tbuckley/cabot-search huggingface dataset:
CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in Rheumatoid Arthritis
Authors: Jhimmy Talbot, Francine J. Bianchini, Danilele C. Nascimento, Rene D. R. Oliveira, Fabricio O. Souto, Larissa G. Pinto, Raphael S. Peres, Jaqueline R. Silva, Sergio C. L. Almeida, Paulo Louzada‐Junior, Thiago M. Cunha, Fernando Q. Cunha, Jose C. Alves‐Filho
Journal: Arthritis & Rheumatology (2015)

Objective Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints. Methods Neutrophils were purified from the peripheral blood of patients with RA or from mice with antigen‐induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints. Results High CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild‐type mouse neutrophils to CCR2‐deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation. Conclusion These findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
Sustained Effects of a Mindfulness-Based Stress-Reduction Intervention in Type 2 Diabetic Patients
Authors: Mechthild Hartmann, Stefan Kopf, Claudia Kircher, Verena Faude-Lang, Zdenka Djuric, Florian Augstein, Hans-Christoph Friederich, Meinhard Kieser, Angelika Bierhaus, Per M. Humpert, Wolfgang Herzog, Peter P. Nawroth
Journal: Diabetes Care (2012)

OBJECTIVE To determine whether a mindfulness-based stress reduction (MBSR) intervention is effective for reducing psychosocial distress (i.e., depression, psychosocial stress) and the progression of nephropathy (i.e., albuminuria) and for improving the subjective health status of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes and microalbuminuria were randomized to a mindfulness-based intervention (n = 53) or a treatment-as-usual control (n = 57) group. The study is designed to investigate long-term outcomes over a period of 5 years. We present data up to the first year of follow-up (FU). RESULTS At FU, the MBSR group showed lower levels of depression (d = 0.71) and improved health status (d = 0.54) compared with the control group. No significant differences in albuminuria were found. Per-protocol analysis also showed higher stress reduction in the intervention group (d = 0.64). CONCLUSIONS MBSR intervention achieved a prolonged reduction in psychosocial distress. The effects on albuminuria will be followed up further.
Caveolin-1 interacts and cooperates with the transforming growth factor-β type I receptor ALK1 in endothelial caveolae
Authors: Juan F. Santibanez, Francisco J. Blanco, Eva M. Garrido-Martin, Francisco Sanz-Rodriguez, Miguel A. del Pozo, Carmelo Bernabeu
Journal: Cardiovascular Research (2007)

Activin receptor-like kinase (ALK)1 is a transforming growth factor (TGF)-β type I membrane receptor restricted almost entirely to endothelial cells (ECs) and involved in vascular remodelling and angiogenesis. Previous reports have shown that the ubiquitous TGF-β type I receptor ALK5 and the type II receptor are located in cholesterol-rich membrane microdomains named caveolae. The aim of this work was to assess the location of ALK1 in endothelial caveolae as well as to study the role of caveolin-1 on the TGF-β/ALK1 signalling pathway. The subcellular distribution of ALK1 was analysed by confocal microscopy and co-fractionation experiments in human ECs. The association between human ALK1 and caveolin-1 was studied in caveolin-1-deficient human epithelial cells by co-immunoprecipitation. The functional role of caveolin-1 on the ALK1-mediated TGF-β signalling was elucidated using ALK1-specific luciferase reporters in human ECs, caveolin-1−/−mouse embryonic fibroblasts, and rat myoblasts. Confocal microscopy analyses, as well as cholesterol depletion experiments in the presence of cholesterol-depleting agents such as nystatin or methyl-β-cyclodextrin, demonstrated that ALK1 is located in endothelial caveolae. Also, co-immunoprecipitation assays showed that ALK1 associates with the main caveolae component caveolin-1. Mapping of the ALK1/caveolin-1 interaction revealed that the caveolin-1 scaffolding domain and the caveolin-1 binding motif in ALK1 are responsible for this association. Moreover, this hitherto not reported interaction had a functional consequence for the ALK1-dependent signalling. In contrast with the previously published ALK5/caveolin-1 interaction, caveolin-1 enhances the TGF-β/ALK1 signalling pathway, promoting the activity of the ALK1-specific reporters. Conversely, specific suppression of caveolin-1 abrogated the ALK1 signalling pathway. ALK1 is located in endothelial caveolae where it functionally interacts with caveolin-1 through its scaffolding domain, suggesting a joint contribution of ALK1 and caveolin-1 as key mediators of the TGF-β pathway in angiogenesis.
Extrahepatic malignancy following long-term immunosuppressive therapy of severe hepatitis B surface antigen-negative chronic active hepatitis
Authors: Kenneth K. Wang, Albert J. Czaja, Sandra J. Beaver, Vay L. W. Go
Journal: Hepatology (1989)

To determine the frequency, predisposing factors and consequences of extrahepatic malignancy following long-term immunosuppressive therapy of severe HBsAg-negative chronic active hepatitis, 149 patients who had received prednisone (20 mg daily) or prednisone (10 mg daily) in combination with azathioprine (50 mg daily) for at least 6 months were evaluated systematically for 109 ± 5 months (range: 7 to 223 months). Seven neoplasms involving cervix (2), lymphatic tissue (1), breast (1), bladder (1), soft tissue (1) and unknown site (1) developed in seven patients after 116 ± 23 months (range: 18 to 164 months). The incidence of extrahepatic neoplasm was 1 per 194 patient-years of surveillance, and the probability of tumor occurrence was 3% after 10 years. Tumor frequency was similar in men and women and the risk was 1.4-fold greater than that in an age-and sex-matched normal population (95% confidence interval, 0.6- to 2.9-fold normal). Patients with extrahepatic malignancy were not distinguished by age, sex, treatment regimen, cumulative duration of treatment (42 ± 9 vs. 60 ± 4 months, p = 0.7) or individual features of the liver disease. Five of the seven patients survived during 48 ± 25 months of follow-up, including two patients who have lived for at least 5 years after the diagnosis of malignancy. We conclude that extrahepatic malignancy develops infrequently during long-term immunosuppressive therapy. Its occurrence is not related to the type or duration of treatment, and long-term survival after tumor detection is possible. The low but probably increased risk of extrahepatic neoplasm does not militate against the use of immunosuppressive therapy in these patients.
Letter by Govindarajan and Salgado Regarding Article, “Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial”
Authors: Raghav Govindarajan, Efrain Salgado
Journal: Circulation (2012)
The Role of Glucagon Deficiency in the Houssay Phenomenon of Dogs
Authors: Hajime Nakabayashi, Richard E. Dobbs, Roger H. Unger
Journal: Journal of Clinical Investigation (1978)

Plasma glucose, immunoreactive glucagon (IRG), and insulin were measured in hypophysectomized dogs receiving cortisol and thyroid replacement therapy. 4 wk after hypophysectomy mean fasting plasma glucose levels had declined from 90±2 mg/100 ml to 64±2; fasting and arginine-stimulated insulin and IRG levels were, respectively, ∼50% lower and unchanged. 12 wk or more after hypophysectomy, despite lower plasma glucose levels, fasting and arginine-stimulated IRG levels were significantly below control dogs. Hypophysectomized and shamhypophysectomized dogs were subjected to total pancreatectomy. Postoperatively, in the sham-hypophysectomized, depancreatized dogs fasting glucose levels ranged from 300-500 mg/100 ml on 8-10 U/day of insulin; IRG levels averaged 215±29 pg/ml. The hypophysectomized, depancreatized dogs required 0-4 U/day and fasting glucose levels under 100 mg/100 ml were not uncommon, even without insulin; fasting IRG levels averaged 63±4 pg/ml (P < 0.001). During arginine infusion in sham-hypophysectomized, depancreatized dogs, IRG levels rose from 215±60 pg/ml to a peak of 404±112 pg/ml; in hypophysectomized, depancreatized dogs, the base line IRG averaged 44±8 and the peak 110±25 pg/ml (P < 0.05). IRG levels in the venous effluent of the gastric fundus, the major source of nonpancreatic glucagon, reached a peak of 4,898±959 pg/ml in the sham-hypophysectomized, depancreatized group during arginine infusion and only 219±128 pg/ml in the hypophysectomized, depancreatized group. In three hypophysectomized, depancreatized dogs, a replacement infusion with glucagon for 10 h promptly increased hyperglycemia by 80-180 mg/100 ml and worsened glycosuria, evidence of a hepatic response to glucagon replacement. It is concluded that hypophysectomy somehow decreased both the hypersecretion of gastric IRG and the severe hyperglycemia that otherwise follows pancreatectomy. The hypophysectomized, depancreatized animal, therefore, has combined insulin and glucagon deficiency, and the latter may contribute to reduced severity of its hyperglycemia.
Wake-up call by breathomics in sleep apnoea
Authors: Peter J. Sterk, Niki Fens, G. Elisiana Carpagnano
Journal: European Respiratory Journal (2013)

Respiratory diseases are amongst the most complex pathophysiological entities in medicine. There is no such thing as a one-item disease in our field, which brings the appeal of respiratory diseases for basic and clinical scientists. The most prevalent respiratory diseases are chronic, exhibiting multiple mechanistic pathways that can vary during the course of the disease. This has not only hampered pathogenetic research, but has also impeded adequate disease phenotyping [1]. Apparently, it takes more than a few clinical and serum markers to establish the true biomedical entity of complex diseases. The good news is that, as we speak, medicine is making a step-change in achieving exactly that [2].

It is now increasingly recognised that the clinical, physiological, cellular and molecular mechanisms of disease cannot be addressed separately. Instead, it is more likely that an integrative approach that links these various domains of disease will get closer to a true understanding of disease [1, 2]. The problem in chronic respiratory medicine has been that each of the disease domains by itself is characterised by multiple perturbed mechanisms in parallel or in series, so that adequately describing various disease states requires capturing this seeming “chaos” by: 1) high-throughput measurements in each of these disease domains; 2) sophisticated multi-scale mathematical integration of these data [3] to come to; 3) unbiased discovery of (changes in) mechanistic pathways. “Omics” techniques follow this approach [4–6].

Based on developments in molecular medicine and bioinformatics during the past decade [7], a “systems medicine” approach has now become a very powerful option for capturing the complexity of diseases in general [1] and respiratory diseases in particular [3]. The required high-throughput “omics” tools are now available for use in blood, secretions …
Effects of age, training background and duration of running on abnormal urinary findings after a half-marathon race.
Authors: H Gür, S Küçükoğlu, E Sürmen, A Müftüoğlu
Journal: British Journal of Sports Medicine (1994)

high potassium diet with large doses of spironolactone could be dangerous!He further proposes that with either the high potassium or the spironolactone regimen, the normal fluid intake be supplemented by the drinking of 10-15 glasses of distilled water over each of the 3 days before competition.The effects of such mineral ion manipulation upon muscle water content are further supplemented by glycogen depletion (pushed to a state of 'borderline ketosis', as an initial allowance of 92 g day-1 is tapered to 23 g day-' over the period 7-4 days before competition), with a final period of 'supercompensation', when 10 separate 40-g carbohydrate meals are taken at 90-min intervals.The sources of carbohydrate are limited to items such as bananas, raisins, dates, yams, tomatoes, apricots and peaches, the objective being to maximize the intake of potassium, and to minimize the intake of sodium.If the muscles still appear 'flat' on the day before competition, the intake of these carbohydrates is further boosted to
Long-term results in children with AML: NOPHO-AML Study Group – report of three consecutive trials
Authors: S O Lie, J Abrahamsson, N Clausen, E Forestier, H Hasle, L Hovi, G Jonmundsson, L Mellander, M A Siimes, M Yssing, B Zeller, G Gustafsson
Journal: Leukemia (2005)
Ofatumumab Exhibits Enhanced <i>In Vitro</i> and <i>In Vivo</i> Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma
Authors: Matthew J. Barth, Cory Mavis, Myron S. Czuczman, Francisco J. Hernandez-Ilizaliturri
Journal: Clinical Cancer Research (2015)

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models.MCL cells were labeled with (51)Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. (51)Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose).Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL.Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149).
Comparative Effectiveness Research to Inform Medical Decisions: The Need for Common Language
Authors: Neal J. Meropol
Journal: Journal of Clinical Oncology (2012)

On a daily basis, oncologists and their patients must make choices regarding the approach to treatment. Although treatment selection is often straightforward, decision making in oncology is increasingly complexbecauseofexpandingtreatmentoptions,thetoxicityoftreatment, uncertain outcomes, out-of-pocket cost of therapy, and a highly charged clinical setting in which mortality is a central element. A key consideration in these decisions is the value of available therapeutic options. The ability to integrate considerations of clinical benefits, toxicities, and costs and compare alternative approaches has become essential for physicians and patients. Reliable information and the skillstoclearlycommunicatethisinformationtopatientsaretoolsthat are needed to assist clinical decision making, but unfortunately, these tools are currently inadequate. Although the importance of integrating patient preferences into the decision-making process has been longrecognized,dataarenotroutinelyavailabletopredictthepatient experience of care and hence inform the application of these preferences.Clearly,oursuccessingrowingtheclinicalarmamentariumhas
Absence of Germline Infection in Male Mice Following Intraventricular Injection of Adenovirus
Authors: Antoine H.F.M. Peters, Jeff Drumm, Carolyn Ferrell, David A. Roth, David M. Roth, Michael McCaman, Patricia L. Novak, Jeffrey Friedman, Robert Engler, Robert E. Braun
Journal: Molecular Therapy (2001)

The possibility of inadvertent exposure of gonadal tissue to gene therapy vectors has raised safety concerns about germline infection. We show here that the receptor for coxsackie B viruses and adenoviruses 2 and 5 (CXADR) is expressed in mouse germ cells, suggesting the possibility that these viruses could infect germ cells. To directly assess the risk of germline infection in vivo, we injected an adenovirus carrying the germ-cell-specific protamine promoter fused to the bacterial lacZ reporter gene into the left ventricular cavity of mice and then monitored expression of the reporter gene in germ cells. To differentiate between infection of stem cells and differ-entiating spermatogenic cells, we analyzed expression of the reporter cassette at different times after viral delivery. Under all conditions tested, mice did not express the Escherichia coli β-galactosidase protein in developing spermatids or in mature epididymal spermatozoa. Primary germ cells cultured in vitro were also refractory to adenoviral infection. Our data suggest that the chance of vertical germline transmission and insertional mutagenesis is highly unlikely following intracoronary adenoviral delivery.
Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology
Authors: Derek J. Hausenloy, Hans Erik Bøtker, Gianluigi Condorelli, Peter Ferdinandy, David Garcia-Dorado, Gerd Heusch, Sandrine Lecour, Linda W. van Laake, Rosalinda Madonna, Marisol Ruiz-Meana, Rainer Schulz, Joost P.G. Sluijter, Derek M. Yellon, Michel Ovize
Journal: Cardiovascular Research (2013)

Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia-reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients.
Ventilatory and gas exchange abnormalities on exercise in chronic heart failure
Authors: OA Al-Rawas, R Carter, D Richens, RD Stevenson, SK Naik, A Tweddel, DJ Wheatley
Journal: European Respiratory Journal (1995)

The mechanism of breathlessness on exertion in patients with chronic heart failure are still not fully understood. We therefore investigated the effects of ventilatory and gas exchange abnormalities on exercise capacity in chronic heart failure. Exercise testing was performed in 30 patients with exertional breathlessness due to chronic heart failure and in 30 controls, using continuous transcutaneous blood gas monitoring. Maximal symptom-limited oxygen consumption as (V'O2) as a percentage predicted was reduced in patients (45 +/- 10%; mean +/- SD) compared to controls (87 +/- 7). The ventilatory response (minute ventilation/carbon dioxide production (V'E/V'CO2)) was significantly increased in patients compared to controls (39.9 +/- 7.7 and 25.9 +/- 3.6, respectively). The dead space to tidal volume ratio (VD/VT) was raised in patients compared to controls at rest (0.45 +/- 0.04 vs 0.35 +/- 0.02, respectively) and this persisted on exertion (0.40 +/- 0.05 in patients and 0.20 +/- 0.05 in controls). At maximal symptom-limited exercise, V'E/V'CO2 was inversely related to the % predicted V'O2 in patients, but not in controls (r = -0.62 and r = -0.24, respectively). In patients, V'E/V'CO2 was significantly correlated with VD/VT at maximum exercise (r = 0.82). Patients with chronic heart failure have a significant degree of "wasted ventilation" on exertion, which is associated with increased ventilatory response. The increased ventilatory response on exertion appears to contribute to exercise limitation in these patients.