tbuckley/cabot-search huggingface dataset:
iNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells
Authors: Sara De Boo, Joanna Kopecka, Davide Brusa, Elena Gazzano, Lina Matera, Dario Ghigo, Amalia Bosia, Chiara Riganti
Journal: Molecular Cancer (2009)

Abstract Background Doxorubicin is one of the few chemotherapeutic drugs able to exert both cytotoxic and pro-immunogenic effects against cancer cells. Following the drug administration, the intracellular protein calreticulin is translocated with an unknown mechanism onto the plasma membrane, where it triggers the phagocytosis of tumour cells by dendritic cells. Moreover doxorubicin up-regulates the inducible nitric oxide (NO) synthase (iNOS) gene in cancer cells, leading to huge amounts of NO, which in turn acts as a mediator of the drug toxicity and as a chemosensitizer agent in colon cancer. Indeed by nitrating tyrosine on the multidrug resistance related protein 3, NO decreases the doxorubicin efflux from tumour cells and enhances the drug toxicity. It is not clear if NO, beside playing a role in chemosensitivity, may also play a role in doxorubicin pro-immunogenic effects. To clarify this issue, we compared the doxorubicin-sensitive human colon cancer HT29 cells with the drug-resistant HT29-dx cells and the HT29 cells silenced for iNOS (HT29 iNOS - ). Results In both HT29-dx and HT29 iNOS - cells, doxorubicin did not induce NO synthesis, had a lower intracellular accumulation and a lower toxicity. Moreover the drug failed to promote the translocation of calreticulin and the phagocytosis of HT29-dx and HT29 iNOS - cells, which resulted both chemoresistant and immunoresistant. However, if NO levels were exogenously increased by sodium nitroprusside, the chemosensitivity to doxorubicin was restored in HT29 iNOS - cells. In parallel the NO donor per se was sufficient to induce the exposure of calreticulin and to increase the phagocytosis of HT29 iNOS - cells by DCs and their functional maturation, thus mimicking the pro-immunogenic effects exerted by doxorubicin in the parental drug-sensitive HT29 cells. Conclusion Our data suggest that chemo- and immuno-resistance to anthracyclines are associated in colon cancer cells and rely on a common mechanism, that is the inability of doxorubicin to induce iNOS . Therefore NO donors might represent a promising strategy to restore both chemosensitivity and immunosensitivity to doxorubicin in resistant cells.
Tattoo removal using infra-red coagulation: a dose comparison
Authors: V.A. YENNING, G.B. COLVER, P.R. MILLARD, T.J. RYAN
Journal: British Journal of Dermatology (1987)

Using an infra-red coagulator, 42 tattoos were treated using pulses of 1.125 s (27 tattoos) or 1.25 s (15 tattoos). Treatment failures occurred only in three professional tattoos. Amateur tattoos were satisfactorily treated in over 80% of cases regardless of dose. Deeper collagen necrosis occurred with 1.25 s, but scarring was clinically similar. Pre-treatment biopsy to assess pigment depth was of no value in selection of the optimum pulse duration and increased the complication rate. The possible mechanism of pigment removal is discussed.
Wetsuits, body density and swimming performance.
Authors: L Cordain, R Kopriva
Journal: British Journal of Sports Medicine (1991)

To determine the influence of body composition upon swimming performance with and without wetsuits, 14 competitive female swimmers (mean (s.d.) age, 19.9 (0.9) years) were measured for body density while wearing both wetsuits and normal swimsuits. Subjects swam 400 and 1500 m trials with and without wetsuits, randomly, over a 12-day period. Six subjects participated in an additional trial while wearing neoprene leg-bands fitted over the wetsuit. Mean (s.d.) subject density without and with wetsuits was 1.048 (.009) and 1.021 (.007) g/ml respectively. Wetsuits reduced (P less than 0.05) swim times for the 400 (-4.96%) and 1500 m swim (-3.23%) compared with swimsuit trials. The neoprene bands increased (P less than 0.05) swim times relative to swimsuit and wetsuit trials. With wetsuits, swim times were inversely (P less than 0.05) related to density for the 400 (r = -0.46) and 1500 m swim (r = -0.54) suggesting that wetsuits increase performance by increasing buoyancy and that lean subjects benefit more from wearing wetsuits than do fatter subjects.
A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill
Authors: W. Antoinette Groenewegen, Mehran Firouzi, Connie R. Bezzina, Saskia Vliex, Irene M. van Langen, Lodewijk Sandkuijl, Jeroen P.P. Smits, Miriam Hulsbeek, Martin B. Rook, Habo J. Jongsma, Arthur A.M. Wilde
Journal: Circulation Research (2003)

Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G). Eight relatives were homozygous for both polymorphisms, which occurred in only approximately 7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS.
Developing appropriate methodology for the study of surgical techniques
Authors: Peter McCulloch
Journal: Journal of the Royal Society of Medicine (2009)

The critical re-examination of practice stimulated by evidence-based medicine revealed that some disciplines were supported by more scientifically valid research than others. Surgery was specifically criticized for failing to adopt randomized controlled trials (RCTs), when the small proportion of practice supported by such evidence was reported. Randomized trials of surgical technique face a range of problems,1 several shared with other disciplines using complex or therapist-dependent interventions, (e.g. Public Health, Physiotherapy), but the problem is more fundamental than surgeons not doing enough RCTs. The development process of surgical techniques simply does not fit well into our current paradigm of clinical investigation.

This has often prevented adequate evaluation ever occurring, leaving much surgical knowledge in a state of arrested development. We need to recognize that the technical development process differs fundamentally from that for drug treatments, having its own recognizable stages. Only by explicitly acknowledging this natural history can we recognize the weak points in current methodological approaches, and develop more appropriate study designs (Table 1 ). In this article the phases of surgical technique development are described, together with the problems which commonly affect their study. Some approaches which might result in more effective evaluation of each stage are proposed.



Table 1

Current weaknesses in the evaluation of surgical techniques




Stages of development
The phases of development for surgical techniques differ significantly from those for new drugs.Operations, for example, are not tested on healthy volunteers, and the dose of surgery cannot beadjusted. Development of surgical techniques begins with description and proof of feasibility (Phase 0) followed by refinement and definition of the procedure (Phase 1). After this, techniques undergo dissemination and evaluation by other surgeons (Phase 2). Ideally, techniques should then be compared with gold standard therapy (Phase 3). Finally, monitoring for long-termadverse effects and deviation from expected outcomes occurs (Phase 4) and is arguably even more important for surgical techniques than for medications.

Phase 0: Proof of principle
The first publication about a new surgical technique is usually a report of a single case or a small case series. This serves the purposes of describing the technique, and of establishing that a satisfactory outcome is feasible. Analogous studies in drug development would be preliminary to a Phase 1 trial.
Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age
Authors: Catherine Ann Byrnes, Suzanna Vidmar, Joyce L Cheney, John B Carlin, David S Armstrong, Peter J Cooper, Keith Grimwood, Marj Moodie, Colin F Robertson, Margaret Rosenfeld, Harm A Tiddens, Claire E Wainwright
Journal: Thorax (2013)

<h3>Background</h3> Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. <h3>Methods</h3> Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. <h3>Results</h3> 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p&lt;0.001) per year of age. Exacerbation rate differed by site (p&lt;0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient −0.39, 95% CI −0.74 to −0.05). <h3>Conclusions</h3> Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.
Randomised, controlled trial of alternating pressure mattresses compared with alternating pressure overlays for the prevention of pressure ulcers: PRESSURE (pressure relieving support surfaces) trial
Authors: Jane Nixon, Gillian Cranny, Cynthia Iglesias, E Andrea Nelson, Kim Hawkins, Angela Phillips, David Torgerson, Su Mason, Nicky Cullum
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To compare whether differences exist between alternating pressure overlays and alternating pressure mattresses in the development of new pressure ulcers, healing of existing pressure ulcers, and patient acceptability. <b>Design</b> Pragmatic, open, multicentre, randomised controlled trial. <b>Setting</b> 11 hospitals in six NHS trusts. <b>Participants</b> 1972 people admitted to hospital as acute or elective patients. <b>Interventions</b> Participants were randomised to an alternating pressure mattress (n = 982) or an alternating pressure overlay (n = 990). <b>Main outcome measures</b> The proportion of participants developing a new pressure ulcer of grade 2 or worse; time to development of new pressure ulcers; proportions of participants developing a new ulcer within 30 days; healing of existing pressure ulcers; and patient acceptability. <b>Results</b> Intention to treat analysis found no difference in the proportions of participants developing a new pressure ulcer of grade 2 or worse (10.7% overlay patients, 10.3% mattress patients; difference 0.4%, 95% confidence interval - 2.3% to 3.1%, P = 0.75). More overlay patients requested change owing to dissatisfaction (23.3%) than mattress patients (18.9%, P = 0.02). <b>Conclusion</b> No difference was found between alternating pressure mattresses and alternating pressure overlays in the proportion of people who develop a pressure ulcer. <b>Trial registration</b> ISRCTN 78646179
The FCRL3 -169T&gt;C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases
Authors: M C Eike, G B N Nordang, T H Karlsen, K M Boberg, K Dahl-Jorgensen, K S Ronningen, G Joner, B Flato, A Bergquist, E Thorsby, O Forre, T K Kvien, D E Undlien, B A Lie
Journal: Annals of the Rheumatic Diseases (2007)

The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs.We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests.RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels.We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.
Sequential unipolar strength-interval curves and conduction times during myocardial ischemia and reperfusion in the dog.
Authors: H J Levine, B Avitall, S G Pauker, S Naimi
Journal: Circulation Research (1978)

Computerized techniques were employed to generate alternating anodal and cathodal or sequential anodal strength-interval curves during and following 15-minute coronary artery ligations in 14 anesthetized dogs. The right atrium was paced at 2.5 Hz, and unipolar ventricular strength-interval curves with simultaneous conduction times were recorded every 45-120 seconds during ischemia and reperfusion. Within 1--2 minutes of ligation, anodal midcurve and late diastolic thresholds fell sharply, and cathodal thresholds fell slightly or changed little. After 5 minutes of ischemia, anodal thresholds remained low, cathodal thresholds rose, and conduction times increased. At 10--15 minutes of ligation, if the ischemic zone was small, anodal thresholds were low, often approaching cathodal values, and conduction returned toward control values. When the ischemic zone was large, unipolar thresholds and conduction times increased late during the ligation period. Throughout the course of ischemia, the falling limb of the strength-interval curve shifted progressively to the left indicating shorter refractory periods. Following abrupt reperfusion, anodal phase 3 dips promptly reappeared; refractory periods returned toward control, and supernormal conduction was noted. By 3--5 minutes of reperfusion, the falling limb of the strength-interval curve had shifted to the right of control and conduction times increased. Thus, vulnerability to arrhythmias during early ischemia (i.e., 5 minutes) is characterized by low anodal midcurves and late diastolic thresholds, short refractory periods, and slow conduction. During the first minute of reperfusion, anodal excitability is increased during the early dip and conduction times are supernormal. Increases in anodal excitability correlate better with the peak incidence of early ligation and reperfusion arrhythmias than do changes in cathodal excitability.
Get With The Guidelines-Stroke Performance Indicators: Surveillance of Stroke Care in the Taiwan Stroke Registry
Authors: Fang-I Hsieh, Li-Ming Lien, Sien-Tsong Chen, Chyi-Huey Bai, Mu-Chien Sun, Hung-Pin Tseng, Yu-Wei Chen, Chih-Hung Chen, Jiann-Shing Jeng, Song-Yen Tsai, Huey-Juan Lin, Chung-Hsiang Liu, Yuk-Keung Lo, Han-Jung Chen, Hou-Chang Chiu, Ming-Liang Lai, Ruey-Tay Lin, Ming-Hui Sun, Bak-Sau Yip, Hung-Yi Chiou, Chung Y. Hsu
Journal: Circulation (2010)

Stroke is a leading cause of death around the world. Improving the quality of stroke care is a global priority, despite the diverse healthcare economies across nations. The American Heart Association/American Stroke Association Get With the Guidelines-Stroke program (GWTG-Stroke) has improved the quality of stroke care in 790 US academic and community hospitals, with broad implications for the rest of the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry, with 30 599 stroke admissions between 2006 and 2008, was used to assess the applicability of GWTG-Stroke in Taiwan, which spends ≈ 1/10 of what the United States does in medical costs per new or recurrent stroke.Taiwan Stroke Registry, sponsored by the Taiwan Department of Health, engages 39 academic and community hospitals and covers the entire country with 4 steps of quality control to ensure the reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applicable to assess Taiwan Stroke Registry quality of stroke care. Demographic and outcome figures are comparable between GWTG-Stroke and Taiwan Stroke Registry. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards, while 3 other indicators (intravenous tissue plasminogen activator, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Preliminary analysis shows that compliance with selected GWTG-Stroke guidelines is associated with better outcomes.Results suggest that GWTG-Stroke performance measures, with modification for ethnic factors, can become global standards across national and economic boundaries for assessing and improving quality of stroke care and outcomes. GWTG-Stroke can be incorporated into ongoing stroke registries across nations.
Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition
Authors: Mariarosaria Bucci, Valentina Vellecco, Anna Cantalupo, Vincenzo Brancaleone, Zongmin Zhou, Stefano Evangelista, Vincenzo Calderone, Andreas Papapetropoulos, Giuseppe Cirino
Journal: Cardiovascular Research (2014)

Therapeutic use of sulfhydrylated inhibitor S-zofenopril has raised different hypotheses regarding the role played by its thiol group in the beneficial clinical effects exerted compared with other angiotensin-converting enzyme (ACE) inhibitors. Here, we investigated hydrogen sulfide (H2S) pathway as accountable for extra-beneficial effects in vascular function. Spontaneously hypertensive rat (SHRs) and control Wistar Kyoto (WKY) rats were treated with either S-zofenopril or enalapril in vivo. Aorta and carotid were harvested and ex vivo vascular reactivity to acetylcholine (Ach) and l-cysteine (l-cys) assessed. Cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptosulfur-transferase (3MST) expression, as well as H2S levels, were evaluated in both vascular tissues. The vascular response to Ach in both carotid and aorta was impaired in SHR (∼30%, P < 0.001). S-zofenopril, but not enalapril, restored this response, while l-cys-induced relaxation was enhanced. CSE expression in vessels and tissue/plasma H2S levels were restored to WKY values in SHRs receiving S-zofenopril. In contrast, CBS and 3MST expression were not modified by treatments. S-zofenoprilat, an active metabolite of S-zofenopril, releases H2S in a 'cell-free' assay and it directly relaxed vessels in vitro in a concentration-dependent manner (P < 0.001). In vivo administration of R-zofenoprilat diasteroisomer, which does not inhibit ACE, did not modify blood pressure; nonetheless, it retained the beneficial effect on SHR vascular function as well as restored plasma/tissue H2S levels. Our findings establish that S-zofenopril improves vascular function by potentiating the H2S pathway in a model of spontaneous hypertension. This novel mechanism, unrelated to ACE inhibition and based on H2S release, could explain the beneficial effects of sulfhydrylated ACE inhibitors reported in the clinical literature.
Double blind controlled study on the effect of sucralfate on gastric prostaglandin formation and microbleeding in normal and aspirin treated man.
Authors: S J Konturek, N Kwiecien, W Obtulowicz, B Kopp, J Oleksy
Journal: Gut (1986)

Two groups A and B each comprising 12 healthy young male subjects were used in a double blind, placebo controlled trial to assess the effects of 1.0 g sucralfate qid on prostaglandin (PG) generation and mucosal integrity in the intact and aspirin-treated stomach. Mucosal formation and luminal release of PGE2, 6-keto-PGE1 alpha and thromboxane B2, gastric microbleeding and DNA loss (integrity indicators) and basal and pentagastrin induced acid secretion were measured after placebo and sucralfate treatment in subjects without (group A) and with administration of 2.5 g aspirin (group B). Sucralfate significantly reduced spontaneous gastric microbleeding and DNA loss in group A and prevented blood loss but not DNA loss caused by aspirin in group B. The protective effects of sucralfate on spontaneous gastric microbleeding were accompanied by increased mucosal biosynthesis and luminal release of PGE2 and 6-keto-PGF1 alpha with a reduction in release of thromboxane B2. In aspirin treated subjects both mucosal generation and luminal release of prostaglandins and thromboxane B2 were greatly suppressed although sucralfate treatment did not influence these prostaglandins in spite of the reduction in mucosal damage. It is concluded that sucralfate has a potent protective action on spontaneous and aspirin treated gastric microbleeding in man and that this protection may be partly because of the increased mucosal biosynthesis of prostaglandins.
Asthma Control Test: reliability, validity, and responsiveness in Korean patients
Authors: K. Hyouk-Soo, K. Deok-In, P. Chang-Han, S. Seong-Wook, L. Sang-Min, S. Woo-Jung, K. Yong-Eun, P. Heung-Woo, K. Sun-Sin, C. Sang-Heon, M. Kyoung-Up, K. You-Young, C. Yoon-Seok
Journal: Journal of Allergy and Clinical Immunology (2007)