tbuckley/cabot-search huggingface dataset:
Induction of rheumatoid antibodies in the mouse. Regulated production of autoantibody in the secondary humoral response.
Authors: D A Nemazee, V L Sato
Journal: The Journal of Experimental Medicine (1983)

A/J mice were found to produce autoreactive IgM anti-IgG1 in response to secondary immunization with a number of protein antigens. No anti-IgG1 was produced after a single such immunization, indicating that antigen: IgG1 antibody complexes were responsible for inducing the autoreactive response. The size of the anti-IgG1 response was in some cases massive and of the same order of magnitude as the response to the foreign immunizing material. No significant anti-IgG2a, anti-IgG2b, or anti-IgG3 response was found in mice producing anti-IgG1. Virtually all of the anti-IgG1 material produced was of the IgM class and bound to the Fc region of autologous IgG1. A component of the anti-IgG1 was shown to be able to distinguish between the two mouse IgG1 allotypes. These results suggest that self-reactive anti-IgG is a common component of the secondary immune response of mice that may have powerful physiological and immunoregulatory effects.
Gene therapy and uterine leiomyoma: a review
Authors: Ayman Al-Hendy, Salama Salama
Journal: Human Reproduction Update (2006)

Leiomyomas (fibroids) are common estrogen-dependent uterine tumours that cause significant morbidity for women and a substantial economic impact on health delivery systems. Currently, there is no effective medical treatment option for this condition—hysterectomy is the mainstay of management. This is not an attractive choice for many women, especially patients desiring to preserve their fertility potential. Gene therapy is becoming a clinical reality, with more than 600 clinical trials worldwide. Researchers have recently attempted to develop a gene-therapy-based approach for the ablation of uterine fibroids. The localized nature of this condition and its accessibility using different imaging or endoscopic techniques make it an attractive target for direct delivery of gene-based vectors. Recent work from our laboratory suggests the potential use of a dominant-negative form of estrogen receptor (ER) to inactivate estrogen signalling in leiomyoma cells and induce apoptosis. Our in vivo data in a mouse model demonstrate the ability of an adenovirus-expressing dominant-negative ER to arrest leiomyoma growth. We and others also have described the utility of the herpes simplex virus-thymidine kinase (HSV-TK) plus ganciclovir (GCV) suicide gene-therapy system to effectively eradicate leiomyoma cells by utilizing the bystandard effect phenomena and the high expression of gap-junction protein in these tumours. Further work on rat models will pave the way for future leiomyoma gene-therapy clinical trials and allow the realization of gene therapy as a viable non-surgical option for this common problem in women's health.
Needlescopy-assisted resection of pulmonary nodule after dual localisation
Authors: D-Y. Kang, H.K. Kim, Y.K. Kim, H.S. Yong, E-Y. Kang, Y.H. Choi
Journal: European Respiratory Journal (2010)

The aim of this study was to evaluate the feasibility of dual localisation with hookwire and lipiodol before needlescopy-assisted resection for pulmonary nodule. Computed tomography-guided dual marking was performed on 36 pulmonary nodules of 32 patients and needlescopy-assisted resection was performed monitored by C-arm fluoroscopy. The mean age of the patients was 58 ± 12 (range 12-77) yrs. The mean size of the nodules was 7.5 ± 3.7 (3-17) mm. Their mean distance from the pleural surface was 7.3 ± 7.5 (0-35) mm. There were nine pure ground-glass opacity lesions, five semi-solid lesions and 22 solid lesions. The time of the dual localisation procedure was 13.1 ± 4.8 (7-23) min. Complications of the marking were pneumothorax in nine patients, and intrapulmonary bleeding in three. One hookwire dislodged during the operation. All nodules were successfully resected under needlescopy without conversion to a conventional thoracoscopy (5 mm or 10 mm thoracoscopy) or a minithoracotomy. There was no complication related to needlescopy-assisted resection. Dual marking with hookwire and lipiodol is a safe and none time consuming procedure, and needlescopy-assisted lung resection for small nodules is technically feasible and useful for histological diagnosis and treatment.
Sensitivity of the 2-oxoglutarate carrier to alcohol intake contributes to mitochondrial glutathione depletion
Authors: Olga Coll, Anna Colell, Carmen García-Ruiz, Neil Kaplowitz, J. C. Fernández-Checa
Journal: Hepatology (2003)

The mitochondrial pool of reduced glutathione (mGSH) is known to play a protective role against liver injury and cytokine–mediated cell death. However, the identification of the mitochondrial carriers involved in its transport in hepatocellular mitochondria remains unestablished. In this study, we show that the functional expression of the 2–oxoglutarate carrier from HepG2 cells in mitochondria from Xenopus laevis oocytes conferred a reduced glutathione (GSH) transport activity that was inhibited by phenylsuccinate, a specific inhibitor of the carrier. In addition, the mitochondrial transport of GSH and 2–oxoglutarate in isolated mitochondria from rat liver exhibited mutual competition and sensitivity to glutamate and phenylsuccinate. Interestingly, the kinetics of 2–oxoglutarate transport in rat liver mitochondria displayed a single Michaelis–Menten component with a Michaelis constant of 3.1 ± 0.3 mmol/L and maximum velocity of 1.9 ± 0.1 nmol/mg protein/25 seconds. Furthermore, the initial rate of 2–oxoglutarate was reduced in mitochondria from alcohol–fed rat livers, an effect that was not accompanied by an alcohol–induced decrease in the 2–oxoglutarate messenger RNA levels but rather by changes in mitochondrial membrane dynamics induced by alcohol. The fluidization of mitochondria by the fluidizing agent 2–(2–methoxyethoxy)ethyl 8–(cis–2–n–octylcyclopropyl) (A 2 C) restored the initial transport rate of both GSH and 2–oxoglutarate. Finally, these changes were reproduced in normal liver mitochondria enriched in cholesterol where the fluidization of cholesterol–enriched mitochondria with A 2 C restored the order membrane parameter and the mitochondrial 2–oxoglutarate uptake. In conclusion, these findings provide unequivocal evidence for 2–oxoglutarate as a GSH carrier and its sensitivity to membrane dynamics perturbation contributes in part to the alcohol–induced mGSH depletion.
Blunted T-lymphocyte response in chronic obstructive pulmonary disease
Authors: J. Pons, J. Sauleda, J. M. Ferrer, B. Barceló, A. Fuster, V. Regueiro, M. R. Julià, A. G. N. Agustí
Journal: European Respiratory Journal (2005)

Chronic obstructive pulmonary disease (COPD) is characterised by an excessive inflammatory response to inhaled particles, mostly tobacco smoking. Although inflammation is present in all smokers, only a percentage of them develop COPD. T-lymphocytes are important effector and regulatory cells that participate actively in the inflammatory response of COPD. They comprise the T-cell receptor (TCR)-αβ (CD4+ and CD8+) and TCR-γδ T-lymphocytes. The latter represent a small percentage of the total T-cell population, but play a key role in tissue repair and mucosal homeostasis. To investigate TCR-αβ (CD4+ and CD8+) and TCR-γδ T-lymphocytes in COPD, the present authors determined, by flow cytometry, the distribution of both subpopulations in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from patients with COPD, smokers with normal lung function and never-smokers. The present study found that: 1) the distribution of CD4+ and CD8+ lymphocytes in blood and BAL was similar in all three groups; 2) compared with nonsmokers, γδ T-lymphocytes were significantly increased in smokers with preserved lung function; and 3) this response was blunted in patients with COPD. These results highlight a novel, potentially relevant, pathogenic mechanism in chronic obstructive pulmonary disease.
The First α Helix of Interleukin (Il)-2 Folds as a Homotetramer, Acts as an Agonist of the IL-2 Receptor β Chain, and Induces Lymphokine-Activated Killer Cells
Authors: Ralph Eckenberg, Thierry Rose, Jean-Louis Moreau, Robert Weil, Franck Gesbert, Sigrid Dubois, Diana Tello, Marc Bossus, Hélène Gras, André Tartar, Jacques Bertoglio, Salem Chouaïb, Michel Goldberg, Yannick Jacques, Pedro M. Alzari, Jacques Thèze
Journal: The Journal of Experimental Medicine (2000)

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Ralphabetagamma and IL-2Rbetagamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the first time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1-30 (containing amino acids 1-30, covering the entire alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rbeta, whereas shorter versions of the peptide lack helical structure and are inactive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2Rbeta. In agreement with its binding to IL-2Rbeta, p1-30 activates Shc and p56(lck) but unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1-30 activates Tyk2, thus suggesting that IL-2Rbeta may bind to different Jaks depending on its oligomerization. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8(low) lymphocytes and natural killer cells, which constitutively express IL-2Rbeta. A significant interferon gamma production is also detected after p1-30 stimulation. A mutant form of p1-30 (Asp20-->Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p1-30 peptide. Altogether, our data suggest that p1-30 has therapeutic potential.
Pathophysiology of Transient Myocardial Ischemia in Acute Coronary Syndromes
Authors: Deven J. Patel, Charles J. Knight, Diana R. Holdright, David Mulcahy, Debbie Clarke, Christine Wright, Henry Purcell, Kim M. Fox
Journal: Circulation (1997)

Background Transient ischemia in stable coronary disease peaks in the morning, reflecting increased myocardial oxygen demand and coronary vasomotor tone after waking. In acute coronary syndromes, however, ischemia may result from transient thrombus formation or coronary spasm at the site of a ruptured plaque. We report on the pathophysiological mechanisms underlying transient ischemia in acute coronary syndromes despite optimal therapy, on the basis of analysis of heart rate changes preceding ischemia and its circadian variation. Methods and Results Two hundred fifty-six patients with unstable angina or non–Q-wave myocardial infarction underwent continuous ST-segment monitoring for 48 hours while receiving maximal medical therapy. All ischemic episodes were characterized by their timing, duration, association with pain, and heart rate changes before the onset of ischemia. During 10 629 hours of monitoring, 44 patients (17.2%) had 176 episodes of transient ischemia. The mean heart rate at onset of ischemia was 68±12.8 bpm, and &gt;55% of ischemic episodes were not preceded by a significant increase in heart rate. Ischemic activity had a single nocturnal peak, with 64% of all episodes occurring between 10 pm and 8 am , this nocturnal preponderance being evident for episodes with or without a preceding increase in heart rate. The characteristics and timing of transient ischemia were similar in unstable angina and non–Q-wave myocardial infarction, but transient ischemia was more frequent (27.3% versus 15.1%; P &lt;.05) and prolonged (median, 20 versus 13.5 minutes; P &lt;.01) in non–Q-wave myocardial infarction. Conclusions In acute coronary syndromes, transient ischemia has a low threshold, occurs predominantly without an increase in myocardial oxygen demand, and is present mainly at night rather than in the morning. These findings in patients receiving maximal medical therapy suggest significant pathophysiological differences underlying transient ischemia compared with stable coronary disease.
The role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: A case control study
Authors: Laurent Cotte, Thomas Bénet, Claire Billioud, Patrick Miailhes, Jean-Yves Scoazec, Tristan Ferry, Corinne Brochier, André Boibieux, Philippe Vanhems, Michèle Chevallier, Fabien Zoulim
Journal: Journal of Hepatology (2010)
Evaluation of Fasting Plasma Glucose as Screening Test for NIDDM in Older Adults: Rancho Bernardo Study
Authors: Barbara A Blunt, Elizabeth Barrett-Connor, Deborah L Wingard
Journal: Diabetes Care (1991)

Objective To examine the efficiency of fasting plasma glucose (FPG) as a screening test for non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH AND METHODS DESIGN: A population-based evaluation was made of FPG as screening test for NIDDM in an upper middle-class white community of Rancho Bernardo, California. NIDDM was defined by 2-h postchallenge plasma glucose (PCPG) level ≥ 11.1 mM, the cutoff point recommended by the World Health Organization. Participants comprised a population-based sample of 1851 men and women 50–79 yr of age that represented 80% of surviving participants surveyed between 1972 and 1974 for the Lipid Research Clinic Prevalence Study. Those with insulin-dependent diabetes were excluded. Results Analyses were stratified by age after logistic regression indicated that FPG and age (but not gender) were significantly related to probability of disease. As FPG cutoff points increased, sensitivity and percentage of the population to be recalled for confirmation decreased, whereas specificity and positive predictive value increased. Negative predictive value was consistently in the 90% range. Specificity did not change with age. In contrast, at virtually every FPG cutoff point, sensitivity decreased with increasing age. For example, at FPG ≥ 6.7 mM, sensitivity was 65.6% for those 50–64 yr of age and 40.0% for those 65–79 yr of age. At FPG ≥ 7.2 mM, these sensitivities were 46.9 and 28.5%, respectively. Positive predictive value increased with increasing age, reflecting the increasing prevalence of NIDDM with age. Conclusions Poorer sensitivity with increasing age reflects the fact that the numerator of the sensitivity equation is not affected by age (mean FPG did not vary significantly between age-groups), whereas the denominator increases with age (mean PCPG increased from 6.6 mM for subjects 50–64 yr of age to 8.2 mM for subjects 65–79 yr of age). Nevertheless, because the clinical significance of increasing PCPG with age in older adults is unknown, age-specific screening criteria probably are not warranted.
Adoptive transfer of<i>ex vivo</i>expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance
Authors: Pascal Lapierre, Kathie Béland, Roland Yang, Fernando Alvarez
Journal: Hepatology (2012)

Abstract Autoimmune hepatitis (AIH) is characterized by a loss of immunological tolerance to hepatocytes. Patients respond well to immunosuppression but progression to endstage liver disease occurs in 10%-20% of cases, leading to liver transplantation. Using a murine model of type 2 AIH, we identified susceptibility factors for autoimmune hepatitis and attempted to restore immunological tolerance to liver autoantigens. An increased ectopic expression of a liver autoantigen (FTCD) in the thymus leading to reduced numbers of circulating autoreactive T cells was sufficient to prevent development of AIH in mice. However, in the presence of a reduced central tolerance to FTCD, a strong regulatory T-cell response was able to inhibit proliferation of liver-specific autoreactive T cells and prevent AIH. Development of a severe AIH stemmed from reduced numbers of functional regulatory T cell (Tregs) leading to an increased proliferation of FTCD-specific autoreactive T and B cells. Adoptive transfer of ex vivo expanded CXCR3 + Tregs in mice with AIH efficiently targeted the inflamed liver, restored peripheral tolerance to FTCD, and induced remission of AIH. Conclusion : Peripheral tolerance to liver autoantigens in AIH is paramount. Autologous infusion of ex vivo expanded CXCR3 + Tregs in AIH patients could be an effective therapeutic approach to restore peripheral tolerance and induce remission of AIH. (Hepatology 2013)
When reasoning is persuasive but wrong
Authors: Robert J. Sternberg
Journal: Behavioral and Brain Sciences (2011)

Abstract Mercier and Sperber (M&amp;S) are correct that reasoning and argumentation are closely related. But they are wrong in arguing that this relationship is one of evolutionary adaptation. In fact, persuasive reasoning that is not veridical can be fatal to the individual and to the propagation of his or her genes, as well as to the human species as a whole.
Cellular Pathology of Atherosclerosis
Authors: G. Ed Rainger, Gerard B. Nash
Journal: Circulation Research (2001)

Abstract— During the development of an atherosclerotic plaque, mononuclear leukocytes infiltrate the artery wall through vascular endothelial cells (ECs). At the same time, arterial smooth muscle cells (SMCs) change from the physiological contractile phenotype to the secretory phenotype and migrate into the plaque. We investigated whether secretory SMCs released cytokines that stimulated ECs in a manner leading to increased leukocyte recruitment and thus might accelerate atheroma formation. SMCs and ECs were established in coculture on the opposite sides of a porous membrane, and the cocultured cells were incorporated into a flow-based assay for studying leukocyte adhesion. We found that coculture primed ECs so that their response to the inflammatory cytokine tumor necrosis factor-α was amplified. ECs cocultured with SMCs supported greatly increased adhesion of flowing leukocytes and were sensitized to respond to tumor necrosis factor-α at concentrations 10 000 times lower than ECs cultured alone. In addition, coculture altered the endothelial selectin adhesion molecules used for leukocyte capture. EC priming was attributable to the cytokine transforming growth factor-β 1 , which was proteolytically activated to a biologically active form by the serine protease plasmin. These results suggest a new role for secretory SMCs in the development of atheromatous plaque. We propose that paracrine interaction between ECs and SMCs has the potential to amplify leukocyte recruitment to sites of atheroma and exacerbate the inflammatory processes believed to be at the heart of disease progression.
Endothelial Markers May Link Kidney Function to Cardiovascular Events in Type 2 Diabetes
Authors: Christina Maier, Martin Clodi, Stephanie Neuhold, Michael Resl, Marie Elhenicky, Rudolf Prager, Deddo Moertl, Guido Strunk, Anton Luger, Joachim Struck, Richard Pacher, Martin Hülsmann
Journal: Diabetes Care (2009)

OBJECTIVE The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes. RESEARCH DESIGN AND METHODS This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively. RESULTS MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 ± 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l). CONCLUSIONS The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.
Curbing U.S. Health Care Costs: Lessons From Europe?
Authors: B. Keogh
Journal: JNCI Journal of the National Cancer Institute (2012)

The U.S. health care system is the world’s most expensive, consuming almost 20% of the economy and forecast to swallow half within decades if current trends continue. Yet despite the hefty cost, the U.S. lags behind many countries in Europe and other developed nations for health outcomes and quality of services, according to metrics from the Organisation for Economic Co-operation and Development (OECD), such as life expectancy, mortality, and safety. “No one would sensibly argue that we don’t have a health care spending problem,” said Peter Bach, M.D., associate attending physician at Memorial Sloan–Kettering Cancer Center in New York. Yet “there is no evidence that we provide better health care to our population as a whole than these other countries.” Although some solutions to bending the health care cost curve, long the norm elsewhere, remain anathema to most Americans (most notably nationalized health care with a single-payer system better able to negotiate lower prices), other options with a view to offering long-term savings are gaining support. These alternatives include establishing panels that assess cost- and clinical-effectiveness in determining which drugs and treatments Medicare covers, emphasizing patient-oriented primary care, and boosting preventive care. “Many countries have better-func t ion i ng, lower-cost health care systems that outperform the United States. We must learn from them,” concluded the American College of Physicians (ACP), which represents 130,000 physicians and medical students, in a report comparing the U.S. with other nations such as Denmark, the UK, and Germany. “The high cost of health care in the U.S. is not correlated with high quality and efficiency in the delivery of services or improved health outcomes,” the group noted the next year in another report on affordable care. A September 2011 Lancet Oncology Commission report, “Delivering Affordable Cancer Care in High-Income Countries,” called particular attention to the high costs of cancer care. The 37 experts in the author group wrote, “Cancer care in the USA is fast becoming unaffordable except for the well insured and most affluent,” while some expenses are “unwarranted and contribute to the high cost.”