tbuckley/cabot-search huggingface dataset:
Heart in Diabetes: A Microvascular Disease
Authors: Markku Laakso
Journal: Diabetes Care (2011)

Diabetes currently affects about 5% of world’s populations, and its prevalence is rapidly increasing particularly in elderly subjects. Because over 80% of all diabetic subjects have type 2 diabetes, the increase in the number of individuals with diabetes implies an epidemic of type 2 diabetes. Diabetes is associated with hyperglycemia-specific microvascular complications. Furthermore, macrovascular complications, especially coronary artery disease (CAD) but also stroke and peripheral vascular disease, are increased by two- to fourfold in type 2 diabetes. Cardiovascular disease (CVD) is the most important long-term complication and by far the greatest cause of death in people with diabetes. In fact, over 50% of all patients with type 2 diabetes die of CAD (1).

Although much of the excess risk of CAD among patients with diabetes is accounted for by the presence of diabetes-associated CVD risk factors such as LDL cholesterol, elevated blood pressure, and smoking, a substantial proportion remains unexplained. A deleterious effect of the diabetic state on vascular and endothelial function is likely to be important via its ability to increase the potential for vasoconstriction and thrombosis. In population-based studies, the relationship of hyperglycemia to CAD is evident but the association is less strong than that of LDL cholesterol and elevated blood pressure. There is also evidence that the role of hyperglycemia with respect to the risk of CVD is larger among patients with type 1 diabetes than in patients with type 2 diabetes. In our study, an increment of 1 unit (%) of glycated hemoglobin increased CVD mortality by 52.5% (95% CI 28.4–81.3) in patients with type 1 diabetes and by 7.5% (4.3–10.8) in patients with type 2 diabetes (2).

CAD also includes a microvascular component. Diabetic cardiomyopathy, a relatively rare condition, associates with the presence of microvascular complications in diabetes. Therefore, changes in small arteries …
Activated, Cytotoxic CD8<sup>+</sup> T Lymphocytes Contribute to the Pathology of Asthma Death
Authors: S. O'SULLIVAN, L. CORMICAN, J. L. FAUL, S. ICHINOHE, S. L. JOHNSTON, C. M. BURKE, L. W. POULTER
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

This study investigates the presence of CD8(+) T lymphocytes and their possible association with viral infection in bronchi of victims of fatal asthma. Postmortem samples from the peribronchial region of the lung were obtained from seven patients who died an asthma death (AD), seven asthmatic patients who died of unrelated causes (AUC), and seven postmortem cases with no history of lung disease (control subjects). Using immunohistochemical techniques, the CD8(+) cytotoxic T-cell population in peribronchial tissue was characterized in three patient groups. The percentage of CD8(+) cells expressing the activation marker CD25 was higher in the AD group than in both the AUC and control groups (11.91 +/- 1.92% versus 3.93 +/- 1.63% and 1.09 +/- 0.56%, respectively (p < 0.001). Perforin expression, a marker of cytotoxicity, was highest in the AD group (9.16 +/- 1.5%) compared with 1.39 +/- 0.9; 1.8 +/- 0.6% in the AUC and control groups respectively (p < 0.001). Expression of interleukin-4 (IL-4) and interferon gamma (IFN-gamma) by CD8(+) T cells was higher in the AD group than the control group (p < 0.05). Furthermore, the IFN-gamma/IL-4 ratio in the AD group was less than half that of the control group (1.46 +/- 0.2 versus 3.2 +/- 0.1; p = 0.02). Using polymerase chain reaction (PCR), viral genome for rhinovirus (RV) was detected in lung tissue from three of the seven cases in the AD group. Two of these cases also had detectable respiratory syncytial virus (RSV). Viral genome for RSV was detected in five of the AUC group and in one of these cases, RV was also detected. No viral genome was detected in the lungs of the control group. In conclusion, this study provides novel evidence of an aberrant CD8(+) T-cell population, possibly in response to viral infection in subjects who die of acute asthma.
Effects of inducible nitric oxide synthase and xanthine oxidase inhibitors on SEB-induced interstitial pneumonia in mice
Authors: H. Miyakawa, K. Sato, T. Shinbori, T. Okamoto, Y. Gushima, M. Fujiki, M. Suga
Journal: European Respiratory Journal (2002)

The authors have previously reported that intratracheal instillation of staphylococcal enterotoxin‐B (SEB) induced interstitial pneumonia (IP) in autoimmune-prone mice. SEB-reactive T‐cells were critically involved in the development of IP in this model. Concern has arisen about the hazards of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the process of lung injury and fibrosis. Therefore, the involvement of nitric oxide (NO) and superoxide anion (O 2 − ) in the pathogenesis of IP in this autoimmune-prone model has been investigated. Nitrite/nitrate levels were increased in bronchoalveolar lavage (BAL) fluid and serum from SEB-injected mice. The signal of the NO-(N‐(dithiocarboxy) sarcosine) 2 -Fe 2+ complex was detected in the SEB-injected lung and whole blood by electron paramagnetic resonance (EPR) spectroscopy. NO production was significantly decreased by aminoguanidine (AG) treatment. Xanthine oxidase (XO) activity in the lung, BAL fluid, and plasma was increased with instillation of SEB, and 4‐amino‐6‐hydroxypyrazolo(3,4‐d)‐pyrimidine (AHPP) significantly inhibited XO activity. Moreover, both AG and AHPP significantly decreased production of pro-inflammatory cytokines, numbers of infiltrated cells in BAL fluid, and the area of thickened alveolar septa in the SEB-injected lung. In conclusion, the overproduction of nitric oxide and super oxide anion were implicated in the pathogenesis of interstitial pneumonia, and inducible nitric oxide synthase and xanthine oxidase inhibitors had protective effects against interstitial pneumonia in this model.
Comparative Prognostic Value of HPV16 E6 mRNA Compared With In Situ Hybridization for Human Oropharyngeal Squamous Carcinoma
Authors: Wei Shi, Hisayuki Kato, Bayardo Perez-Ordonez, Melania Pintilie, Shaohui Huang, Angela Hui, Brian O'Sullivan, John Waldron, Bernard Cummings, John Kim, Jolie Ringash, Laura A. Dawson, Patrick Gullane, Lillian Siu, Maura Gillison, Fei-Fei Liu
Journal: Journal of Clinical Oncology (2009)

A significant proportion of oropharyngeal squamous cell carcinomas (OSCC) are associated with the human papilloma virus (HPV), particularly HPV16. The optimal method for HPV determination on archival materials however, remains unclear. We compared a quantitative real-time polymerase chain reaction (qRT-PCR) assay for HPV16 mRNA to a DNA in situ hybridization (ISH) method, and evaluated their significance for overall (OS) and disease-free (DFS) survival.Matched, archival biopsies from 111 patients with OSCC were evaluated for HPV16 using a qRT-PCR for E6 mRNA and ISH for DNA. Immunohistochemistry for p16, p53, and epidermal growth factor receptor were also performed.HPV16 E6 mRNA was positive in 73 (66%) of 111 samples; ISH was positive in 62 of 106 samples (58%), with 86% concordance. P16 was overexpressed in 72 samples (65%), which was strongly associated with HPV16 status by either method. E6 mRNA presence or p16 overexpression were significantly associated with superior OS; E6 mRNA, HPV16 ISH, or p16 were all significantly associated with DFS. On multivariate analysis adjusted for age, stage, and treatment, positive E6 mRNA was the only independent predictor for superior OS; for DFS, p16 expression or HPV16 status determined by either method was significant.The prevalence of HPV16 in OSCC ranges from 58% to 66%, in a recently treated Canadian cohort. Classification of HPV-positivity by HPV16 E6 mRNA, HPV16 ISH or p16 immunohistochemistry (IHC) is associated with improved DFS. However, the latter two assays are technically easier to perform; hence, HPV16 ISH or p16 IHC should become standard evaluations for all patients with OSCC.
Synovial tissue hypoxia and inflammation in vivo
Authors: C. T. Ng, M. Biniecka, A. Kennedy, J. McCormick, O. FitzGerald, B. Bresnihan, D. Buggy, C. T. Taylor, J. O'Sullivan, U. Fearon, D. J. Veale
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Introduction</h3> Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO<sub>2</sub>) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators. <h3>Methods</h3> Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO<sub>2</sub> under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. <h3>Results</h3> The tPO<sub>2</sub> was 22.5 (range 3.2–54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p&lt;0.01) and sublining CD68 cells (r=−0.615, p&lt;0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO<sub>2</sub> in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO<sub>2</sub> &lt;20 mm Hg (all p values &lt;0.05). <h3>Conclusions</h3> This is the first study to show a direct in vivo correlation between synovial tPO<sub>2</sub>, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.
Are mental states assessed relative to what most people “should” or “would” think? Prescriptive and descriptive components of expected attitudes
Authors: Tamar A. Kreps, Benoît Monin
Journal: Behavioral and Brain Sciences (2010)

Abstract For Knobe, observers evaluate mental states by comparing agents' statements with “defaults,” the attitudes they are expected to hold. In our analysis, Knobe's model relies primarily on what agents should think, and little on expectancies of what they would think. We show the importance and complexity of including descriptive and prescriptive norms if one is to take expectancies seriously.
The respiratory system in connective tissue disorders
Authors: B. Crestani
Journal: Allergy (2005)

The connective tissue disorders (also called collagen vascular diseases) represent an heterogeneous group of immunologically mediated inflammatory disorders with a large variety of affected organs besides the lungs. The respiratory system may be involved in all its components: airways, vessels, parenchyma, pleura, respiratory muscles, etc. The frequency, clinical presentation, prognosis and response to therapy vary, depending on the pattern of involvement as well as on the underlying connective tissue disorders. The subject of this review is to describe the most frequent type of lung disorders observed in patients with connective tissue disease (CTD). We will focus on the most frequent CTD: systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, dermatopolymyositis and mixed CTD.
Sympathetic nervous activity during exercise in relation to age
Authors: J. Conway, R. Wheeler, R. Sannerstedt
Journal: Cardiovascular Research (1971)

Journal Article Sympathetic nervous activity during exercise in relation to age Get access James Conway, James Conway 2 From the Department of Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. 2Present address: I.C.I. Pharmaceuticals Division, Macclesfield, Cheshire, England. Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Wheeler, Richard Wheeler From the Department of Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Rune Sannerstedt Rune Sannerstedt From the Department of Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 5, Issue 4, October 1971, Pages 577–581, https://doi.org/10.1093/cvr/5.4.577 Published: 01 October 1971
Triple-Negative Breast Cancer
Authors: William D. Foulkes, Ian E. Smith, Jorge S. Reis-Filho
Journal: New England Journal of Medicine (2010)

Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.
Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
Authors: Mohammad Atefi, Earl Avramis, Amanda Lassen, Deborah J.L. Wong, Lidia Robert, David Foulad, Michael Cerniglia, Bjoern Titz, Thinle Chodon, Thomas G. Graeber, Begonya Comin-Anduix, Antoni Ribas
Journal: Clinical Cancer Research (2014)

Abstract Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1–exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1–exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. Clin Cancer Res; 20(13); 3446–57. ©2014 AACR.
Anticoagulation in the Treatment of Established Venous Thromboembolism in Patients With Cancer
Authors: Agnes Y.Y. Lee
Journal: Journal of Clinical Oncology (2009)

Cancer-associated thrombosis is a frequent and costly complication in patients with cancer. Significant morbidity and mortality not only result from thrombotic events, but may also occur as a result of the therapeutic interventions. The established treatment for cancer-associated thrombosis is anticoagulant therapy. Of the few options available, low molecular weight heparin (LMWH) is the preferred agent because of its efficacy, safety, and convenience. Alternatives to LMWH have undesirable limitations and have demonstrated poorer efficacy and safety in the oncology population. Treatment of recurrent thrombosis, patients with concurrent bleeding issues, role of vena cava filter insertion, and duration of therapy are all areas in need of urgent research. Treatment of cancer-associated thrombosis remains a challenging task and is limited by the paucity of evidence-based data. Research is urgently needed to advance current practice and improve patient care.
Real-time optical recording of β1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol
Authors: Francesca Rochais, Jean-Pierre Vilardaga, Viacheslav O. Nikolaev, Moritz Bünemann, Martin J. Lohse, Stefan Engelhardt
Journal: Journal of Clinical Investigation (2007)

Antagonists of β-adrenergic receptors (β-ARs) have become a main therapeutic regimen for the treatment of heart failure even though the mechanisms of their beneficial effects are still poorly understood. Here, we used fluorescent resonance energy transfer–based (FRET-based) approaches to directly monitor activation of the β1-AR and downstream signaling. While the commonly used β-AR antagonists metoprolol, bisoprolol, and carvedilol displayed varying degrees of inverse agonism on the Gly389 variant of the receptor (i.e., actively switching off the β1-AR), surprisingly, only carvedilol showed very specific and marked inverse agonist effects on the more frequent Arg389 variant. These specific effects of carvedilol on the Arg389 variant of the β1-AR were also seen for control of beating frequency in rat cardiac myocytes expressing the 2 receptor variants. This FRET sensor permitted direct observation of activation of the β1-AR in living cells in real time. It revealed that β1-AR variants dramatically differ in their responses to diverse beta blockers, with possible consequences for their clinical use.
Medical Care Costs Associated With Progression of Diabetic Nephropathy
Authors: Gregory A. Nichols, Suma Vupputuri, Helen Lau
Journal: Diabetes Care (2011)

OBJECTIVE To estimate the direct medical costs of hypertensive patients with type 2 diabetes by the level of proteinuria and to evaluate the differences between patients whose nephropathy did and did not progress. RESEARCH DESIGN AND METHODS We identified 7,758 patients with diabetes and hypertension who had a urine albumin-to-creatinine ratio (UACR) during 2001–2003 and at least one follow-up UACR 3–5 years later. Patients were followed for up to 8 years for progression of nephropathy, which was defined by increasing levels of proteinuria: normoalbuminuria (UACR &amp;lt;30 mg/g), microalbuminuria (30–299 mg/g), macroalbuminuria (≥300 mg/g), and end-stage renal disease (dialysis or transplant). We calculated annualized inpatient, outpatient, pharmaceutical, and total medical costs incurred by patients after the baseline measure through 2008, comparing patients who did and did not progress to a higher nephropathy stage. We also compared pre- and postprogression costs among those whose nephropathy progressed. RESULTS Patients with normoalbuminuria who progressed to microalbuminuria experienced an annualized change in baseline costs that was $396 higher (P &amp;lt; 0.001) than those who maintained normal albuminuria ($902 vs. $506). Among those with microalbuminuria, progression was significantly associated with a $747 difference (P &amp;lt; 0.001) in annualized change in outpatient costs compared with no progression ($1,056 vs. $309). Among patients who progressed, costs were 37% higher following progression from normoalbuminuria to microalbuminuria ($10,188 vs. $7,424; P &amp;lt; 0.001), and 41% higher following progression from microalbuminuria to macroalbuminuria ($12,371 vs. $8,753; P &amp;lt; 0.001). CONCLUSIONS Progression of nephropathy was strongly associated with higher subsequent medical care costs in hypertensive patients with diabetes. Greater prevention efforts may reduce the substantial economic burden of diabetic nephropathy.
Critical Appraisal of Continuous Ambulatory Peritoneal Dialysis
Authors: E A Friedman
Journal: Annual Review of Medicine (1984)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Concomitant Cisplatin Plus Radiotherapy and High–Dose-Rate Brachytherapy Versus Radiotherapy Alone for Stage IIIB Epidermoid Cervical Cancer: A Randomized Controlled Trial
Authors: Antonio Carlos Zuliani, Sergio Carlos Barros Esteves, Luiz Carlos Teixeira, Júlio César Teixeira, Gustavo Antonio de Souza, Luis Otávio Sarian
Journal: Journal of Clinical Oncology (2014)

The benefits of chemoradiotherapy (CRT) for cervical cancer compared with radiation (RT) alone seem to diminish in later-stage disease. However, these modalities have not been directly compared for disease-free interval (DFI) and overall survival (OS) of women with stage IIIB cervical cancer.We conducted a randomized controlled clinical trial comparing DFI and OS of 147 women with stage IIIB squamous cervical cancer who received either cisplatin plus RT (CRT) or RT alone (72 patients in the CRT group and 75 patients in the RT-only group).The CRT group had significantly better DFI (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; P = .02). However, patients in the CRT group did not have significantly better OS than those in the RT-only group (HR, 0.67; 95% CI, 0.38 to 1.17; P = .16). Toxicity was graded according to criteria of the Radiation Therapy Oncology Group. The organs affected (excluding hematologic effects) did not differ significantly between groups. Also, late toxicity events and organs affected were not significantly disproportionate between the study groups.For stage IIIB cervical cancer, the addition of cisplatin offers a small but significant benefit in DFI, with acceptable toxicity.
Gap junction hemichannels contribute to the generation of diarrhoea during infectious enteric disease
Authors: Julian Andrew Guttman, Ann En-Ju Lin, Yuling Li, John Bechberger, Christian C Naus, A Wayne Vogl, B Brett Finlay
Journal: Gut (2009)

Objective The attaching and effacing (A/E) pathogens enterohaemorrhagic Escherichia coli , enteropathogenic E coli and Citrobacter rodentium colonise intestinal tracts, attach to enterocytes, collapse infected cell microvilli and alter numerous host cell processes during infection. Enterocyte alterations result in numerous small molecules being released from host cells that likely contribute to diarrhoeal phenotypes observed during these infections. One possible route for small molecules to be released from intestinal cells may be through functional gap junction hemichannels. Here we examine the involvement of these hemichannels during the diarrhoeal disease caused by A/E pathogens in vivo. Design Mice were infected with the diarrhoea-causing murine A/E pathogen C rodentium for 7 days. Connexin43 (Cx43) protein levels and immunolocalisation in the colon were initially used to determine alterations during A/E bacterial infections in vivo. Connexin mimetic peptides and connexin permeable tracer molecules were used to gage the presence and function of unpaired connexin hemichannels. The role of Cx43 in diarrhoea generation was assessed by comparing infections of wild-type mice to Cx43 mutant mice and determining the water abundance in the colonic luminal material. Results We demonstrate that Cx43 protein levels are increased in colonocytes during in vivo A/E bacterial infections, resulting in functionally open connexon hemichannels in apical membranes of infected cells. Moreover, infected Cx43 +/− mice do not suffer from diarrhoeal disease. Conclusions This study provides the first evidence that functional connexon hemichannels can occur in the intestine and are a novel molecular mechanism of water release during infectious diarrhoea.