Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease

OBJECTIVES: Increased homocysteine contributes to the pathophysiology of several chronic inflammatory diseases. Whether homocysteine could participate in mucosal inflammation in inflammatory bowel disease (IBD) has not been explored yet. Our aims were to study the levels of plasma and mucosal homocysteine in IBD patients and to assess whether homocysteine can trigger an inflammatory reaction on human intestinal microvascular endothelial cells (HIMECs). METHODS: Homocysteine was measured in the plasma, mucosal biopsy, and lamina propria mononuclear cell (LPMC) supernatants from normal and IBD subjects. HIMEC were cultured in presence of homocysteine, TNF-alpha, or folic acid, alone or in combination. Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule 1 was measured by flow cytometry and monocyte chemoattractant protein-1 (MCP-1) production by ELISA. Phosphorylation of p38 and p42/44 was assessed by immunoblot in HIMEC extracts. T-cell- and monocyte-HIMEC adhesion assays were used to evaluate the impact of homocysteine on leukocyte adhesion to intestinal endothelial cells. RESULTS: Patients with IBD displayed significantly higher homocysteine plasma and mucosal levels than control subjects. IBD-derived LPMC released higher homocysteine than control-derived LPMC. Treatment of HIMEC with homocysteine, and synergistically with the combination of TNF-alpha and homocysteine, triggered HIMEC inflammation, resulting in VCAM-1 up-regulation, MCP-1 production, and p38 phosphorylation. These events lead to an increased capacity of HIMEC to adhere T- and monocyte cells and were blocked by folic acid treatment. CONCLUSIONS: Homocysteine is increased in both the mucosa and plasma of patients with Crohn's disease and ulcerative colitis and contributes to the inflammatory state of the mucosal IBD endothelium. Therefore, homocysteine could play a proinflammatory role in IBD, which can be efficiently targeted by folic acid supplementation.     

The impact of test loads on the accuracy of 1RM prediction using the load-velocity relationship

Background

Numerous methods have been proposed that use submaximal loads to predict one repetition maximum (1RM). One common method applies standard linear regression equations to load and average vertical lifting velocity (V_mean) data developed during squat jumps or three bench press throw (BP-T). The main aim of this project was to determine which combination of three submaximal loads during BP-T result in the most accurate prediction of 1RM Smith Machine bench press strength in healthy individuals.

Methods

In this study combinations of three BP-T loads were used to predict 1RM Smith Machine bench press strength. Additionally, we examined whether regression models developed using peak vertical bar velocity (V_peak), rather than V_mean, provide the most accurate prediction of Smith Machine bench press 1RM. 1RM Smith Machine bench press strength was measured directly in 12 healthy regular weight trainers (body mass?=?80.8?±?5.7 kg). Two to three days later a linear position transducer attached to the collars on a Smith Machine was used to record V_mean and V_peak during BP-T between 30 and 70% of 1RM (10% increments).

Results

Repeated measures analysis of variance testing showed that the mean values for slope and ordinate intercept for the regression models at each of the load ranges differed significantly depending on whether V_mean or V_peak were used in the prediction models (P?<?0.001). Conversely, the abscissa intercept did not differ significantly between either measure of vertical bar velocity at each load range. The key finding in this study was that 1RM Smith Machine bench press strength can be determined with high relative accuracy by examining V_mean and V_peak during BP-T over three loads, with the most precise models using V_peak during loads representing 30, 40 and 50% of 1RM (R ² ?=?0.96, SSE?=?4.2 kg).

Conclusions

These preliminary findings indicate that exercise programmers working with normal healthy populations can accurately predict Smith Machine 1RM bench press strength using relatively light load Smith Machine BP-T testing, avoiding the need to expose their clients to potentially injurious loads.

     

Angiopoietin-2-induced lymphatic endothelial cell migration drives lymphangiogenesis via the β1 integrin-RhoA-formin axis

Lymphangiogenesis is an essential physiological process but also a determining factor in vascular-related pathological conditions. Angiopoietin-2 (Ang2) plays an important role in lymphatic vascular development and function and its upregulation has been reported in several vascular-related diseases, including cancer. Given the established role of the small GTPase RhoA on cytoskeleton-dependent endothelial functions, we investigated the relationship between RhoA and Ang2-induced cellular activities. This study shows that Ang2-driven human dermal lymphatic endothelial cell migration depends on RhoA. We demonstrate that Ang2-induced migration is independent of the Tie receptors, but dependent on β1 integrin-mediated RhoA activation with knockdown, pharmacological approaches, and protein sequencing experiments. Although the key proteins downstream of RhoA, Rho kinase (ROCK) and myosin light chain, were activated, blockade of ROCK did not abrogate the Ang2-driven migratory effect. However, formins, an alternative target of RhoA, were identified as key players, and especially FHOD1. The Ang2-RhoA relationship was explored in vivo, where lymphatic endothelial RhoA deficiency blocked Ang2-induced lymphangiogenesis, highlighting RhoA as an important target for anti-lymphangiogenic treatments.

     

Infective endocarditis in diabetic and non-diabetic patients

We compared clinical, microbiological, and prognostic characteristics of infective endocarditis in patients with and without diabetes mellitus. In 1987--1996, 213 patients with definite or possible infective endocarditis were included, of which 39 (18%) had diabetes mellitus. Diabetic patients were older than non-diabetic (median age of 71 vs 65 y, respectively; p =0.04), had more aortic valve and less mitral valve involvement (71% vs 27%, and 21% vs 62%; p = 0.004). There was no significant difference in the frequency of Staphylococcus aureus involvement between the 2 groups (21% in diabetic vs 20% in non-diabetic group; p = ns). On multivariate analysis diabetes mellitus was not found to be an independent factor for mortality. Unlike other infections diabetes mellitus does not significantly affect clinical and microbiological features, and outcome of infective endocarditis.     

Experience with the continuous glucose monitoring system in a medical intensive care unit

Strict glycemic control improves clinical outcomes in critically ill patients. However, practical tools for frequent monitoring of blood glucose (BG) levels in the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for detecting glycemic excursions in outpatients with diabetes mellitus. The use of this device has never been carefully examined in the inpatient setting. This preliminary study was designed to investigate the accuracy of the CGMS in critically ill patients admitted to a medical ICU (MICU). Subjects at risk for hyperglycemia were recruited from among all patients admitted to our MICU. CGMS sensors were implanted for up to 72 h. Study subjects wore between one and five consecutive sensors. Four or more standard capillary BG readings were recorded per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors, yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was 0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable" zones A and B. The CGMS is promising for potential use in critically ill patients. If validated in larger studies, the device could serve as a useful research tool for investigating the role of hyperglycemia (and strict glycemic control) in ICU patients. If further developed as a "real-time" glucose sensor, CGMS technology could ultimately prove clinically useful in the ICU, by decreasing nursing workload and/or by providing alarm signals for impending glycemic excursions.     

Mitral valve repair for dilated cardiomyopathy: predictive role of right ventricular dysfunction.

AIMS: To evaluate the impact of right ventricular (RV) dysfunction on early and mid-term outcome of patients with ischaemic or dilated cardiomyopathy (DCM) undergoing mitral valve annuloplasty. METHODS AND RESULTS: From January 1997 to December 2005, 111 patients with DCM (89 ischaemic, 22 non-ischaemic) were enrolled in this retrospective study. Mean age was 67 +/- 10 years. Average pre-operative NYHA class was 3.0 +/- 0.6. Tricuspid annular plane systolic excursion (TAPSE), tricuspid annular pleak systolic velocity (TAPSV), and RV fractional area change were considered as an index of RV function. A strong relationship between TAPSE and TAPSV were found (r = 0.76). Thirty-day mortality was 10.8%. Five-year survival and possibility to be alive in NYHA classes I-II were 66.5 +/- 5.0 and 59.5 +/- 5.0%. TAPSE, TAPSV, and MV coaptation depth (MVCD) were found to be risk factors for worse early and mid-term outcome; functional class impaired mid-term outcome. ROC analysis identified TAPSE < or = 12 mm, TAPSV < or = 10 cm/s, and MVCD>10 mm as predictive cut-offs. CONCLUSION: Pre-operative assessment of some echocardiographic parameters (TAPSE, TAPSV) is very easy, low cost, and provides accurate information on RV function. A good pre-operative clinical compensation has to be necessarily reached before the operation. MVCD should be evaluated to decide surgical strategy (repair or replace).