tbuckley/cabot-search huggingface dataset:
Formyl-methionyl-leucyl-phenylalanine–Induced Dopaminergic Neurotoxicity via Microglial Activation: A Mediator between Peripheral Infection and Neurodegeneration?
Authors: Xi Gao, Xiaoming Hu, Li Qian, Sufen Yang, Wei Zhang, Dan Zhang, Xuefei Wu, Alison Fraser, Belinda Wilson, Patrick M Flood, Michelle Block, Jau-Shyong Hong
Journal: Environmental Health Perspectives (2008)

BackgroundParkinson disease (PD), a chronic neurodegenerative disease, has been proposed to be a multifactorial disorder resulting from a combination of environmental mechanisms (chemical, infectious, and traumatic), aging, and genetic deficits. Microglial activation is important in the pathogenesis of PD.ObjectivesWe investigated dopaminergic (DA) neurotoxicity and the underlying mechanisms of formyl-methionyl-leucyl-phenylalanine (fMLP), a bacteria-derived peptide, in relation to PD. METHODS: We measured DA neurotoxicity using a DA uptake assay and immunocytochemical staining (ICC) in primary mesencephalic cultures from rodents. Microglial activation was observed via ICC, flow cytometry, and superoxide measurement.ResultsfMLP can cause selective DA neuronal loss at concentrations as low as 10−13 M. Further, fMLP (10−13 M) led to a significant reduction in DA uptake capacity in neuron/glia (N/G) cultures, but not in microglia-depleted cultures, indicating an indispensable role of microglia in fMLP-induced neurotoxicity. Using ICC of a specific microglial marker, OX42, we observed morphologic changes in activated microglia after fMLP treatment. Microglial activation after fMLP treatment was confirmed by flow cytometry analysis of major histocompatibility antigen class II expression on a microglia HAPI cell line. Mechanistic studies revealed that fMLP (10−13 M)-induced increase in the production of extracellular superoxide from microglia is critical in mediating fMLP-elicited neurotoxicity. Pharmacologic inhibition of NADPH oxidase (PHOX) with diphenylene-iodonium or apocynin abolished the DA neurotoxicity of fMLP. N/G cultures from PHOX-deficient (gp91PHOX−/ −) mice were also insensitive to fMLP-induced DA neurotoxicity.ConclusionfMLP (10−13 M) induces DA neurotoxicity through activation of microglial PHOX and subsequent production of superoxide, suggesting a role of fMLP in the central nervous system inflammatory process.
Novel Mechanism of HERG Current Suppression in LQT2
Authors: Tadashi Nakajima, Tetsushi Furukawa, Toshihiro Tanaka, Yoshifumi Katayama, Ryozo Nagai, Yusuke Nakamura, Masayasu Hiraoka
Journal: Circulation Research (1998)

In a Xenopus oocyte heterologous expression system, we characterized the electrophysiology of 3 novel missense mutations of HERG identified in Japanese LQT2 families: T474I (within the S2-S3 linker), A614V, and V630L (in the outer mouth of pore-forming region). For each of the 3 mutations, injection of mutant cRNA alone did not express detectable currents. Coinjection of wild-type (WT) along with each mutant cRNA (T474I/WT, A614V/WT, and V630L/WT) suppressed HERG current in a dominant-negative manner, and the order of magnitude of current suppression was V630L/WT>A614V/WT>T474I/WT. In addition to decreases in slope conductance for all 3 mutants, the voltage dependence of steady-state inactivation was shifted to negative potentials for V630L/WT and A614V/WT. Consequently, channel availability at positive potentials was diminished, and inward rectification was enhanced for these 2 mutants. Thus, missense mutations of HERG caused dominant-negative suppression through multiple mechanisms. The shift in voltage dependence of HERG inactivation and the resulting enhanced inward rectification in A614V/WT and V630L/WT provide a novel mechanism for suppression of the HERG current carrying outward current during the repolarization phase of the action potential.
Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population
Authors: E. J Wallis
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To examine the accuracy of a new version of the Sheffield table designed to aid decisions on lipids screening and detect thresholds for risk of coronary heart disease needed to implement current guidelines for primary prevention of cardiovascular disease. <b>Design:</b> Comparison of decisions made on the basis of the table with absolute risk of coronary heart disease or cardiovascular disease calculated by the Framingham risk function. The decisions related to statin treatment when coronary risk is ≥years; aspirin treatment when the risk is ≥ 15% over 10 years; and the treatment of mild hypertension when the cardiovascular risk is≥0% over 10 years. <b>Setting:</b> The table is designed for use in general practice. <b>Subjects:</b> Random sample of 1000 people aged 35–64 years from the 1995 Scottish health survey. <b>Main outcome measures:</b> Sensitivity, specificity, and positive and negative predictive values of the table. <b>Results:</b> 13% of people had a coronary risk of ≥15%, and 2.2% a risk of ≥30%, over 10 years. 22% had mild hypertension (systolic blood pressure 140–159 mm Hg). The table indicated lipids screening for everyone with a coronary risk of ≥15% over 10 years, for 95% of people with a ratio of total cholesterol to high density lipoprotein cholesterol of ≥8.0, but for &lt;50% with a coronary risk of &lt;5% over 10 years. Sensitivity and specificity were 97% and 95% respectively for a coronary risk of ≥15% over 10 years; 82% and 99% for a coronary risk of ≥30% over 10 years; and 88% and 90% for a cardiovascular risk of ≥20% over 10 years in mild hypertension. <b>Conclusion:</b> The table identifies all high risk people for lipids screening, reduces screening of low risk people by more than half, and ensures that treatments are prescribed appropriately to those at high risk, while avoiding inappropriate treatment of people at low risk.
CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis
Authors: Anna Nolan, Michael Weiden, Ann Kelly, Yoshihiko Hoshino, Satomi Hoshino, Nehal Mehta, Jeffrey A. Gold
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Costimulatory molecules, including the CD40–CD154 and CD80/86–CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans.Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86−/− mice, and novel CD40/80/86−/− mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry.Measurements and Main Results: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86−/− mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86−/− mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived.Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.
Response to steroid treatment in “DE novo” autoimmune hepatitisafter liver transplantation in adults
Authors: M. Salcedo, R. Bañares, M. Rodriguez-Mahou, E. Alvárez, J. Vaquero, A. Hdez-Albújar, D. Rincón, L. Santos, G. Clemente
Journal: Journal of Hepatology (2000)
Treatment with blockers in people with COPD
Authors: S. Kazani, E. Israel
Journal: BMJ (2011)

May reduce respiratory symptoms and mortality independently of cardiovascular effects

Treatment with β blockers reduces mortality associated with cardiovascular diseases. Unfortunately, doctors tend to avoid β blockers in patients who have concomitant obstructive lung disease. This stems from the fear of precipitating a catastrophic respiratory event—acute bronchospasm has been reported after administration of β blockers to patients with asthma and chronic obstructive pulmonary disease (COPD).1 2 3 4 However, evidence suggests that β blockers reduce mortality in patients with COPD, which makes sense because patients often have concomitant cardiovascular disease.5 A study of 462 patients with COPD undergoing major vascular surgery found a 27% reduction in perioperative mortality in those who were receiving cardioselective β blockers compared with those who were not.6

Surprisingly, in addition to reducing overall mortality and death from cardiovascular disease in patients with COPD, long term use of β blockers may also reduce respiratory events …
Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.
Authors: Jane Y C Ma, Apavoo Rengasamy, Dave Frazer, Mark W Barger, Ann F Hubbs, Lori Battelli, Seith Tomblyn, Samuel Stone, Vince Castranova
Journal: Environmental Health Perspectives (2003)

Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential toxic effects in the lung.
Thromboxane A2 receptor is highly expressed in mouse immature thymocytes and mediates DNA fragmentation and apoptosis.
Authors: F Ushikubi, Y Aiba, K Nakamura, T Namba, M Hirata, O Mazda, Y Katsura, S Narumiya
Journal: The Journal of Experimental Medicine (1993)

We have recently revealed that the thymus is the organ showing the highest expression of thromboxane (TX) A2 receptor in mice. In this study, thymic cell populations expressing the receptor were identified, and the effects of a TXA2 agonist on these cells were examined. Radioligand binding using a TXA2 receptor-specific radioligand revealed a single class of binding sites in the thymocytes with an affinity and specificity identical to those reported for the TXA2 receptor. The receptor density in these cells was comparable to that seen in blood platelets. This receptor is most highly expressed in CD4-8- and CD4+8+ immature thymocytes, followed by CD4+8- and CD4-8+ cells. The receptor density in splenic T cells was less than one fifth of that in CD4+8+ cells and no binding activity was detectable in splenic B cells. The addition of a TXA2 agonist, STA2, to thymocytes induced the disappearance of the CD4+8+ cells in a time- and concentration-dependent manner and caused DNA fragmentation. These changes were blocked by a specific TXA2 antagonist, S-145. These results demonstrate that TXA2 induces apoptotic cell death in immature thymocytes by acting on the TXA2 receptor on their cell surface and suggest a role for the TXA2/TXA2 receptor system in the thymic micro-environment.
The Effects of Red Blood Cell Infusion on 10-km Race Time
Authors: Anthony J. Brien
Journal: JAMA (1987)

The purpose of this study was to investigate the effect of infusion of 400 mL of red blood cells (RBCs) on 10-km track race time, submaximal heart rate, hematocrit, 2,3-diphosphoglycerate, and partial pressure of oxygen at 50% hemoglobin saturation. Six highly trained, male, distance runners twice donated a unit of RBCs, which was frozen for subsequent reinfusion. Eleven weeks after the second donation, they undertook a series of three competitive 10-km races on a standard 400-m track: before infusion, after 100 mL of saline solution, and after 400 mL of autologous, previously frozen deglycerolized RBCs. All subjects took all trials in this double-blind, placebo, crossover, experimental design. Running time was recorded at each 400-m split, and blood was collected prior to each trial. The data were analyzed by analysis of variance. Results following the RBC infusion showed a significantly higher hematocrit concentration, a significantly faster 10-km run, a nonsignificant decrease in submaximal heart rate (10 beats per minute), and no significant changes in either 2,3-diphosphoglycerate or partial pressure of oxygen at 50% hemoglobin saturation. Erythrocythemia induced by the infusion of 400 mL of autologous packed RBCs effectively increased performance capacity in a 10-km track race, probably due to an increase in oxygen delivery to the working muscles. (<i>JAMA</i>1987;257:2761-2765)
Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles.
Authors: O P Barry, D Pratico, J A Lawson, G A FitzGerald
Journal: Journal of Clinical Investigation (1997)

Microparticles are released during platelet activation in vitro and have been detected in vivo in syndromes of platelet activation. They have been reported to express both pro- and anticoagulant activities. Nevertheless, their functional significance has remained unresolved. To address the mechanism(s) of cellular activation by platelet microparticles, we examined their effects on platelets and endothelial cells. Activation of human platelets by diverse stimuli (thrombin, 0.1 U/ml; collagen, 4 microg/ml; and the calcium ionophore A23187, 1 microM) results in shedding of microparticles. Pretreatment of these particles, but not membrane fractions from resting platelets, with (s)PLA2 evokes a dose-dependent increase in platelet aggregation, intracellular [Ca2+] movement, and inositol phosphate formation. These effects localize to the arachidonic acid fraction of the microparticles and are mimicked by arachidonic acid isolated from them. However, platelet activation requires prior metabolism of microparticle arachidonic acid to thromboxane A2. Thus, pretreatment of platelets with the cyclooxygenase (COX) inhibitor, indomethacin (20 microM), the thromboxane antagonist SQ29,548 (1 microM), or the protein kinase C inhibitor GF109203X (5 microM) prevents platelet activation by microparticles. However, platelet microparticles fail to evoke an inositol phosphate response directly, via either of the cloned thromboxane receptor isoforms stably expressed in human embryonic kidney (HEK) 293 cells. Prelabeling platelets with [2H(8)] arachidonate was used to demonstrate platelet metabolism of the microparticle-derived substrate to thromboxane. Platelet microparticles can also induce expression of COX-2 and prostacyclin (PGI2) production, but not expression of COX-1, in human endothelial cells. These effects are prevented by pretreatment with actinomycin D (12 microM) or cycloheximide (5 microg/ml). Expression of COX-2 is again induced by the microparticle arachidonate fraction, which it may then use to synthesize PGI2. Both PGE2 and iloprost, a stable PGI2 analog, evoke human umbilical vein endothelial cell COX-2 expression, albeit with kinetics that differ from the response to platelet microparticles. These studies indicate a novel mechanism of transcellular lipid metabolism whereby platelet activation may be amplified or modulated by concentrated delivery of arachidonic acid to adjacent platelets and endothelial cells.
Women smokers and sudden death. The relationship of cigarette smoking to coronary disease
Authors: D. M. Spain
Journal: JAMA (1973)

A retrospective autopsy study was made of the smoking habits of women who died suddenly and unexpectedly of a first clinical episode of coronary heart disease (CHD). A close correlation between heavy cigarette smoking and sudden CHD deaths was found. In the sudden deaths from causes other than CHD, only 28% of the women were heavy smokers, whereas in the CHD sudden deaths there were 62%. The mean age at the time of sudden death was 19 years less for those who smoked cigarettes heavily than for the nonsmokers, while the mean age at death for lighter smokers was intermediate. During the period 1949 to 1959, there were 12 CHD sudden deaths in men for every similar death in women. In contrast, there were only four CHD sudden deaths in men for every similar death in 1967 through 1971 among women. This shift has been associated with an increase in heavy cigarette smoking among women.
Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells
Authors: T.-D. Chuang, J.-Y. Guh, S.-J. Chiou, H.-C. Chen, J.-S. Huang, Y.-L. Yang, L.-Y. Chuang
Journal: Kidney International (2007)
Beyond 'Abortion': RU-486 and the Needs of the Crisis Constituency
Authors: William Regelson
Journal: JAMA (1990)

FOR THE first time, the medical needs of patients are being thwarted by a political and economic battle involving the "unborn." The threat of boycott by the antiabortion advocates is blocking or delaying the availability of RU-486 (mifepristone) as a drug of proven or potential value in Cushing's disease, meningioma, and breast cancer. As RU-486 poses no religious or moral issue in patients who are not pregnant, have no intention of getting pregnant, or are incapable of pregnancy, it may be concluded that the drug ban self-imposed by Hoechst-Roussel because of the issue of abortion and contraception should be lifted from studies of its medical application. RU-486 ([11β(4-dimethyl-amino phenyl)]17β hydroxy[17α prop-1-ynyl]estra-4,9-dien-3-one), or mifepristone (originally named RU38486), is best known as an antiprogestin abortifacient or contraceptive,<sup>1-3</sup>but its clinical potential extends beyond this. Apart from its antiprogesterone effects, the focal action of this drug as a blocking agent to corticosteroid
Hypertension after renal transplantation.
Authors: C Bachy, G P Alexandre, C van Ypersele de Strihou
Journal: BMJ (1976)

The incidence of hypertension (mean diastolic pressure above 90 mm Hg) was evaluated in 85 patients with renal transplants whose follow-up ranged from 3 to 84 months. Bilateral nephrectomy had been performed in 80 recipients. The proportion of hypertensive subjects rose during the first three months, subsequently stabilised around 50-60% for up to five years, and then decreased slightly during the next two years. Over the years hypertension fluctuated so that one-third of the initially hypertensive patients became normotensive, and over one-third of the initially normotensive patients became hypertensive. The main single aetiological factor was renal failure. A significant relation between steroid dosage and blood pressure was found in only a quarter of the hypertensive patients, and in another quarter no cause could be found.
Letter by Naqvi and Motallebi Regarding Article, “Left Ventricular Resynchronization Is Mandatory for Response to Cardiac Resynchronization Therapy”
Authors: Tasneem Z. Naqvi, Mazda Motallebi
Journal: Circulation (2008)

Bleeker et al 1 propose that in patients selected on the basis of both electrical and a single mechanical dyssynchrony measure derived from maximum delay during left ventricular (LV) ejection between peak systolic velocities among 4 basal LV segments, immediate resynchronization (of at least 20%) after cardiac resynchronization treatment (CRT) predicts reduction in LV end-systolic volume by at least 10% at 6-month follow-up.The editorial accompanying the article by Bleeker and colleagues 2 appropriately "cautions" against relying on a single "dyssynchrony" measure and on "early resynchronization" as predictors of reduction in LV volume.A number of single-center studies reported impressive CRT results based on mechanical rather than electrical dyssynchrony criteria.These results have not been reproducible however.The multicenter Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study found that individual mechanical dyssynchrony variables added only 11% to 13% response to the clinical composite score and 13% to 23% to LV end-systolic volume. 3Interestingly, septolateral delay did not predict clinical response to CRT. 3 Data on the number of patients with traditional CRT criteria screened to get 100 eligible patients in Bleekers study are lacking. 1Feasibility of mechanical dyssynchrony measurement from lack of measurable peak during ejection or double or variable peaks between cardiac cycles is not reported.The discussion of intersegmental delay does not provide data on the location of delay.Is it the lateral wall, inferior wall, anterior wall, or inferior interventricular septum?Previous work has shown that those with delay in the interventricular septum respond less favorably to CRT. 4 No data on the type of bundle-branch block or on heart rate between responders and nonresponders are provided.Is intersegmental delay of 65 ms in someone with a heart rate of 90 bpm of the same significance as in someone with a heart rate of 70 bpm?On the basis of this group's earlier study, 5 a significant number of patients, particularly those with an ischemic pathogenesis, should have transmural scar that would have precluded early resynchronization and hence response to CRT, despite the presence of mechanical dyssynchrony.It therefore appears rather simplistic that evaluation of dyssynchrony in the longitudinal direction alone using a method with technical limitations in a mixed cohort of ischemic and nonischemic patients without evaluation of myocardial viability or scar could be sufficient in predicting a very high response rate.In addition, data on immediate post-CRT LV ejection fraction and volumes are not reported.Early resynchronization could have been a secondary phenomenon related to an immediate improvement in LV systolic function and size.Thus, early resynchronization merely picked up patients who responded early and were destined to continue to respond later.