tbuckley/cabot-search huggingface dataset:
Novel Mechanism of Endothelial Nitric Oxide Synthase Activation Mediated by Caveolae Internalization in Endothelial Cells
Authors: Nikolaos A. Maniatis, Viktor Brovkovych, Scott E. Allen, Theresa A. John, Ayesha N. Shajahan, Chinnaswamy Tiruppathi, Stephen M. Vogel, Randal A. Skidgel, Asrar B. Malik, Richard D. Minshall
Journal: Circulation Research (2006)

Caveolin-1, the caveolae scaffolding protein, binds to and negatively regulates eNOS activity. As caveolin-1 also regulates caveolae-mediated endocytosis after activation of the 60-kDa albumin-binding glycoprotein gp60 in endothelial cells, we addressed the possibility that endothelial NO synthase (eNOS)-dependent NO production was functionally coupled to caveolae internalization. We observed that gp60-induced activation of endocytosis increased NO production within 2 minutes and up to 20 minutes. NOS inhibitor N(G)-nitro-L-arginine (L-NNA) prevented the NO production. To determine the role of caveolae internalization in the mechanism of NO production, we expressed dominant-negative dynamin-2 mutant (K44A) or treated cells with methyl-beta-cyclodextrin. Both interventions inhibited caveolae-mediated endocytosis and NO generation induced by gp60. We determined the role of signaling via Src kinase in the observed coupling of endocytosis to eNOS activation. Src activation induced the phosphorylation of caveolin-1, Akt and eNOS, and promoted dissociation of eNOS from caveolin-1. Inhibitors of Src kinase and Akt also prevented NO production. In isolated perfused mouse lungs, gp60 activation induced NO-dependent vasodilation, whereas the response was attenuated in eNOS(-/-) or caveolin-1(-/-) lungs. Together, these results demonstrate a critical role of caveolae-mediated endocytosis in regulating eNOS activation in endothelial cells and thereby the NO-dependent vasomotor tone.
No miracles in the NHS
Authors: Liam Farrell
Journal: BMJ (2007)

“It's Our Lord,” said my receptionist, “and before you ask, He has ID, a gold credit card.”

“Hang on,” He said as He entered the surgery, “I'd asked for a doctor that believes in Me.”

“Nothing personal, Lord,” I said, “but to rational people you're slightly less believable than Santa Claus or homoeopathy, all that Samson and Goliath stuff.”

“Hey,” He said, “Samson was a decent hardworking man; runs a barber shop now—or was it then? Omnipresence can be confusing.”

“I'm feeling a bit depressed,” He continued, idly bringing my …
Randomized Controlled Community-Based Nutrition and Exercise Intervention Improves Glycemia and Cardiovascular Risk Factors in Type 2 Diabetic Patients in Rural Costa Rica
Authors: Jeremy D. Goldhaber-Fiebert, Sara N. Goldhaber-Fiebert, Mario L. Tristán, David M. Nathan
Journal: Diabetes Care (2003)

OBJECTIVE—The prevalence of type 2 diabetes, especially in developing countries, has grown over the past decades. We performed a controlled clinical study to determine whether a community-based, group-centered public health intervention addressing nutrition and exercise can ameliorate glycemic control and associated cardiovascular risk factors in type 2 diabetic patients in rural Costa Rica. RESEARCH DESIGN AND METHODS—A total of 75 adults with type 2 diabetes, mean age 59 years, were randomly assigned to the intervention group or the control group. All participants received basic diabetes education. The subjects in the intervention group participated in 11 weekly nutrition classes (90 min each session). Subjects for whom exercise was deemed safe also participated in triweekly walking groups (60 min each session). Glycosylated hemoglobin, fasting plasma glucose, total cholesterol, triglycerides, HDL and LDL cholesterol, height, weight, BMI, and blood pressure were measured at baseline and the end of the study (after 12 weeks). RESULTS—The intervention group lost 1.0 ± 2.2 kg compared with a weight gain in the control group of 0.4 ± 2.3 kg (P = 0.028). Fasting plasma glucose decreased 19 ± 55 mg/dl in the intervention group and increased 16 ± 78 mg/dl in the control group (P = 0.048). Glycosylated hemoglobin decreased 1.8 ± 2.3% in the intervention group and 0.4 ± 2.3% in the control group (P = 0.028). CONCLUSIONS—Glycemic control of type 2 diabetic patients can be improved through community-based, group-centered public health interventions addressing nutrition and exercise. This pilot study provides an economically feasible model for programs that aim to improve the health status of people with type 2 diabetes.
Alternate Endpoints for Screening Phase II Studies
Authors: Neesha Dhani, Dongsheng Tu, Daniel J. Sargent, Lesley Seymour, Malcolm J. Moore
Journal: Clinical Cancer Research (2009)

Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development and those for which further evaluation should be halted. Although definitive phase III trials use progression-free or overall survival to confirm clinical benefit, earlier endpoints are preferable for phase II trials. Traditionally, tumor shrinkage of a predetermined degree (response) has been used as a surrogate of eventual survival benefit based on the observation that high response rates (RR), and particularly complete responses, in the phase II setting resulted in survival benefit in subsequent phase III trials. Recently, some molecularly targeted agents have shown survival and clinical benefit despite very modest RRs in early clinical trials. These observations provide a major conundrum, with concerns of inappropriate termination of development for active agents with low RRs being balanced by concerns of inactive agents being taken to late-phase development with resultant increases in the failure rate of phase III trials. Numerous alternate or complementary endpoints have been explored, incorporating multinomial endpoints (including progression and response), progression-free survival, biomarkers, and, more recently, evaluation of tumor size as a continuous variable. In this review, we discuss the current status of phase II endpoints and present retrospective analyses of two international gastrointestinal cancer studies showing the potential utility of one novel approach. Alternate endpoints, although promising, require additional evaluation and prospective validation before their use as a primary endpoint for phase II trials.
Gastrointestinal Features of Chronic Granulomatous Disease Found During Endoscopy
Authors: Sajneet K. Khangura, Natasha Kamal, Nancy Ho, Martha Quezado, Xiongce Zhao, Beatriz Marciano, Jennifer Simpson, Christa Zerbe, Gulbu Uzel, Michael D. Yao, Suk See DeRavin, Colleen Hadigan, Douglas B. Kuhns, John I. Gallin, Harry L. Malech, Steven M. Holland, Theo Heller
Journal: Clinical Gastroenterology and Hepatology (2015)
THE HISTOLOGICAL LESIONS OF EXPERIMENTAL GLANDERS
Authors: Charles W. Duval, Percival G. White
Journal: The Journal of Experimental Medicine (1907)

The bacillus of glanders may be so modified in virulence as to produce experimentally lesions differing widely in their histological features. The highly virulent culture causes primary necrosis and disintegration of the tissue followed by the invasion of the injured area by polymorphonuclear leucocytes. The bacilli of moderate virulence give rise to a primary lesion of an acute inflammatory nature in which the cells show no evidence of necrosis or disintegration. The attenuated bacilli produce primary tissue proliferation with the formation of epithelioid and giant cells. There is every grade of lesion between the acute exudative and the chronic proliferative depending upon the toxicity of the cultures. The glanders lesion whether exudative or proliferative is focal in character. The strong toxins of the glanders bacilli cause degeneration or necrosis of cells and exudation, while the dilute and weak toxins produce proliferation. The giant cell of glanders undoubtedly originates from the endothelial cell of the blood and lymph channels and is formed by division of the nucleus of the endothelial cell and not by cell fusion. Histologically the lesion of glanders resulting from the culture of a low degree of virulence is proliferative and is analogous to tuberculosis; the lesions are focal and bear an intimate relation to the glanders bacillus.
An unusual case of bowel obstruction
Authors: I Rosa
Journal: Gut (2004)

Background and aims: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis.Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress.We hypothesised that peripheral administration of a-helical CRH (ahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients.Methods: Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied.The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline.Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale.The same measurements were repeated after administration of ahCRH (10 mg/kg).Results: ES induced significantly higher motility indices of the colon in IBS patients compared with controls.This response was significantly suppressed in IBS patients but not in controls after administration of ahCRH.Administration of ahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients.ahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients.Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by ahCRH.Conclusion: Peripheral administration of ahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.
ON IMPIANTATION OF THE URETERS INTO THE RECTUM BY THE SACRAL ROUTE, Illustrated by a Case of Inveterate Vesico-vaginal Fistula in which the Left Ureter was Implanted and the Right Kidney Removed
Authors: R L. Knaggs
Journal: BMJ (1910)

IMPLANTATION OF URETERS IN RECTUM.[MsY 21, 19O.formation and healing, but also that iE may be delayed in its healiug, or exsend, and so form the inihial stage of chronic gastric ulcer.The natural conclusions to which one is driven from a consideration of the above points are that gastrostaxis as an independent disease is not yet indisputably proved to exist; and, on the otber hand, thit acute gastric ulcer is a most important and very common malady, and one which is worthy of more consideration than appears to be given to it.
SUBCELLULAR TYROSINASE ACTIVITY IN FORTNER'S MALIGNANT MELANOMA
Authors: YUTAKA MISHIMA, K. E. E. JOHNSON
Journal: British Journal of Dermatology (1968)

SUMMARY. —Biochemical and macromolecular characterizations of Fortner's melanotic melanoma of Syrian (golden) hamsters and of B-16 melanotic mouse melanoma were made using the Warburg manometric technique for estimation of the subcellular distribution of tyrosinase activity. The results showed that the major amount of tyrosinase activity was located in the soluble fraction of Fortner's malignant melanoma. This differs from the B-16 melanoma in which the major activity was in the large granule fraction with virtual absence of activity in the soluble fraction. Substantial increase in the tyrosinase activity of Fortner's melanoma fractions was observed after prolonged incubation. The biological significance of this delay in attaining Vmax is discussed.
Loss of heterozygosity in childhood de novo acute myelogenous leukemia
Authors: David A. Sweetser, Chien-Shing Chen, Adam A. Blomberg, David A. Flowers, Patricia C. Galipeau, Michael T. Barrett, Nyla A. Heerema, Jonathan Buckley, William G. Woods, Irwin D. Bernstein, Brian J. Reid
Journal: Blood (2001)
Management of food allergy
Authors: K. Nekarn
Journal: Allergy (1998)

Our present options for the management of food allergy are avoidance and pharmacotherapy. There are, however, many promising perspectives for better future management such as the more extensive use of hydrolyzed and elemental formulas for therapy and prevention, or greater emphasis on diagnosis and treatment of accompanying diseases linked with increased gut permeability. In selected situations, specific immunotherapy might be helpful. Rapid progress is expected in the search for the conditions of induction of oral tolerance. The latest results in genetic engineering can give us very effective tools for mass production of less allergenic foods with high nutritional value--if all safety, stability, productivity, and antigenicity problems can be solved.
From paternalism to partnership
Authors: S. MacGregor
Journal: BMJ (1998)

Medical reporting on the radio has changed from the paternalistic advice given by the early radio doctors to a consumerist, partnership approach to health care, says broadcaster Sue MacGregor

The anniversary celebrations of the NHS–and don't we journalists love anniversaries?–and an invitation from the Royal College of Physicians to address them on their college day gave me a highly entertaining chance to trawl through the BBC's archives to look at how radio had reflected medical issues over 50 years.

I'd heard of Charles Hill, the radio doctor, of course, but until I listened to some of his early broadcasts I'd no idea how pioneering he really was in those wartime days and beyond. It wasn't all roly poly references to bowels and muddy tongues; there was a pretty frank discussion that he chaired about venereal disease and how you could (and couldn't) catch it, …
Barriers to Children Walking and Biking to School—United States, 1999
Authors: Ann M. Dellinger, Usa Prevention
Journal: JAMA (2002)

PHYSICAL ACTIVITY IS AN IMPORTANT PART of a healthy lifestyle; however, many children in the United States do not meet recommended levels of physical activity. 1Although walking and biking to school can increase physical activity among children, motor-vehicle traffic and other factors can make these activities difficult.The majority of U.S. children do not walk or bike to school, approximately one third ride a school bus, and half are driven in a private vehicle.Less than one trip in seven is made by walking or biking. 2 To examine why the majority of children do not walk or bike to school, CDC analyzed data from the national HealthStyles Survey.This report summarizes the results of that analysis, which indicate that long distances and dangerous motor-vehicle traffic pose the most common barriers to children walking and biking to school.Public health and community-based efforts that encourage walking and biking to school should address these barriers.CDC provides technical assistance to Porter/Novelli (Washington, D.C.) in conducting the HealthStyles Survey, an annual mail survey of health-related attitudes and behaviors in the United States.In 1999, investigators solicited 3,550 households that had previously indicated a willingness to respond to survey questions.This sample was selected as representative of the U.S. population on the basis of eight demographic variables: age, sex, marital status, race/ethnicity, income, region, household size, and population density.A total of 2,636 (74%) house-
Arterial Hemodynamics in Patients After Kawasaki Disease
Authors: Hideaki Senzaki, Chen-Huan Chen, Hirotaka Ishido, Satoshi Masutani, Tamotsu Matsunaga, Mio Taketazu, Toshiki Kobayashi, Nozomu Sasaki, Shunei Kyo, Yuji Yokote
Journal: Circulation (2005)

Background— Histopathological findings in the acute stage of Kawasaki disease (KD) indicate widespread vascular inflammation that involves not only coronary arteries but also systemic arteries. This may cause changes in systemic arterial wall properties after KD, which could have adverse effects on arterial hemodynamics (an important predictor of cardiovascular morbidity and mortality). Methods and Results— Systemic arterial hemodynamics were investigated by measuring aortic input impedance during cardiac catheterization in 42 KD patients who had developed coronary artery lesions (CALs) in the acute stage of KD. The KD patients were subdivided into 2 groups according to the angiographic findings (group 1A, 26 patients with persistent CALs; group 1B, 16 patients with regressed CALs), and results were compared with those of 36 referents (group 2). Compared with referents, characteristic impedance was significantly higher for KD patients (137.0±5.1, 125.7±8.2, and 97.9±4.1 dyne · s · cm −5 · m 2 for group 1A, group 1B, and group 2, respectively), and total peripheral arterial compliance indexed to age-specific values was significantly lower for KD patients (group 1A 72.9±4.2% of normal; group 1B 70.6±5.9% of normal; group 2 97.7±4.0% of normal; for both variables, P &lt;0.05 for each KD group versus group 2; P =NS between KD groups), which suggests that both central and peripheral arterial wall stiffness increase after KD regardless of persistence of CALs. Also, indices of arterial wave reflection (reflection coefficient, reflection factor, and augmentation index) were all significantly higher in KD patients than in referents ( P &lt;0.05), with the result that the aortic pressure waveforms of the present KD patients resembled those generally observed in the elderly. In addition, levels of circulating markers of endothelial dysfunction (ACE and von Willebrand factor) were associated with increased vascular stiffening in KD patients but not in referents. Conclusions— These results indicating abnormal arterial hemodynamics after KD highlight the importance of regular monitoring of the systemic arterial bed and potentially relevant cardiovascular events in long-term follow-up of KD.
Induction of Heme Oxygenase-1 During Endotoxemia Is Downregulated by Transforming Growth Factor-β1
Authors: Andrea Pellacani, Philippe Wiesel, Arunabh Sharma, Lauren C. Foster, Gordon S. Huggins, Shaw-Fang Yet, Mark A. Perrella
Journal: Circulation Research (1998)

Abstract —Heme oxygenase (HO)-1 generates CO, a gas with vasodilatory properties, during heme metabolism. HO-1 is expressed highly in vascular tissue after endotoxin stimulation, and generation of CO through the HO-1 pathway contributes to the hemodynamic compromise of endotoxic shock. Shock related to endotoxemia is an immune-mediated process that involves the generation of proinflammatory cytokines such as interleukin (IL)-1β. Because transforming growth factor (TGF)-β1 is a modulator of immune-mediated inflammatory responses and it blocks the hypotension of endotoxic shock, we determined whether TGF-β1 could be used to reduce expression of HO-1 in vascular tissue and smooth muscle cells. In a rat model of endotoxic shock, lipopolysaccharide-induced HO-1 mRNA and protein expression was reduced by TGF-β1 in highly vascularized tissue, such as heart and lung, by Northern and Western analysis. Furthermore, TGF-β1 downregulated HO-1 mRNA after its induction by IL-1β in vascular smooth muscle cells in culture. TGF-β1 also decreased HO-1 but not HO-2 protein expression in these cells. TGF-β1 decreased HO enzyme activity induced in IL-1β–treated vascular smooth muscle cells to a level not different from that in vehicle-treated cells. These studies suggest that this downregulation of HO-1 mRNA and protein expression and decrease in IL-1β–induced HO enzyme activity may contribute to the beneficial effect of TGF-β1 on endotoxic shock.
2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease
Authors: B. Besse, A. Adjei, P. Baas, P. Meldgaard, M. Nicolson, L. Paz-Ares, M. Reck, E.F. Smit, K. Syrigos, R. Stahel, E. Felip, S. Peters, Rolf Stahel, Enriqueta Felip, Solange Peters, Keith Kerr, Benjamin Besse, Johan Vansteenkiste, Wilfried Eberhardt, Martin Edelman, Tony Mok, Ken O'Byrne, Silvia Novello, Lukas Bubendorf, Antonio Marchetti, Paul Baas, Martin Reck, Konstantinos Syrigos, Luis Paz-Ares, Egbert F. Smit, Peter Meldgaard, Alex Adjei, Marianne Nicolson, Lucio Crinò, Paul Van Schil, Suresh Senan, Corinne Faivre-Finn, Gaetano Rocco, Giulia Veronesi, Jean-Yves Douillard, Eric Lim, Christophe Dooms, Walter Weder, Dirk De Ruysscher, Cecile Le Pechoux, Paul De Leyn, Virginie Westeel
Journal: Annals of Oncology (2014)
Bone marrow graft rejection as a function of antibody-directed natural killer cells.
Authors: J F Warner, G Dennert
Journal: The Journal of Experimental Medicine (1985)

There is conclusive evidence that acute bone marrow transplant rejection in lethally irradiated mice is caused by natural killer (NK) cells. The rejection of marrow allografts is exquisitely specific and is controlled by antigenic determinants encoded in or near the H-2 gene complex. The specificity of in vivo marrow graft rejection contrasts with the in vitro specificity pattern of NK cells in cytotoxicity assays. We therefore examined how NK cells cause H-2-specific marrow graft rejection in vivo. Several experimental approaches are presented that suggest that natural antibody, present in responder strains of mice, specifically directs NK cells in an antibody-dependent cytolytic and/or cytostatic reaction, resulting in marrow graft rejection. The following evidence for this mechanism is documented. The ability to reject a marrow graft can be passively transferred by serum from responder to allogeneic nonresponder mice and the specificity of rejection can be mapped within the H-2 region. Serum-induced marrow graft rejection is abrogated following depletion of immunoglobulin, and the serum of responder mice is able to induce a specific antibody-dependent cytotoxic reaction in vitro.
A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder
Authors: Yujing Liu, Ryuichi Wada, Hiromichi Kawai, Kazunori Sango, Chuxia Deng, Tadashi Tai, Michael P. McDonald, Kristlyn Araujo, Jacqueline N. Crawley, Uwe Bierfreund, Konrad Sandhoff, Kinuko Suzuki, Richard L. Proia
Journal: Journal of Clinical Investigation (1999)

Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.