Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment

<p>Abstract</p> <p>Background</p> <p>Methotrexate (MTX) is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis. ATP-binding cassette transporter-A1 (ABCA1) and 27-Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. In THP-1 macrophages, MTX can promote the reversal of cholesterol transport, limit foam cell formation and also reverse COX-2 inhibitor-mediated downregulation of ABCA1. Despite its antiatherogenic potential <it>in vitro</it>, the impact of clinical use of low-dose MTX on cholesterol metabolism in humans is unknown. Objective of the study was to examine whether clinical MTX use is associated with altered blood lipids and/or <it>ABCA1/HY27 </it>expressions.</p> <p>Methods</p> <p>In all, 100 rheumatoid arthritis subjects were recruited from a medical center in central Taiwan. Plasma lipid profiles and peripheral blood mononuclear cell <it>HY27 </it>and <it>ABCA1 </it>expressions were compared between subjects taking MTX (MTX+) and other disease-modifying antirheumatic drugs (DMARDs) (MTX-). Dietary intake was assessed by a registered dietician.</p> <p>Results</p> <p>Though no difference observed in the blood lipids between MTX+ and MTX- subjects, the expressions of <it>ABCA1 </it>and <it>HY27 </it>were significantly elevated in MTX+ subjects (n = 67) compared to MTX- subjects (n = 32, p < 0.05). ABCA expression correlated with MTX doses (r = 0.205, p = 0.042), and MTX+ subjects are more likely to have increased <it>HY27 </it>compared to MTX- subjects (OR = 2.5, p = 0.038). Prevalence of dyslipidemia and overweight, and dietary fat/cholesterol intake were lower than that of the age-matched population. Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions may still be present in those persons with pre-existing dyslipidemia.</p> <p>Conclusions</p> <p>We demonstrated novel findings on the increased gene expressions of atheroprotective protein <it>HY27 </it>and <it>ABCA1 </it>in human peripheral blood mononuclear cells (PBMCs) with clinical use of low-dose MTX. Whether MTX induced <it>HY27 </it>and <it>ABCA1 </it>expressions can protect against cardiovascular disease in patients with chronic inflammation through the facilitation of cholesterol export remains to be established. Further studies on the impacts of low-dose MTX on hypercholesterolemic patients are underway.</p

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

Monitoring of lung edema by microwave reflectometry during lung ischemia-reperfusion injury in vivo

It is still unclear whether lung edema can be monitored by microwave reflectometry and whether the measured changes in lung dry matter content (DMC) are accompanied by changes in PaO(2) and in pro-to anti-inflammatory cytokine expression (IFN-gamma and IL-10). Right rat lung hili were cross-clamped at 37 degrees C for 0, 60, 90 or 120 min ischemia followed by 120 min reperfusion. After 90 min (DMC: 15.9 +/- 1.4%; PaO(2): 76.7 +/- 18 mm Hg) and 120 min ischemia (DMC: 12.8 +/- 0.6%; PaO(2): 43 +/- 7 mm Hg), a significant decrease in DMC and PaO(2) throughout reperfusion compared to 0 min ischemia (DMC: 19.5 +/- 1.11%; PaO(2): 247 +/- 33 mm Hg; p < 0.05) was observed. DMC and PaO(2) decreased after 60 min ischemia but recovered during reperfusion (DMC: 18.5 +/- 2.4%; PaO(2) : 173 +/- 30 mm Hg). DMC values reflected changes on the physiological and molecular level. In conclusion, lung edema monitoring by microwave reflectometry might become a tool for the thoracic surgeon. Copyright (c) 2006 S. Karger AG, Basel

Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy

Uterine serous papillary cancer (USPC) represents a rare but highly aggressive variant of endometrial cancer, the most common gynecologic tumour in women. We used oligonucleotide microarrays that interrogate the expression of some 10 000 known genes to profile 10 highly purified primary USPC cultures and five normal endometrial cells (NEC). We report that unsupervised analysis of mRNA fingerprints readily distinguished USPC from normal endometrial epithelial cells and identified 139 and 390 genes that exhibited >5-fold upregulation and downregulation, respectively, in primary USPC when compared to NEC. Many of the genes upregulated in USPC were found to represent adhesion molecules, secreted proteins and oncogenes, such as L1 cell adhesion molecule, claudin-3 and claudin-4, kallikrein 6 (protease M) and kallikrein 10 (NES1), interleukin-6 and c-erbB2. Downregulated genes in USPC included SEMACAP3, ras homolog gene family, member I (ARHI), and differentially downregulated in ovarian carcinoma gene 1. Quantitative RT–PCR was used to validate differences in gene expression between USPC and NEC for several of these genes. Owing to its potential as a novel therapeutic marker, expression of the high-affinity epithelial receptor for Clostridium perfringens enterotoxin (CPE) claudin-4 was further validated through immunohistochemical analysis of formalin-fixed paraffin-embedded specimens from which the primary USPC cultures were obtained, as well as an independent set of archival USPC specimens. Finally, the sensitivity of primary USPC to the administration of scalar doses of CPE in vitro was also demonstrated. Our results highlight the novel molecular features of USPC and provide a foundation for the development of new type-specific therapies against this highly aggressive variant of endometrial cancer

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Influence of mercury exposure on blood pressure, resting heart rate and heart rate variability in French Polynesians: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Populations which diet is rich in seafood are highly exposed to contaminants such as mercury, which could affect cardiovascular risk factors</p> <p>Objective</p> <p>To assess the associations between mercury and blood pressure (BP), resting heart rate (HR) and HR variability (HRV) among French Polynesians</p> <p>Methods</p> <p>Data were collected among 180 adults (≥ 18 years) and 101 teenagers (12-17 years). HRV was measured using a two-hour ambulatory electrocardiogram (Holter) and BP was measured using a standardized protocol. The association between mercury and HRV and BP parameters was studied using analysis of variance (ANOVA) and analysis of covariance (ANCOVA)</p> <p>Results</p> <p>Among teenagers, the high frequency (HF) decreased between the 2^ndand 3^rdtertile (380 vs. 204 ms², p = 0.03) and a similar pattern was observed for the square root of the mean squared differences of successive R-R intervals (rMSSD) (43 vs. 30 ms, p = 0.005) after adjusting for confounders. In addition, the ratio low/high frequency (LF/HF) increased between the 2^ndand 3^rdtertile (2.3 vs. 3.0, p = 0.04). Among adults, the standard deviation of R-R intervals (SDNN) tended to decrease between the 1^stand 2^ndtertile (84 vs. 75 ms, p = 0.069) after adjusting for confounders. Furthermore, diastolic BP tended to increase between the 2^ndand 3^rdtertile (86 vs. 91 mm Hg, p = 0.09). No significant difference was observed in resting HR or pulse pressure (PP)</p> <p>Conclusions</p> <p>Mercury was associated with decreased HRV among French Polynesian teenagers while no significant association was observed with resting HR, BP, or PP among teenagers or adults</p