Synergistic effect of simvastatin and ezetimibe on lipid and pro-inflammatory profiles in pre-diabetic subjects

Background: Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol and plant sterols. Synergism of ezetimibe-statin therapy on LDL-cholesterol has been demonstrated, but data concerning the pleiotropic effects of this combination are controversial. Objective: This open-label trial evaluated whether the combination of simvastatin and ezetimibe also results in a synergistic effect that reduces the pro-inflammatory status of pre-diabetic subjects. Methods: Fifty pre-diabetic subjects were randomly assigned to one of 2 groups, one receiving ezetimibe (10 mg/day), the other, simvastatin (20 mg/d) for 12 weeks, followed by an additional 12-week period of combined therapy. Blood samples were collected at baseline, 12 and 24 weeks. RESULTS: Total cholesterol, LDL-cholesterol and apolipoprotein B levels decreased in all the periods analyzed (p < 0.01), but triglycerides declined significantly only after combined therapy. Both drugs induced reductions in C-reactive protein, reaching statistical significance after combining ezetimibe with the simvastatin therapy (baseline 0.59 +/- 0.14, simvastatin monotherapy 0.48 +/- 0.12 mg/dL and 0.35 +/- 0.12 mg/dL, p < 0.023). Such a reduction was independent of LDL-cholesterol change. However, mean levels of TNF-alpha and interleukin-6 and leukocyte count did not vary during the whole study. Conclusion: Expected synergistic lowering effects of a simvastatin and ezetimibe combination on LDL-cholesterol, apolipoprotein B and triglycerides levels were confirmed in subjects with early disturbances of glucose metabolism. We suggest an additive effect of this combination also on inflammatory status based on the reduction of C-reactive protein. Attenuation of pro-inflammatory conditions may be relevant in reducing cardiometabolic risk.

PKC beta II inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses

Protein kinase C beta II (PKC beta II) levels increase in the myocardium of patients with end-stage heart failure (HF). Also targeted overexpression of PKC beta II in the myocardium of mice leads to dilated cardiomyopathy associated with inflammation, fibrosis and myocardial dysfunction. These reports suggest a deleterious role of PKC beta II in HF development. Using a post-myocardial infarction (MI) model of HF in rats, we determined the benefit of chronic inhibition of PKC beta II on the progression of HF over a period of 6 weeks after the onset of symptoms and the cellular basis for these effects. Four weeks after MI, rats with HF signs that were treated for 6 weeks with the PKC beta II selective inhibitor (beta IIV5-3 conjugated to TAT(47-57) carrier peptide) (3 mg/kg/day) showed improved fractional shortening (from 21% to 35%) compared to control (TAT(47-57) carrier peptide alone). Formalin-fixed mid-ventricle tissue sections stained with picrosirius red, haematoxylin and eosin and toluidine blue dyes exhibited a 150% decrease in collagen deposition, a two-fold decrease in inflammation and a 30% reduction in mast cell degranulation, respectively, in rat hearts treated with the selective PKC beta II inhibitor. Further, a 90% decrease in active TGF beta 1 and a significant reduction in SMAD2/3 phosphorylation indicated that the selective inhibition of PKC beta II attenuates cardiac remodelling mediated by the TGF-SMAD signalling pathway. Therefore, sustained selective inhibition of PKC beta II in a post-MI HF rat model improves cardiac function and is associated with inhibition of pathological myocardial remodelling.

Effect of UV Radiation and Pro-Oxidant on PP Biodegradability

The effect of ultraviolet exposure on the biodegration of poly(propylene) without (PP) and with 0.3 (wt/wt) (PPOx) pro-oxidant additives, produced by extrusion was studied. After UV exposure the samples were submitted to biodegradation (weight loss) in prepared soils. The samples before and after UV exposure were analyzed using differential scanning calorimetry, Fourier transform infrared spectroscopy, size exclusion chromatography, and optical microscopy. The exposure to UV radiation lead to more intense degradation of PPOx than of PP; the amount of carbonyl groups was larger for the PPOx samples than for PP, as well as the decrease in the T(m) and in the molecular weight. The samples exposed to UV radiation showed some level of fragmentation after 56 days when placed in the prepared soil; the samples which were exposed to UV for 480 h presented just a small weight loss. POLYM. ENG. SCI., 49:123-128, 2009. (C) 2008 Society of Plastics Engineers

The choice of the best among the shortest routes in transparent optical networks

This work introduces the problem of the best choice among M combinations of the shortest paths for dynamic provisioning of lightpaths in all-optical networks. To solve this problem in an optimized way (shortest path and load balance), a new fixed routing algorithm, named Best among the Shortest Routes (BSR), is proposed. The BSR`s performance is compared in terms of blocking probability and network utilization with Dijkstra`s shortest path algorithm and others algorithms proposed in the literature. The evaluated scenarios include several representative topologies for all-optical networking and different wavelength conversion architectures. For all studied scenarios, BSR achieved superior performance. (C) 2010 Elsevier B.V. All rights reserved.

Substratum choice for nesting in male Nile tilapia Oreochromis niloticus

Four substrata were offered to groups of adult Nile tilapia Oreochromis niloticus (one male and two females) simultaneously: pure sand, a mixture of sand and shells, stones and no substratum. The results showed that males chose to dig nests in a lighter and more homogeneous substratum.

Ruthenium-nitrite complex as pro-drug releases NO in a tissue and enzyme-dependent way

Nitric oxide (NO) plays an important role in the control of the vascular tone and the most often employed NO donors have limitations due to their harmful side-effects. In this context, new NO donors have been prepared, in order to minimize such undesirable effects. cis-[Ru(bpy)(2)(py)NO(2)](PF(6)) (RuBPY) is a new nitrite complex synthesized in our laboratory that releases NO in the presence of the vascular tissue only. In this work the vasorelaxation induced by this NO donor has been studied and compared to that obtained with the well known NO donor SNP. The relaxation induced by RuBPY is concentration-dependent in denuded rat aortas pre-contracted with phenylephrine (EC(50)). This new compound induced relaxation with efficacy similar to that of SNP, although its potency is lower. The time elapsed until maximum relaxation is achieved (E(max) = 240 s) is similar to measured for SNP (210 s). Vascular reactivity experiments demonstrated that aortic relaxation by RuBPY is inhibited by the soluble guanylyl-cyclase inhibitor 1H-[1,2,4] oxadiozolo[4,3-a]quinoxaline-1-one (ODQ 1 mu M). In a similar way, 1 mu M ODQ also reduces NO release from the complex as measured with DAF-2 DA by confocal microscopy. These findings suggest that this new complex RuBPY that has nitrite in its structure releases NO inside the vascular smooth muscle cell. This ruthenium complex releases significant amounts of NO only in the presence of the aortic tissue. Reduction of nitrite to NO is most probably dependent on the soluble guanylyl-cyclase enzyme, since NO release is inhibited by ODQ. (C) 2011 Elsevier Inc. All rights reserved.

Melatonin enhances pro-inflammatory cytokine levels and protects against Chagas disease

Pro-inflammatory and modulatory cytokines have an essential role in host defense against human and murine Trypanosoma cruzi infection. Control of T. cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. Melatonin has been proposed to regulate the immune system by affecting cytokine production in immunocompetent cells, enhancing the production of several T helper (Th)1 cytokines. The aims of this work were to evaluate in rats, the influences of exogenous melatonin treatment on T. cruzi-infected host`s immune responses. With this in mind, several immunological parameters were analyzed, including tumor necrosis factor-alpha, gamma-interferon, interleukin-12, nitric oxide (NO) and macrophage count. The melatonin therapy was provided in one of two different treatment regimens, that is, either beginning 7 days prior to infection or concomitant with the infection. Both treatments triggered an up-regulation of the immune response, with the concomitant treatment being more effective; in this case all cytokines studied, with exception of NO, displayed enhanced concentrations and there was a higher number of peritoneal macrophages, which displayed reduced concentrations under melatonin therapy. We conclude that melatonin plays a pivotal role in up-regulating the Th1 immune response thus controlling parasite replication.

Choice of macroinvertebrate metrics to evaluate stream conditions in Atlantic Forest, Brazil

The development of biomonitoring programs based on the macroinvertebrate community requires the understanding of species distribution patterns, as well as of the responses of the community to anthropogenic stressors. In this study, 49 metrics were tested as potential means of assessing the condition of 29 first- and second-order streams located in areas of differing types of land use in So Paulo State, Brazil. Of the sampled streams, 15 were in well-preserved regions in the Atlantic Forest, 5 were among sugarcane cultivations, 5 were in areas of pasture, and 4 were among eucalyptus plantations. The metrics were assessed against the following criteria: (1) predictable response to the impact of human activity; (2) highest taxonomic resolution, and (3) operational and theoretical simplicity. We found that 18 metrics were correlated with the environmental and spatial predictors used, and seven of these satisfied the selection criteria and are thus candidates for inclusion in a multimetric system to assess low-order streams in So Paulo State. These metrics are family richness; Ephemeroptera, Plecoptera and Trichoptera (EPT) richness; proportion of Megaloptera and Hirudinea; proportion of EPT; Shannon diversity index for genus; and adapted Biological Monitoring Work Party biotic index.

Extrahepatic portal vein thrombosis after umbilical catheterization: is it a good choice for Rex shunt?

Background: Extrahepatic portal vein thrombosis (EHPVT) is an important cause of portal hypertension in children. Rex shunt has been used successfully to treat these patients. Methods: We report our experience in 19 infants and children (5 months to 14 years) with HPVT eligible for a mesenteric-portal surgical shunt with left internal jugular vein autograft. Eight children had idiopathic EHPVT, nine had post-umbilical catheterization EHPVT, one had portal vein agenesis, and one had posttransplant EHPVT. Results: It was possible to perform the Rex shunt in all patients except for 8 of 9 cases in the post-umbilical catheterization EHPVT group. A Warren procedure was performed in 4 of those patients and a proximal splenorenal shunt in 1. Current follow-up ranges from 3 to 26 months. Shunt thrombosis occurred in one patient with portal vein agenesis and associated cardiac anomaly. Portal hypertension has significantly improved after surgery. None of our patients have experienced new bleeding episodes until now. Conclusions: The Rex shunt should be considered in the treatment of children with idiopathic EHPVT experiencing repeated gastrointestinal bleeding episodes refractory to endoscopic treatment. Nevertheless, the role of this operation for children with post-umbilical catheterization EHPVT is yet to be clearly evaluated. (C) 2011 Elsevier Inc. All rights reserved.

Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease - A randomized placebo-controlled study

The balance between different immunological stimuli is essential in the progression and stabilization of atherosclerotic plaques. Immune regulation has been suggested as potential target for the treatment of atherosclerotic disease. We sought to determine whether treatment with pentoxifylline, a phosphodiesterase inhibitor with immunomodulating properties, could reduce the pro-inflammatory response observed in patients with acute coronary syndromes (ACS) and increase anti-inflammatory activity. In a double-blind, prospective, placebo-controlled study, 64 patients with ACS were randomized to receive pentoxifylline 400 mg TID or placebo for 6 months. Analysis of the pro-inflammatory markers, Greactive protein (CRP), interleukin (IL)-6, IL-12, interferon-gamma and tumor necrosis factor (TNF)-alpha and the anti-inflammatory cytokines, transforming growth factor (TGF)-beta 1 and IL-10 were done at baseline, 1 and 6 months. Pentoxifylline treatment significantly reduced the adjusted levels of CRP and TNF-alpha compared to placebo after 6 months (P=0.04 and P < 0.01, respectively). IL-12 increase was significantly less pronounced with pentoxifylline (P=0.04). The levels of the anti-inflammatory cytokine, IL-10, also declined significantly less in the pentoxifylline group compared to placebo (P < 0.01) with a trend towards a higher increase of TGF-beta 1 in the former group (P=0.16). Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory response in patients with ACS and may have beneficial clinical effects on cardiovascular events. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Pro- and Anti-inflammatory Cytokines in Steatosis and Steatohepatitis

Fatty liver disease is a problem in both bariatric patients and in patients with moderate obesity. Tumor necrosis factor (TNF)-alpha has been frequently measured in nonalcoholic steatohepatitis (NASH) with or without diabetes, but less is known about interleukin (IL)-6 and IL-10. Moderately obese patients (n = 80) with histologically proven steatosis (n = 29) and NASH (n = 51) were recruited. Serum levels of cytokines were documented along with clinical information. The aim was to identify the correlates of such biomolecules in a stable population. Diabetes tended to be more associated with NASH (52.5% instead of 41.4%, P = 0.015), with no difference of age, gender, or body mass index regarding steatosis. For the entire population, cytokine changes were not significant, including TNF-alpha and IL-6. In diabetics only, all markers tended to diminish with NASH, especially IL-10 (P = 0.000). IL-10 correlated with homeostatic model assessment index (P = 0.000) and other variables of glucose homeostasis in diabetes, thus representing a major marker of the disease. (1) Generally inconsistent changes in pro- and anti-inflammatory cytokines occurred when NASH was globally compared to steatosis. (2) In contrast, downregulation of IL-6 and IL-10 was perceived in diabetics with NASH. (3) Arterial hypertension did not play a role in these circumstances. (4) IL-10 maintained strong correlations with glucose metabolism indices. (5) TNF-alpha could not be incriminated for progressive liver damage, as values failed to increase in NASH. (6) Investigations of IL-10 and other counterregulatory cytokines are lacking in this context and deserve further studies.

Increased circulating pro-inflammatory cytokines and imbalanced regulatory T-cell cytokines production in chronic idiopathic urticaria

The immunologic characterization of chronic idiopathic urticaria (CIU), mainly regarding cytokine profile needs more investigation. We examined circulating inflammatory cytokine levels, T-cell induced secretion, and cytokine mRNA expression in patients with CIU subjected to the intradermal autologous serum skin test (ASST). Increased levels of circulating pro-inflammatory cytokines, such as TNF-alpha, IL-1 beta, IL-12p70, and IL-6 have been observed in most of patients with CIU, together with an enhancement of IL-2 secretion following T-cell stimulation. Highlighting the inflammatory profile in CIU found in ASST positive, is the enhanced B-cell proliferative responsiveness and increased IL-17 secretion levels. ASST-positive patients also exhibited impaired IL-4 secretion associated with increased IL-10 production. Altered cytokine expression in patients with ASST-negative, was the down-modulation of spontaneous IL-10 mRNA expression levels in peripheral blood mononuclear cells. Our findings support the concept of immunologic dysregulation in CIU, revealing a systemic inflammatory profile associated with disturbed cytokine production by T cells, mainly related to IL-17 and IL-10 production. (c) 2008 Elsevier B.V. All rights reserved.

Using a combination of MLPA kits to detect chromosomal imbalances in patients with multiple congenital anomalies and mental retardation is a valuable choice for developing countries

Conventional karyotyping detects anomalies in 3-15% of patients with multiple congenital anomalies and mental retardation (MCA/MR). Whole-genome array screening (WGAS) has been consistently suggested as the first choice diagnostic test for this group of patients, but it is very costly for large-scale use in developing countries. We evaluated the use of a combination of Multiplex Ligation-dependent Probe Amplification (MLPA) kits to increase the detection rate of chromosomal abnormalities in MCA/MR patients. We screened 261 MCA/MR patients with two subtelomeric and one microdeletion kits. This would theoretically detect up to 70% of all submicroscopic abnormalities. Additionally we scored the de Vries score for 209 patients in an effort to find a suitable cut-off for MLPA screening. Our results reveal that chromosomal abnormalities were present in 87 (33.3%) patients, but only 57 (21.8%) were considered causative. Karyotyping detected 15 abnormalities (6.9%), while MLPA identified 54 (20.7%). Our combined MLPA screening raised the total detection number of pathogenic imbalances more than three times when compared to conventional karyotyping. We also show that using the de Vries score as a cutoff for this screening would only be suitable under financial restrictions. A decision analytic model was constructed with three possible strategies: karyotype, karyotype + MLPA and karyotype + WGAS. Karyotype + MLPA strategy detected anomalies in 19.8% of cases which account for 76.45% of the expected yield for karyotype + WGAS. Incremental Cost Effectiveness Ratio (ICER) of MLPA is three times lower than that of WGAS, which means that, for the same costs, we have three additional diagnoses with MLPA but only one with WGAS. We list all causative alterations found, including rare findings, such as reciprocal duplications of regions deleted in Sotos and Williams-Beuren syndromes. We also describe imbalances that were considered polymorphisms or rare variants, such as the new SNP that confounded the analysis of the 22q13.3 deletion syndrome. (C) 2011 Elsevier Masson SAS. All rights reserved.

Pancreatic fistula after pancreaticoduodenectomy: the conservative treatment of choice

Background: A pancreatic fistula (PF) is the most common complication after pancreaticoduodenectomy (PD), and its reported incidence varies from 2% to 28%. The aim of the present study was to analyse the treatment of a complicated PF comparing the surgical approach with conservative techniques. Methods: From January 2000 through to August 2006, 121 patients were submitted for PD. The study consisted of 70 men and 47 women, with a median age of 60 years (SD +/- 12). The main indications for PD were pancreatic duct carcinoma in 52 patients (44.5%), ampullary carcinoma or adenoma in 18 (15.4%) and islet cell tumour in 11 (9.4%). Reconstruction by pancreatogastrostomy was performed in 65 patients (55.6%), and pancreatojejunostomy in 52 patients (44%). Results: Thirty-five patients (30%) developed a PF. Amongst these, 20 were managed conservatively and 14 were reoperated. These two groups of patients were compared with patients without a PF for analysis. There was no significant difference in the mean age, the gender ratio, American Society of Anesthesiologists (ASA) classification, surgical time and blood replacement, number of associated procedures, vascular resection and type of reconstruction between the three groups. There were five post-operative deaths (4.2%), three patients (21.4%) in the surgical treatment group (P < 0.01). Mean total number of complications (P = 0.02) and mean length of hospital stay (P < 0.001) were greater in the surgical group. The medium delay between the pancreatic resection and reoperation was 10 days (range, 3-32 days). Completion splenopancreatectomy was required in five patients whereas conservative treatment including debridement and drainage was applied in nine patients. Conclusion: The surgical approach for a PF is associated with a higher mortality and morbidity. There is no advantage in performing completion pancreatectomy (CP) instead of extensive drainage as a result of the same mortality and morbidity rates and the risk of endocrine insufficiency. In cases of complicated PF, radiological or surgical conservative treatment is recommended.

UPGRADING THE GLEASON SCORE IN EXTENDED PROSTATE BIOPSY: IMPLICATIONS FOR TREATMENT CHOICE

Purpose: To determine the incidence of overestimation of Gleason score (GS) in extended prostate biopsy, and consequently circumventing unnecessary aggressive treatment. Methods and Materials: This is a retrospective study of 464 patients who underwent prostate biopsy and radical prostatectomy between January 2001 and November 2007. The GS from biopsy and radical prostatectomy were compared. The incidence of overestimation of GS in biopsies and tumor volume were studied. Multivariate analysis was applied to find parameters that predict upgrading the GS in prostate biopsy. Results: The exact agreement of GS between prostate biopsy and radical prostatectomy occurred in 56.9% of cases. In 29.1% cases it was underestimated, and it was overestimated in 14%. One hundred and six (22.8%) patients received a diagnosis of high GS (8, 9, or 10) in a prostate biopsy. In 29.2% of cases, the definitive Gleason Score was 7 or lower. In cases in which GS was overestimated in the biopsy, tumors were significantly smaller. In multivariate analysis, the total percentage of tumor was the only independent factor in overestimation of GS. Tumors occupying less than 33% of cores had a 5.6-fold greater chance of being overestimated. Conclusion: In the extended biopsy era and after the International Society of Urological Pathology consensus on G, almost one third of tumors considered to have high GS at the biopsy may be intermediate-risk cancers. In that condition, tumors are smaller in biopsy. This should be remembered by professionals involved with prostate cancer to avoid overtreatment and undesirable side effects. (c) 2009 Elsevier Inc.