tbuckley/cabot-search huggingface dataset:
Moving toward Tuberculosis Elimination
Authors: Kevin P. Cain, Katie N. Garman, Kayla F. Laserson, Odile P. Ferrousier-Davis, Abraham G. Miranda, Charles D. Wells, Connie A. Haley
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

From 1993 to 2010, annual U.S. tuberculosis (TB) rates declined by 58%. However, this decline has slowed and disproportionately occurred among U.S.-born (78%) versus foreign-born persons (47%). Addressing the high burden of latent TB infection (LTBI) must be prioritized.Only Tennessee has implemented a statewide program for finding and treating people with LTBI. The program was designed to address high statewide TB rates and growing burden among the foreign-born. We sought to assess the feasibility and yield of Tennessee's program.Analyzing data from the 4.8-year period from program inception in March 2002 through December 2006, we quantified patients screened using a TB risk assessment tool, tuberculin skin tests (TST) placed and read, TST results, and patients initiating and completing LTBI treatment. We then estimated the number needed to screen to find and treat one person with LTBI and to prevent one case of TB.Of 168,517 persons screened, 102,709 had a TST placed and read. Among 9,090 (9%) with a positive TST result, 53% initiated treatment, 54% of whom completed treatment. An estimated 195 TB cases were prevented over the 4.8 years analyzed, and program performance measures improved annually. The number of TSTs placed to prevent one TB case ranged from 150 for foreign-born persons to 9,834 for persons without TB risk.Targeted tuberculin testing and LTBI treatment is feasible and likely to reduce TB rates over time. Yield and cost-effectiveness are maximized by prioritizing foreign-born persons, a large population with high TB risk.
The Mal/TIRAP S180L and TLR4 G299D polymorphisms are not associated with susceptibility to, or severity of, rheumatoid arthritis
Authors: F J Sheedy, I Marinou, L A J O'Neill, A G Wilson
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Toll-like receptors (TLRs), including TLR4, have been implicated in the pathogenesis of rheumatoid arthritis (RA). Signalling by these receptors involves interactions with intracellular proteins, including the MyD88 adapter-like (Mal) protein. Recently, a polymorphism (Mal S180L) has been described which contributes to susceptibility to common infectious diseases and inhibits proinflammatory cytokine production. A non-synonymous variant in the extracellular domain of TLR4 (G299D) has been shown to interrupt TLR4-mediated signalling, resulting in endotoxin hyporesponsiveness. <h3>Objective:</h3> To investigate the role of TLR4 G299D and Mal S180L variants in RA. <h3>Methods:</h3> A total of 964 Caucasians with RA and 965 controls were genotyped. Deviation from Hardy–Weinberg equilibrium was tested for each single nucleotide polymorphism in cases and controls separately using a χ<sup>2</sup> test with a threshold of p&lt;0.05. The odd ratios were calculated with asymptotic 95% confidence intervals, and p values &lt;0.05 were considered significant. Epistasis was assessed using both stratified analysis and the linkage disequilibrium-based statistic. <h3>Results:</h3> Mal S180L genotypes were similar in cases and controls (OR = 0.9, 95% CI 0.7 to 1.0, p = 0.2). Similarly, no difference for TLR4 G299D genotypes was seen (OR = 1.7, 95% CI 0.3 to 11.1, p = 0.5). No association with either rheumatoid factor or anti-cyclic citrullinated peptide status or with radiological damage was detected. Finally, no evidence of epistasis was detected between Mal S180L and TLR4 G299D and RA susceptibility. <h3>Conclusions:</h3> The Mal S180L and TLR4 G299D polymorphisms do not contribute to RA susceptibility or severity either individually or in combination.
Increase of CD4+CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma
Authors: Xiu Hua Yang, Satoshi Yamagiwa, Takafumi Ichida, Yasunobu Matsuda, Satoshi Sugahara, Hisami Watanabe, Yoshinobu Sato, Toru Abo, David A. Horwitz, Yutaka Aoyagi
Journal: Journal of Hepatology (2006)
Detection of Hepatitis C Virus Antibody in the Absence of Viral RNA in Patients with Autoimmune Hepatitis
Authors: S Nishiguchi, T Kuroki, T Ueda, K Fukuda, T Takeda, S Nakajima, S Shiomi, K Kobayashi, S Otani, N Hayashi
Journal: Annals of Internal Medicine (1992)

Objective: To determine whether laboratory findings showing antibodies to hepatitis C virus (HCV) in patients with autoimmune hepatitis represent false-positive results and to identify possible explanations for true-positive results in these patients. Design: Cross-sectional. Setting: University-based hospital. Patients: Fifty-two patients with non-A, non-B chronic hepatitis as a control group and 26 patients with classic chronic active autoimmune hepatitis. Measurements: Comparison of the results of five kinds of assays of HCV antibodies and HCV RNA. Main Results: Of 52 patients with non-A, non-B chronic hepatitis, HCV antibodies (anti-HCV) were detected in 42 patients (81%; 95% Cl, 67% to 90%) by a first-generation enzyme-linked immunosorbent assay (ELISA-I), in 39 patients (75%) by Sp42 ELISA, in 37 patients (71%) by RIA-I, in 49 patients (94%) by ELISA-II, and in 48 patients (92%) by RIBA-II. We found HCV RNA in 47 patients (90%; Cl, 79% to 97%). Of the 26 patients with autoimmune hepatitis, anti-HCV were detected in 23 patients (88%; Cl, 70% to 98%) by ELISA-I, in 12 (46%) by both RIA-I and Sp42 ELISA, in 20 (77%) by ELISA-II, and in 9 (35%) by RIBA-II. However, HCV RNA was found in only five of these patients (19%; Cl, 7% to 39%). None of our patients, including controls, had antibodies to superoxide dismutase. Of the 21 patients who had autoimmune hepatitis that was completely responsive to steroid therapy, 18 had anti-HCV by ELISA-I, but 13 of these patients had negative results by RIBA-II, and only two patients had HCV RNA. Of the five patients who did not respond to steroid treatment, all had anti-HCV by ELISA-I, four had negative results by RIBA-II, and three had HCV RNA. Conclusions: Testing for HCV antibodies in patients with autoimmune hepatitis frequently elicits positive results when the ELISA-I or ELISA-II tests are used. Most of these appear to represent false-positive results because HCV RNA is usually absent from the serum. Such false positivity may result from previous infection with HCV or from cross-reaction of an epitope of HCV. Other patients with apparent autoimmune hepatitis who fail to respond to corticosteroid therapy may actually have chronic hepatitis C (or other non-A, non-B hepatitis) infection.
Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction
Authors: Zequan Yang, Christina M. Bove, Brent A. French, Frederick H. Epstein, Stuart S. Berr, Joseph M. DiMaria, Jennifer J. Gibson, Robert M. Carey, Christopher M. Kramer
Journal: Circulation (2002)

Background — The role of the angiotensin II type 2 receptor (AT 2 -R) in left ventricular (LV) remodeling may depend on the underlying stimulus. We hypothesized that cardiac AT 2 -R overexpression in transgenic (TG) mice would attenuate remodeling after myocardial infarction (MI). Methods and Results — Ten wild-type (WT) C57BL/6 mice and 12 TG mice that overexpress the AT 2 -R in the heart were studied by cardiac MRI at baseline and days 1, 7, and 28 post-MI induced by 1 hour of occlusion of the LAD followed by reperfusion. Short-axis imaging from apex to base was used to determine LV mass index, end-diastolic and end-systolic volume indices (EDVI, ESVI), regional wall thickness and thickening, and ejection fraction (EF). Gadolinium-DTPA was infused 20 minutes before day 1 imaging to assess infarct size. At baseline, heart rate, blood pressure, LV mass index, and EDVI were similar between groups. Baseline ESVI was lower (0.20±0.07 versus 0.45±0.15 μL/g, P &lt;0.001) and EF higher (82.3±4.9% versus 67.7±5.3%, P &lt;0.001) in TG than WT. Infarct size was similar (36.6±7.2% in WT, 34.0±7.8% in TG, P =NS). When controlled for baseline differences, ESVI was significantly less and EF significantly higher at all time points in TG versus WT. At day 28, ESVI was 1.05±0.32 μL/g in TG and 1.63±0.41 μL/g in WT, P &lt;0.03, and EF was 47.3±5.8% versus 34.1±9.2%, P &lt;0.003, respectively. Regional wall thickness and thickening were greater in TG both at baseline and at day 28. At day 28, blood pressure and LV dP/dt were higher in TG. Conclusions — Cardiac AT 2 -R overexpression improves LV systolic function at baseline and preserves function during post-MI remodeling.
15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation
Authors: Mark J. Paul-Clark, Thong van Cao, Niloufar Moradi-Bidhendi, Dianne Cooper, Derek W. Gilroy
Journal: The Journal of Experimental Medicine (2004)

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1β–induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1β–stimulated mouse mesentery. Not only did aspirin inhibit leukocyte–endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A4 had markedly reduced effects on leukocyte–endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A4, which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte–endothelium interactions.
Five-Year Survival in Patients With ST-Segment–Elevation Myocardial Infarction According to Modalities of Reperfusion Therapy
Authors: Nicolas Danchin, Etienne Puymirat, Philippe Gabriel Steg, Patrick Goldstein, François Schiele, Loïc Belle, Yves Cottin, Jean Fajadet, Khalife Khalife, Pierre Coste, Jean Ferrières, Tabassome Simon
Journal: Circulation (2014)

Background— Although primary percutaneous coronary intervention (pPCI) is the preferred reperfusion method for ST-segment–elevation myocardial infarction, it remains difficult to implement in many areas, and fibrinolytic therapy is still widely used. Methods and Results— We assessed 5-year mortality in patients with ST-segment–elevation myocardial infarction from the French Registry of Acute ST-Elevation or Non-ST Elevation Myocardial Infarction (FAST-MI) 2005 according to use and type of reperfusion therapy. Of 1492 patients with ST-segment–elevation myocardial infarction with a first call ≤12 hours from onset, 447 (30%) received fibrinolysis (66% prehospital; 97% with subsequent angiography, 84% with subsequent PCI), 583 (39%) had pPCI, and 462 (31%) received no reperfusion. Crude 5-year survival was 88% for the fibrinolytic-based strategy, 83% for pPCI, and 59% for no reperfusion. Adjusted hazard ratios for 5-year death were 0.73 (95% confidence interval, 0.50–1.06) for fibrinolysis versus pPCI, 0.57 (95% confidence interval, 0.36–0.88) for prehospital fibrinolysis versus pPCI, and 0.63 (95% confidence interval, 0.34–0.91) for fibrinolysis versus pPCI beyond 90 minutes of call in patients having called ≤180 minutes from onset. In propensity score–matched populations, however, survival rates were not significantly different for fibrinolysis and pPCI, both in the whole population (88% lysis, 85% pPCI) and in the population seen early (87% fibrinolysis, 85% pPCI beyond 90 minutes from call). Conclusions— In a real-world setting, on a nationwide scale, a pharmaco-invasive strategy constitutes a valid alternative to pPCI, with 5-year survival at least equivalent to that of the reference reperfusion method. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00673036.
New developments and future opportunities in biomarkers for amyotrophic lateral sclerosis
Authors: Xueping Chen, Hui-Fang Shang
Journal: Translational Neurodegeneration (2015)

Modern technology has improved the ability to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients with ALS, as well as to monitor functional and structural changes during the course of disease. While effective treatments for ALS are lacking, the discovery of sensitive biomarkers to disease activity offers clinicians tools for rapid diagnosis and insights into the pathophysiology of ALS. The ultimate aim is to lessen reliance on clinical measures and survival as trial endpoints and broaden the therapeutic options for patients with this disease.
Timothy Roper Peskett
Journal: BMJ (2006)

​SeniorSenior general practitioner Denbigh, North Wales (b 1959; q Cardiff 1982; DCH, FRCGP), died from colon cancer on 5 February 2006.



Figure 1



Tim was on the North Clwyd GP Vocational Training Scheme for three years before joining an established rural training practice with a branch surgery, dispensary, and a 52 bed community hospital (with maternity and casualty beds). The practice was the first in Wales to have a course organiser, a post Tim held for his last eight years. He started the first child surveillance clinic in general practice in North Clwyd in 1987, and the practice was recognised nationally in 1998 for screening for schizophrenia and reintegrating patients. He leaves a wife and five children.
The ubiquitin–proteasome system in cardiovascular diseases—a hypothesis extended
Authors: J Herrmann
Journal: Cardiovascular Research (2003)

During recent years, the ubiquitin-proteasome system has become known as the major pathway of non-lysosomal degradation of intracellular proteins, involving two sequential steps. In the first step, multiple moieties of ubiquitin are covalently bound to target proteins to be recognized and degraded by the multi-enzymatic proteasome complex in the second step. In addition to the elimination of damaged and unneeded proteins, this system fulfills an important function in the regulation of cellular mediators in various biological pathways. Foremost, these biological pathways include inflammation, cell proliferation, and apoptosis, all of which constitute important characteristics of atherosclerosis. Indeed, recent experimental evidence supports a potential involvement of the ubiquitin-proteasome system in the initiation, progression, and complication stage of atherogenesis. This review summarizes recent findings regarding the ubiquitin-proteasome system in cardiovascular diseases and discusses the potential use of proteasome inhibitors in cardiovascular therapy.
Angiotensin II Induces Apoptosis of Human Endothelial Cells
Authors: Stefanie Dimmeler, Volker Rippmann, Ulrike Weiland, Judith Haendeler, Andreas M. Zeiher
Journal: Circulation Research (1997)

Abstract Angiotensin II (Ang II) importantly contributes to the pathobiology of atherosclerosis. Since endothelial injury is a key event early in the pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure endothelial cells by activation of cellular suicide pathways leading to apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by ELISA specific for histone-associated DNA fragments and confirmed by DNA laddering and nuclear staining. Ang II dose-dependently induced apoptosis of HUVECs. Simultaneous blockade of both the AT 1 and AT 2 receptor prevented Ang II–induced apoptosis, whereas each individual receptor blocker alone was not effective. Selective agonistic stimulation of the AT 2 receptor also dose-dependently induced apoptosis. Ang II–mediated as well as selective AT 2 receptor stimulation–mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program. Specific inhibition of caspase-3 activity abrogated Ang II–induced apoptosis. In addition, the NO donors sodium nitroprusside and S -nitrosopenicillamine completely inhibited Ang II–induced apoptosis and eliminated caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of the caspase cascade, the central downstream effector arm executing the cell death program. NO completely abrogated Ang II–induced apoptosis by interfering with the activation of the caspase cascade.
Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits
Authors: Y. Ding, Y.-L. Li, M. C. Zimmerman, R. L. Davisson, H. D. Schultz
Journal: Cardiovascular Research (2008)

Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase-derived superoxide mediates angiotensin II (Ang II)-enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II- and CHF-enhanced superoxide anion effect. Here we investigated the role of cytoplasmic SOD [CuZn superoxide dismutase (CuZnSOD)] in the CB on chemoreceptor activity and function in CHF rabbits.CuZnSOD protein expression was decreased in CBs from CHF rabbits vs. sham (P < 0.05). Adenoviral CuZnSOD (Ad CuZnSOD) gene transfer to the CBs increased CuZnSOD protein expression and significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits (P < 0.05). Single-fibre discharge from CB chemoafferents during normoxia (baseline, at approximately 100 mmHg PO2) and in response to hypoxia were enhanced in CHF vs. sham rabbits (P < 0.05). Ad CuZnSOD decreased the baseline discharge (7.6 +/- 1.3 vs. 12.6 +/- 1.7 imp/s at approximately 100 mmHg PO2) and the response to hypoxia (22.4 +/- 1.6 vs. 32.3 +/- 1.2 imp/s at approximately 40 mmHg PO2, P < 0.05) in CHF rabbits. Ad CuZnSOD also normalized the blunted outward K+ current (IK) in CB glomus cells from CHF rabbits (369 +/- 14 vs. 565 +/- 31 pA/pF at +70 mV, P < 0.05). In addition, Ad CuZnSOD reduced the elevation of superoxide level in CBs from CHF rabbits.Downregulation of CuZnSOD in the CB contributes to the enhanced activity of CB chemoreceptors and chemoreflex function in CHF rabbits.
Phase I Study of Antisense Oligonucleotide Against Vascular Endothelial Growth Factor: Decrease in Plasma Vascular Endothelial Growth Factor With Potential Clinical Efficacy
Authors: Alexandra M. Levine, Anil Tulpule, David I. Quinn, Gerardo Gorospe, D. Lynne Smith, Laurie Hornor, William D. Boswell, Byron M. Espina, Susan G. Groshen, Rizwan Masood, Parkash S. Gill
Journal: Journal of Clinical Oncology (2006)

Purpose Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies. Methods VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined. Results The maximum-tolerated dose was 200 mg/m 2 . Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m 2 . Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t 1/2β (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively. Conclusion VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.
Physical and Functional Association of the Major Histocompatibility Complex Class I Heavy Chain α3 Domain with the Transporter Associated with Antigen Processing
Authors: Kimary Kulig, Dipankar Nandi, Igor Bacik, John J. Monaco, Stanislav Vukmanovic
Journal: The Journal of Experimental Medicine (1998)

CD8+ T lymphocytes recognize antigens as short, MHC class I-associated peptides derived by processing of cytoplasmic proteins. The transporter associated with antigen processing translocates peptides from the cytosol into the ER lumen, where they bind to the nascent class I molecules. To date, the precise location of the class I-TAP interaction site remains unclear. We provide evidence that this site is contained within the heavy chain α3 domain. Substitution of a 15 amino acid portion of the H-2Db α3 domain (aa 219-233) with the analogous MHC class II (H-2IAd) β2 domain region (aa 133-147) results in loss of surface expression which can be partially restored upon incubation at 26°C in the presence of excess peptide and β2-microglobulin. Mutant H-2Db (Db219-233) associates poorly with the TAP complex, and cannot present endogenously-derived antigenic peptides requiring TAP-dependent translocation to the ER. However, this presentation defect can be overcome through use of an ER targeting sequence which bypasses TAP-dependent peptide translocation. Thus, the α3 domain serves as an important site of interaction (directly or indirectly) with the TAP complex and is necessary for TAP-dependent peptide loading and class I surface expression.
Treatment of primary osteosarcoma with intra-arterial and intravenous high-dose methotrexate.
Authors: N Jaffe, J Prudich, J Knapp, Y M Wang, R Bowman, A Cangir, A Ayala, V Chuang, S Wallace
Journal: Journal of Clinical Oncology (1983)

In an effort to achieve high concentrations and prolonged exposure times, high-dose methotrexate (MTX) was administered by the intra-arterial route over 6 hours at a dose of 12.5 g/m2 to nine patients with osteosarcoma. This was followed by citrovorum factor (CF) rescue, which was initiated 12 hours after completion of the infusion (MTX-CF). The regimen achieved high local concentrations over a finite period. No toxicity was encountered. Treatment was administered at weekly intervals, during which intravenous MTX-CF was interposed if facilities for intra-arterial administration were not available. However, despite increases in local venous concentrations and exposure times, only four of nine patients (44%) responded. This is similar to responses achieved with 7.5 g/m2 (48%) with CF initiated 2 hours after completion of the infusion. Higher MTX doses, intra-arterial administration, and prolongation of cytotoxic exposure time did not confer a therapeutic advantage as opposed to "conventional" intravenous high doses.