tbuckley/cabot-search huggingface dataset:
Cardiac-Specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-Dependent Manner
Authors: Laurie K. Russell, Carolyn M. Mansfield, John J. Lehman, Attila Kovacs, Michael Courtois, Jeffrey E. Saffitz, Denis M. Medeiros, Maria L. Valencik, John A. McDonald, Daniel P. Kelly
Journal: Circulation Research (2004)

Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1alpha in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy.
Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of <i>INK4a/ARF</i>
Authors: Gregory R. Bean, Andrew D. Bryson, Patrick G. Pilie, Vanessa Goldenberg, Joseph C. Baker, Catherine Ibarra, Danielle M.U. Brander, Carolyn Paisie, Natalie R. Case, Mona Gauthier, Paul A. Reynolds, Eric Dietze, Julie Ostrander, Victoria Scott, Lee G. Wilke, Lisa Yee, Bruce F. Kimler, Carol J. Fabian, Carola M. Zalles, Gloria Broadwater, Thea D. Tlsty, Victoria L. Seewaldt
Journal: Clinical Cancer Research (2007)

p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation. These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer.To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index.INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-beta2, estrogen receptor-alpha, and breast cancer-associated 1 genes (P = 0.001).Because INK4a/ARF promoter hypermethylation does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation.
Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report*
Authors: Steven O. Stapel, R. Asero, B. K. Ballmer‐Weber, E. F. Knol, S. Strobel, S. Vieths, J. Kleine‐Tebbe
Journal: Allergy (2008)

Serological tests for immunoglobulin G4 (IgG4) against foods are persistently promoted for the diagnosis of food-induced hypersensitivity. Since many patients believe that their symptoms are related to food ingestion without diagnostic confirmation of a causal relationship, tests for food-specific IgG4 represent a growing market. Testing for blood IgG4 against different foods is performed with large-scale screening for hundreds of food items by enzyme-linked immunosorbent assay-type and radioallergosorbent-type assays in young children, adolescents and adults. However, many serum samples show positive IgG4 results without corresponding clinical symptoms. These findings, combined with the lack of convincing evidence for histamine-releasing properties of IgG4 in humans, and lack of any controlled studies on the diagnostic value of IgG4 testing in food allergy, do not provide any basis for the hypothesis that food-specific IgG4 should be attributed with an effector role in food hypersensitivity. In contrast to the disputed beliefs, IgG4 against foods indicates that the organism has been repeatedly exposed to food components, recognized as foreign proteins by the immune system. Its presence should not be considered as a factor which induces hypersensitivity, but rather as an indicator for immunological tolerance, linked to the activity of regulatory T cells. In conclusion, food-specific IgG4 does not indicate (imminent) food allergy or intolerance, but rather a physiological response of the immune system after exposition to food components. Therefore, testing of IgG4 to foods is considered as irrelevant for the laboratory work-up of food allergy or intolerance and should not be performed in case of food-related complaints.
Clinical Implications of Human Papillomavirus in Head and Neck Cancers
Authors: Carole Fakhry, Maura L. Gillison
Journal: Journal of Clinical Oncology (2006)

Human papillomavirus (HPV) is now recognized to play a role in the pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within the oropharynx. High-risk HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have molecular-genetic alterations indicative of viral oncogene function. Measures of HPV exposure, including sexual behaviors, seropositivity to HPV16, and oral, high-risk HPV infection, are associated with increased risk for oropharyngeal cancer. HPV infection may be altering the demographics of HNSCC patients, as these patients tend to be younger, nonsmokers, and nondrinkers. There is sufficient evidence to conclude that a diagnosis of HPV-positive HNSCC has significant prognostic implications; these patients have at least half the risk of death from HNSCC when compared with the HPV-negative patient. The HPV etiology of these tumors may have future clinical implications for the diagnosis, therapy, screening, and prevention of HNSCC.
Oxidant and antioxidant mechanisms of lung disease caused by asbestos fibres
Authors: V.l. Kinnula
Journal: European Respiratory Journal (1999)

The pathogenesis of asbestos-related lung diseases is complicated and still poorly understood. Studies on animal models and cell cultures have indicated that asbestos fibres generate reactive oxygen and nitrogen species and cause oxidation and/or nitrosylation of proteins and deoxyribonucleic acid as a marker of cell injury. These effects are potentiated by the inflammation caused by the fibres. Recent studies have shown that individual variability in the antioxidant and/or detoxifying mechanisms probably has an important role in the development of asbestos-related lung diseases. Asbestos fibres cause both cell proliferation and apoptosis by multiple mechanisms, one of them being activation of signal transduction pathways by reactive oxygen and nitrogen species. Asbestos activates transcription factors such as nuclear factor kappa B, which has been shown to lead to the upregulation of antioxidant enzymes, most importantly manganese superoxide dismutase. This enzyme is also overexpressed in asbestos-related human malignant mesothelioma, whereas the induction of other antioxidant enzymes (copper-zinc superoxide dismutase, catalase, glutathione peroxidase) by asbestos fibres appears to be marginal. The significance of antioxidant enzymes in asbestos related diseases has, however, remained unclear. Furthermore, previous studies have not been able to offer successful therapies to the patients with asbestos-associated diseases. Only an improved understanding of the pathogenetic mechanisms in the human lung provides a basis for future therapies for asbestos-related diseases.
Reports on Sanitary Engineering in Houses, Hospitals, and Public Institutions
Authors: W. Eassie
Journal: BMJ (1873)

III.-TRAPS AND TRAPPING.PERHAPS in the whole history of sanitary matters no article can be found which has more perplexed the British householder than the article known as a trap.Each inventor, vendor, and fitter-up, has lauded such and such a contrivance; and, believing that the artisan knew better than himself, the householder has patronised it, persevered in its use-nay, in some cases, even argued enthusiastically in its favour, although really ignorant of its exact working.Now, it may be taken for granted that more disease is traceable to injudicious draining than to aught else in the way of sanitary neglects.And first of all " in pride of place" amongst the many defaults of drainage, sits what we will term imprudenm trapping.How can it be otherwise, when, as is mostly the case, the cesspool is unventilated, the sewer insufficiently so, the house portion of the drain boxed up, and there is no escape for the compressed gases, unless they bubble up through the water contained in the trap ?The consequence of this is, that, independently of the suction which the house fires will exert under ordinary circumstances upon the drains, the germs of dis- ease will find their way, with the offensive and other gases, into the very bed-rooms.Honestly speaking, traps are dangerous articles to.deal with: they should be treated merely as auxiliaries to a good drain- age system.If the house be disconnected from the sewer in any of the ways pointed out in my last article, a trap to all else than the closet izght safely be dispensed with.Nevertheless it will be found very convenient to use traps in the sink, the lavatory basin, the bath overflow, and the kitchen waste, if only to prevent the rush of cold air.Some little effluvium may also escape from the portion of the drain on the house side of the disconnection, and other contingencies might arise, where a barrier of water, however slight, would be advisable.I will now indicate the various species of traps which are used in and around buildings, and point out their merits.
C/EBP-β Modulates Transcription of Tubulointerstitial Nephritis Antigen in Obstructive Uropathy
Authors: Ping Xie, Lin Sun, Baibasawata Nayak, Yoshisuke Haruna, Fu-you Liu, Naoki Kashihara, Yashpal S. Kanwar
Journal: Journal of the American Society of Nephrology (2009)

Tubulointerstitial injury leading to fibrosis is a common pathway of many renal diseases. During this type of injury, modeled by unilateral ureteral obstruction (UUO), cells undergo epithelial-to-mesenchymal transition (EMT), a process that is mediated by various cytokines that modulate the biology of extracellular matrix proteins. Here, we studied the tubulointerstitial nephritis antigen (TINag), a tubular basement membrane protein, in the UUO model of tubulointerstitial injury. We observed upregulation of type IV collagen but downregulation of both laminin and TINag in obstructed kidneys. TINag downregulation was a result of oxidative stress; in the proximal tubular epithelial cell line HK-2, TINag expression and its promoter activity decreased after treatment with H2O2. We identified multiple CCAAT/enhancer binding protein beta (C/EBP-beta) motifs in the TINag promoter and observed that oxidant stress perturbed interactions between TINag DNA and C/EBP-beta protein. Oxidant stress reduced nuclear translocation of C/EBP-beta in HK-2 cells, which was restored by antioxidants. In addition, overexpression of C/EBP-beta restored the H2O2-induced reduction of TINag promoter activity and expression. Furthermore, in vivo, renal obstruction reduced nuclear expression of C/EBP-beta. Cells grown on a TINag substratum maintained their normal epithelial phenotype and cytoskeletal organization, similar to those grown on type IV collagen, and demonstrated reduced synthesis of fibronectin. Taken together, these findings suggest that altered interactions between C/EBP-beta and TINag play a critical role in the pathophysiology of renal injury after obstruction.
Cost-effectiveness of Practice-Initiated Quality Improvement for Depression
Authors: Michael Schoenbaum, Jürgen Unützer, Cathy Sherbourne, Naihua Duan, Lisa V. Rubenstein, Jeanne Miranda, Lisa S. Meredith, Maureen F. Carney, Kenneth Wells
Journal: JAMA (2001)

Depression is a leading cause of disability worldwide, but treatment rates in primary care are low.To determine the cost-effectiveness from a societal perspective of 2 quality improvement (QI) interventions to improve treatment of depression in primary care and their effects on patient employment.Group-level randomized controlled trial conducted June 1996 to July 1999.Forty-six primary care clinics in 6 community-based managed care organizations.One hundred eighty-one primary care clinicians and 1356 patients with positive screening results for current depression.Matched practices were randomly assigned to provide usual care (n = 443 patients) or to 1 of 2 QI interventions offering training to practice leaders and nurses, enhanced educational and assessment resources, and either nurses for medication follow-up (QI-meds; n = 424 patients) or trained local psychotherapists (QI-therapy; n = 489). Practices could flexibly implement the interventions, which did not assign type of treatment.Total health care costs, costs per quality-adjusted life-year (QALY), days with depression burden, and employment over 24 months, compared between usual care and the 2 interventions.Relative to usual care, average health care costs increased $419 (11%) in QI-meds (P =.35) and $485 (13%) in QI-therapy (P =.28); estimated costs per QALY gained were between $15 331 and $36 467 for QI-meds and $9478 and $21 478 for QI-therapy; and patients had 25 (P =.19) and 47 (P =.01) fewer days with depression burden and were employed 17.9 (P =.07) and 20.9 (P =.03) more days during the study period.Societal cost-effectiveness of practice-initiated QI efforts for depression is comparable with that of accepted medical interventions. The intervention effects on employment may be of particular interest to employers and other stakeholders.
The Suicide Substrate Reaction Between Plasminogen Activator Inhibitor 1 and Thrombin Is Regulated by the Cofactors Vitronectin and Heparin
Authors: Marja van Meijer, Annelies Smilde, Guido Tans, Michael E. Nesheim, Hans Pannekoek, Anton J.G. Horrevoets
Journal: Blood (1997)
Characteristics of the enteroaggregative Shiga toxin/verotoxin-producing Escherichia coli O104:H4 strain causing the outbreak of haemolytic uraemic syndrome in Germany, May to June 2011
Authors: F Scheutz, E Møller Nielsen, J Frimodt-Møller, N Boisen, S Morabito, R Tozzoli, J P Nataro, A Caprioli
Journal: Eurosurveillance (2011)

The Escherichia coli strain causing a large outbreak of haemolytic uraemic syndrome and bloody diarrhoea in Germany in May and June 2011 possesses an unusual combination of pathogenic features typical of enteroaggregative E. coli together with the capacity to produce Shiga toxin. Through rapid national and international exchange of information and strains the known occurrence in humans was quickly assessed.We describe simple diagnostic screening tools to detect the outbreak strain in clinical specimens and a novel real-time PCR for its detection in foods.
Identification of Lipocalin and Apolipoprotein A1 as Biomarkers of Chronic Obstructive Pulmonary Disease
Authors: Benjamin L. Nicholas, Paul Skipp, Sheila Barton, Dave Singh, Dinesh Bagmane, Richard Mould, Gilbert Angco, Jon Ward, Binita Guha-Niyogi, Susan Wilson, Peter Howarth, Donna E. Davies, Stephen Rennard, C. David O'Connor, Ratko Djukanović
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Much effort is being made to discover noninvasive biomarkers of chronic airway disease that might enable better management, predict prognosis, and provide new therapeutic targets.Objectives: To undertake a comprehensive, unbiased proteomic analysis of induced sputum and identify novel noninvasive biomarkers for chronic obstructive pulmonary disease (COPD).Methods: Induced sputum was obtained from patients with COPD with a spectrum of disease severity and from control subjects. Two-dimensional gel electrophoresis and mass spectrometric identification of differentially expressed proteins were first applied to induced sputum from patients with GOLD stage 2 COPD and healthy smoker control subjects. Initial results thus obtained were validated by a combination of immunoassays (Western blotting and ELISA) applied to a large subject cohort. The biomarkers were localized to bronchial mucosa by immunohistochemistry.Measurements and Main Results: Of 1,325 individual protein spots identified, 37 were quantitatively and 3 qualitatively different between the two groups (P < 0.05%). Forty protein spots were subjected to tandem mass spectrometry, which identified 15 separate protein species. Seven of these were further quantified in induced sputum from 97 individuals. Using this sequential approach, two of these potential biomarkers (apolipoprotein A1 and lipocalin-1) were found to be significantly reduced in patients with COPD when compared with healthy smokers. Their levels correlated with FEV1/FVC, indicating their relationship to disease severity.Conclusions: A potential role for apolipoprotein A1 and lipocalin-1 in innate defense has been postulated previously; our discovery of their reduction in COPD indicates a deficient innate defense system in airway disease that could explain increased susceptibility to infectious exacerbations.
Sleep, sleep-disordered breathing and metabolic consequences
Authors: P. Lévy, M. R. Bonsignore, J. Eckel
Journal: European Respiratory Journal (2009)

Sleep profoundly affects metabolic pathways. In healthy subjects, experimental sleep restriction caused insulin resistance (IR) and increased evening cortisol and sympathetic activation. Increased obesity in subjects reporting short sleep duration leads to speculation that, during recent decades, decreased sleeping time in the general population may have contributed to the increasing prevalence of obesity. Causal inference is difficult due to lack of control for confounders and inconsistent evidence of temporal sequence. In the general population, obstructive sleep apnoea (OSA) is associated with glucose intolerance. OSA severity is also associated with the degree of IR. However, OSA at baseline does not seem to significantly predict the development of diabetes. Prevalence of the metabolic syndrome is higher in patients with OSA than in obese subjects without OSA. Treatment with continuous positive airway pressure seems to improve glucose metabolism both in diabetic and nondiabetic OSA but mainly in nonobese subjects. The relative role of obesity and OSA in the pathogenesis of metabolic alterations is still unclear and is intensively studied in clinical and experimental models. In the intermittent hypoxia model in rodents, strong interactions are likely to occur between haemodynamic alterations, systemic inflammation and metabolic changes, modulated by genetic background. Molecular and cellular mechanisms are currently being investigated.
Interaction between Polyamines and the Mitogen-Activated Protein Kinase Pathway in the Regulation of Cell Cycle Variables in Breast Cancer Cells
Authors: Xin Hu, Sharlene Washington, Michael F. Verderame, Andrea Manni
Journal: Cancer Research (2005)

Abstract Inhibition of polyamine biosynthesis with α-difluoromethylornithine (DFMO) has been shown to inhibit proliferation of breast cancer cells although its mechanism of action has not been fully elucidated. To address this issue, we tested the effects of DFMO on cell cycle variables of MDA-MB-435 human breast cancer cells in culture. We also focused on the possible mediatory role of the mitogen-activated protein kinase (MAPK) pathway on the cell cycle effects of DFMO because this compound has been shown to activate MAPK signaling. We found that DFMO caused a p53-independent increase in p21 and its association with cyclin-dependent kinase (cdk)-2 and decreased cdk-2 protein as well as its phosphorylation on Thr160. In addition, DFMO markedly suppressed the expression of the full-length and low molecular weight forms of cyclin E. These effects of DFMO were reversible with exogenous putrescine, thus indicating that they are specifically mediated through polyamine depletion. Cdk-2 activity was drastically reduced in DFMO-treated breast cancer cells which exhibited a reduction in retinoblastoma (Rb) phosphorylation and protein. As a predictable consequence of these effects, DFMO caused a G1-S block. In addition, DFMO inhibited G2-M transition, most likely as a result of its induction of p21 expression. Inhibition of the MAPK pathway with PD98059 or U0126 blocked the DFMO-induced induction of p21 and the reduction of cdk-2 protein. PD98059 reversed the G2-M block induced by DFMO (probably as a result of suppression of p21) but not the G1-S arrest. MDA-MB-435 cells treated with PD98059 or U0126 in the presence and absence of DFMO exhibited a marked increase in the expression of p27 and its association with cdk-2, a decrease in phosphorylation of cdk-2 on Thr160, and a decrease in cyclin E expression. As predicted, PD98059 treatment reduced cdk-2 activity and Rb phosphorylation while reversing the decrease in Rb protein induced by DFMO. Neither DFMO nor PD98059, either alone or in combination, reduced cdk-4 activity despite a marked induction in p15 expression caused by DFMO. Our results indicate that activation of the MAPK pathway accounts for some of the effects of DFMO on cell cycle events of breast cancer cells. Inhibition of the MAPK pathway, however, does not reverse the cell cycle arrest induced by DFMO because of activation of alternative mechanisms leading to suppression of cdk-2 activity.