Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis.

BACKGROUND AND PURPOSE: Inflammation plays a key role in atherosclerosis. The protective role of angiotensin 1-7 (Ang-(1-7)) in vascular pathologies suggested the therapeutic use of low MW, non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms underlying the vaso-protective effects of AVE0991, a Mas receptor agonist, remain to be explored. EXPERIMENTAL APPROACH: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)-/- mice, in the context of vascular inflammation and plaque stability. KEY RESULTS: AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (PVAT) and adventitial infiltration with macrophages and T-cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability (a measure of endothelial function). AVE0991 inhibited perivascular inflammation, by reducing chemokine expression in PVAT and through direct actions on monocytes/macrophages inhibiting their activation, characterized by production of IL-1ß, TNF-α, CCL2 and CXCL10, and differentiation to M1 phenotype. Pretreatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in PVAT and in THP-1 cells in vitro, and the anti-inflammatory effects of AVE0991 were partly Mas dependent. CONCLUSIONS AND IMPLICATIONS: The selective Mas receptor agonist AVE0991 exhibited anti-atherosclerotic and anti-inflammatory actions, affecting monocyte/macrophage differentiation and recruitment to the perivascular space during early stages of atherosclerosis in ApoE-/- mice. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Soil features and indoor radon concentration prediction: radon in soil gas, pedology, permeability and 226Ra content.

This work aims at relating some physicochemical features of soils and their use as a tool for prediction of indoor radon concentrations of the Metropolitan Region of Belo Horizonte (RMBH), Minas Gerais, Brazil. The measurements of soil gas radon concentrations were performed by using an AlphaGUARD monitor. The (226)Ra content analysis was performed by gamma spectrometry (high pure germanium) and permeabilities were performed by using the RADON-JOK permeameter. The GEORP indicator and soil radon index (RI) were also calculated. Approximately 53 % of the Perferric Red Latosols measurement site could be classified as 'high risk' (Swedish criteria). The Litholic Neosols presented the lowest radon concentration mean in soil gas. The Perferric Red Latosols presented significantly high radon concentration mean in soil gas (60.6 ± 8.7 kBq m(-3)), high indoor radon concentration, high RI, (226)Ra content and GEORP. The preliminary results may indicate an influence of iron formations present very close to the Perferric Red Latosols in the retention of uranium minerals.

Toward personalized medicine in renal transplantation.

BACKGROUND: The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. METHODS: Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with χ2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. RESULTS: Two patient groups were identified to show a difference in TRL dose requirements: a control (0.014-0.10 mg/kg/per day) and an high-dose group (0.14-0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P=.01 and P=.04) with the need for higher immunosuppressive doses (>0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. CONCLUSION: Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose.

Effect of insulin-like growth factor-I on Leishmania amazonensis promastigote arginase activation and reciprocal inhibition of NOS2 pathway in macrophage in vitro.

We showed previously that insulin-like growth factor (IGF)-I induces an exacerbation of the lesion development in experimental cutaneous leishmaniasis favouring parasite growth within host macrophages. Here we studied the effect of IGF-I in vitro in BALB/c mouse peritoneal macrophages infected with stationary phase Leishmania amazonensis promastigotes. IGF-I was used to pre-incubate either macrophage or parasite before infection of the macrophages or adding it at the start of the Leishmania-macrophage culture and maintaining it throughout the experimental period. Independent of stimulation protocol, IGF-I induced significantly increased parasite growth within macrophages. Arginase activation considered as a key factor in Leishmania growth was studied, and its expression and activity were increased in Leishmania-infected macrophages but significantly more in infected cells upon IGF-I stimulus, an effect specifically inhibited by NOHA. Arginase known to be present on Leishmania was also studied, and its expression and activity were seen in the absence of any stimulus but significantly increased after 5 min of incubation with IGF-I. In addition, Leishmania was pre-incubated with NOHA for 5 min, washed, then macrophages infected observing a significantly reduced parasite burden in both IGF-I-stimulated and non-stimulated macrophages. Reciprocal decrease in the nitric oxide (NO) level and inhibition of nitric oxide synthase (NOS2) expression were also observed in IGF-I-stimulated infected macrophages. Our data strongly suggest that IGF-I induces preferential expression and activation of Leishmania promastigote arginase, contributes to the alternative activation of macrophages in the context of innate immunity and interferes with NOS pathway in infected macrophages probably as a reciprocal effect.

Cratylia argentea seed lectin, a possible defensive protein against plant-eating organisms: effects on rat metabolism and gut histology.

This present work was undertaken to answer two basic questions (a) is C. argentea lectin part of the general defensive strategy of the plant against predation by animals? (b) if so, how does it act on them? To achieve these goals the lectin from C. argentea seeds was purified to homogeneity and included at a 2% level in a diet containing 10% total protein and given to growing rats for 10 days. In vivo it was noted that the lectin from C. argentea is resistant to gut proteolysis, binds to the cells lining the small intestine and induces enlargement in the small intestine, caecum and colon, kidneys and pancreas compared to control rats exposed to the egg-white diet (EW). As the diet containing the purified C. argentea lectin has the same basic composition and protein content of EW diet, the small intestine, kidney and pancreas enlargements are clearly lectin-specific effects. Moreover the animals exposed to the lectin-containing diet presented a significant reduction in the growth rate and lower values of digestibility, NPU and biological value compared to animals fed on a control lectin-free diet. Thus the data from this present study and the report that the C. argentea lectin has insecticidal activity upon Callosobruchus maculatus larvae which attacks cowpea (Vigna unguiculata) seeds reinforce the hypothesis that lectins take part in the mechanisms against herbivory.

Application of biofiltration to the degradation of hydrogen sulfide in gas effluents.

A laboratory scale bioreactor has been designed and set up in order to degrade hydrogen sulfide from an air stream. The reactor is a vertical column of 7 litre capacity and 1 meter in height. It is divided into three modules and each module is filled with pellets of agricultural residues as packing bed material. The gas stream fed into the reactor through the upper inlet consists of a mixture of hydrogen sulfide and humidified air. The hydrogen sulfide content in the inlet gas stream was increased in stages until the degradation efficiency was below 90%. The parameters to be controlled in order to reach continuous and stable operation were temperature, moisture content and the percentage of the compound to be degraded at the inlet and outlet gas streams (removal or elimination efficiency). When the H2S mass loading rate was between 10 and 40 g m(-3) h(-1), the removal efficiency was greater than 90%. The support material had a good physical performance throughout operation time, which is evidence that this material is suitable for biofiltration purposes.

[Thrombolysis in unstable angina. A perspective before and after TIMI IIIB]. / Trombolisis en angina inestable. Una perspectiva antes y después del TIMI IIIB.

To identify the utility and security of thrombolytic therapy in unstable angina, we performed: a) retrospective analysis of controlled trials through computers system and cross references; b) analysis of TIMI IIIB trial to identify variables that explain, why thrombolytic therapy was unsuccessful; c) analysis of our clinical experience. For the three models of research, variables of primary and secondary effectivity were designed. Twenty two controlled trials with 3,544 patients were analyzed, the variables of primary effectivity suggest that in patients with unstable angina with sustained and recurrent clinical and electrocardiographic manifestations of acute ischemia, the use thrombolytic therapy could produce benefit, if the main mechanism is an intracoronary thrombus and if it is associated with maximum pharmacologic treatment and anticoagulation in acute phase. In the TIMI IIIB trial, variables that explain unsuccessful thrombolytic therapy were identified. The clinical experience in 17 patients with high risk unstable angina that received streptokinase in accelerated and standard infusion, proved success in 100% of the cases by improvement of ischemia, avoidance of infarction and recurrence, without hemorrhagic complications, without mortality. The results suggest, that in unstable angina with high clinical suspicion of disruption and thrombogenesis, refractory acute ischemia, jeopardized myocardium, and hemodynamic unstability, thrombolytic therapy could be an alternative that eliminates acute ischemia, as a bridge to the use in a second time of a definitive therapy. These data require in our environment revalidation with controlled trials and inclusion of more patients.

[The results in chronic ischemia of the lower limbs. The Granada-90 Geriatric Angiology Study (2)]. / Resultados sobre la isquemia crónica de los miembros inferiores. Estudio angiogeriátrico Granada-90 (segunda parte).

Results of a study about the chronic ischaemia of the lower limbs and its correlation with age, sex and previous diagnosis, are presented. Also, a comparison between previous diagnosis and results following the methodology exposed, was made. Study group included 433 older patients, randomizadely selected and permanent residents of some geriatric centers of the Oriental Andalucy.