Angiotensin 1-7 as Means to Prevent the Metabolic Syndrome: Lessons From the Fructose-Fed Rat Model

We studied the effects of chronic angiotensin 1-7 (Ang 1-7) treatment in an experimental model of the metabolic syndrome, i.e., rats given high-fructose/low-magnesium diet (HFrD). Rats were fed on HFrD for 24 weeks with and without Ang 1-7 (576 µg/kg/day, s.c., Alzet pumps). After 6 months, Ang 1-7–treated animals had lower body weight (−9.5%), total fat mass (detected by magnetic resonance imaging), and serum triglycerides (−51%), improved glucose tolerance, and better insulin sensitivity. Similar metabolic effects were also evident, albeit in the absence of weight loss, in rats first exposed to HFrD for 5 months and then subjected to short-term (4 weeks) treatment with Ang 1-7. Six months of Ang 1-7 treatment were associated with lower plasma renin activity (−40%) and serum aldosterone (−48%), less hepatosteatatitis, and a reduction in epididymal adipocyte volume. The marked attenuation of macrophage infiltration in white adipose tissue (WAT) was associated with reduced levels of the pP65 protein in the epididymal fat tissue, suggesting less activation of the nuclear factor-κB (NFκB) pathway in Ang 1-7–treated rats. WAT from Ang 1-7–treated rats showed reduced NADPH-stimulated superoxide production. In single muscle fibers (myofibers) harvested and grown ex vivo for 10 days, myofibers from HFrD rats gave rise to 20% less myogenic cells than the Ang 1-7–treated rats. Fully developed adipocytes were present in most HFrD myofiber cultures but entirely absent in cultures from Ang 1-7–treated rats. In summary, Ang 1-7 had an ameliorating effect on insulin resistance, hypertriglyceridemia, fatty liver, obesity, adipositis, and myogenic and adipogenic differentiation in muscle tissue in the HFrD rats.The metabolic syndrome (MetSyn) encompasses cardiometabolic risk determinants including visceral obesity, insulin resistance, glucose intolerance, dyslipidemia, nonalcoholic fatty liver disease, and hypertension (1). Ectopic fat accumulating in the liver, muscle, and pancreas may play an important role, presumably by releasing adipocytokines, which decrease sensitivity to insulin (2) and promote inflammation (3).Blockade of the renin-angiotensin system, by inhibiting the formation of angiotensin II (Ang II) with angiotensin-converting enzyme inhibitors or by angiotensin receptor blockers, yields a significant (25%) reduction in the incidence of new-onset type 2 diabetes (4). The renin-angiotensin system may also be involved in hepatic inflammation and fibrogenesis (5) and to adversely affect insulin-mediated glucose uptake in skeletal muscles (6). In cultured myofibers, Ang II was shown to induce insulin resistance via impaired insulin signaling, independent of its vascular effects (7). Skeletal muscles are lost in diabetic patients (8), possibly due to local accumulation of adipocytes that potentially replace muscle cells (9). Moreover, the skeletal muscle stem cells, satellite cells, of obese Zucker rats apparently display increased adipogenic potential (10,11). This may account, at least in part, for the inter- and intramuscular adipocyte accumulation characteristics of obesity and the MetSyn and even the sarcopenia associated with aging.Angiotensin 1-7 (Ang 1-7) opposes many of the adverse cardiovascular effects of Ang II (12), including hypertension, pregnancy-induced hypertension (preeclampsia), renal disease, heart failure, and cardiac arrhythmia (13–15). The best-studied effects of Ang 1-7 are its vasodilator, blood pressure–lowering, and antiproliferative actions in the cardiovascular system. These effects are apparently mediated through Mas, a specific G protein–coupled receptor for Ang 1-7 (16–22). Santos et al. (23) showed that Mas is expressed in the adipose tissue and that Mas-deficient mice develop a MetSyn-like state. In the current study, we evaluated the effect of long-term activation of the Mas receptor by chronic Ang 1-7 treatment on MetSyn in rats fed a high-fructose diet.     

Risk factors for bacteriuria with carbapenem-resistant Klebsiella pneumoniae and its impact on mortality: a case–control study

Background

The objective of this study was to evaluate the mortality of and risk factors for bacteriuria due to carbapenem-resistant Klebsiella pneumoniae (CRKp) versus carbapenem-susceptible K. pneumoniae (CSKp) producing extended spectrum β lactamase (ESBL).

Methods

This was a retrospective case–control study in which 135 case-patients with bacteriuria due to CRKp were compared with 127 control patients with CSKp producing ESBL. In a first step, multivariate Cox regression and Kaplan–Meier survival analysis models were used to determine the difference in mortality between the two groups and risk factors for mortality. In a second step, a univariate analysis was used to identify risk factors for CRKp colonization.

Results

There were no significant demographic or clinical differences between the groups. In-hospital mortality in the study and control groups was 29 and 25 %, respectively (non-significant difference). Multivariate analysis revealed that the most important risk factor for mortality in both groups was being bed ridden [hazard ratio 2.2, 95 % confidence interval (CI) 1.23–3.93; P = 0.008]. Patients with CRKp bacteriuria had a longer hospitalization time with a mean ± standard deviation of 28 ± 33 days compared to 22 ± 28 days in the control group (P < 0.05). Several univariate risk factors for acquiring CRKp bacteriuria were identified: antibiotic use [odds ratio (OR) 1.93, 95 % CI 1.18–3.17, p = 0.008], especially colistin (OR 2.04, 95 % CI 1.04–4.02; P = 0.036), presence of a urinary catheter (OR 2.09, 95 % CI 1.2–3.63; P = 0.008), surgery (OR 3.94, 95 % CI 1.85–8.37; P = 0.0002), invasive procedures (OR 3.06, 95 % CI 1.61–5.8; P = 0.0004), and intensive care unit admission (OR 2.49, 95 % CI 1.18–5.37; P = 0.015).

Conclusion

Bacteriuria caused by CRKp as compared that caused by CSKp was not found to be a risk factor for death.     

Use of a computerized database to study the effectiveness of an attenuated varicella vaccine

BACKGROUND: The varicella vaccine Varilrix (GlaxoSmithKline) was introduced in Israel in June 2000 as an optional vaccination for children. METHODS: We used the database of a single health maintenance organization that serves 25% of the population in Israel to assess the effectiveness of the vaccine retrospectively. Incidence and complications of varicella were derived from the database from January 1, 1998 until December 31, 2002. RESULTS: Since licensure >30000 individuals younger than 10 years in this health maintenance organization have been immunized with the vaccine. Annual incidence of disease per 1000 in the study population was 86.6 in 1998, 74.6 in 1999, 74.0 in 2000, 37.1 in 2001 and 44.6 in 2002. This declining trend in incidence of disease was statistically significant. Complications of varicella occurred in approximately 1% of patients throughout the 5-year study period, but there was a parallel decline in the number of patients with complications corresponding to the decline in disease incidence. Vaccine effectiveness for prevention of clinical disease in this population was 92% (95% confidence interval, 91.0 to 92.7). There were varying rates of utilization within communities of varied socioeconomic class, so that in the higher socioeconomic class there was an increased utilization and a corresponding decrease of attack rate; whereas in communities where there were lower utilization rates, corresponding increased numbers of varicella cases were seen. CONCLUSION: This database enables long term follow-up of the effectiveness of this vaccine in a large population.     

Enhanced sensitivity of P-glycoprotein-positive multidrug resistant tumor cells to complement-mediated lysis

The interaction of KB-V1, a multidrug resistant (MDR) variant of the KB-3–1 human oral carcinoma, with human complement was investigated. KB-V1 cells were found to be more sensitive than KB-3–1 cells to complement-mediated lysis. Detailed analysis of the capacity of KB cells to activate human complement demonstrated that both C3b deposition and formation of the membrane attack complex (MAC) are higher on KB-V1 than on KB-3–1 cells. Furthermore, the MAC formed on KB-V1 cells, but not on KB-3–1 cells, was found to be resistant to trypsin treatment, i.e. more stably inserted into the plasma membrane. Immunofluorescence analysis by flow cytometry showed that KB-V1 cells express less decay-accelerating factor (DAF, CD55) than KB-3–1 cells. Two other complement regulatory proteins, membrane cofactor protein (MCP, CD46) and CD59 are expressed to a similar extent on both KB-V1 and KB-3–1 cells. Treatment of KB-V1 cells with neutralizing anti-P-glycoprotein (P-gp) monoclonal antibodies reduced their sensitivity to complement. In addition, KB-V1 revertants which cease to express P-gp become more resistant to complement. These results indicate that multiple factors, such as reduced expression of DAF, enhanced deposition of C3b and increased binding and stability of the MAC may contribute to the increased complement sensitivity of KB-V1 cells. It is suggested that P-gp is responsible for the complement-sensitive phenotype of KB-V1 cells.