tbuckley/cabot-search huggingface dataset:
Function of the Th17/Interleukin‐17A Immune Response in Murine Lupus Nephritis
Authors: Tilman Schmidt, Hans‐Joachim Paust, Christian F. Krebs, Jan‐Eric Turner, Anna Kaffke, Sabrina B. Bennstein, Tobias Koyro, Anett Peters, Joachim Velden, Stefanie Hünemörder, Friedrich Haag, Oliver M. Steinmetz, Hans‐Willi Mittrücker, Rolf A. K. Stahl, Ulf Panzer
Journal: Arthritis & Rheumatology (2014)

The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin-17 (IL-17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL-17A immune response in 2 murine models of lupus nephritis.IL-17A-deficient MRL/MPJ-Fas(lpr) /2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus-prone (NZB × NZW)F1 (NZB/NZW) mice were treated with anti-IL-17A and anti-interferon-γ (anti-IFNγ) antibodies, and their effects on the clinical course of lupus nephritis were assessed.Characterization of renal IL-17A-producing and IFNγ-producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL-17A+ cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL-17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti-IFNγ treatment attenuated the severity of the disease.The Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL-17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.
Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization
Authors: Claudia Traidl-Hoffmann, Valentina Mariani, Hubertus Hochrein, Kathrin Karg, Hermann Wagner, Johannes Ring, Martin J. Mueller, Thilo Jakob, Heidrun Behrendt
Journal: The Journal of Experimental Medicine (2005)

Pollen grains induce allergies in susceptible individuals by release of allergens upon contact with mucosal membranes of the upper respiratory tract. We recently demonstrated that pollen not only function as allergen carriers but also as rich sources of bioactive lipids that attract cells involved in allergic inflammation such as neutrophils and eosinophils. Here we demonstrate that soluble factors from birch (Betula alba L.) pollen activate human dendritic cells (DCs) as documented by phenotypical and functional maturation and altered cytokine production. Betula alba L. aqueous pollen extracts (Bet.-APE) selectively inhibited interleukin (IL)-12 p70 production of lipopolysaccharide (LPS)- or CD40L-activated DC, whereas IL-6, IL-10, and TNFα remained unchanged. Presence of Bet.-APE during DC activation resulted in DC with increased T helper type 2 (Th2) cell and reduced Th1 cell polarizing capacity. Chemical analysis of Bet.-APE revealed the presence of phytoprostanes (dinor isoprostanes) with prostaglandin E1-, F1-, A1-, or B1-ring systems of which only E1-phytoprostanes dose dependently inhibited the LPS-induced IL-12 p70 release and augmented the Th2 cell polarizing capacity of DC. These results suggest that pollen-derived E1-phytoprostanes not only resemble endogenous prostaglandin E2 structurally but also functionally in that they act as regulators that modulate human DC function in a fashion that favors Th2 cell polarization.
Faecal stasis and diverticular disease in ulcerative colitis
Authors: K. N. Jalan, R. J. Walker, R. J. Prescott, S. T. G. Butterworth, A. N. Smith, W. Sircus
Journal: Gut (1970)

The incidence of faecal stasis and of diverticular disease has been studied in a group of 399 patients with ulcerative colitis. Sixty-one patients had faecal stasis and 23 patients had diverticular disease. Pathological studies demonstrated an increase in the thickness of the inner spiral muscle in colitis patients with faecal stasis. The thickening was not as great as that seen in diverticular disease. Preliminary studies on the motility patterns in patients with faecal stasis show a higher mean activity in the pelvic colon than in normals but not as great as that seen in diverticular disease. Pressure studies in patients with faecal stasis have shown hypotonia in the proximal colon associated with dilatation. The possible significance of these results is discussed. It is suggested that ulcerative colitis may initiate a motility disturbance which leads to muscle thickening similar to that in diverticular disease. Diverticula associated with ulcerative colitis are usually not involved in the mucosal inflammatory process.
Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis
Authors: Sam Schulman, Ajay K. Kakkar, Samuel Z. Goldhaber, Sebastian Schellong, Henry Eriksson, Patrick Mismetti, Anita Vedel Christiansen, Jeffrey Friedman, Florence Le Maulf, Nuala Peter, Clive Kearon
Journal: Circulation (2013)

Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings.In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79).Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE.www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.
Is life-long exercise damaging to the heart?
Authors: Mathew G Wilson, Gregory P Whyte
Journal: British Journal of Sports Medicine (2012)

Oscar Wilde once said, ‘Moderation is a fatal thing. Nothing succeeds like excess’. Some would say that, for elite athletes, ignoring this aphorism can only lead to failure. With the stoichiometric rise in the number of veteran athletes taking part in ultra-endurance exercise, it is apparent that a growing number of athletes are adopting Wilde's maxim with some impressive results. The winner of the 2011 Virgin London Marathon male 60–64 year age group clocked 3 h 3 min 25 s, while the 2010 New York Marathon male 70–74 year group winner ran 3 h 18 min 45 s! In support of the endurance obsession, we have recently published a case study of a 68-year-old male runner who had accurately recorded a total distance of 148 561 miles throughout 43 years of daily running.1 While we are assured that moderate intensity, duration and frequency exercise are positive for ciovascular health, can we be sure that running 7 min 30 s repeatedly over 3 h at 70 years of age or 150 000 miles throughout a 70-year lifetime is not damaging to the myocium? In essence, can one have too much of a good thing?

Ageing is associated with changes to the ciovascular system that reduce functional capacity. Regular endurance exercise training appears to slow this progressive decline, however; do such benefits apply …
Polycystic Ovary Syndrome as a Form of FunctionalOvarian Hyperandrogenism Due to Dysregulation ofAndrogen Secretion*
Authors: DAVID A. EHRMAN, RANDALL B. BARNES, ROBERT L. ROSENFIELD
Journal: Endocrine Reviews (1995)

IN 1935, Stein and Leventhal (1) reported the association of polycystic ovaries in women with amenorrhea, hirsutism, and obesity. Morphological and histological studies of the ovaries from these patients revealed a thickened tunica albuginea, hyperplasia of the theca interna and cortical stroma, and multiple subcapsular follicles that were in various stages of atresia (1). Subsequently, the heterogeneity of both the ovarian histology and clinical findings in women with polycystic ovaries was recognized and led to the establishment of the term polycystic ovary syndrome (PCOS) (2, 3). Indeed, patients with the severest cases may have hyperthecosis, a form in which there are no cysts (2,4,5), and those with milder ovarian dysfunction tend to have normal ovarian morphology (6). Later, increased concentrations of serum LH or an increase in the ratio of LH to FSH were shown to be characteristic (7) and became common diagnostic criteria in lieu of biopsy evidence of polycystic ovaries. More recently, hyperandrogenemia was shown to be typical (8), and improvements in imaging techniques have made it possible to noninvasively demonstrate polycystic ovaries (9).
Prognosis research strategy (PROGRESS) 4: Stratified medicine research
Authors: A. D. Hingorani, D. A. v. d. Windt, R. D. Riley, K. Abrams, K. G. M. Moons, E. W. Steyerberg, S. Schroter, W. Sauerbrei, D. G. Altman, H. Hemingway
Journal: BMJ (2013)

In patients with a particular disease or health condition, stratified medicine seeks to identify those who will have the most clinical benefit or least harm from a specific treatment. In this article, the fourth in the PROGRESS series, the authors discuss why prognosis research should form a cornerstone of stratified medicine, especially in regard to the identification of factors that predict individual treatment response
Darbepoetin Alfa for the Treatment of Anemia in Patients With Active Cancer Not Receiving Chemotherapy or Radiotherapy: Results of a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Authors: Robert E. Smith, Matti S. Aapro, Heinz Ludwig, Tamás Pintér, Martin Šmakal, Tudor E. Ciuleanu, Li Chen, Tom Lillie, John A. Glaspy
Journal: Journal of Clinical Oncology (2008)

The efficacy and safety of darbepoetin alpha (DA) for treating patients with active cancer and anemia not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy was evaluated.Patients with active cancer and anemia not receiving or planning to receive chemotherapy or radiotherapy were enrolled onto a phase III, multicenter, randomized, placebo-controlled study and administered placebo or DA 6.75 microg/kg every 4 weeks (Q4W) for up to 16 weeks with a 2-year follow-up for survival. Patients who completed 16 weeks of treatment could receive the same treatment as randomized Q4W for an additional 16 weeks. The primary end point was all occurrences of transfusions from weeks 5 through 17; safety end points included incidence of adverse events and survival.The incidence of transfusions between weeks 5 and 17 was lower in the DA group but was not statistically significantly different from that of placebo. DA was associated with an increased incidence of cardiovascular and thromboembolic events and more deaths during the initial 16-week treatment period. Long-term survival data demonstrated statistically significantly poorer survival in patients treated with DA versus placebo (P = .022). This effect varied by baseline covariates including, sex, tumor type, and geographic region; statistical significance diminished (P = .12) when the analysis was adjusted for baseline imbalances or known prognostic factors.DA was not associated with a statistically significant reduction in transfusions. Shorter survival was observed in the DA arm; thus, this study does not support the use of erythropoiesis-stimulating agents in this subset of patients with anemia of cancer.
Increased Survival of Glioblastoma Patients Who Respond to Antiangiogenic Therapy with Elevated Blood Perfusion
Authors: A. Gregory Sorensen, Kyrre E. Emblem, Pavlina Polaskova, Dominique Jennings, Heisoog Kim, Marek Ancukiewicz, Meiyun Wang, Patrick Y. Wen, Percy Ivy, Tracy T. Batchelor, Rakesh K. Jain
Journal: Cancer Research (2011)

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.
Patient-Derived Tumor Xenografts: Transforming Clinical Samples into Mouse Models
Authors: Despina Siolas, Gregory J. Hannon
Journal: Cancer Research (2013)

Tumor graft models (also known as patient-derived xenografts or PDX) are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse. Because PDX mice are derived from human tumors, they offer a tool for developing anticancer therapies and personalized medicine for patients with cancer. In addition, these models can be used to study metastasis and tumor genetic evolution. This review examines the development, challenges, and broad use of these attractive preclinical models.
Toward a Meningitis-Free World
Authors: Steven Black, Mariagrazia Pizza, Mikkel Nissum, Rino Rappuoli
Journal: Science Translational Medicine (2012)

A conjugate vaccine against the A, C, W, and Y, serogroups of meningococcus and a protein-based vaccine against serogroup B should bring to an end the scourge of meninogococcal meningitis.
Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA
Authors: Nancy B. Y. Tsui, Rezan A. Kadir, K. C. Allen Chan, Claudia Chi, Gillian Mellars, Edward G. Tuddenham, Tak Y. Leung, Tze K. Lau, Rossa W. K. Chiu, Y. M. Dennis Lo
Journal: Blood (2011)
cGMP inhibits the activity of single calcium channels in embryonic chick heart cells.
Authors: N Tohse, N Sperelakis
Journal: Circulation Research (1991)

Effects of cGMP on the slow (L-type) Ca2+ channels of cultured chick embryonic cardiomyocytes were investigated by a cell-attached patch-clamp method. Superfusion of the single cells with 8-bromo-cGMP, a membrane-permeable derivative of cGMP, inhibited the single-channel activity. The cyclic nucleotide decreased, in a concentration-dependent manner, the ensemble averaged currents obtained from multichannel patches. 8-Bromo-cGMP (1 mM) completely abolished the currents (n = 8), whereas 0.1 mM only slightly decreased the currents (n = 4). The influence of cGMP on the characteristics of the single Ca2+ channels was examined using 0.3 mM 8-bromo-cGMP. Unit amplitude and slope conductance of the Ca2+ channel was not changed (25 pS in control versus 24 pS in the presence of cGMP). Analysis of single-channel kinetics showed that cGMP prolonged the slow time constant for the closed-time histogram (from 6.7 to 15.4 msec); the other time constants (for the open-time and closed-time histograms) were not affected. cGMP-induced inhibition of the Ca2+ channels may be mediated by cGMP-dependent protein kinase, because 8-bromo-cGMP is a potent activator of this protein kinase and does not stimulate cAMP hydrolysis. The present results suggest that cGMP opposes the effects of cAMP on the L-type Ca2+ channels in myocardial cells.
C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha.
Authors: S Okusawa, K B Yancey, J W van der Meer, S Endres, G Lonnemann, K Hefter, M M Frank, J F Burke, C A Dinarello, J A Gelfand
Journal: The Journal of Experimental Medicine (1988)

We have demonstrated that purified C5a is a potent stimulus to human PBMC secretion of TNF-alpha, IL-1 beta, and IL-1 alpha, which proceeds in a dose-dependent fashion. At a given concentration of C5a, TNF-alpha and IL-1 beta secretion did not differ significantly; both were secreted in significantly greater quantity than IL-1 alpha. Clinical conditions such as Gram-positive and Gram-negative bacterial infections, trauma, and immune complex diseases activate complement. Through the mediation of TNF and IL-1 secreted in response to C5a, these diverse disorders can share common features of fever, coagulopathy, acute phase protein production, and disordered metabolism.
Cellular events in the induction of experimental allergic encephalomyelitis in rats.
Authors: L Ortiz-Ortiz, W O Weigle
Journal: The Journal of Experimental Medicine (1976)

Although both the T and B cells of the Lewis rat have immunoglobulin receptors for basic protein (BP) of myelin, and both cell types are required for antibody production to BP, the present results demonstrate that the T cells are the only cells required for the induction of experimental allergic encephalomyelitis (EAE). Both EAE and anti-BP were readily induced in thymectomized, irradiated Lewis rats reconstituted with normal thymus and bone marrow cells and challenged with BP in complete Freund's adjuvant. If the thymus cells were first treated with BP heavily labeled with 125I so as to eliminate (sucide) specific T cells, the recipients neither develop EAE nor produce antibody to BP. On the other hand, if the thymus cells were untreated and the specific B cells of bone marrow were eliminated by treatment with 125I-BP, EAE was not inhibited, although no antibody was produced. These results strongly suggest that the T cell is responsible for the induction of EAE although both the T and B cells are competent to respond to BP. Evidence was presented which suggests that neither suppressor T cells nor circulating antibody are involved in the inhibition of EAE by injection of Lewis rats with nonencephalitogenic preparations of BP. The immune status of T and B cells of the Lewis rat to BP was compared with the immune status of these cells in other species to thyroglobulin, where only the B cells appear to be competent. In this context, Brown Norway rats, which are resistant to the induction of EAE, also appear to lack T cells reactive to BP, although competent B cells are present.
Symptomatic eosinophilic gastritis cured with Helicobacter pylori eradication
Authors: A A Papadopoulos
Journal: Gut (2005)

Pitfalls in diagnosing acute pancreatitisWe thank Jolobe for his letter (Gut 2005;54:1207-8) which mentions the difficulty of establishing the diagnosis of acute pancreatitis in patients with diabetic ketoacidosis.We did not address diagnostic tests and medical intensive care treatment of acute pancreatitis in our article, 1 but reviewed the interventional and surgical treatment strategies in acute pancreatitis.There is no doubt that treatment of acute pancreatitis, including organ failure in its early phase, is solely supportive. 2 Due to improvements in inten- sive care medicine, mortality of severe disease has decreased dramatically over the past decades.However, to treat patient adequately, the correct diagnosis has to be made.Therefore, the first step in the diagnostic process of acute pancreatitis is to think of this disease.According to the latest classification from Atlanta, 3 acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems.From a clinical point of view, acute upper abdominal pain and elevated pancreatic enzyme levels are needed to diagnose acute pancreatitis.As pointed out by Jolobe in his letter, acute pancreatitis is still underdiagnosed under certain clinical conditions, including diabetic ketoacidosis, but also in other clinical situations, such as shock of unknown origin, patients under intensive care treatment, as well as rare causes of the disease.As acute pancreatitis can be associated with diabetic ketoacidosis and the association between these two is a two way cause-and-effect relationship, early imaging of the pancreas is recommended in these patients to establish the correct diagnosis.Our article focused on the surgical and interventional treatment of severe acute pancreatitis.
A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia
Authors: Francoise Pousset, Lise Legrand, Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles, Michel Komajda, Alexis Brice, Massimo Pandolfo, Richard Isnard, Sophie Tezenas du Montcel, Alexandra Durr
Journal: JAMA Neurology (2015)

Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival.To assess FRDA survival and cardiac outcome to adapt future therapeutic trials.In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013. The setting was the French National Reference Center for Rare Diseases and the Department of Cardiology, Salpêtrière University Hospital, Paris, France. In total, 138 patients with FRDA were followed up. Among 133 patients homozygous for expanded GAA repeats, the mean (SD) age was 31 (10) years (age range, 11-62 years), with a mean (SD) age at disease onset of 16 (8) years (age range, 3-50 years) and a mean (SD) age at first wheelchair use of 26 (9) years (age range, 11-64 years). Cardiac hypertrophy was present in 57.9% (77 of 133), and electrocardiography was normal in 6.8% (9 of 133).Long-term cardiac outcome and predictors of survival in FRDA.After a mean (SD) follow-up of 10.5 (5.5) years (range, 0.6-23.0 years), the 10-year survival rate was 88.5%. In 80.0% of patients (12 of 15), death was due to cardiac causes. Predictors of survival were a shorter GAA repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.69), left ventricular ejection fraction (HR, 0.42; 95% CI, 0.20-0.89), and left ventricular mass index (HR, 1.19; 95% CI, 1.04-1.36). Two cardiac evolutions were distinguished with a group-based trajectory model, including a low-risk cardiac group (78.6% [81 of 103] with normal ejection fraction at baseline that declined slightly over time but remained within the normal range) and a high-risk cardiac group (21.4% [22 of 103] in which the ejection fraction progressively declined during follow-up). The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time.Survival in FRDA is determined by cardiac complications, which are dependent on the mutation (ie, the size of the expanded GAA repeat). Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications.