tbuckley/cabot-search huggingface dataset:
Inhibitory Effects of Novel AP-1 Decoy Oligodeoxynucleotides on Vascular Smooth Muscle Cell Proliferation In Vitro and Neointimal Formation In Vivo
Authors: Jong Deok Ahn, Ryuichi Morishita, Yasufumi Kaneda, Sang-Jun Lee, Ki-Young Kwon, Se-Young Choi, Ki-Up Lee, Joong-Yeol Park, Ik-Jae Moon, Jong-Gu Park, Masao Yoshizumi, Yasuyoshi Ouchi, In-Kyu Lee
Journal: Circulation Research (2002)

Excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation are critical steps in the pathogenesis of atherosclerosis and restenosis after percutaneous transluminal angioplasty. In this study, we investigated the hypothesis that the activator protein-1 (AP-1) plays an important role in neointimal formation after vascular injury. A circular dumbbell AP-1 decoy oligodeoxynucleotide (CDODN) was developed as a novel therapeutic strategy for restenosis after angioplasty. This CDODN was more stable than the conventional phosphorothioate linear decoy ODN (PSODN) and maintained structural integrity on exposure to exonuclease III or serum. Transfection with AP-1 decoy ODNs strongly inhibited VSMC proliferation and migration, as well as glucose- and serum-induced expression of PCNA and cyclin A genes. Administration of AP-1 decoy ODNs in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished neointimal formation after balloon injury to the rat carotid artery. Compared with PSODN, CDODN was more effective in inhibiting the proliferation of VSMCs in vitro and neointimal formation in vivo. Our results collectively indicate that AP-1 activation is crucial for the mediation of VSMC proliferation in response to vascular injury. Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans.
The effect of amiloride on the airway response to metabisulphite in asthma: a negative report
Authors: DR Baldwin, KL Grange, I Pavord, AJ Knox
Journal: European Respiratory Journal (1992)

Frusemide, a loop diuretic, has been shown to potently inhibit several indirect bronchoconstrictor challenges in asthma. The mechanism by which nebulized frusemide protects against indirect bronchoconstrictor stimuli in asthma is not known. One mechanism could be related to inhibition of sodium transport. If this is the case, then amiloride, another inhibitor of sodium transport, should also protect against indirect bronchoconstrictor challenges. Ten subjects with mild asthma were administered either 10(-2) M amiloride or placebo, by nebulizer, in a double-blind crossover fashion. After each inhalation, forced expiratory volume in one second (FEV1) was recorded at 10 min intervals for 30 min, after which a metabisulphite challenge was performed. No significant difference in the response to metabisulphite was seen between placebo and amiloride treatment. The mean difference in provocative dose of metabisulphite producing a 20% fall in FEV1 (PD20) between placebo and amiloride was 1.015 doubling doses, 95% confidence interval (95% CI) -0.201 to 2.231, (p = 0.09). This result does not support the hypothesis that frusemide is acting to protect against bronchoconstrictor challenges in asthma by an effect on sodium transport.
Evaluating Health System Reform
Authors: Jim McDermott
Journal: JAMA (1994)

THROUGHOUT history, the medical profession has struggled in its conflict between belief and science. In the late 18th century, this struggle was exemplified by a religious adherence to Dr Benjamin Rush's theory that bleeding patients would restore health. The result of this mistaken belief—as opposed to proven hypothesis—was that George Washington is historically thought to have been bled to death therapeutically. Two hundred years later, American medicine is still locked in its ambivalence between science and belief. But in 1993, the issue is health care system reform. In the debate emerging from the presentation of President Clinton's plan, the challenge for our profession will be whether it can move beyond time-honored mantras to examine objectively and scientifically the options with which it is presented. <h3>THE NEED FOR CHANGE</h3> Few would dispute the need for change. American physicians are the most dissatisfied and frustrated in the industrialized world.<sup>1</sup>Approximately 15%
Effects of Segregation on an Epidemic <i>Pseudomonas aeruginosa</i> Strain in a Cystic Fibrosis Clinic
Authors: Amanda L. Griffiths, Kris Jamsen, John B. Carlin, Keith Grimwood, Rosemary Carzino, Philip J. Robinson, John Massie, David S. Armstrong
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

The detection of a clonal Pseudomonas aeruginosa strain in 21% of children attending a cystic fibrosis clinic during 1999, which may have led to a worse prognosis, prompted strict infection control measures, including cohort segregation. We determined whether these strategies interrupted cross-infection within the clinic. Patients from 1999 were observed and a cross-sectional study of the 2002 clinic was performed. By 2002, the epidemic strain prevalence had decreased from 21 to 14% (p = 0.03), whereas the proportion of patients with nonepidemic P. aeruginosa strains was unchanged. The age- and sex-adjusted relative risk for epidemic strains among sputum producers in 2002 compared with 1999 was 0.64 (95% confidence interval, 0.47, 0.87; p = 0.004). Increased mortality or transfer to another clinic did not explain this reduction. Although children with epidemic strains may have had increased mortality (adjusted odds ratio, 2.0; 95% confidence interval, 0.6–6.8), they did not demonstrate greater morbidity than those with other P. aeruginosa isolates. Successful infection control measures provided additional indirect evidence for person-to-person transmission of an epidemic strain within the clinic. Further studies are needed to resolve whether cohort segregation completely eliminates cross-infection and if acquisition of epidemic isolates is associated with worse outcomes.
Compliance with return-to-play regulations following concussion in Australian schoolboy and community rugby union players
Authors: Stephanie J Hollis, Mark R Stevenson, Andrew S McIntosh, E Arthur Shores, Caroline F Finch
Journal: British Journal of Sports Medicine (2011)

Background There is a risk of concussion when playing rugby union. Appropriate management of concussion includes compliance with the return-to-play regulations of the sports body for reducing the likelihood of premature return-to-play by injured players. Purpose To describe the proportion of rugby union players who comply with the sports body's regulations on returning to play postconcussion. Study design Prospective cohort study. Methods 1958 community rugby union players (aged 15–48 years) in Sydney (Australia) were recruited from schoolboy, grade and suburban competitions and followed over ≥1 playing seasons. Club doctors/physiotherapists/coaches or trained injury recorders who attended the game reported players who sustained a concussion. Concussed players were followed up over a 3-month period and the dates when they returned to play (including either a game or training session) were recorded, as well as any return-to-play advice they received. Results 187 players sustained ≥1 concussion throughout the follow-up. The median number of days before players returned to play (competition game play or training) following concussion was 3 (range 1–84). Most players (78%) did not receive return-to-play advice postconcussion, and of those who received correct advice, all failed to comply with the 3-week stand-down regulation. Conclusions The paucity of return-to-play advice received by community rugby union players postconcussion and the high level of non-compliance with return-to-play regulations highlight the need for better dissemination and implementation of the return-to-play regulations and improved understanding of the underlying causes of why players do not adhere to return-to-play practices.
Interactions Between Ca <sup>2+</sup> and H <sup>+</sup> and Functional Consequences in Vascular Smooth Muscle
Authors: Clare Austin, Susan Wray
Journal: Circulation Research (2000)

Ca(2+) and H(+) ions can profoundly alter vascular tone. In many physiological and pathological processes, changes in the concentration of both ions occur. Thus, to understand the processes and mechanisms that modify force, it is necessary to understand what changes occur in these ions and, importantly, how they interact with each other. In this minireview, we highlight the quantitatively important mechanisms involved in the contractile responses of vascular tissues to pH change and discuss the cellular and molecular reasons underlying these responses.
Occurrence and distribution of a newly discovered peptide, galanin, in the mammalian enteric nervous system.
Authors: A E Bishop, J M Polak, F E Bauer, N D Christofides, F Carlei, S R Bloom
Journal: Gut (1986)

Galanin, a newly discovered peptide, was found throughout the gastrointestinal tract of man, pig, and rat, exclusively in nerves. The concentrations of immunoreactive galanin ranged from 3.7 +/- 0.7 (mean +/- SEM) pmol/g in rat antrum to 76.5 +/- 14.3 pmol/g in pig colon. The predominantly intrinsic origin of the galanin nerves was shown by the finding of the peptide in submucosal ganglion cells, the majority of which also contained VIP. Furthermore, neither extrinsic denervation of the gut nor administration of capsaicin, which selectively destroys extrinsic afferent fibres, had any significant effect on the galanin innervation. The caudal projection of galanin-immunoreactive fibres was demonstrated by complete transection of the gut, which led to their reduction in the 1 to 2 cm distal to the cut. The abundance of galanin in the innervation of the mammalian gut and its reported action on smooth muscle contractility suggest this peptide to be a novel regulatory factor in the control of bowel function.
Crohn's disease of the vulva—two further cases
Authors: H.A. LAVERY, J.H.M. PINKERTON, J. SLOAN
Journal: British Journal of Dermatology (1985)

Crohn's disease of the vulva is a rare disease, only eight cases having been described in the literature (Parks, Morson & Pegum, 1965; Mountain, 1970; Ansell & Hogbin, 1973; Devroede et al., 1975; Kao, Paulson & Askin, 1975; Levine, Barton & Grier, 1982). Two additional cases are presented, one of whom is the sixth reported with metastatic Crohn's disease of the vulva.
HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial
Authors: Henry C Kitchener, Maribel Almonte, Claire Thomson, Paula Wheeler, Alexandra Sargent, Boyka Stoykova, Clare Gilham, Helene Baysson, Christopher Roberts, Robin Dowie, Mina Desai, Jean Mather, Andrew Bailey, Andrew Turner, Sue Moss, Julian Peto
Journal: The Lancet Oncology (2009)
Economic Evaluation of Sunitinib Malate for the First-Line Treatment of Metastatic Renal Cell Carcinoma
Authors: Edit Remák, Claudie Charbonneau, Sylvie Négrier, Sindy T. Kim, Robert J. Motzer
Journal: Journal of Clinical Oncology (2008)

To assess the cost effectiveness and cost utility of sunitinib malate as a first-line treatment in metastatic renal cell carcinoma (mRCC) compared with interferon-alfa (IFN-alpha) and interleukin-2 (IL-2) from a US societal perspective.A Markov model was developed to simulate disease progression and to determine progression-free survival, total life-years (LYs), and quality-adjusted life-years (QALYs) gained. Model parameters were derived from the pivotal trial of sunitinib, published literature, government sources, and clinical experts' opinions. The model included trial-based adverse events (AEs). Costs of drug treatment, routine follow-up, AEs, disease progression, and best supportive care (BSC) of terminally ill patients were included. Results were tested using probabilistic and deterministic sensitivity analyses.Treatment with sunitinib is associated with a gain in progression-free years of 0.41 and 0.35 over IFN-alpha and IL-2. The estimated gains over IFN-alpha were 0.11 LYs and 0.14 QALYs, and over IL-2 were 0.24 LYs and 0.20 QALYs. Both IFN-alpha and sunitinib treatments dominate IL-2 treatment; the incremental cost-effectiveness ratio of sunitinib versus IFN-alpha was $18,611 per progression-free year gained and $67,215 per LY gained, and the cost-utility ratio is $52,593 per QALY gained (at a 5% discount rate). Sensitivity analyses found the results to be most sensitive to utility values during treatment, the cost of sunitinib, and the cost of BSC. Model results were robust to changes in other model variables.These results suggest that sunitinib is a cost-effective alternative to IFN-alpha as a first-line treatment for mRCC.
Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease
Authors: J D Soderholm
Journal: Gut (2002)

Background: Crohn9s disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohn9s disease. Aims: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohn9s disease. Patients: Surgical specimens from the distal ileum of patients with Crohn9s disease (n=12) were studied, and ileal specimens from colon cancer patients (n=13) served as controls. Methods: Mucosal permeability to <sup>51</sup>Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. Results: Baseline permeability was the same in non-inflamed ileum of Crohn9s disease and controls. Sodium caprate induced a rapid increase in paracellular permeability—that is, increased permeation of <sup>51</sup>Cr-EDTA and decreased electrical resistance—which was more pronounced in non-inflamed ileum of Crohn9s disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohn9s disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. Conclusions: The tight junctions in the non-inflamed distal ileum of Crohn9s disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohn9s disease.
Kinematics of a slip-catch mechanism for anterior cruciate ligament injury in world cup alpine skiing
Authors: H Koga, T Bere, R Bahr, T Krosshaug
Journal: British Journal of Sports Medicine (2011)

Background We have identified that a slip-catch situation is the main mechanism for anterior cruciate ligament (ACL) injuries in World Cup alpine skiing by simple visual inspection of injury videos. This occurs when the skier loses pressure on the outer ski during turning, and while extending the outer knee to regain grip, the inside edge of the outer ski catches abruptly, forcing the knee into valgus and internal rotation. To develop injury prevention methods based on this mechanism, a more precise description is needed. Objective To describe the detailed joint kinematics in a slip-catch situation using a model-based image-matching (MBIM) technique. Design Case study. Setting Men's World Cup alpine skiing. Methods Video of a slip-catch injury situation in slalom captured with two nearly perpendicular camera views was analyzed using the MBIM method to obtain the time course of knee and hip joint kinematics. Results Knee valgus and internal rotation angle increased by 13° and 13°, respectively, in the last 60 ms before the time of ACL rupture, which was estimated to occur 100 ms after the catching the edge. Knee flexion angle increased by 32° in the last 20 ms from 22° at snow contact to a final position. Hip flexion and adduction angle increased by 18° and 13°, respectively, in the last 20 ms and the hip stayed at approximately 30° of internal rotation in the last 60 ms. Conclusion Abrupt compression, valgus and internal rotation loading seems to be the main mechanism of slip-catch injury situations in ACL injuries in World Cup alpine skiing. The knee loading pattern described from the previous simple visual inspection study matched well with the more detailed analysis using the MBIM technique. Prevention efforts should focus on avoiding valgus and internal rotation loading on the knee.
The pharmacological response of ischemia-related atrial fibrillation in dogs: Evidence for substrate-specific efficacy
Authors: L RIVARD, H SINNO, A SHIROSHITATAKESHITA, G SCHRAM, T LEUNG, S NATTEL
Journal: Cardiovascular Research (2007)

Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF.Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective.Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.
Metabolic Modulation of Glioblastoma with Dichloroacetate
Authors: E. D. Michelakis, G. Sutendra, P. Dromparis, L. Webster, A. Haromy, E. Niven, C. Maguire, T.-L. Gammer, J. R. Mackey, D. Fulton, B. Abdulkarim, M. S. McMurtry, K. C. Petruk
Journal: Science Translational Medicine (2010)

Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, shifts metabolism away from aerobic glycolysis in glioblastoma tumor cells and may have clinical efficacy in patients.
Prospective study of phobic anxiety and risk of coronary heart disease in men.
Authors: I Kawachi, G A Colditz, A Ascherio, E B Rimm, E Giovannucci, M J Stampfer, W C Willett
Journal: Circulation (1994)

BACKGROUND To examine prospectively the association between self-reported symptoms of phobic anxiety and subsequent risk of coronary heart disease, a 2-year follow-up study was conducted of a cohort of 33,999 US male health professionals, aged 42 to 77 years in 1988, who were free of diagnosed cardiovascular disease at baseline. Levels of phobic anxiety were assessed using the Crown-Crisp index, a short, diagnostic self-rating scale used for common phobias. Main outcomes were incidents of coronary heart disease consisting of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD). METHODS AND RESULTS One hundred sixty-eight incident cases of CHD occurred during 2 years of follow-up (128 cases of nonfatal MI and 40 cases of fatal CHD). The age-adjusted relative risk of fatal CHD among men with highest levels of phobic anxiety (scoring 4 or higher on the Crown-Crisp index) was 3.01 (95% confidence interval, 1.31 to 6.90) compared with men with the lowest levels of anxiety (scoring 0 or 1 on the phobia index). Risk of fatal CHD increased with levels of phobic anxiety (P trend = .002). When fatal CHD was further categorized into sudden and nonsudden coronary death, the excess risk was confined to sudden death (relative risk among men scoring 3 or higher on the phobia index was 6.08; 95% confidence interval, 2.35 to 15.73). No association was found between phobic anxiety and risk of nonfatal MI. These findings remained essentially unchanged after adjusting for a broad range of cardiovascular risk factors. CONCLUSIONS The specificity, strength, and dose-response gradient of the association, together with the consistency and biological plausibility of the experimental and epidemiologic evidence, support a strong causal association between phobic anxiety and fatal CHD.
Circulating KL-6, a biomarker of lung injury, in obstructive sleep apnoea
Authors: D. J. Lederer, S. Jelic, R. C. Basner, A. Ishizaka, J. Bhattacharya
Journal: European Respiratory Journal (2009)

In obstructive sleep apnoea (OSA), oxidative stress contributes to endothelial dysfunction in the peripheral circulation. In the lung, oxidative stress can lead to alveolar injury. The present authors hypothesised that patients with OSA would have biomarker evidence of increased alveolar wall permeability. Sleep characteristics, brachial artery flow-mediated dilation and plasma KL-6 levels were observed in 11 otherwise healthy patients with OSA and 10 controls. Median (interquartile range) plasma KL-6 levels were higher in patients with OSA compared with controls: 317 (232-506) U.mL(-1) versus 226 (179-257) U.mL(-1), respectively. Higher plasma KL-6 levels were associated with greater time spent asleep with an oxyhaemoglobin saturation <90%, lower nadir saturation, more frequent desaturation of >4% during sleep and lower brachial artery flow-mediated dilation. Adjustment for nadir saturation or flow-mediated dilation attenuated the association between plasma KL-6 levels and OSA. Circulating KL-6 levels are elevated in some patients with obstructive sleep apnoea, possibly reflecting increased alveolar wall permeability.