tbuckley/cabot-search huggingface dataset:
Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis
Authors: Sophie Couvé, Charline Ladroue, Elodie Laine, Karène Mahtouk, Justine Guégan, Sophie Gad, Hélène Le Jeune, Marion Le Gentil, Gregory Nuel, William Y. Kim, Bernard Lecomte, Jean-Christophe Pagès, Christine Collin, Françoise Lasne, Patrick R. Benusiglio, Brigitte Bressac-de Paillerets, Jean Feunteun, Vladimir Lazar, Anne-Paule Gimenez-Roqueplo, Nathalie M. Mazure, Philippe Dessen, Luba Tchertanov, David R. Mole, William Kaelin, Peter Ratcliffe, Stéphane Richard, Betty Gardie
Journal: Cancer Research (2014)

The classic model of tumor suppression implies that malignant transformation requires full "two-hit" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a "continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease. Individuals with classic, heterozygous VHL mutations have VHL disease and are at high risk of multiple tumors (e.g., CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma). We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional, and transcriptomic studies of these mutants in comparison with classical mutants involved in the different VHL phenotypes. We demonstrate that the complex pattern of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of VHL protein (pVHL) dysfunction in hypoxia signaling pathways. Thus, by studying naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor suppression.
Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis
Authors: Sadaf Ashraf, Helen Wibberley, Paul Ian Mapp, Roger Hill, Deborah Wilson, David Andrew Walsh
Journal: Annals of the Rheumatic Diseases (2010)

Objectives Meniscal damage is a recognised feature of knee osteoarthritis (OA), although its clinical relevance remains uncertain. This study describes vascular penetration and nerve growth in human menisci, providing a potential mechanism for the genesis of pain in knee OA. Methods Menisci obtained post mortem were screened on the basis of high or low macroscopic tibiofemoral chondropathy as a measure of the presence and degree of OA. Forty cases (20 per group) were selected for the study of meniscal vascularity, and 16 (eight per group) for the study of meniscal innervation. Antibodies directed against α-actin and calcitonin gene-related peptide (CGRP) were used to localise blood vessels and nerves by histochemistry. Image analysis was used to compare vascular and nerve densities between groups. Data are presented as median (IQR). Results Menisci from knees with high chondropathy displayed degeneration of collagen bundles in their outer regions, which were more vascular than the inner regions, with an abrupt decrease in vascularity at the fibrocartilage junction. Vascular densities were increased in menisci from the high compared with low chondropathy group both in the synovium (3.8% (IQR 2.6–5.2), 2.0% (IQR 1.4–2.9), p=0.002) and at the fibrocartilage junction (2.3% (IQR 1.7–3.1), 1.1% (IQR 0.8–1.9), p=0.003), with a greater density of perivascular sensory nerve profiles in the outer region (high chondropathy group, 144 nerve profiles/mm 2 (IQR 134–189); low chondropathy group, 119 nerve profiles/mm 2 (IQR 104–144), p=0.049). Conclusion Tibiofemoral chondropathy is associated with altered matrix structure, increased vascular penetration, and increased sensory nerve densities in the medial meniscus. The authors suggest therefore that angiogenesis and associated sensory nerve growth in menisci may contribute to pain in knee OA.
A Breath of Fresh Air for Lung Transplant Recipients
Authors: David S. Wilkes
Journal: Science Translational Medicine (2009)

Abstract Lung transplantation is a definitive therapy for the treatment of many end-stage lung diseases. However, because of donor-related morbidities, only 15% of donor lungs are suitable for transplantation, which leads to an increased risk of death for prospective patients waiting for this lifesaving procedure. A technique reported by Keshavjee’s group in this issue of Science Translational Medicine may help address this problem, not only by repairing donor lungs before transplant, but also by possibly preventing lung injury after transplantation.
Modafinil for Excessive Sleepiness Associated with Shift-Work Sleep Disorder
Authors: Charles A. Czeisler, James K. Walsh, Thomas Roth, Rod J Hughes, Kenneth P. Wright, Lilliam Kingsbury, Sanjay Arora, Jonathan R.L. Schwartz, Gwendolyn E. Niebler, David F. Dinges
Journal: New England Journal of Medicine (2005)

Patients with shift-work sleep disorder chronically have excessive sleepiness during night work and insomnia when attempting to sleep during the day. We evaluated the use of modafinil for treating sleepiness in patients with this disorder.In a three-month, double-blind trial, we randomly assigned 209 patients with shift-work sleep disorder to receive either 200 mg of modafinil or placebo before the start of each shift. Assessments were performed with the use of the nighttime Multiple Sleep Latency Test, the Clinical Global Impression of Change, the Psychomotor Vigilance Test, diaries of patients, and daytime polysomnography. After randomization, we conducted monthly assessments.Treatment with modafinil, as compared with placebo, resulted in a modest improvement from baseline in mean (+/-SEM) nighttime sleep latency (the interval between the time a person attempts to fall asleep and the onset of sleep) (1.7+/-0.4 vs. 0.3+/-0.3 minutes, respectively; P=0.002), and more patients had improvement in their clinical symptoms (74 percent vs. 36 percent, respectively; P<0.001). Patients who were receiving modafinil also had a reduction in the frequency and duration of lapses of attention during nighttime testing of their performance on the Psychomotor Vigilance Test (change from baseline, a reduction in lapse frequency of 2.6 vs. an increase of 3.8, respectively; P<0.001), and proportionally fewer patients reported having had accidents or near accidents while commuting home (29 percent vs. 54 percent, respectively; P<0.001). Despite these benefits, patients treated with modafinil continued to have excessive sleepiness and impaired performance at night. Modafinil did not adversely affect daytime sleep as compared with placebo. Headache was the most common adverse event.Treatment with 200 mg of modafinil reduced the extreme sleepiness that we observed in patients with shift-work sleep disorder and resulted in a small but significant improvement in performance as compared with placebo. However, the residual sleepiness that was observed in the treated patients underscores the need for the development of interventions that are even more effective.
Pulmonary Vein Anatomy in Patients Undergoing Catheter Ablation of Atrial Fibrillation
Authors: Ritsushi Kato, Lars Lickfett, Glenn Meininger, Timm Dickfeld, Richard Wu, George Juang, Piamsook Angkeow, Jennifer LaCorte, David Bluemke, Ronald Berger, Henry R. Halperin, Hugh Calkins
Journal: Circulation (2003)

Background— This study sought to define the technique and results of magnetic resonance imaging (MRI) of pulmonary vein (PV) anatomy before and after catheter ablation of atrial fibrillation (AF). Methods and Results— Twenty-eight patients with AF underwent ablation. Patients underwent gadolinium-enhanced MRI before and 6 weeks after their procedures. A control group of 27 patients also underwent MRI. Variant PV anatomy was observed in 38% of patients. AF patients had larger PV diameters than control subjects, but no difference was observed in the size of the PV ostia among AF patients. The PV ostia were oblong in shape with an anteroposterior dimension less than the superoinferior dimension. The left PVs had a longer “neck” than the right PVs. A detectable PV narrowing was observed in 24% of veins. The severity of stenosis was severe in 1 vein (1.4%), moderate in 1 vein (1.4%), and mild in 15 veins (21.1%). All patients were asymptomatic, and none required treatment. Conclusions— This study demonstrates that AF patient have larger PVs than control subjects and demonstrates the value of MRI in facilitating AF ablation. The benefits of preprocedural MRI of PVs include the ability to evaluate the number, size, and shape of the PVs. MRI also provides an assessment of the severity of PV stenosis.
Comparison of delayed release 5 aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse.
Authors: S A Riley, V Mani, M J Goodman, M E Herd, S Dutt, L A Turnberg
Journal: Gut (1988)

Oral formulations of 5-aminosalicylic acid (mesalazine) appear less toxic than sulphasalazine. We have therefore compared sulphasalazine, low dose mesalazine and high dose mesalazine in the treatment of mild to moderate relapse of ulcerative colitis. Sixty one patients (32 men, aged 20-78 years) were randomly allocated to sulphasalazine 2 g daily, mesalazine 800 mg daily, or mesalazine 2.4 g daily in a double blind, double dummy, four week trial. Groups were comparable for age, sex, extent of disease, and pretrial sulphasalazine intake. Four patients were unable to complete the study because of treatment failure (two taking sulphasalazine and two high dose mesalazine). A further two patients taking sulphasalazine developed side effects necessitating withdrawal. Within treatment comparisons revealed significant improvement of: sigmoidoscopic grade in the sulphasalazine group; rectal bleeding, sigmoidoscopic and histological grade in the low dose mesalazine group; stool frequency, rectal bleeding and sigmoidoscopic grade in the high dose mesalazine group. Greater improvement in rectal bleeding (p less than 0.05) and sigmoidoscopic appearances (p less than 0.05) occurred in patients taking high dose mesalazine than in those taking sulphasalazine. In two patients taking high dose mesalazine minor rises of plasma creatinine concentrations occurred, suggesting the need to monitor renal function.
International Committee of the Red Cross set to accept new symbol
Authors: Judy Siegel-Itzkovich
Journal: BMJ (2005)

The International Committee of the Red Cross has announced that it is intending to change its rules to allow national first aid societies to use a new symbol—that of a “crystal”—in the place of a cross or a crescent if they object to these existing symbols.

The organisation's decision comes in response to sustained pressure from Israel's national first aid and ambulance organisation, Magen David Adom, which has been campaigning for a change for …
Outcomes in Adults With Bicuspid Aortic Valves
Authors: Nikolaos Tzemos, Judith Therrien, James Yip, George Thanassoulis, Sonia Tremblay, Michal T. Jamorski, Gary D. Webb, Samuel C. Siu
Journal: JAMA (2008)

Bicuspid aortic valve is the most common congenital cardiac anomaly in the adult population. Cardiac outcomes in a contemporary population of adults with bicuspid aortic valve have not been systematically determined.To determine the frequency and predictors of cardiac outcomes in a large consecutive series of adults with bicuspid aortic valve.Cohort study examining cardiac outcomes in 642 consecutive ambulatory adults (mean [SD] age, 35 [16] years; 68% male) with bicuspid aortic valve presenting to a Canadian congenital cardiac center from 1994 through 2001 and followed up for a mean (SD) period of 9 (5) years. Frequency and predictors of major cardiac events were determined by multivariate analysis. Mortality rate in the study group was compared with age- and sex-matched population estimates.Mortality and cause of death were determined. Primary cardiac events were defined as the occurrence of any of the following complications: cardiac death, intervention on the aortic valve or ascending aorta, aortic dissection or aneurysm, or congestive heart failure requiring hospital admission during the follow-up period.During the follow-up period, there were 28 deaths (mean [SD], 4% [1%]). One or more primary cardiac events occurred in 161 patients (mean [SD], 25% [2%]), which included cardiac death in 17 patients (mean [SD], 3% [1%]), intervention on aortic valve or ascending aorta in 142 patients (mean [SD], 22% [2%]), aortic dissection or aneurysm in 11 patients (mean [SD], 2% [1%]), or congestive heart failure requiring hospital admission in 16 patients (mean [SD], 2% [1%]). Independent predictors of primary cardiac events were age older than 30 years (hazard ratio [HR], 3.01; 95% confidence interval [CI], 2.15-4.19; P<.001), moderate or severe aortic stenosis (HR, 5.67; 95% CI, 4.16-7.80; P<.001), and moderate or severe aortic regurgitation (HR, 2.68; 95% CI, 1.93-3.76; P<.001). The 10-year survival rate of the study group (mean [SD], 96% [1%]) was not significantly different from population estimates (mean [SD], 97% [1%]; P = .71). At last follow-up, 280 patients (mean [SD], 45% [2%]) had dilated aortic sinus and/or ascending aorta.In this study population of young adults with bicuspid aortic valve, age, severity of aortic stenosis, and severity of aortic regurgitation were independently associated with primary cardiac events. Over the mean follow-up duration of 9 years, survival rates were not lower than for the general population.
Psoriasis: epidemiology, clinical features, and quality of life
Authors: R G B Langley
Journal: Annals of the Rheumatic Diseases (2005)

Psoriasis is a common chronic, recurrent, immune mediated disease of the skin and joints. It can have a significant negative impact on the physical, emotional, and, psychosocial wellbeing of affected patients. Psoriasis is found worldwide but the prevalence varies among different ethnic groups. It has a strong genetic component but environmental factors such as infections can play an important role in the presentation of disease. There are several clinical cutaneous manifestations of psoriasis but most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques. The epidemiology, clinical features, and impact on quality of life of psoriasis are reviewed.
DILATION VERSUS GASTROSTOMY AS A PALLIATIVE TREATMENT OF CARCINOMA OF THE ESOPHAGUS
Authors: PORTER P. VINSON
Journal: JAMA (1925)

Carcinoma of the esophagus is uniformly fatal, and in treating the disease, efforts should be directed along lines of greatest palliation. The forms of treatment generally employed are gastrostomy and mechanical dilation of the malignant stricture. If gastrostomy is performed early in the disease, the operative risk is relatively slight; but if obstruction is at all pronounced, the mortality increases to at least 10 per cent., in the hands of the average surgeon. The operation necessitates hospitalization for a period of from ten days to three weeks, and a nurse, relative or friend is usually required in constant attendance during the remaining days of the patient's life. Although the details of the operation and the possible benefits from it may have been fully discussed, the patient is likely to think that the placing of the tube in the stomach is a curative measure, or that other treatment may be more
Cost analysis of nurse telephone consultation in out of hours primary care: evidence from a randomised controlled trial
Authors: V. Lattimer
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To undertake an economic evaluation of nurse telephone consultation using decision support software in comparison with usual general practice care provided by a general practice cooperative. <b>Design:</b> Cost analysis from an NHS perspective using stochastic data from a randomised controlled trial. <b>Setting:</b> General practice cooperative with 55 general practitioners serving 97 000 registered patients in Wiltshire, England. <b>Subjects:</b> All patients contacting the service, or about whom the service was contacted during the trial year (January 1997 to January 1998). <b>Main outcome measures:</b> Costs and savings to the NHS during the trial year. <b>Results:</b> The cost of providing nurse telephone consultation was £81 237 per annum. This, however, determined a £94 422 reduction of other costs for the NHS arising from reduced emergency admissions to hospital. Using point estimates for savings, the cost analysis, combined with the analysis of outcomes, showed a dominance situation for the intervention over general practice cooperative care alone. If a larger improvement in outcomes is assumed (upper 95% confidence limit) NHS savings increase to £123 824 per annum. Savings of only £3728 would, however, arise in a scenario where lower 95% confidence limits for outcome differences were observed. To break even, the intervention would have needed to save 138 emergency hospital admissions per year, around 90% of the effect achieved in the trial. Additional savings of £16 928 for general practice arose from reduced travel to visit patients at home and fewer surgery appointments within three days of a call. <b>Conclusions:</b> Nurse telephone consultation in out of hours primary care may reduce NHS costs in the long term by reducing demand for emergency admission to hospital. General practitioners currently bear most of the cost of nurse telephone consultation and benefit least from the savings associated with it. This indicates that the service produces benefits in terms of service quality, which are beyond the reach of this cost analysis.
Diagnosis and Management of Sports-Related Concussion
Authors: Ross Zafonte
Journal: JAMA (2011)

Concussion in youth athletes is a growing problem worldwide. During the past decade, significant progress has been made in standardization of the assessment of young athletes, and a growing appreciation of metabolic vulnerability, activity, and cognitive challenges has led to guidelines and suggestions for rest from the field as well as cognitive rest from school. Outcome data have begun to establish groups linked to symptom class, genetics, and sex who are at risk of worse outcomes from concussions. Decisions regarding return to activity are now based on at-rest symptoms, graded increases in activity, and neuropsychological testing. Using the case of Ms X, a 15-year-old otherwise healthy high school student who fell while skiing, evaluation, prognosis, and management of concussion are discussed.
Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
Authors: Annika Malmström, Bjørn Henning Grønberg, Christine Marosi, Roger Stupp, Didier Frappaz, Henrik Schultz, Ufuk Abacioglu, Björn Tavelin, Benoit Lhermitte, Monika E Hegi, Johan Rosell, Roger Henriksson
Journal: The Lancet Oncology (2012)
NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3
Authors: Byung-Hak Kim, Jun-Goo Jee, Chang-Hong Yin, Claudio Sandoval, Somasundaram Jayabose, Daisuke Kitamura, Erika A Bach, Gyeong-Hun Baeg
Journal: Molecular Cancer (2010)

Abstract Background Human or animals lacking either JAK3 or the common gamma chain (γc) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activating JAK3 mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of those JAK3 mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds. Results We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family members in vitro . In addition, treatment of 32D/IL-2Rβ cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3. Conclusions NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.
Relationship between age at menarche and early-life nutritional status in India
Authors: Monika Dahiya, Vinod K Rathi
Journal: British Journal of Sports Medicine (2010)

Age at menarche is associated with anthropometry in adolescence. Recently, there has been growing support for the hypothesis that timing of menarche may be set early in life but modified by changes in body size and composition in childhood. To evaluate this, a cohort of 100 girls aged ≤14 years recruited in 2006 were followed up in 2009 in NCR Delhi, India. The analysis was based on nutritional status as assessed by anthropometry and recalled age at menarche. Data were examined using life-table techniques and the Cox regression model. The association between nutritional status indicators and age at menarche was examined in a multivariate model adjusting for potential confounding variables. Censored cases were accounted for. The median age at menarche was 14·7 year. After controlling for early-life predictors (birth size, childhood underweight, childhood stunting) it appeared that adolescent stunting stood out as the most important determinant of age at menarche. Birth size was not a significant predictor of age at menarche. It is concluded that age at menarche is strongly influenced by nutritional status in adolescence, notably the level of stunting, which is in turn highly dependent on the level of stunting in early childhood. A ‘late’ menarche due to stunting may be detrimental for reproductive health in case of early childbearing because of the association between height and pelvic size.
Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy
Authors: John J. Poterucha, Michael J. Krowka, Rolland E. Dickson, Denis A. Cortese, Anthony W. Stanson, Ruud A. F. Krom
Journal: Hepatology (1995)

The hepatopulmonary syndrome is an uncommon accompaniment of chronic liver disease. The outcome of this disorder after orthotopic liver transplantation is variable. We describe a patient with the hepatopulmonary syndrome who underwent orthotopic liver transplantation for autoimmune hepatitis. Her platypnea and orthodeoxia failed to improve postoperatively. Pulmonary angiography showed large pulmonary arteriovenous shunts that were successfully treated with coil embolotherapy.
Muir‐Torre syndrome in patients with hematologic malignancies
Authors: Philip R. Cohen
Journal: American Journal of Hematology (1992)

Abstract The Muir‐Torre syndrome (MTS) is defined as the concurrent or sequential discovery of at least one sebaceous gland tumor and a minimum of one internal malignancy. A man with Hodgkin's lymphoma who subsequently developed an ocular sebaceous carcinoma in situ is described and the world literature of patients with the MTS and hematologic malignancies is reviewed. © 1992 Wiley‐Liss, Inc.