tbuckley/cabot-search huggingface dataset:
Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells
Authors: Paolo Cravedi, Joaquin Manrique, Katherine E. Hanlon, Jessica Reid-Adam, Joshua Brody, Praeophayom Prathuangsuk, Anita Mehrotra, Peter S. Heeger
Journal: Journal of the American Society of Nephrology (2014)

Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4(+) and CD8(+) T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4(+) T-cell proliferation (EPO 1000 U/ml: 44.6%±22.9% of vehicle, P<0.05; 2000 U/ml: 11.1%±4% of vehicle, P<0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4(+) T cells after adoptive transfer into NOD scid γc(null) mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients.
Lactadherin promotes VEGF-dependent neovascularization
Authors: Jean-Sébastien Silvestre, Clotilde Théry, Ghislaine Hamard, Jacques Boddaert, Barbara Aguilar, Alain Delcayre, Christophe Houbron, Radia Tamarat, Olivier Blanc-Brude, Sylvia Heeneman, Michel Clergue, Micheline Duriez, Régine Merval, Bernard Lévy, Alain Tedgui, Sebastian Amigorena, Ziad Mallat
Journal: Nature Medicine (2005)
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Authors: D. Moher, A. Liberati, J. Tetzlaff, D. G Altman
Journal: BMJ (2009)

Structured summary 2 Provide a structured summary including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings, systematic review registration number Flow of information through the different phases of a systematic review No of records identified through database searching No of additional records identified through other sources No of records after duplicates removed No of studies included in qualitative synthesis No of studies included in quantitative synthesis (meta-analysis)
Decreased atherosclerosis in CX3CR1–/– mice reveals a role for fractalkine in atherogenesis
Authors: Philippe Lesnik, Christopher A. Haskell, Israel F. Charo
Journal: Journal of Clinical Investigation (2003)

The hallmark of early atherosclerosis is the accumulation of lipid-laden macrophages in the subendothelial space. Circulating monocytes are the precursors of these “foam cells,” and recent evidence suggests that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Fractalkine (FK) is a structurally unusual chemokine that can act either as a soluble chemotactic factor or as a transmembrane-anchored adhesion receptor for circulating leukocytes. A polymorphism in the FK receptor, CX3CR1, has been linked to a decrease in the incidence of coronary artery disease. To determine whether FK is critically involved in atherogenesis, we deleted the gene for CX3CR1 and crossed these mice into the apoE–/– background. Here we report that FK is robustly expressed in lesional smooth muscle cells, but not macrophages, in apoE–/– mice on a high-fat diet. CX3CR1–/– mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation. Taken together, these data provide strong evidence that FK plays a key role in atherogenesis.
Only patients with dysplasia progress to adenocarcinoma in Barrett's oesophagus.
Authors: M Miros, P Kerlin, N Walker
Journal: Gut (1991)

Columnar lined oesophagus (Barrett's oesophagus) carries a risk for the development of adenocarcinoma. Epithelial dysplasia appears to be a precursor but the utility of this marker for predicting subsequent adenocarcinoma is unsettled. We therefore prospectively studied 81 patients with histologically proven columnar epithelium of at least the distal 3 cm of the tubular oesophagus with regular endoscopic biopsies for a total of 289.2 patient years (mean 3.6 years, range 0.5-8). Twenty three patients (28%) had epithelial dysplasia detected during follow up. Both patients with persistent high grade dysplasia present on initial biopsies developed adenocarcinoma after 2.6-4.5 years, despite the absence of gross macroscopic change. The initial single layer pleomorphic high grade dysplasia in one patient regressed to low grade dysplasia which has persisted for 1.5 years. Of 10 patients with initial low grade dysplasia, one progressed to adenocarcinoma in 4.3 years. The low grade dysplasia persisted unchanged in seven patients for 1.5-7 years and appears to have regressed in two patients after three to five years. Ten patients developed low grade dysplasia during the surveillance period. This has persisted unchanged in six patients from 0.5-5 years, regressed in three for 0.5-5 years and has appeared after the first yearly biopsy in one patient. No patient without dysplasia has developed adenocarcinoma. The incidence of adenocarcinoma in Barrett's oesophagus in this study is one case per 96 patient years. This is 61 times (95% confidence limits 12-176) the age adjusted incidence of oesophageal cancer in Australia. Persistent high grade dysplasia appears to be a sensitive indicator for the development of subsequent adenocarcinoma.
Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade
Authors: James A Frank, Jean-Francois Pittet, Charlie Wray, Michael A. Matthay
Journal: Thorax (2007)

Clinical studies have shown that injurious mechanical ventilation is associated with increased airspace and plasma levels of interleukin-1beta (IL-1beta); however, the potential therapeutic value of IL-1 inhibition in acute lung injury has not been thoroughly investigated. A study was undertaken to determine if IL-1 signalling is a necessary early event in the pathogenesis of experimental ventilator-induced lung injury.Mice deficient in IL-1 receptor type 1 (IL1R1) and rats treated with IL-1 receptor antagonist (IL-1Ra) were mechanically ventilated with high tidal volume (30 ml/kg) and the effect of IL-1 signalling blockade on the severity of lung injury was determined.Permeability, as measured by radiolabelled albumin flux, was significantly lower in IL1R1 null mice than in wild-type mice during injurious ventilation (p<0.05). IL-1Ra significantly decreased protein permeability and pulmonary oedema in rats during injurious ventilation and also decreased airspace and plasma levels of the chemokine CXCL1 and airspace neutrophils. IL-1Ra decreased expression of NOS2 and ICAM-1 mRNA in whole lung. Bronchoalveolar lavage fluid levels of RTI40, a marker of type I cell injury, were 2.5 times lower following IL-1Ra treatment (p<0.05). In isolated type II pneumocytes, IL-1beta reduced electrical resistance and increased transepithelial permeability.IL-1 contributes to alveolar barrier dysfunction in VILI by promoting lung neutrophil recruitment and by increasing epithelial injury and permeability. Because preserved alveolar barrier function is associated with better outcomes in patients with acute lung injury, these data support further testing of IL-1Ra for the treatment of acute lung injury.
INSULIN-RECEPTOR ANTIBODY AND HYPOGLYCAEMIA ASSOCIATED WITH HODGKIN'S DISEASE
Authors: M.A. Khokher, N. Avasthy, A.M. Taylor, V.A. Fonseca, P. Dandona, E.G. Walters, J.M. Tavaré, R.M. Denton, G. Walters, W.J. Braund, H.M. Chapel, R.C. Turner
Journal: The Lancet (1987)
Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies
Authors: Philip A. Ruzycki, Nicholas M. Tran, Alexander V. Kolesnikov, Vladimir J. Kefalov, Shiming Chen
Journal: Genome biology (2015)

Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data. Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration. Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies.
Molecular Control of Systemic Bile Acid Homeostasis by the Liver Glucocorticoid Receptor
Authors: Adam J. Rose, Mauricio Berriel Díaz, Anja Reimann, Johanna Klement, Tessa Walcher, Anja Krones-Herzig, Oliver Strobel, Jens Werner, Achim Peters, Anna Kleyman, Jan P. Tuckermann, Alexandros Vegiopoulos, Stephan Herzig
Journal: Cell Metabolism (2011)
Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors
Authors: Marios Chatzigeorgiou, Sungjae Yoo, Joseph D Watson, Wei-Hsiang Lee, W Clay Spencer, Katie S Kindt, Sun Wook Hwang, David M Miller III, Millet Treinin, Monica Driscoll, William R Schafer
Journal: Nature Neuroscience (2010)
Introduction of IADPSG Criteria for the Screening and Diagnosis of Gestational Diabetes Mellitus Results in Improved Pregnancy Outcomes at a Lower Cost in a Large Cohort of Pregnant Women: The St. Carlos Gestational Diabetes Study
Authors: Alejandra Duran, Sofía Sáenz, María J. Torrejón, Elena Bordiú, Laura del Valle, Mercedes Galindo, Noelia Perez, Miguel A. Herraiz, Nuria Izquierdo, Miguel A. Rubio, Isabelle Runkle, Natalia Pérez-Ferre, Idalia Cusihuallpa, Sandra Jiménez, Nuria García de la Torre, María D. Fernández, Carmen Montañez, Cristina Familiar, Alfonso L. Calle-Pascual
Journal: Diabetes Care (2014)

The use of the new International Association of the Diabetes and Pregnancy Study Groups criteria (IADPSGC) for the diagnosis of gestational diabetes mellitus (GDM) results in an increased prevalence of GDM. Whether their introduction improves pregnancy outcomes has yet to be established. We sought to evaluate the cost-effectiveness of one-step IADPSGC for screening and diagnosis of GDM compared with traditional two-step Carpenter-Coustan (CC) criteria.GDM risk factors and pregnancy and newborn outcomes were prospectively assessed in 1,750 pregnant women from April 2011 to March 2012 using CC and in 1,526 pregnant women from April 2012 to March 2013 using IADPSGC between 24 and 28 weeks of gestation. Both groups received the same treatment and follow-up regimes.The use of IADPSGC resulted in an important increase in GDM rate (35.5% vs. 10.6%) and an improvement in pregnancy outcomes, with a decrease in the rate of gestational hypertension (4.1 to 3.5%: -14.6%, P < 0.021), prematurity (6.4 to 5.7%: -10.9%, P < 0.039), cesarean section (25.4 to 19.7%: -23.9%, P < 0.002), small for gestational age (7.7 to 7.1%: -6.5%, P < 0.042), large for gestational age (4.6 to 3.7%: -20%, P < 0.004), Apgar 1-min score <7 (3.8 to 3.5%: -9%, P < 0.015), and admission to neonatal intensive care unit (8.2 to 6.2%: -24.4%, P < 0.001). Estimated cost savings was of €14,358.06 per 100 women evaluated using IADPSGC versus the group diagnosed using CC.The application of the new IADPSGC was associated with a 3.5-fold increase in GDM prevalence in our study population, as well as significant improvements in pregnancy outcomes, and was cost-effective. Our results support their adoption.
Does TRPC3 macrodominate the myoendothelial gap junction microdomain?
Authors: P. I. Aaronson
Journal: Cardiovascular Research (2012)

This editorial refers to ‘Transient receptor potential canonical type 3 channels facilitate endothelium-derived hyperpolarization-mediated resistance artery vasodilator activity’ by S. Senadheera et al ., pp. 439–447, this issue. 

In 1998, Griffith and colleagues1 proposed that myoendothelial gap junctions (MEGJs) play a central role in endothelium-dependent hyperpolarization (EDH), the key mechanism coupling the activation of the endothelium by shear stress and blood borne-stimuli to vasodilation in the resistance vasculature. They envisioned that MEGJs, which are found at the ends of endothelial cell (EC) projections that protrude through holes in the internal elastic lamina of arteries and arterioles and link the EC to adjacent vascular smooth muscle cells (VSMCs), enabled EDH by acting as low-resistance pathways allowing the flow of hyperpolarizing current from the endothelium to the adjacent smooth muscle. Subsequently, however, it has become apparent that far from merely providing a locus for MEGJ, myoendothelial projections (MEPs) are unique microdomains that are capable of generating localized Ca2+ signals.2 This may enable them to influence the flow of information between ECs and VSMCs and also probably allows them to play a pivotal active role in triggering EDH ( Figure 1 ). 



Figure 1 
Signalling components and pathways within myoendothelial projections which may contribute to endothelium-dependent hyperpolarization and myoendothelial feedback. The illustrated scheme is speculative, but is consistent with proposals and results described in a number of the references listed. See text for abbreviations and a more detailed explanation.



In the current …
The 2.3 kb smooth muscle myosin heavy chain promoter directs gene expression into the vascular system of transgenic mice and rabbits,
Authors: W Franz
Journal: Cardiovascular Research (1999)

Background: Smooth muscle cells (SMC) are a preferential target for gene therapeutic approaches in atherosclerosis and restenosis. However, the undesirable expression of putative therapeutic genes in tissues other than the vascular wall is a considerable safety limitation for clinical trials, thus requiring the identification of a smooth-muscle-specific promoter sequence. Since the 2.3 kb rabbit Smooth Muscle Myosin Heavy Chain (SMHC) promoter was shown to be transcriptionally active in primary vascular but not visceral or other non-SMC in vitro, this fragment was chosen for in vivo analysis. Methods and Results: Transgenic mice and rabbits were established expressing a luciferase reporter gene under control of the 2.3 kb rabbit SMHC promoter. In contrast to the endogenous expression pattern of the SMHC gene both species revealed light emission predominantly in the arterial system including coronary arteries. Low activities were measured in large veins and the gastrointestinal system. In situ hybridization of murine embryos using a luciferase riboprobe confirmed reporter gene expression in large arteries with no detectable mRNA in the viscera. Unlike adult animals, ectopic luciferase activities were found in ventricular myocardium during murine development ceasing 1 week post partum. Conclusions: In two animal species, the 2.3 kb SMHC promoter appeared to be effective in discriminating between the pathways regulating vascular and visceral smooth muscle gene expression. The vascular-specific expression profile of the 2.3 kb SMHC promoter suggests that the 2.3 kb SMHC promoter contains the regulatory elements necessary for selective gene targeting into vascular SMC of large arteries including coronary arteries in vivo.
Timed sequential induction chemotherapy and risk‐adapted postremission therapy for acute myelogenous leukemia
Authors: Matt Kalaycio, Anjali Advani, Brad Pohlman, Mikkael Sekeres, Barbara Tripp, Lisa Rybicki, Ronald Sobecks
Journal: American Journal of Hematology (2008)

Cytogenetic analysis at the time of diagnosis predicts outcome in patients with acute myelogenous leukemia (AML). For those patients with favorable risk cytogenetics, stem cell transplant can be delayed until the time of relapse. For those patients with nonfavorable cytogenetic risk profiles, stem cell transplant may be required for optimal survival benefit. We treated patients with de novo AML and age less than 60 years first with etoposide, mitoxantrone, cytarabine, and G-CSF (EMA-G) to induce remission. Patients in complete remission were assigned to treatment with chemotherapy alone if they had favorable risk cytogenetics defined as the identification of a core-binding factor translocation. Patients with any other cytogenetic profile were assigned to treatment with either autologous or allogeneic stem cell transplant depending on the availability of an HLA-matched donor. Following EMA-G, 33 of 40 patients (83%) achieved CR. Of the 25 patients who actually were treated with postremission chemotherapy, 21 were treated with their assigned risk-adapted therapy. Of the 33 patients in remission, 5 year relapse-free survival (RFS) and overall survival (OS) was 46 and 38%, respectively. Our intensive and risk-adapted, stem cell transplant approach to the treatment of patients with AML requires a better definition of risk and does not appear to substantially improve results compared with more standard approaches.
Microalbuminuria as an Early Marker for Cardiovascular Disease
Authors: Dick de Zeeuw, Hans-Henrik Parving, Robert H. Henning
Journal: Journal of the American Society of Nephrology (2006)

Excretion of albumin in the urine is highly variable, ranging from nondetectable quantities to milligrams of albumin and even grams of albumin. Microalbuminuria is defined as low levels of urinary albumin excretion of 30 to 300 mg/d. Microalbuminuria is highly prevalent; in hypertensive and diabetic populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found frequently in seemingly healthy individuals (5 to 7%). The variable excretion of albumin in the urine is related to the risk for the individual to develop cardiovascular (CV) disease: Absence or very low levels of albuminuria is associated with low CV risk, whereas the CV risk increases markedly with increasing amount of albumin in the urine (even within the now considered normal range). The predictive power of urinary albumin levels for CV risk is independent of other CV risk factors and not only is present in individual with diabetes and/or hypertension but also in healthy individuals. Treatments that lower albuminuria are associated with CV protection, as demonstrated in randomized, controlled trials of patients with diabetes as well as in patients with hypertension. There is preliminary evidence that albuminuria lowering is CV protective in healthy individuals with an elevated albumin excretion rate. Differences between individuals in their level of albumin excretion are already observed at a very early age (just after birth). In fact, the interindividual variability seems to be relatively constant in the first 5 decades of life, indicating that microalbuminuria is not necessarily a consequence of vascular damage at later age. Higher levels of urinary albumin seem to reflect the ordinary interindividual variability in (renal and systemic) endothelial function. Experimental data show that between strains and even within strains, rats at young age show a remarkable difference in individual endothelial function, and this is strongly related to the susceptibility of that rat to organ damage. In conclusion, albuminuria seems to be a sensitive marker very early in life for the susceptibility of an individual to CV disease. It therefore may be an ideal target for early primary prevention using CV-protective therapy regimens.
The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction
Authors: C Krüger
Journal: Cardiovascular Research (2000)

Objective: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). Methods: Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. Results: In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400±15 to 350±19 and in SH-rats from 390±19 to 324±6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. Conclusions: Both BRS and HRV are reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.