tbuckley/cabot-search huggingface dataset:
Retinal Vascular Caliber as a Biomarker for Diabetes Microvascular Complications
Authors: M. Kamran Ikram, Carol Y. Cheung, Mara Lorenzi, Ronald Klein, Teresa L.Z. Jones, Tien Yin Wong
Journal: Diabetes Care (2013)

Globally, the number of people with diabetes is expected to reach 552 million in 2030 (1). Both the macrovascular (coronary artery disease, peripheral artery disease, and stroke) and microvascular (retinopathy, nephropathy, and neuropathy) complications of diabetes are major causes of morbidity and mortality (2). In theory, the long preclinical phase should provide a window to apply interventions that preempt progression to clinical disease, but to date no strategy achieves this aim for diabetes complications. Intensive control of hyperglycemia and blood pressure implemented with the imperfect means available today delays the appearance and reduces the severity of most complications, but does not prevent their development (3). Drugs such as fenofibrate have reduced the risk of diabetic retinopathy (DR) progression in type 2 diabetic patients, and inhibitors of the renin-angiotensin system (e.g., enalapril, losartan) have reduced the risk of progression in type 1 diabetic patients, but have not reduced the risk of DR incidence. Thus, new approaches are required to derive further benefit from current interventions at an earlier stage of diabetes and to support the development of new interventions. One such approach is to identify biomarkers that will enable systematic patient surveillance and the identification of high-risk patients and also surrogate end points that will accelerate the discovery of new interventions.

The retinal vessels are early and prevalent targets of diabetic damage. They can be seen, measured, and tested by noninvasive means (4). Hence, investigators have attempted over the decades to identify early changes in the retinal vessels in diabetes and determine whether they could inform about the development of retinopathy and other complications. New measuring techniques have steadily come along, and others are in development. It seems timely to assess which concepts have emerged and which needs must be met toward fulfilling the expectation that retinal vessels may be able …
Indoor Pollutant Exposures Modify the Effect of Airborne Endotoxin on Asthma in Urban Children
Authors: Elizabeth C. Matsui, Nadia N. Hansel, Charles Aloe, Allison M. Schiltz, Roger D. Peng, Nathan Rabinovitch, Mary Jane Ong, D’Ann L. Williams, Patrick N. Breysse, Gregory B. Diette, Andrew H. Liu
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

The effect of endotoxin on asthma morbidity in urban populations is unclear.To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity.One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms.Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner.The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes.
A Novel Alphavirus Vaccine Encoding Prostate-Specific Membrane Antigen Elicits Potent Cellular and Humoral Immune Responses
Authors: Robert J. Durso, Sofija Andjelic, Jason P. Gardner, Dennis J. Margitich, Gerald P. Donovan, Robert R. Arrigale, Xinning Wang, Maureen F. Maughan, Todd L. Talarico, Robert A. Olmsted, Warren D.W. Heston, Paul J. Maddon, William C. Olson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for active immunotherapy. Alphavirus vaccines have shown promise in eliciting immunity to tumor antigens. This study investigated the immunogenicity of alphavirus vaccine replicon particles (VRP) that encode PSMA (PSMA-VRP). Experimental Design: Cells were infected with PSMA-VRP and evaluated for PSMA expression and folate hydrolase activity. Mice were immunized s.c. with PSMA-VRP or purified PSMA protein. Sera, splenocytes, and purified T cells were evaluated for the magnitude, durability, and epitope specificity of the anti-PSMA response. Antibodies were measured by flow cytometry, and cellular responses were measured by IFN-γ enzyme-linked immunospot and chromium release assays. Cellular responses in BALB/c and C57BL/6 mice were mapped using overlapping 15-mer PSMA peptides. A Good Laboratory Practice–compliant toxicology study was conducted in rabbits. Results: PSMA-VRP directed high-level expression of active PSMA. Robust T-cell and B-cell responses were elicited by a single injection of 2 × 105 infectious units, and responses were boosted following repeat immunizations. Anti-PSMA responses were detected following three immunizations with 102 infectious units and increased with increasing dose. PSMA-VRP was more immunogenic than adjuvanted PSMA protein. Responses to PSMA-VRP were characterized by Th-1 cytokines, potent CTL activity, and IgG2a/IgG2b antibodies. T-cell responses in BALB/c and C57BL/6 mice were directed toward different PSMA peptides. Immunogenic doses of PSMA-VRP were well tolerated in mice and rabbits. Conclusions: PSMA-VRP elicited potent cellular and humoral immunity in mice, and specific anti-PSMA responses were boosted on repeat dosing. PSMA-VRP represents a promising approach for immunotherapy of prostate cancer.
A Putative Role for Psoriasin in Breast Tumor Progression
Authors: Ian Krop, Annette März, Hanna Carlsson, Xiaochun Li, Noga Bloushtain-Qimron, Min Hu, Rebecca Gelman, Michael S. Sabel, Stuart Schnitt, Sridhar Ramaswamy, Celina G. Kleer, Charlotta Enerbäck, Kornelia Polyak
Journal: Cancer Research (2005)

Abstract Psoriasin (S100A7) was identifi`ed as a gene highly expressed in psoriatic keratinocytes and highly and more frequently expressed in ductal carcinoma in situ (DCIS) than in invasive breast carcinomas (IBC), suggesting a potential role in tumor progression. Psoriasin expression is associated with poor prognostic factors in both DCIS and IBC. Several putative functions have been proposed for psoriasin in various disease types, but none of these can fully explain its involvement in breast tumor progression. Here, we show that down-regulation of endogenous psoriasin expression via stable short hairpin RNAs in a human IBC cell line (MDA-MB-468) increases cell migration and invasion without influencing cell proliferation and survival in vitro but inhibits tumor growth in vivo. These seemingly paradoxical results are potentially explained by the dramatic up-regulation and down-regulation of matrix metalloproteinase-13 and vascular endothelial growth factor (VEGF), respectively, observed in cells with decreased psoriasin levels compared with controls. Correlating with this, high psoriasin expression in human IBC is associated with increased angiogenesis and worse clinical outcome, and psoriasin mRNA levels are coordinately regulated with VEGF and other genes related to hypoxia and mitochondrial reactive oxygen species (ROS). Based on these results, we propose that psoriasin may play a role in breast tumor progression by promoting angiogenesis and enhancing the selection for cells that overcome its anti-invasive function. This hypothesis may explain why psoriasin expression is highest in high-grade and/or estrogen receptor–negative tumors, as these are associated with increased hypoxia and ROS, a setting in which the angiogenic effects of psoriasin are most important. (Cancer Res 2005; 65(24): 11326-34)
Double-Chambered Right Ventricle and Bicuspid Pulmonic Valve
Authors: Teerapat Yingchoncharoen, Luke J. Burchill, Janine Arruda, Rodolfo Denadai Benatti, Karen James, W.H. Wilson Tang, Robert D. Stewart, Gösta B. Pettersson, Karunakaravel Karuppasamy
Journal: Journal of the American College of Cardiology (2013)
Human melanoma antigen AH is an autoantigenic ganglioside related to GD2.
Authors: T Watanabe, C S Pukel, H Takeyama, K O Lloyd, H Shiku, L T Li, L R Travassos, H F Oettgen, L J Old
Journal: The Journal of Experimental Medicine (1982)

AH antigen, initially defined by an antibody present in a melanoma patient, is a cell surface antigen found on approximately 65% of melanoma cell lines. Absorption analysis indicates that AH is a differentiation antigen marking normal and malignant cells of neuroectodermal origin. The AH determinant has been found to be related to GD2 ganglioside.
Independent Contribution of Diabetes to Increased Prevalence and Incidence of Atrial Fibrillation
Authors: Gregory A. Nichols, Kyndaron Reinier, Sumeet S. Chugh
Journal: Diabetes Care (2009)

Diabetes has long been recognized as a risk factor for atrial fibrillation, but its independent contribution to atrial fibrillation has not been fully evaluated. We sought to compare the prevalence and incidence of atrial fibrillation in age- and sex-matched patients with and without type 2 diabetes.Using an observational cohort design, we selected 10,213 members of an HMO diabetes registry as of 1 January 1999 plus 7,159 patients who entered the registry by 31 December 2004 and matched them to patients without diabetes on year of birth and sex. All patients were followed until they died, left the health plan, or until 31 December 2008. We compared the baseline prevalence of atrial fibrillation and then followed patients without atrial fibrillation to compare atrial fibrillation incidence while controlling for known risk factors.Atrial fibrillation prevalence was significantly greater among patients with diabetes (3.6 vs. 2.5%, P < 0.0001). Over a mean follow-up of 7.2 +/- 2.8 years, diabetic patients without atrial fibrillation at baseline developed atrial fibrillation at an age- and sex-adjusted rate of 9.1 per 1,000 person-years (95% CI 8.6-9.7) compared with a rate of 6.6 (6.2-7.1) among nondiabetic patients. After full adjustment for other risk factors, diabetes was associated with a 26% increased risk of atrial fibrillation among women (hazard ratio 1.26 [95% CI 1.08-1.46]), but diabetes was not a statistically significant factor among men (1.09 [0.96-1.24]).In this population, diabetes was an independent determinant of atrial fibrillation prevalence but predicted incidence only among women. These findings have potential public health implications and emphasize the need for further investigation of the mechanistic links between diabetes and atrial fibrillation.
The role of the spinal cord in bowel dysfunction secondary to multiple sclerosis: a comparison with supra-conal spinal cord injury
Authors: G. Preziosi, A. Roy, P. Boulos, A. Emmanuel
Journal: Gut (2011)

<h3>Introduction</h3> Bowel dysfunction in multiple sclerosis (MS) and spinal cord injury (SCI) is common, affecting up to 2/3 of patients, with constipation and incontinence often co-existing. In MS we have shown that spinal cord involvement by the disease predicts bowel dysfunction. Spinal disease burden is easily measured clinically by EDSS (expanded disability status scale, 0–4.5 = mild disability, 5–10 = high disability). In supraconal-SCI the autonomic dysfunction underlying bowel symptoms causes increased rectal compliance (RC). We hypothesised that spinal cord involvement by MS is responsible for the autonomic dysfunction affecting the rectum, hence compared RC between MS, supraconal-SCI patients and normal controls. <h3>Methods</h3> Forty-five MS patients with bowel symptoms were divided in two groups according to EDSS: MS-A (EDSS &lt; 5, n = 25) and MS-B (EDSS &gt; 5, n = 20). Rectal compliance and Wexner constipation and incontinence scores were compared with 19 Supraconal-SCI patients and 25 normal controls. Age, gender and parity were well-matched between groups. <h3>Results</h3> <i>Rectal compliance (ml/mmHg)</i> post-hoc analysis in table 1. <i>Wexner-Incontinence:</i> <b>MS-A</b> (6.12 ± 4.72) vs <b>MS-B</b> (9.8 ± 6.4) p = 0.96 <b>MS-A</b> (6.12 ± 4.72) vs <b>Spinal</b>(10.8 ± 5.3)p = 0.033 <b>MS-B</b> (9.8 ± 6.4) vs <b>Spinal</b>(10.8 ± 5.3) p = 0.883. <i>Wexner-Constipation:</i> <b>MS-A</b> (10.8 ± 5.3) vs <b>MS-B</b> (11.3 ± 4.3) p = 0.951 <b>MS-A</b> (10.8 ± 5.3) vs <b>Spinal</b> (15.4 ± 5.8) p = 0.025 <b>MS-B</b> (11.3 ± 4.3) vs <b>Spinal</b> (15.4 ± 5.8) p = 0.065. In the MS group there was a strong relationship between EDSS and RC (r = 0.438, p = 0.003; β = 0.487, p = 0.001). <h3>Conclusion</h3> Rectal compliance is increased similarly in both MS patients with high disability and supraconal-SCI patients, suggesting that similar autonomic dysfunction underlies bowel symptoms in both groups. Bowel dysfunction in MS is multifactorial, but spinal cord involvement by MS seems critical to development of both constipation and incontinence.
Unmasking tuberculosis in the era of antiretroviral treatment
Authors: Giuseppe Lapadula, Alessandro Soria, Alessandra Bandera, Nicola Squillace, Francesca Sabbatini, Fabio Franzetti, Giovanni Battista Migliori, Andrea Gori
Journal: European Respiratory Journal (2011)

Tuberculosis (TB) can develop soon after antiretroviral treatment initiation, as the result of restoration of the anti-TB specific immune response. This form of the disease is often defined as "unmasked TB", and it represents a major challenge for severely immune-suppressed HIV-infected subjects initiating treatment. Emergence of previously unrecognised TB disease occurs frequently in countries where TB/HIV co-infection is common, and where antiretroviral treatment has become increasingly accessible. The challenges posed by unmasked TB, such as its high incidence, the lack of reliable diagnostic tools and the uncertainties on its optimal management, may hamper our ability to face the TB/HIV epidemic. Therefore, unmasked TB appears a major threat to global health and poses additional barriers to successful HIV/AIDS care and treatment programmes. This review focuses on the epidemiology, immunopathogenesis and clinical manifestations of unmasked TB, and provides evidence-based recommendations for management and care of the disease.
Sarcomeric cardiomyopathies: from bedside to bench and back
Authors: G. Hasenfuss
Journal: Cardiovascular Research (2015)

Sarcomeric cardiomyopathies represent a perfect example of the power of translation and clinic/research interactions: The question arises from the clinical phenotype of the patient (signs and symptoms), basic laboratory research identifies molecular and cellular aspects of the phenotype and develops diagnostics and treatment strategies for the patient. In clinical terms, 25 years ago patients with unexplained left ventricular hypertrophy suffering from dyspnoea and potentially life-threatening arrhythmias were observed, since then underlying genetic mutations and molecular mechanisms have been identified, which already have helped to understand the disease and diagnose the patients, and nowadays molecular treatment options are on the way. The cycle from bedside to bench and back is ongoing.

What are sarcomeric cardiomyopathies? As implied by the name, these cardiomyopathies are caused by mutations in a number of sarcomeric genes. The prototype is hypertrophic cardiomyopathy (HCM), which is clinically defined by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading conditions.1 The frequency of unexplained left ventricular thickness ranges from 0.02 to 0.23% in adults or up to 1:500.2 Patterns …
Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk
Authors: Jonathan M. Hill, Gloria Zalos, Julian P.J. Halcox, William H. Schenke, Myron A. Waclawiw, Arshed A. Quyyumi, Toren Finkel
Journal: New England Journal of Medicine (2003)

Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression.
Causal Relationships in Medicine: A Practical System for Critical Appraisal
Authors: J. Mark Elwood
Journal: Annals of Internal Medicine (1991)

The importance of causal relationships in medicine study designs which can demonstrate and test causation the results obtained from studies of causation selection of subjects for study error and bias in observations confounding chance variation the diagnosis of causation critical appraisal of published work - introduction. (Part contents)
Cushing's syndrome with suppression of the hypothalamic-pituitary-adrenal axis after intra-articular steroid injections.
Authors: M M O'Sullivan, W R Rumfeld, M K Jones, B D Williams
Journal: Annals of the Rheumatic Diseases (1985)

A case of Cushing's syndrome after long term intra-articular corticosteroid injections is described. Prolonged suppression of the hypothalamic-pituitary-adrenal axis occurred as assessed by an insulin tolerance test 11 weeks after the last intra-articular injection. Replacement steroid therapy was required.
Nonsteroidal Anti-inflammatory Drugs Suppress Glioma via 15-Hydroxyprostaglandin Dehydrogenase
Authors: Naoki Wakimoto, Ido Wolf, Dong Yin, James O'Kelly, Tadayuki Akagi, Lilach Abramovitz, Keith L. Black, Hsin-Hsiung Tai, H. Phillip Koeffler
Journal: Cancer Research (2008)

Abstract Studies have conjectured that nonsteroidal anti-inflammatory drugs (NSAID) inhibit growth of various malignancies by inhibiting cyclooxygenase-2 (COX-2) enzyme activity. Yet, several lines of evidence indicate that a COX-2–independent mechanism may also be involved in their antitumor effects. Here, we report that NSAIDs may inhibit the growth of glioblastoma multiforme (GBM) cells through COX-2–independent mechanisms, including up-regulation of both 15-hydroxyprostaglandin dehydrogenase (15-PGDH, the key prostaglandin catabolic enzyme) and the cell cycle inhibitor p21. Using Western blot and real-time PCR analysis in various GBM cell lines, we observed up-regulation of 15-PGDH and p21 after NSAIDs treatment. To elucidate the role of 15-PGDH in GBM, transfection assays were conducted using the T98G GBM cell line. Overexpression of 15-PGDH suppressed cell growth and was associated with increased expression of p21. In an attempt to investigate the roles of COX-2, 15-PGDH, and p21 in the inhibition of growth of GBM, small interfering RNA (siRNA) against each of these proteins was transfected into T98G cells. Inhibition of growth mediated by NSAIDs was partially reversed after knockdown of either 15-PGDH or p21, but not after COX-2 knockdown. Moreover, expression level of p21 was not affected in COX-2 siRNA transfected cells. Our studies provide evidence that the up-regulation of 15-PGDH induced by NSAIDs has the potential to inhibit growth of GBM, in part, by up-regulation of p21 possibly independent from COX-2 enzymatic function. [Cancer Res 2008;68(17):6978–86]
Hypothyroidism and associated acute renal failure
Authors: Bhushan Joshi, Daniel Jones, Andrew Rochford, Louise Giblin
Journal: Journal of the Royal Society of Medicine (2009)

We report a case of profound hypothyroidism with associated and otherwise unexplained acute renal failure in which replacement of the hormonal deficiency led to correction of the renal dysfunction. Electrolyte disorders are occasionally observed in hypothyroidism but associated renal impairment without any other clear underlying cause is relatively rare. There have been previous case reports documenting this association but it is something that is rarely found in medical textbooks. We describe our case of a middle-aged gentleman who presented with profound clinical hypothyroidism who was found on further investigation to also have significant renal impairment.
A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils)
Authors: H L Petsky, C J Cates, T J Lasserson, A M Li, C Turner, J A Kynaston, A B Chang
Journal: Thorax (2010)

Asthma severity and control can be measured both subjectively and objectively. Traditionally asthma treatments have been individualised using symptoms and spirometry/peak flow. Increasingly treatment tailored in accordance with inflammatory markers (sputum eosinophil counts or fractional exhaled nitric oxide (FeNO) data) is advocated as an alternative strategy. The objective of this review was to evaluate the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) in comparison with clinical symptoms (with or without spirometry/peak flow) for asthma-related outcomes in children and adults. Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles were searched. The last searches were in February 2009. All randomised controlled comparisons of adjustment of asthma treatment based on sputum analysis or FeNO compared with traditional methods (primarily clinical symptoms and spirometry/peak flow) were selected. Results of searches were reviewed against predetermined criteria for inclusion. Relevant studies were selected, assessed and data extracted independently by at least two people. The trial authors were contacted for further information. Data were analysed as ‘intervention received’ and sensitivity analyses performed. Six (2 adults and 4 children/adolescent) studies utilising FeNO and three adult studies utilising sputum eosinophils were included. These studies had a degree of clinical heterogeneity including definition of asthma exacerbations, duration of study and variations in cut-off levels for percentage of sputum eosinophils and FeNO to alter management in each study. Adults who had treatment adjusted according to sputum eosinophils had a reduced number of exacerbations compared with the control group (52 vs 77 patients with ≥1 exacerbation in the study period; p=0.0006). There was no significant difference in exacerbations between groups for FeNO compared with controls. The daily dose of inhaled corticosteroids at the end of the study was decreased in adults whose treatment was based on FeNO in comparison with the control group (mean difference −450.03 μg, 95% CI −676.73 to −223.34; p&lt;0.0001). However, children who had treatment adjusted according to FeNO had an increase in their mean daily dose of inhaled corticosteroids (mean difference 140.18 μg, 95% CI 28.94 to 251.42; p=0.014). It was concluded that tailoring of asthma treatment based on sputum eosinophils is effective in decreasing asthma exacerbations. However, tailoring of asthma treatment based on FeNO levels has not been shown to be effective in improving asthma outcomes in children and adults. At present, there is insufficient justification to advocate the routine use of either sputum analysis (due to technical expertise required) or FeNO in everyday clinical practice.