tbuckley/cabot-search huggingface dataset:
A role for the CXCL12 receptor, CXCR7, in the pathogenesis of human pulmonary vascular disease
Authors: Christine M. Costello, Brian McCullagh, Katherine Howell, Michelle Sands, John A. Belperio, Michael P. Keane, Sean Gaine, Paul McLoughlin
Journal: European Respiratory Journal (2011)

Given the critical role that endothelial cell dysfunction plays in the pathogenesis of pulmonary hypertensive diseases, we set out to establish if CXCR7, a receptor for the pro-angiogenic ligand CXCL12, is expressed in the vasculature of human lung diseases and examine its role in mediating CXCL12-induced responses in primary pulmonary human microvascular endothelial cells. Receptor and ligand expression was examined in control and explanted human hypertensive lungs, in human plasma and in hypoxic rodent lungs, by ELISA and immunohistochemical studies. Functional in vitro experiments examined the role of CXCR7 in CXCL12-induced lung microvascular endothelial cell proliferation, migration, and wound regeneration and repair. CXCR7 is elevated in the endothelium of explanted human hypertensive lungs and circulating CXCL12 concentrations are significantly elevated in disease. We demonstrate that alveolar hypoxia similar to that found in lung disease increases CXCR7 expression in the pulmonary endothelium. Furthermore, CXCR7 is the receptor through which endothelial cell regeneration and repair, and proliferation, is mediated, whereas signalling via CXCR4 is essential for chemotactic cell migration. Our findings demonstrate that CXCR7 has a critical but previously unrecognised role to play in endothelial cell proliferation, suggesting that CXCR7-mediated signalling may be functionally important in pulmonary vascular diseases.
Initial Severity of Schizophrenia and Efficacy of Antipsychotics
Authors: Toshi A. Furukawa, Stephen Z. Levine, Shiro Tanaka, Yair Goldberg, Myrto Samara, John M. Davis, Andrea Cipriani, Stefan Leucht
Journal: JAMA Psychiatry (2014)

Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia, and their efficacy is well established in hundreds of randomized clinical trials. However, it is not known whether they are effective or how effective they are across the wide range of baseline symptom severity.To examine the influence of baseline severity of schizophrenia on the efficacy of antipsychotic drugs.Meta-analysis of participant-level data from 3 pivotal randomized trials of acute schizophrenia (n = 611) and 3 pivotal trials in patients with predominantly negative symptoms of schizophrenia (n = 475).Olanzapine or risperidone vs placebo, and amisulpride vs placebo.Change scores on the Positive and Negative Syndrome Scale (PANSS; score range, 30-210) and the Scale for the Assessment of Negative Symptoms (SANS; score range, 0-125) up to 6 weeks after baseline. The relationship between baseline and change scores for the drug and placebo groups was examined with 8 competing mixed-effects models for repeated measures.The best-fitting models showed that, for both types of patients, the interactions between baseline symptom severity and treatment were statistically significant (P < .01). The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo. In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116). In treatment of predominantly negative symptoms, the mean differences in SANS change scores were 1.7 for those who were moderately ill (baseline SANS score of 55), 5.7 for markedly ill patients (baseline SANS score of 70), and 9.7 for severely ill patients (baseline SANS score of 85).We can expect benefits of antipsychotic drugs for the full spectrum of patients likely to be treated for acute schizophrenia and for highly symptomatic patients with predominantly negative symptoms. Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics. Clinicians also need to be aware that in addition to the treatment of active symptoms, which was the focus of this study, antipsychotics have another important action, namely to prevent relapses among patients in remission.
Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias
Authors: Michael J Domanski, Sanjeev Sakseena, Andrew E Epstein, Alfred P Hallstrom, Michael A Brodsky, Soo Kim, Scott Lancaster, Eleanor Schron
Journal: Journal of the American College of Cardiology (1999)
Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication
Authors: David A. Garber, Guido Silvestri, Ashley P. Barry, Andrew Fedanov, Natalia Kozyr, Harold McClure, David C. Montefiori, Christian P. Larsen, John D. Altman, Silvija I. Staprans, Mark B. Feinberg
Journal: Journal of Clinical Investigation (2004)

In vivo blockade of CD28 and CD40 T cell costimulation pathways during acute simian immunodeficiency virus (SIV) infection of rhesus macaques was performed to assess the relative contributions of CD4+ T cells, CD8+ T cells, and Ab responses in modulating SIV replication and disease progression. Transient administration of CTLA4-Ig and anti-CD40L mAb to SIV-infected rhesus macaques resulted in dramatic inhibition of the generation of both SIV-specific cellular and humoral immune responses. Acute levels of proliferating CD8+ T cells were associated with early control of SIV viremia but did not predict ensuing set point viremia or survival. The level of in vivo CD4+ T cell proliferation during acute SIV infection correlated with concomitant peak levels of SIV plasma viremia, whereas measures of in vivo CD4+ T cell proliferation that extended into chronic infection correlated with lower SIV viral load and increased survival. These results suggest that proliferating CD4+ T cells function both as sources of virus production and as antiviral effectors and that increased levels of CD4+ T cell proliferation during SIV infections reflect antigen-driven antiviral responses rather than a compensatory homeostatic response. These results highlight the interrelated actions of CD4+ and CD8+ T cell responses in vivo that modulate SIV replication and pathogenesis.
Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats
Authors: Ikram Merroun, Cristina Sánchez-González, Rosario Martínez, Carlos López-Chaves, Jesús M. Porres, Pilar Aranda, Juan Llopis, Milagros Galisteo, Antonio Zarzuelo, Mohammed Errami, María López-Jurado
Journal: Metabolism (2013)
The management of childhood asthma in the community
Authors: W. Maziak, E. von Mutius, C. Beimfohr, T. Hirsch, W. Leupold, U. Keil, S.K. Weiland
Journal: European Respiratory Journal (2002)

The aim of the present study was to assess the management of children with asthma in the community. Community-based random samples of children aged 5–7 and 9–11 yrs in Dresden and Munich, Germany, were studied in 1995–1996 using the phase II protocol of the International Study of Asthma and Allergies in Childhood. Detailed information on the use of antiasthma drugs and accessory treatment in the past year was collected by parental questionnaire. A total of 11,094 (response rate 83%) children participated. Among children with wheeze in the last year, 36% had used bronchodilators and 19% were on regular anti-inflammatory treatment. The strongest determinant of treatment was a physician's diagnosis of asthma. Forty-seven per cent of the children with current wheeze had not been diagnosed as asthmatics and received hardly any treatment (9% bronchodilators and 2% anti-inflammatory drugs), despite an increased prevalence of severe asthma symptoms, bronchial hyperresponsiveness and atopic sensitisation compared with children without asthma symptoms. The proportion of children regularly using inhaled steroids was small (6%) among current wheezers and reached only 21% among children with diagnosed asthma and &gt;12 wheezing attacks in the last year. Inhaled steroid use was lower in Munich than in Dresden and inversely related to the use of alternative remedies. Further efforts to improve the diagnosis and treatment of childhood asthma are needed. These should aim to increase awareness of the chronic nature of asthma and the need for treatment according to current guidelines.
Patient-Centered Medical Home and Diabetes
Authors: Trajko Bojadzievski, Robert A. Gabbay
Journal: Diabetes Care (2011)

The current model of health care delivery is designed to address acute health problems and is based on episodic face-to-face interactions between health care provider and patient, which often do not address the needs of chronically ill individuals (1). Diabetes is a well-documented example of a high cost prevalent chronic illness where a significant quality chasm exists. It is one of the most expensive chronic illnesses affecting over 23 million Americans (2) at a cost of $174 billion in 2007 (3). Despite the high expenditures for diabetes care, very few patients with diabetes are at goal for evidence based recommendations, with only 7% of patients at goal for A1C, blood pressure, and LDL cholesterol (4).

In the recent years, much discussion has taken place regarding future health policies and the need to strengthen primary care. It is believed that improvements in the mode of delivery of primary care will better serve the needs of the chronically ill (5). Health outcomes are better in regions in which there is an adequate supply of primary care physicians, and patients receiving care from primary care physicians are healthier (6) and have fewer inpatient hospitalizations (7), fewer emergent admissions (8), a lower length of stay (8), and lower costs of care (9–11).

The Patient-Centered Medical Home (PCMH) has been proposed as a practical solution to the primary care crisis and holds promise to deliver better chronic care. Diabetes lends itself well to the principles of the PCMH given its robust evidence-based guidelines, high cost, and well demonstrated quality gap. Although a common definition of the PCMH has remained elusive (12), the basic elements of a PCMH are well described by the Joint Principles of the American Academy of Family Medicine, American Academy of Pediatrics, American College of Physicians and the …
Dysregulated Hematopoiesis Caused by Mammary Cancer Is Associated with Epigenetic Changes and <i>Hox</i> Gene Expression in Hematopoietic Cells
Authors: Alexander Sio, Manreet K. Chehal, Kevin Tsai, Xueling Fan, Morgan E. Roberts, Brad H. Nelson, Jolanta Grembecka, Tomasz Cierpicki, Danielle L. Krebs, Kenneth W. Harder
Journal: Cancer Research (2013)

Abstract Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes. Cancer Res; 73(19); 5892–904. ©2013 AACR.
Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas
Authors: C. Gerin, J. Pallud, C. Deroulers, P. Varlet, C. Oppenheim, F.-X. Roux, F. Chretien, S. R. Thomas, B. Grammaticos, M. Badoual
Journal: Neuro-Oncology (2013)

Supratentorial diffuse low-grade gliomas in adults extend beyond maximal visible MRI-defined abnormalities, and a gap exists between the imaging signal changes and the actual tumor margins. Direct quantitative comparisons between imaging and histological analyses are lacking to date. However, they are of the utmost importance if one wishes to develop realistic models for diffuse glioma growth. In this study, we quantitatively compared the cell concentration and the edema fraction from human histological biopsy samples (BSs) performed inside and outside imaging abnormalities during serial imaging-based stereotactic biopsy of diffuse low-grade gliomas. The cell concentration was significantly higher in BSs located inside (1189 ± 378 cell/mm2) than outside (740 ± 124 cell/mm2) MRI-defined abnormalities (P = .0003). The edema fraction was significantly higher in BSs located inside (mean, 45% ± 23%) than outside (mean, 5 %± 9%) MRI-defined abnormalities (P < .0001). At borders of the MRI-defined abnormalities, 20% of the tissue surface area was occupied by edema and only 3% by tumor cells. The cycling cell concentration was significantly higher in BSs located inside (10 ± 12 cell/mm2), compared with outside (0.5 ± 0.9 cell/mm2), MRI-defined abnormalities (P = .0001). We showed that the margins of T2-weighted signal changes are mainly correlated with the edema fraction. In 62.5% of patients, the cycling tumor cell fraction (defined as the ratio of the cycling tumor cell concentration to the total number of tumor cells) was higher at the limits of the MRI-defined abnormalities than closer to the center of the tumor. In the remaining patients, the cycling tumor cell fraction increased towards the center of the tumor.
Glycemic Control and Absenteeism Among Individuals With Diabetes
Authors: Kaan Tunceli, Cathy J. Bradley, Jennifer E. Lafata, Manel Pladevall, George W. Divine, Allen C. Goodman, Sandeep Vijan
Journal: Diabetes Care (2007)

The associations between adverse labor market outcomes and diabetes/diabetes complications are well described (1–8). Clinical guidelines have recommended standards for glycemic, lipid, and blood pressure control (9) that have been shown to prevent or delay the onset and progression of diabetes complications (10–16). It is possible that control of these symptoms can reduce absenteeism in employed patients. Two studies have examined the relationship between glycemic control and labor market outcomes including absenteeism (17,18), and this study adds to that literature by examining the cross-sectional associations between absenteeism from work and glycemic, lipid, and blood pressure control among individuals with diabetes.

Patients were identified as having diabetes ( n = 27,407) from administrative data available within a medical group in southeast Michigan between 1 June 2003 and 31 May 2004. From these patients, we selected those who were tested for A1C during the prior 12 months and aged 30–64 years ( n = 11,324). Next, we drew a random sample of 1,000 patients stratified by glycemic control level (A1C <7.0, 7.0–7.99, 8.0–8.99, 9.0–9.99, or ≥10.0%). Several exclusions were made, including subjects who had died ( n = 5), absence of a physician from whom to obtain permission for patient contacts ( n = 72), patients’ inclusion in other research studies ( n = 132), physician refusal ( n = 46), incorrect diagnosis ( n = 5), and language barrier ( n = 13). The final sample comprised 727 patients for a telephone survey and had an overall participation rate among eligible subjects of 59% ( n = 427). The response rate for eligible subjects who were contacted was 81% ( n = 525).

The primary outcome was hours absent from work for any reason during the 4 weeks …
EXPERIMENTAL GLOMERULONEPHRITIS
Authors: Emil Unanue, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1964)

Rats with nephrotoxic serum nephritis may show fixation of complement (C') in the glomeruli during two periods. The first period occurs immediately after the injection of the antisera and extends until the host response occurs. The second period is related to the deposit of rat gamma globulin in the glomeruli presumably occurring at the time of the immune response to the heterologous nephrotoxic serum (NTS). This second period terminates about 2 to 3 weeks after injection of NTS, presumably at the time the rat stops making antibodies to the nephrotoxic gamma globulin fixed in the glomeruli. After this period, the glomerular lesion is incapable of fixing detectable amounts of circulating C' unless the antibody response to the heterologous globulin is reactivated. The immunological events which take place in the initial 2 to 3 week period appear to produce a permanent and irreparable lesion in the glomeruli leading to chronic nephritis. Rabbit NTS produces fixation of rat C' during both periods. Duck NTS shows no detectable fixation of rat C' until rat gamma globulin fixes in the glomeruli at the time of the host immune response to the heterologous nephrotoxic gamma globulin. Decomplementation of rats injected with rabbit NTS produces an amelioration of the initial period of nephrotoxic serum nephritis. The fixation of C' in the glomerular lesions was studied with the use of fluorescent antibody methods. The detection of host beta-1C globulin and gamma globulin in the glomerulus pointed to an immune reaction but not necessarily an active one. The tissue C' fixation test using kidney slices and guinea pig C' proved to be a more sensitive method of detecting tissue reactants capable of fixing C', but its relationship to in vivo events is not certain.
Long-lived Inflammatory Signaling in Irradiated Bone Marrow Is Genome Dependent
Authors: Sally A. Lorimore, Debayan Mukherjee, Joanne I. Robinson, Jennifer A. Chrystal, Eric G. Wright
Journal: Cancer Research (2011)

Ionizing radiation is carcinogenic, but genotype is a key determinant of susceptibility. Mutational DNA damage is generally attributed to cause disease, but irradiation also affects multicellular interactions as a result of poorly understood bystander effects that may influence carcinogenic susceptibility. In this study, we show that the bone marrow of irradiated mice will retain the ability to kill hemopoietic clonogenic stem cells and to induce chromosomal instability for up to 3 months after irradiation. Chromosomal instability was induced in bone marrow cells derived from CBA/Ca mice, a strain that is susceptible to radiation-induced acute myeloid leukemia (r-AML), but not in C57BL6 mice that are resistant to r-AML. Similarly, clonogenic cell lethality was exhibited in C57BL/6 mice but not CBA/Ca mice. Mechanistic investigations revealed that these genotype-dependent effects involved cytokine-mediated signaling and were mediated by a cyclooxygenase-2-dependent mechanism. Thus, our results suggested that inflammatory processes were responsible for mediating and sustaining the durable effects of ionizing radiation observed on bone marrow cells. Because most exposures to ionizing radiation are directed to only part of the body, our findings imply that genotype-directed tissue responses may be important determinants of understanding the specific consequence of radiation exposure in different individuals.
Left Ventricular Function and Exercise Capacity
Authors: Jasmine Grewal
Journal: JAMA (2009)

Context Limited information exists regarding the role of left ventricular function in predicting exercise capacity and impact on age-and sex-related differences.Objectives To determine the impact of measures of cardiac function assessed by echocardiography on exercise capacity and to determine if these associations are modified by sex or advancing age.Design Cross-sectional study of patients undergoing exercise echocardiography with routine measurements of left ventricular systolic and diastolic function by 2-dimensional and Doppler techniques.Analyses were conducted to determine the strongest correlates of exercise capacity and the age and sex interactions of these variables with exercise capacity.Setting Large tertiary referral center in Rochester, Minnesota, in 2006.Participants Patients undergoing exercise echocardiography using the Bruce protocol (N=2867).Patients with echocardiographic evidence of exercise-induced ischemia, ejection fractions lower than 50%, or significant valvular heart disease were excluded. Main Outcome Measure Exercise capacity in metabolic equivalents (METs).Results Diastolic dysfunction was strongly and inversely associated with exercise capacity.Compared with normal function, after multivariate adjustment, those with moderate/severe resting diastolic dysfunction (-1.30METs; 95% confidence interval [CI], -1.52 to -0.99; PϽ.001) and mild resting diastolic dysfunction (-0.70 METs; 95% CI, -0.88 to -0.46; PϽ.001) had substantially lower exercise capacity.Variation of left ventricular systolic function within the normal range was not associated with exercise capacity.Left ventricular filling pressures measured by resting E/eЈ of 15 or greater (-0.41 METs; 95% CI, -0.70 to -0.11; P=.007) or postexercise E/eЈ of 15 or greater (-0.41 METs; 95% CI, -0.71 to -0.11; P=.007) were similarly associated with a reduction in exercise capacity, each in separate multivariate analyses.Individuals with impaired relaxation (mild dysfunction) or resting E/eЈ of 15 or greater had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (PϽ.001 and P=.02, respectively).Other independent correlates of exercise capacity were age (unstandardized ␤ coefficient, -0.85 METs; 95% CI, -0.92 to -0.77, per 10-year increment; PϽ.001), female sex (-1.98 METs; 95% CI, -2.15 to -1.84; PϽ.001), and body mass index greater than 30 (-1.24 METs; 95% CI, -1.41 to -1.10; PϽ.001). ConclusionIn this large cross-sectional study of those referred for exercise echocardiography and not limited by ischemia, abnormalities of left ventricular diastolic function were independently associated with exercise capacity.