tbuckley/cabot-search huggingface dataset:
Injury prevention advances in alpine ski racing: Harnessing collaboration with the International Ski Federation (FIS), long-term surveillance and digital technology to benefit athletes
Authors: Tone Bere, Roald Bahr
Journal: British Journal of Sports Medicine (2014)

Everything that can be counted does not necessarily count; everything that counts cannot necessarily be counted (Albert Einstein 1879-1955).

Alpine ski racing is an Olympic winter sport where athletes ski one by one down the mountain on a demanding course, often in challenging snow and weather conditions. The Athletes must ski as efficiently as possible, as performance is determined by the racing time measured to 0.01 s, but at the same time they have to adapt speed and trajectory to their technical skills and manage risk responsibly. In this issue, Gilgien et al 1 quantify and describe the mechanical characteristics (such as skier speed, turn radius, air drag force, ground reaction force, jump distance and airtime) of World Cup alpine skiing under real race conditions, and interestingly they link these data to the risk of injury. With their biomechanical approach, they add new and valuable information to the field of injury prevention …
A combination of a fixed dose rate infusion of gemcitabine associated to a bolus 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)
Authors: S. Cascinu, L. Frontini, R. Labianca, V. Catalano, S. Barni, C. Graiff, G. Picone, F. Farinati, S. Zonato, M.A. Pessi, C. Curti, G. Catalano
Journal: Annals of Oncology (2000)
Forensic Injury Biomechanics
Authors: Wilson C. Hayes, Mark S. Erickson, Erik D. Power
Journal: Annual Review of Biomedical Engineering (2007)

Forensic injury biomechanics is the science that relates mechanical forces to disruption of anatomical regions of the human body. In this review, we introduce (a) how scaling techniques can be used to describe injury severity and probability of death; (b) how a simple ratio, the factor of risk, and more sophisticated injury risk functions can be used to determine the probability of injury; and (c) how injury criteria (also known as tolerance limits) are defined for the head and neck. Methods for establishing injury causation are then illustrated by real-world examples drawn from litigation involving motor vehicle collisions and slips, trips and falls. Those factors that distinguish litigation from basic and applied research are also discussed, including the criteria for admissibility of expert opinions and the level of certainty used as the basis for these opinions. The criteria that must be met to support opinions on causation at both epidemiological and individual levels are also noted. If the expert appreciates the difference between the demands of ligation and those of basic and applied research, expert opinion can play a crucial role in the decision-making process that characterizes litigation. Because forensic injury biomechanics is central to opinions on injury causation, and because causation is often the key to determinations of who is at fault, forensic injury biomechanics can be the deciding factor in many personal injury, products and premises liability, wrongful death, and criminal cases.
Electrophysiological Consequences of Purinergic Receptor Stimulation in Isolated Rat Pulmonary Arterial Myocytes
Authors: S. Anthony Hartley, Roland Z. Kozlowski
Journal: Circulation Research (1997)

Neither the electrophysiological effects of purinergic receptor stimulation nor the role of ATP in regulating the tone of pulmonary arterial smooth muscle has been determined. Therefore, we investigated the effects of purine nucleotides on acutely dissociated smooth muscle cells from rat small pulmonary arteries using the patch-clamp recording technique. Extracellular application of ATP activated a fast transient inward current (which decayed in the continued presence of the nucleotide) and produced sustained periodic oscillations of predominantly inward current. Pharmacological and anion substitution experiments revealed that the transient inward current was carried by the movement of cations. In contrast, the periodic oscillations of current were due primarily to a Ca(2+)-activated Cl- current (ICl,Ca) dependent on the release of Ca2+ from intracellular stores. Experiments using ATP analogues revealed the following order of potency for activation of the fast transient inward current: 2-methylthio ATP (2-meSATP) > ATP > alpha,beta-methylene ATP (alpha,beta-meATP) > > ADP > UTP = adenosine. Cross desensitization was seen between applications of ATP, alpha,beta-meATP, and 2-meSATP, suggesting that these agonists act via a common site. The order of potency for activation of ICl,Ca was UTP = ATP > > ADP > or = 2-meSATP > alpha,beta-meATP = adenosine. Both the fast transient inward current and ICl,Ca evoked by ATP and its analogues were abolished by the nonselective P2 purinoceptor antagonist suramin. These results show the existence of P2x and P2U purinoceptor subtypes in pulmonary arterial smooth muscle cells. Stimulation of these receptors results in activation of a fast transient inward cation current and ICl,Ca, respectively. It is likely that ATP acts via these receptor subtypes to regulate pulmonary arterial tone under physiological or pathological conditions.
Phase I Trials of Molecularly Targeted Agents: Should We Pay More Attention to Late Toxicities?
Authors: Sophie Postel-Vinay, Carlos Gomez-Roca, L. Rhoda Molife, Bhavesh Anghan, Antonin Levy, Ian Judson, Johann De Bono, Jean-Charles Soria, Stan Kaye, Xavier Paoletti
Journal: Journal of Clinical Oncology (2011)

Purpose Phase I trials traditionally aim at determining the recommended phase II dose (RP2D) using grade ≥ 3 toxicity data from cycle 1 (C1) only. This design dates from the era of conventional chemotherapy and may not be relevant for new molecularly targeted agents (MTAs) usually administered in a chronic fashion and for which late or moderate toxicities may deserve particular attention. Patients and Methods All consecutive patients treated in phase I trials of MTAs at the Royal Marsden Hospital and Institut Gustave Roussy between January 2005 and July 2008 were included. Gastrointestinal, skin, and clinical renal toxicities of any grade and grades 3 to 4 toxic events of any type occurring at any cycle on treatment were recorded. Doses administered, treatment interruptions, dose modifications, and prescription of comedications were analyzed. Results A total of 445 patients (1,566 cycles; median treatment duration, 55 days) were included in 36 eligible trials; 790 toxicities (590, grade 1; 176, grade, 2; 24 grades, 3 to 4) and 1,819 toxicities (1,521, grade 1; 265, grade 2; 33, grades 3 to 4) were recorded during and after C1, respectively; 57% of the grades 3 to 4 toxicities occurred after C1; 50% of patients presented their worst-grade toxicity after C1. The risk of grades 3 to 4 toxicity was 3% in cycles 1 to 6 and was almost null afterwards. No cumulative toxicities were observed. Median toxicity duration was 15 days, with comedication administered in 68% of events. Conclusion Moderate and severe toxicities occur regularly after the first cycle in phase I trials of MTAs and may deserve increased attention in the RP2D process for these agents.
Ulcers and Nonvariceal Bleeding
Authors: N. I. Church, K. R. Palmer
Journal: Endoscopy (2003)

Peptic ulcer remains the commonest and most significant cause of nonvariceal upper gastrointestinal bleeding. The incidence of peptic ulcer bleeding is rising in elderly patients, particularly for duodenal ulcer. Patients presenting with upper gastrointestinal bleeding who have low Rockall scores are at low risk of rebleeding and death. These patients currently utilize considerable health-care resources, but could safely be managed at home. The Rockall score can be used to predict the risk of rebleeding and death following variceal bleeding, but for patients with ulcer bleeding, its ability to predict death is questioned.Acid suppression is effective in preventing rebleeding from peptic ulcer. Standard doses of intravenous omeprazole may be as effective as high-dose regimens. Oral omeprazole also reduces rebleeding following endoscopic therapy for peptic ulcer.Mallory-Weiss tears result in significant bleeding in 23 % of cases. Endoscopic therapy may only be required in cases in which active bleeding is present.
Targeted Delivery of IFNγ to Tumor Vessels Uncouples Antitumor from Counterregulatory Mechanisms
Authors: Flavio Curnis, Anna Gasparri, Angelina Sacchi, Angela Cattaneo, Fulvio Magni, Angelo Corti
Journal: Cancer Research (2005)

Abstract Because of its immunomodulatory and anticancer activities, IFNγ has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that targeted delivery of low doses of IFNγ to CD13, a marker of angiogenic vessels, can overcome major counterregulatory mechanisms and delay tumor growth in two murine models that respond poorly to IFNγ. Tumor vascular targeting was achieved by coupling IFNγ to GCNGRC, a CD13 ligand, by genetic engineering technology. The dose-response curve was bell-shaped. Maximal effects were induced with a dose of 0.005 μg/kg, about 500-fold lower than the dose used in patients. Nontargeted IFNγ induced little or no effects over a range of 0.003 to 250 μg/kg. Studies on the mechanism of action showed that low doses of targeted IFNγ could activate tumor necrosis factor (TNF)-dependent antitumor mechanisms, whereas high doses of either targeted or nontargeted IFNγ induced soluble TNF-receptor shedding in circulation, a known counterregulatory mechanism of TNF activity. These findings suggest that antitumor activity and counterregulatory mechanisms could be uncoupled by tumor vascular targeting with extremely low doses of IFNγ.
Parallel synthesis of immunoglobulins and J chain in pokeweed mitogen-stimulated normal cells and in lymphoblastoid cell lines.
Authors: J Mestecky, R J Winchester, T Hoffman, H G Kunkel
Journal: The Journal of Experimental Medicine (1977)

The synthesis of intracellular J chains was found to be closely associated with that of intracellular immunoglobulin, regardless of its class, during the process of B-cell differentiation. This parallelism between the synthesis of J chain and immunoglobulin was particularly evident in their coincident appearance in serial observations of pokeweed mitogen (PWM)-stimulated lymphocytes. The intensity of J-chain staining by fluorescent reagents in the stimulated cells synthesizing IgG was similar to that found in cells synthesizing IgA or IgM. Evidence was obtained that the presence of J chain in the IgG-producing cells did not reflect antecedent synthesis of IgA or IgM. T cells stimulated by phytohemagglutinin and PWM failed to show J-chain synthesis. Observations on lymphoid cell lines showed a similar parallelism between intracellular Ig and J-chain synthesis; no relation to surface Ig was found.
C3a and C5a Promote Renal Ischemia-Reperfusion Injury
Authors: Qi Peng, Ke Li, Lesley A. Smyth, Guolan Xing, Naiyin Wang, Lucy Meader, Bao Lu, Steven H. Sacks, Wuding Zhou
Journal: Journal of the American Society of Nephrology (2012)

Renal ischemia reperfusion injury triggers complement activation, but whether and how the small proinflammatory fragments C3a and C5a contribute to the pathogenesis of this injury remains to be elucidated. Using C3aR-, C5aR-, or C3aR/C5aR-deficient mice and models of renal ischemia-reperfusion injury, we found that deficiency of either or both of these receptors protected mice from injury, but the C3aR/C5aR- and C5aR-deficient mice were most protected. Protection from injury was associated with less cellular infiltration and lower mRNA levels of kidney injury molecule-1, proinflammatory mediators, and adhesion molecules in postischemic kidneys. Furthermore, chimera studies showed that the absence of C3aR and C5aR on renal tubular epithelial cells or circulating leukocytes attenuated renal ischemia-reperfusion injury. In vitro, C3a and C5a stimulation induced inflammatory mediators from both renal tubular epithelial cells and macrophages after hypoxia/reoxygenation. In conclusion, although both C3a and C5a contribute to renal ischemia-reperfusion injury, the pathogenic role of C5a in this injury predominates. These data also suggest that expression of C3aR and C5aR on both renal and circulating leukocytes contributes to the pathogenesis of renal ischemia-reperfusion injury.
Malignancy and mortality in people with coeliac disease: population based cohort study
Authors: Joe West, Richard F A Logan, Chris J Smith, Richard B Hubbard, Timothy R Card
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To quantify the risks of malignancy and mortality in people with coeliac disease compared with the general population. <b>Design</b> Population based cohort study. <b>Setting</b> General practice research database. <b>Participants</b> 4732 people with coeliac disease and 23 620 matched controls. <b>Main outcome measures</b> Hazard ratios for malignancy and mortality. <b>Results</b> Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy and 237 (5.0%) died. The overall hazard ratios were: for any malignancy 1.29 (95% confidence interval 1.06 to 1.55), for mortality 1.31 (1.13 to 1.51), for gastrointestinal cancer 1.85 (1.22 to 2.81), for breast cancer 0.35 (0.17 to 0.72), for lung cancer 0.34 (0.13 to 0.95), and for lymphoproliferative disease 4.80 (2.71 to 8.50). The increased risk was primarily in the first year after diagnosis, with the risk for only lymphoproliferative disease remaining significantly raised thereafter. After excluding events in the year after diagnosis, the hazard ratio for malignancy was 1.10 (0.87 to 1.39) and for mortality was 1.17 (0.98 to 1.38), giving absolute excess rates of 6 and 17 per 10 000 person years, respectively. <b>Conclusions</b> People with coeliac disease have modest increases in overall risks of malignancy and mortality. Most of this excess risk occurs in the year of follow up after diagnosis. People with coeliac disease also have a noticeably reduced risk of breast cancer. The mechanism of this merits further attention as it may provide insights into the cause of this common malignancy.
The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
Authors: Kenji Kabashima, Tomomi Saji, Takahiko Murata, Miyako Nagamachi, Toshiyuki Matsuoka, Eri Segi, Kazuhito Tsuboi, Yukihiko Sugimoto, Takuya Kobayashi, Yoshiki Miyachi, Atsushi Ichikawa, Shuh Narumiya
Journal: Journal of Clinical Investigation (2002)

We used mice deficient in each of the eight types and subtypes of prostanoid receptors and examined the roles of prostanoids in dextran sodium sulfate–induced (DSS-induced) colitis. Among the prostanoid receptor–deficient mice, only EP4-deficient mice and not mice deficient in either DP, EP1, EP2, EP3, FP, IP, or TP developed severe colitis with 3% DSS treatment, which induced only marginal colitis in wild-type mice. This phenotype was mimicked in wild-type mice by administration of an EP4-selective antagonist (AE3-208). The EP4 deficiency impaired mucosal barrier function and induced epithelial loss, crypt damage, and aggregation of neutrophils and lymphocytes in the colon. Conversely, administration of an EP4-selective agonist (AE1-734) to wild-type mice ameliorated severe colitis normally induced with 7% DSS, while that of AE3-208 suppressed recovery from colitis and induced significant proliferation of CD4+ T cells. In vitro AE3-208 enhanced and AE1-734 suppressed the proliferation and Th1 cytokine production of lamina propria mononuclear cells from the colon. DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice. We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response.
Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Florian Custodis, Magnus Baumhäkel, Nils Schlimmer, Franka List, Christoph Gensch, Michael Böhm, Ulrich Laufs
Journal: Circulation (2008)

Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I(f) current inhibitor ivabradine in apolipoprotein E-deficient mice.Male apolipoprotein E-deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg . kg(-1) . d(-1)) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472+/-9 versus 545+/-11 bpm; P<0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals (P<0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48+/-6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg . kg(-1) . d(-1) for 6 weeks) reduced blood pressure (-15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress.Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice.
Weekly Paclitaxel Improves Pathologic Complete Remission in Operable Breast Cancer When Compared With Paclitaxel Once Every 3 Weeks
Authors: Marjorie C. Green, Aman U. Buzdar, Terry Smith, Nuhad K. Ibrahim, Vicente Valero, Marguerite F. Rosales, Massimo Cristofanilli, Daniel J. Booser, Lajos Pusztai, Edgardo Rivera, Richard L. Theriault, Cynthia Carter, Debra Frye, Kelly K. Hunt, W. Fraser Symmans, Eric A. Strom, Aysegul A. Sahin, William Sikov, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). Patients and Methods Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. Results A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). Conclusion The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.
Humidifier Disinfectant–associated Children’s Interstitial Lung Disease
Authors: Kyung Won Kim, Kangmo Ahn, Hyeon Jong Yang, Sooyoung Lee, June Dong Park, Woo Kyung Kim, Jin-Tack Kim, Hyun Hee Kim, Yeong Ho Rha, Yong Mean Park, Myung Hyun Sohn, Jae-Won Oh, Hae Ran Lee, Dae Hyun Lim, Ji Tae Choung, Man Yong Han, Eun Lee, Hyung-Young Kim, Ju-Hee Seo, Byoung-Ju Kim, Young Ah Cho, Kyung-Hyun Do, Sun-A Kim, Se-Jin Jang, Moo-Song Lee, Hwa-Jung Kim, Geun-Yong Kwon, Ji-Hyuk Park, Jin Gwack, Seung-Ki Youn, Jun-Wook Kwon, Byung-Yool Jun, Bok Yang Pyun, Soo-Jong Hong
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Beginning in 2006, epidemics of a fatal lung injury of unknown cause in children were observed in Korea every spring. A recent study demonstrated that this type of children's interstitial lung disease (chILD) is associated with humidifier disinfectant use.Objectives: To determine the clinical characteristics of this type of chILD and to assess whether the nationwide suspension of humidifier disinfectant sales in the autumn of 2011 affected its incidence.Methods: The clinical characteristics of suspected cases between 2006 and 2011 were determined by a nationwide retrospective study. The potential causal relationship with humidifier disinfectants was examined by a prospective surveillance study after humidifier disinfectant sales were suspended.Measurements and Main Results: In total, 138 children were diagnosed with this type of chILD, which was characterized by rapid progression, high mortality, predominance in the spring season, and a familial tendency. The annual incidence increased in 2011 and then dropped to zero in 2012. The children were on average 30.4 months old. The most frequent symptoms at admission were cough and dyspnea. As the disease progressed, the typical complication was spontaneous air leak. Eighty children (58%) died. Two years after humidifier disinfectant-sale suspension, no more new cases were found.Conclusions: This study suggests that humidifier disinfectant inhalation causes an idiopathic type of chILD that is characterized by spontaneous air leak, rapid progression, lack of response to treatment, and high mortality. Further safety studies must be performed on common environmental compounds, particularly those that enter the human body by an unusual route.