mutations were homozygous, in agreement with consanguinity in the parents. ABCC6 deficiency may have increased the severity of amyloidosis by increasing the deposition in target tissues of heparan sulphate, which colocalizes spatially and temporally with amyloid proteins, and/or by decreasing the therapeutic activity of colchicine.
Separation of Alveolar Surfactant into Subtypes
Authors: NICHOLAS J. GROSS, MATTHEW KELLAM, JARED YOUNG, SUBBIAH KRISHNASAMY, RAJIV DHAND
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Alveolar surfactant is known to exist in several morphologic forms or subtypes which have been separated from bronchoalveolar lavage fluid (BAL) by two types of methods-differential centrifugation (DC) and equilibrium buoyant density gradient centrifugation (EBDC). DC separates BAL into large aggregates (LA) and small aggregates (SA); EBDC separates BAL into three peaks called ultraheavy (UH), heavy (H), and light (L). We compared these two separation methods by subjecting replicates of the same pools of BALF from groups of mice to DC and EBDC in parallel assays. We found that each method was highly internally consistent, but that the amount of phospholipid in the LA fraction of DC was consistently and substantially less (by 33 to 43%) than that found in the UH + H fractions of EBDC. This appeared to be due to failure of DC to sediment all of the phospholipid that banded as UH or H in EBDC despite adjustments in the time and g-force of DC. In experiments where differentially labeled purified H and L subtypes were subjected to DC over a wide range of g-force and time conditions, cross-contamination of the DC pellet and supernatant with heterologous subtypes was always present (4 to 33% cross-contamination). Addition of extraneous serum proteins to the BAL, as a model of lung damage, resulted in further inconsistencies in DC but not EBDC. Investigators may wish to bear these considerations in mind when planning or interpreting the results of experiments bearing on surfactant subtype analysis.
Mitochondria and Tumor Progression in Ulcerative Colitis
Authors: Cigdem Himmetoglu Ussakli, Anoosheh Ebaee, Jennifer Binkley, Teresa A. Brentnall, Mary J. Emond, Peter S. Rabinovitch, Rosa Ana Risques
Journal: JNCI Journal of the National Cancer Institute (2013)

The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis. Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C oxidase (COX), a component of the electron transport chain, and were quantified by multispectral imaging. For six additional progressors, nondysplastic and dysplastic biopsies were stained for COX and additional mitochondrial proteins including PGC1α, the master regulator of mitochondrial biogenesis. Mitochondrial DNA (mtDNA) copy number was determined by quantitative polymerase chain reaction. Generalized estimating equations with two-sided tests were used to account for correlation of measurements within individuals. Nondysplastic biopsies of UC progressors showed statistically significant COX loss compared with UC nonprogressors by generalized estimating equation (−18.5 units, 95% confidence interval = −12.1 to −24.9; P < .001). COX intensity progressively decreased with proximity to dysplasia and was the lowest in adjacent to dysplasia and dysplastic epithelium. Surprisingly, COX intensity was statistically significantly increased in cancers. This bimodal pattern was observed for other mitochondrial proteins, including PGC1α, and was confirmed by mtDNA copy number. Mitochondrial loss precedes the development of dysplasia, and it could be used to detect and potentially predict cancer. Cancer cells restore mitochondria, suggesting that mitochondria are needed for further proliferation. This bimodal pattern might be driven by transcriptional regulation of mitochondrial biogenesis by PGC1α.
<i>Cryptococcus neoformans STE12α</i> Regulates Virulence but Is Not Essential for Mating
Authors: Y.C. Chang, B.L. Wickes, G.F. Miller, L.A. Penoyer, K.J. Kwon-Chung
Journal: The Journal of Experimental Medicine (2000)

The Cryptococcus neoformans STE12alpha gene, a homologue of Saccharomyces cerevisiae STE12, exists only in mating type (MAT)alpha cells. In S. cerevisiae, STE12 was required for mating and filament formation. In C. neoformans, haploid fruiting on filament agar required STE12alpha. The ability to form hyphae, however, was not affected by deletion of STE12alpha when convergently growing MATa strains were present. Furthermore, ste12alpha disruptants were fertile when mated with MATa strains, albeit with reduced mating frequency. Most importantly, the virulence of a ste12alpha disruptant of serotype D strain was significantly reduced in a mouse model. When the ste12alpha locus was reconstituted with the wild-type allele by cotransformation, virulence was restored. Histopathological analysis demonstrated a reduction in capsular size of yeast cells, less severe cystic lesions, and stronger immune responses in meninges of mice infected with ste12alpha cells than those of mice infected with STE12alpha cells. Using reporter gene constructs, we found that STE12alpha controls the expression of several phenotypes known to be involved in virulence, such as capsule and melanin production. These results demonstrate a clear molecular link between mating type and virulence in C. neoformans.
Interleukin 1?-stimulated production of nitric oxide in rat hepatocytes is mediated through endogenous synthesis of interferon gamma
Authors: Rebecca A. Schroeder, Jian S. Gu, Paul C. Kuo
Journal: Hepatology (1998)

The multiple interlocking regulatory mechanisms that underlie induction of hepatocyte inducible nitric oxide synthase (iNOS) expression are largely unknown. Although previous work has indicated the requirement for multiple proinflammatory cytokines to induce hepatocyte NO production, investigators have recently shown that interleukin-1beta (IL-1beta) alone can initiate iNOS expression. In contrast, interferon gamma (IFN-gamma) serves as the sole initiating factor in other cell systems. On the basis of the known ability of IL-1beta to induce transcription and translation of the IFN family of genes, we hypothesized that IL-1beta-mediated hepatocyte expression of iNOS is dependent on endogenous IFN-gamma synthesis. In a system of rat hepatocytes in primary culture, IL-1beta induced production of both NO and IFN-gamma. Using in situ hybridization and immunoblot analysis, IFN-gamma messenger RNA (mRNA) and protein were detected in hepatocytes exposed to IL-1beta. Inhibition of NO synthesis using the competitive substrate inhibitor N-monomethyl-L-arginine (100 micromol/L) did not alter the extent of IL-1beta-mediated IFN-gamma synthesis. In contrast, anti-IFN-gamma antibody or inhibition of IFN-gamma mRNA translation by addition of antisense IFN-gamma oligodeoxynucleotide probes resulted in undetectable levels of NO metabolites and iNOS protein. Repletion of IFN-gamma to the system restored NO production to levels noted in the presence of IL-1beta alone. Transient transfection analysis using a rat hepatocyte iNOS promoter-reporter gene plasmid construct showed that IL-1beta-induced promoter activation was abolished in the presence of anti-IFN-gamma or antisense IFN-gamma. Again, addition of IFN-gamma to the system restored activity of the iNOS promoter. Parallel experiments examining IL-1beta-mediated endogenous hepatocyte IL-1beta and TNF-alpha synthesis indicated no role for these cytokines in the induction of iNOS expression by IL-1beta. It is concluded that IL-1beta-mediated hepatocyte synthesis of NO is dependent on the simultaneous endogenous synthesis of IFN-gamma.
Changing carriage rate of Neisseria meningitidis among university students during the first week of term: cross sectional study
Authors: K. R Neal
Journal: BMJ (2000)

To determine the rates of, and risk factors for, meningococcal carriage and acquisition among university students.Repeated cross sectional study.2,507 students in their first year at university.Prevalence of carriage of meningococci and risk factors for carriage and acquisition of meningococci.Carriage rates for meningoccoci increased rapidly in the first week of term from 6.9% on day 1, to 11.2% on day 2, to 19.0% on day 3, and to 23.1% on day 4. The average carriage rate during the first week of term in October among students living in catered halls was 13.9%. By November this had risen to 31.0% and in December it had reached 34. 2%. Independent associations for acquisition of meningococci in the autumn term were frequency of visits to a hall bar (5-7 visits: odds ratio 2.7, 95% confidence interval 1.5 to 4.8), active smoking (1.6, 1.0 to 2.6), being male (1.6, 1.2 to 2.2), visits to night clubs (1. 3, 1.0 to 1.6), and intimate kissing (1.4, 1.0 to 1.8). Lower rates of acquisition were found in female only halls (0.5, 0.3 to 0.9). The most commonly acquired meningococcal strain was C2a P1.5 (P1.2), which has been implicated in clusters of invasive meningococcal disease at other UK universities.Carriage rates of meningococci among university students increase rapidly in the first week of term, with further increases during the term. The rapid rate of acquisition may explain the increased risk of invasive meningococcal disease and the timing of cases and outbreaks in university students.
Age at Immigration and Duration of Stay in Relation to Risk for Testicular Cancer Among Finnish Immigrants in Sweden
Authors: A. Ekbom, L. Richiardi, O. Akre, S. M. Montgomery, P. Sparen
Journal: JNCI Journal of the National Cancer Institute (2003)

Although the incidence of testicular cancer is increasing, substantial differences in incidence between countries and populations exist. These differences cannot be explained solely by genetic differences, but environmental exposures, particularly early exposures, have been implicated in the etiology of testicular cancer. To assess whether early exposures contribute to the incidence of testicular cancer, we identified 93 172 Finnish men who immigrated to Sweden between 1969 and 1996 and followed them for the occurrence of testicular cancer. The risk of testicular cancer was lower for Finnish immigrants to Sweden than for the Swedish general population (standardized incidence ratio [SIR] = 0.34, 95% confidence interval [CI] = 0.21 to 0.53). The reduced risk was associated with both seminomas and non-seminomas. Neither age at immigration nor duration of stay in Sweden had any impact on the reduced risk. Although the type of environmental exposures remains unknown, the results strongly indicate that early exposures are major determinants for testicular cancer.
Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis
Authors: Alfred Mahr, Sandrine Katsahian, Hugo Varet, Loïc Guillevin, E Christiaan Hagen, Peter Höglund, Peter A Merkel, Christian Pagnoux, Niels Rasmussen, Kerstin Westman, David R W Jayne
Journal: Annals of the Rheumatic Diseases (2012)

Granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV.This study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes.The analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named 'renal AAV with proteinase 3 (PR3)-ANCA' (40% of subjects), 'renal AAV without PR3-ANCA' (32%) and 'non-renal AAV' (12%), 'cardiovascular AAV' (9%) and 'gastrointestinal AAV' (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes.This analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA-MPA separation, this classification system may better reflect the phenotypic spectrum of AAV.
Preclinical Pharmacologic Evaluation of MST-997, an Orally Active Taxane with Superior <i>In vitro</i> and <i>In vivo</i> Efficacy in Paclitaxel- and Docetaxel-Resistant Tumor Models
Authors: Deepak Sampath, Lee M. Greenberger, Carl Beyer, Malathi Hari, Hao Liu, Michelle Baxter, Sharon Yang, Carol Rios, Carolyn Discafani
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought. The aim of this study was to evaluate the efficacy and oral activity of a novel taxane (MST-997) in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Experimental Design: Tubulin polymerization assays, immunohistochemistry, and cell cycle analysis was used to evaluate mechanism of action of MST-997. The effect of MST-997 on growth inhibition in a panel of paclitaxel- and docetaxel-resistant cell lines that overexpressed P-glycoprotein (MDR1) or harbored β-tubulin mutations were assayed in vitro and in murine xenografts. Results: MST-997 induced microtubule polymerization (EC50 = 0.9 μmol/L) and bundling, resulting in G2-M arrest and apoptosis. In addition, MST-997 was a potent inhibitor of paclitaxel- and docetaxel-sensitive tumor cell lines that did not have detectable P-glycoprotein (IC50 = 1.8 ± 1.5 nmol/L). Minimal resistance (1- to 8-fold) to MST-997 was found in cell lines that either overexpressed MDR1 or harbored point mutations in β-tubulin. Most notable, MST-997 displayed superior in vivo efficacy as a single i.v. or p.o. dose either partially or completely inhibited tumor growth in paclitaxel- and docetaxel-resistant xenografts. Conclusions: MST-997 represents a potent and orally active microtubule-stabilizing agent that has greater pharmacologic efficacy in vitro and in vivo than the currently approved taxanes. Our findings suggest that MST-997, which has entered phase I clinical trials, may have broad therapeutic value.
Outcome of Patients with Idiopathic Pulmonary Fibrosis Admitted to the Intensive Care Unit
Authors: Ghulam Saydain, Ashiq Islam, Bekele Afessa, Jay H. Ryu, John P. Scott, Steve G. Peters
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

This retrospective study describes the clinical course of 38 patients with idiopathic pulmonary fibrosis (IPF) admitted to the intensive care unit (ICU). There were 25 males and 13 females who were the mean age of 68.3 ± 11.5 years. Twenty patients were on corticosteroids at the time of admission to the hospital, and 24 had been on home oxygen therapy. The most common reason for ICU admission was respiratory failure. The Acute Physiology and Chronic Health Evaluation III–predicted ICU and hospital mortality rates were 12% and 26%, whereas the actual ICU and hospital mortality rates were 45% and 61%, respectively. We did not find significant differences in pulmonary function or echocardiogram findings between survivors and nonsurvivors. Mechanical ventilation was used in 19 patients (50%). Sepsis developed in nine patients. Multiple organ failure developed in 14% of the survivors and in 43% of the nonsurvivors (p = 0.14). Ninety-two percent of the hospital survivors died at a median of 2 months after discharge. These findings suggest that patients with IPF admitted to the ICU have poor short- and long-term prognosis. Patients with IPF and their families should be informed about the overall outlook when they make decisions about life support and ICU care.
First fellows of the Royal College of General Practitioners
Authors: B. D. M. Williams
Journal: BMJ (1967)

A. M. Poornan (19 August, p. 500) and G. Murtaza (28 October, p. 239) about the rejection of their claims for seniority allow- ance by the Ministry of Health.The ruling of the Ministry is incompatible with the spirit and principle with which the Review Body introduced this payment.In para.159 of the Report' it states that this payment " will recognize the development of experience in the general practitioner, and will provide him with the prospect of maintaining the level of his remuneration at a time when he may wish with advancing age . . .