tbuckley/cabot-search huggingface dataset:
Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma
Authors: M Silvestri
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Increased fractional exhaled NO concentrations (Feno) and blood/tissue eosinophilia are frequently reported in allergic children with mild asthma and are thought to reflect the intensity of the inflammation characterising the disease. The aim of this study was to investigate possible differences in Feno levels or in the intensity of the blood eosinophilia in allergic and non-allergic asthmatic children. <h3>METHODS</h3> 112 children with stable, mild, intermittent asthma with a positive bronchial challenge to methacholine were consecutively enrolled in the study; 56 were skin prick test and RAST negative (non-sensitised) while 56 were sensitised to house dust mites (23 only to house dust mites (monosensitised) and 33 were sensitised to mites and at least another class of allergens (pollens, pet danders, or moulds)). Nineteen sex and age matched healthy children formed a control group. <h3>RESULTS</h3> Compared with non-allergic patients, allergic children had a significantly higher rate of blood eosinophilia (p=0.0001) with no differences between mono- and polysensitised individuals. Forced expiratory volume in 1 second (FEV<sub>1</sub>), forced vital capacity (FVC), forced expiratory flow at 25–75% of vital capacity (FEF<sub>25–75%</sub>), and the degree of bronchial reactivity to methacholine were similar in non-atopic and atopic children, with no differences between mono- and polysensitised individuals. Feno levels measured by chemiluminescence analyser were higher in asthmatic children (15.9 (14.3) ppb) than in the control group (7.6 (1.6) ppb, p=0.04) and higher in allergic patients (23.9 (2.1) ppb) than in non-allergic patients (7.9 (0.8) ppb, p=0.0001), but there were no differences between mono- and polysensitised individuals (p&gt;0.1). Significant correlations between blood eosinophilia and Feno levels were seen only in allergic (<i>r</i>=0.35, p&lt;0.01) and in polysensitised individuals (<i>r</i>=0.45, p&lt;0.05). <h3>CONCLUSIONS</h3> In children with mild asthma, a similar degree of functional disease severity may be associated with a higher inflammatory component in allergic than in non-allergic subjects.
Leptin-to-Adiponectin Ratio as a Potential Atherogenic Index in Obese Type 2 Diabetic Patients
Authors: Noriko Satoh, Mitsuhide Naruse, Takeshi Usui, Tetsuya Tagami, Takayoshi Suganami, Kazunori Yamada, Hideshi Kuzuya, Akira Shimatsu, Yoshihiro Ogawa
Journal: Diabetes Care (2004)

Obesity promotes the progression of atherosclerosis by inducing multiple cardiovascular and metabolic derangements such as diabetes, hypertension, and dyslipidemia, all of which have high atherogenic potential. Adipose tissue has been considered an important endocrine organ that secretes many biologically active substances, collectively known as adipocytokines (1). Two major adipocytokines, leptin and adiponectin, are thought to play important roles in the regulation of cardiovascular and metabolic homeostasis. Leptin acts directly on the hypothalamus, thereby regulating food intake and energy expenditure (2). Plasma leptin concentrations are significantly elevated in obese subjects in proportion to the degree of adiposity (3), suggesting that hyperleptinemia may play a role in the pathogenesis of obesity-related complications. On the other hand, adiponectin increases tissue fat oxidation, leading to reduced levels of fatty acids and tissue triglyceride content, thus increasing insulin sensitivity (4). Paradoxically, plasma adiponectin concentrations are decreased in obese subjects (5), suggesting that hypoadiponectinemia is involved in the pathophysiology of obesity. Two recent studies have demonstrated that vascular remodeling and neointimal formation are markedly attenuated in leptin-deficient ob/ob mice and db/db mice with leptin receptor mutation (6,7), suggesting that leptin may accelerate the development of vascular injury. Conversely, studies with adiponectin-deficient mice have revealed that adiponectin plays a protective role in the development of atherosclerosis (8,9). In obese type 2 diabetic patients who are susceptible to atherosclerosis, plasma concentrations of leptin are increased, whereas those of adiponectin …
Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α
Authors: Fenghua Liu, Ruisheng Song, Yuanqing Feng, Jiaojiao Guo, Yanmin Chen, Yong Zhang, Tao Chen, Yanru Wang, Yanyi Huang, Chuan-Yun Li, Chunmei Cao, Yan Zhang, Xinli Hu, Rui-ping Xiao
Journal: Circulation (2015)

Diabetic cardiomyopathy, which contributes to >50% diabetic death, is featured by myocardial lipid accumulation, hypertrophy, fibrosis, and cardiac dysfunction. The mechanism underlying diabetic cardiomyopathy is poorly understood. Recent studies have shown that a striated muscle-specific E3 ligase Mitsugumin 53 (MG53, or TRIM72) constitutes a primary causal factor of systemic insulin resistance and metabolic disorders. Although it is most abundantly expressed in myocardium, the biological and pathological roles of MG53 in triggering cardiac metabolic disorders remain elusive.Here we show that cardiac-specific transgenic expression of MG53 induces diabetic cardiomyopathy in mice. Specifically, MG53 transgenic mouse develops severe diabetic cardiomyopathy at 20 weeks of age, as manifested by insulin resistance, compromised glucose uptake, increased lipid accumulation, myocardial hypertrophy, fibrosis, and cardiac dysfunction. Overexpression of MG53 leads to insulin resistant via destabilizing insulin receptor and insulin receptor substrate 1. More importantly, we identified a novel role of MG53 in transcriptional upregulation of peroxisome proliferation-activated receptor alpha and its target genes, resulting in lipid accumulation and lipid toxicity, thereby contributing to diabetic cardiomyopathy.Our results suggest that overexpression of myocardial MG53 is sufficient to induce diabetic cardiomyopathy via dual mechanisms involving upregulation of peroxisome proliferation-activated receptor alpha and impairment of insulin signaling. These findings not only reveal a novel function of MG53 in regulating cardiac peroxisome proliferation-activated receptor alpha gene expression and lipid metabolism, but also underscore MG53 as an important therapeutic target for diabetes mellitus and associated cardiomyopathy.
Where is the evidence based on hard endpoints for the safety and effectiveness of sitagliptin in type 2 diabetes?
Authors: J. M. F. de Oliveira
Journal: BMJ (2013)

I have several questions arising from the study by Eurich and colleagues on the safety and effectiveness of sitagliptin in patients with type 2 diabetes.1

Firstly, is an observational study qualified to suggest a “safety” message when the patients were followed-up for a mean of only 2.5 years,1 whereas most patients have to live …
Tumor-Cell Homing to Lymph Nodes and Bone Marrow and CXCR4 Expression in Esophageal Cancer
Authors: Jussuf T. Kaifi, Emre F. Yekebas, Paulus Schurr, Dennis Obonyo, Robin Wachowiak, Philipp Busch, Antje Heinecke, Klaus Pantel, Jakob R. Izbicki
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: The chemokine and bone marrow-homing receptor CXCR4 has been implicated in metastatic dissemination of various cancers. We investigated CXCR4 expression in esophageal cancer specimens and its association with survival, lymph node microinvolvement, and bone marrow micrometastasis. Methods: We analyzed frozen tumor specimens from 136 patients with completely resected esophageal cancer for CXCR4 expression by immunohistochemistry. Lymph node microinvolvement and bone marrow micrometastasis were assessed by immunohistochemistry with monoclonal antibodies Ber-EP4 (against epithelial cell adhesion molecule) and pancytokeratin A45-B/B3 (against several cytokeratins), respectively. Associations between CXCR4 expression and clinicopathologic features, including tumor stage, histologic grade, lymph node metastasis and microinvolvement, bone marrow micrometastasis, and survival, were investigated with Fisher's test, log-rank test, and Cox multivariable analysis. All statistical tests were two-sided. Results: CXCR4 protein was expressed in 75 (55%) of 136 esophageal tumors examined. CXCR4 expression was statistically significantly associated with reduced median overall and disease-specific survival, compared with CXCR4 nonexpression ( P <.001; log-rank test). The median overall survival of patients with CXCR4-positive tumors was 20 months and with CXCR4-negative tumors, 76 months (difference = 56 months, 95% confidence interval [CI] = 4 to 108 months; P <.001). The median disease-specific survival of patients with CXCR4-positive tumors was 25 months and with CXCR4-negative tumors was 97 months (difference = 72 months, 95% CI = 34 to 110 months; P <.001). CXCR4 expression was statistically significantly associated with increased lymph node microinvolvement ( P <.001) and with increased bone marrow micrometastasis ( P <.001). In multivariable analysis, CXCR4 expression, compared with its nonexpression, was identified as the independent variable that was most strongly associated with reduced disease-specific survival (relative risk [RR] of death = 2.03, 95% CI = 1.20 to 3.41; P = .008) and overall survival (RR of death = 2.18, 95% CI = 1.33 to 3.59; P = .002). Conclusion: CXCR4 expression was associated with poor clinical outcome in esophageal cancer patients. CXCR4 may have a role in early metastatic spread because its expression was associated with micrometastases to both the lymph nodes and bone marrow. Thus, CXCR4 should be explored further as a target for adjuvant therapy for micrometastatic disease.
RBP1L1, a Retinoblastoma-Binding Protein-Related Gene Encoding an Antigenic Epitope Abundantly Expressed in Human Carcinomas and Normal Testis
Authors: J Cao, T Gao, E J Stanbridge, R Irie
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Antibodies isolated from cancer patients have been used to identify genes encoding tumor-associated antigen epitopes relevant to immune responses in cancer patients. In this report, we used an immunoglobulin G (IgG) purified from serum of a patient with breast cancer to identify its corresponding epitope, gene, and protein—retinoblastoma-binding protein-1-like protein-1 (RBP1L1)—and determined whether it is a potential molecular marker for various cancers. Methods: IgG purified from the serum of a patient with breast cancer was used to screen an MCF-7 breast cancer cell complementary DNA (cDNA) expression library for immunoreactive clones. The cDNAs identified were cloned and sequenced. Immunoreactivity of specific amino acids in the epitope was determined by western blot analysis and enzyme-linked immunosorbent assay. The cellular location of the antigen was determined by immunoperoxidase staining with purified RBP1L1-specific IgG. Gene expression in various human carcinomas and normal tissues was examined by northern blot analysis and the reverse transcription–polymerase chain reaction. Results: Our purified IgG recognized just one epitope on RBP1L1. The complete 5802-base-pair RBP1L1 cDNA encodes a 1226-amino acid protein containing the antigenic epitope IKPSLGSKK. The derived protein sequence of RBP1L1 shares 74% and 37% amino acid identity, respectively, with a partial sequence of the retinoblastoma-binding protein and the complete sequence of retinoblastoma-binding protein-1. The RBP1L1 epitope was localized to the cytoplasm of MCF-7 cells but was not detected in peripheral blood mononuclear cells. High expression of RBP1L1 messenger RNA was found in human breast, lung, colon, pancreatic, and ovarian cancers and in normal testis, but expression was limited in other normal tissues. Conclusions: RBP1L1 appears to be a molecular marker associated with a broad range of human malignancies.
No detectable increase in sister chromatid exchanges in lymphocytes from mycosis fungoides patients after topical treatment with nitrogen mustard
Authors: L. STUDSTRUP, H.-I. BECK, P. BJERRING, H.C. WULF, K. LUNDGREN
Journal: British Journal of Dermatology (1988)

We measured sister chromatid exchanges (SCEs) in lymphocytes of eight MF patients before, and 2 h, and 24 h after treatment with topical nitrogen mustard. The mean number of SCEs/cell (+/- SEM) were 8.15 (+/- 0.62), 8.34 (+0.55) and 8.26 (+/- 0.56), respectively. The 2 h and 24 h results do not differ significantly from pretreatment levels. Our results show that concentrations of nitrogen mustard used to control MF do not induce SCEs in peripheral blood lymphocytes.
Urticaria Associated with Acute Viral Hepatitis Type B
Authors: JULES L. DIENSTAG
Journal: Annals of Internal Medicine (1978)

To determine whether skin deposition of circulating immune complexes contributes to prodromal urticaria of acute hepatitis B, we studied two patients with hepatitis B who presented with urticaria and fever. During the urticarial prodrome but not thereafter, we found activation of both classic and alternative complement pathways. Hepatitis B surface antigen (HBsAg)-antibody complexes were identified (by electron microscopy) in cryoprecipitates from both patients and IgG (by immunodiffusion) in cryoprecipitates of one patient during urticaria. Light and electron microscopy of involved urticarial skin revealed necrotizing venulitis in both patients. Immunofluorescence microscopy showed fibrin within involved cutaneous vessel walls in one patient and C3, IgM, and HBsAg, which were not detected in simultaneously obtained uninvolved skin, in both patients. Our findings suggest that deposition of circulating immune complexes containing HBsAg is important in the pathogenesis of urticaria associated with acute hepatitis B virus infection.
Myocardial Function Following Thermal Injury
Authors: Thornton W. Merriam
Journal: Circulation Research (1962)

Several investigators have suggested that a defect in myocardial function occurs in the dog following severe thermal burn. A study was therefore undertaken in which myocardial contractility was measured before and after burn. The left ventricular function curve was used as an index of contractility. Ventricular function was measured immediately before and 30 minutes following 30 per cent body surface area burn in 25 dogs, and before and after a sham burn in 13 control dogs. It was found that the burn produced a significantly greater impairment of myocardial contractility than did the sham burn. The mechanism by which the burn produced this alteration in contractility was not apparent from the results of this study.
Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2–Induced Vascular Leak
Authors: Diana C. Gallagher, Rupal S. Bhatt, Samir M. Parikh, Parin Patel, Virginia Seery, David F. McDermott, Michael B. Atkins, Vikas P. Sukhatme
Journal: Clinical Cancer Research (2007)

Abstract Purpose: High-dose interleukin 2 (HDIL2) produces durable tumor regressions in 10% of patients with metastatic renal cell carcinoma and melanoma. However, a major toxicity is vascular leak syndrome (VLS). We previously reported elevated serum angiopoietin 2 (Ang2) in septic patients with vascular leak and hypothesized that Ang2 might also contribute to HDIL2 VLS. Experimental Design: Blood was collected from 14 patients receiving HDIL2 and from 4 patients receiving HDIL2 and bevacizumab, an antibody against vascular endothelial growth factor (VEGF). The effect of Ang2 was studied in vitro by incubating high Ang2 patient serum with cultured endothelial cells. Results: Pretreatment Ang2 levels were in the reference range (median, 3.3 ng/mL) and rose with each day of IL-2 therapy (median peak, 29.7 ng/mL). No trend was seen in free VEGF levels during therapy. Patients treated with HDIL2 and bevacizumab all developed VLS and elevated Ang2. High Ang2 patient sera induced propermeability structural changes in endothelial cells, an effect reversed by blockade with the competitive ligand angiopoietin 1 (Ang1). Conclusions: Ang2 may be a mediator of HDIL2 VLS as evidenced by (a) an increase in Ang2 in all patients on HDIL2; (b) the effect of high Ang2 patient serum on cultured endothelial cells; (c) rescue of those structural changes by Ang1. The lack of correlation between VLS and serum VEGF levels in patients treated with HDIL2 alone or in combination with bevacizumab suggests that VEGF is not a major contributor to VLS or Ang2 release. These data suggest that the inhibition of Ang2 may mitigate VLS in patients receiving HDIL2.
Interaction of sequential stimuli applied during the relative refractory period in relation to determination of fibrillation threshold in the canine ventricle.
Authors: J Tamargo, B Moe, G K Moe
Journal: Circulation Research (1975)

An ineffective stimulus applied to cardiac tissue within the relative refractory period can alter the response to an immediately subsequent stimulus. We observed three response patterns that can coexist at different sites of stimulation in the same heart. In the first pattern, a stimulus of two to ten times diastolic threshold, applied too early to elicit a propagated response, becomes effective when a stimulus of equal strength is delivered 10 msec earlier. In the second pattern, a stimulus applied just late enough to evoke a response fails to do so when a stimulus of equal strenght precedes it by as much as 30 msec. Finally, in the third pattern, two stimuli, separated by 10 msec, both of which are late enough to be effective when they are given alone, fail to yield a propagated response when they are applied together. These results have a bearing on the use of trains of stimuli to assess the ventricular fibrillation threshold. Possible interpretations are based on the temporal dispersion of recovery from the refractory state.
The public health agenda and minority ethnic health: a reflection on priorities
Authors: R. S Bhopal
Journal: Journal of the Royal Society of Medicine (2006)

The National Health Service priorities are dictated either by the disease and health patterns of the population and population subgroups, or by the expectations and explicit standards of public services. These priorities include: the prevention and management of disease; the promotion of health; health education; reduction of inequalities in health; high quality healthcare; cost-effective and value-for-money services delivered within budget; and respectful, sensitive and equitable service. These priorities are the core of the NHS, and though the phraseology and emphasis change, they can be found in every important NHS policy document.
Primary lysis/necrosis of eosinophils and clinical control of asthma
Authors: Carl Persson
Journal: Thorax (2012)

I read with interest the demonstration by Volbeda et al 1 that clinical asthma control associates significantly with ‘lower activated eosinophil numbers in the bronchial wall, yet only weakly with sputum eosinophils’. I was particularly intrigued by the online supplemental information1: ‘EPX staining showed widely spread distribution of eosinophilic granules, not necessarily in close proximity to EPX+ cells. Therefore, degranulation of eosinophils was determined by quantification of the EPX immunopositive area by computer-assisted image analysis’. This statement suggests to me that …
Prevalence of chronic ischaemic heart disease in idiopathic pulmonary fibrosis: A single center study
Authors: Maria Martino, Maurizia Lanza, Maria D'Amato, Giovanna Caccavo, Giovanna Calabrese, Carolina Vitale, Anna Agnese Stanziola
Journal: European Respiratory Journal (2014)

Background : Idiopathic Pulmonary Fibrosis ( IPF ) is a progressive disease with poor prognosis. Major comorbidities such as cardiovascular diseases have been described.   Aim:  To investigate the prevalence of chronic ischaemic heart disease ( IHD ) in IPF patients.   Methods:  110 consecutive IPF patients (73M; mean age 66±7, range 27-84 years; never smokers 50, former smokers 41; current smokers 19) were prospectively studied. IPF diagnosis was made by current ATS guidelines. The diagnosis of IHD was considered on medical history and coronary angiograms or stress echo test.   Results:  63 IPF patients (57.2%) (38M; mean age 65±8, range 45-82 years; 13current smokers, 26 former smokers ) were affected by ischemic heart disease. Pulmonary function test: FEV 1  65±18% vs Th; FVC 63±15% vs Th; DLCO 37±13% vs Th and DLCO/VA75±10% vs Th.   Conclusions.  An increased prevalence of ischaemic heart disease in IPF patients was observed. The high IHD prevalence did not appear to be correlate with the IPF severity. Further studies are needed to investigate the clinical impact of IHD on interstitial lung disease.
Peroxisome Proliferator-Activated Receptor-δ Induces Cell Proliferation by a Cyclin E1–Dependent Mechanism and Is Up-regulated in Thyroid Tumors
Authors: Lingchun Zeng, Yan Geng, Maria Tretiakova, Xuemei Yu, Peter Sicinski, Todd G. Kroll
Journal: Cancer Research (2008)

Abstract Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARδ induces cell proliferation through a novel cyclin E1–dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARδ was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARδ increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARδ agonist GW501516 augmented these PPARδ proliferation effects in a dose-dependent manner. Overexpression of PPARδ increased cyclin E1 protein by 9-fold, whereas knockdown of PPARδ by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARδ was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARδ pathway. In addition, the mean expression of native PPARδ was increased by 2-fold to 5-fold (P &amp;lt; 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARδ mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARδ antagonists as antineoplastic agents and implicate altered PPARδ–cyclin E1 signaling in thyroid and other carcinomas. [Cancer Res 2008;68(16):6578–86]