Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity

The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 jig apolipoprotein B/ml) in the presence or absence of control HDL subfiractions (25 mu g protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p < 0.05) in MetS subjects (n = 16) relative to normolipidemic controls (n = 7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p < 0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Skeletal Microstructural Abnormalities in Postmenopausal Women With Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is associated with osteoporosis and fragility fractures. The objectives of this study were to assess static and dynamic indices of cancellous and cortical bone structure in postmenopausal women with COPD. Twenty women with COPD who had not received chronic oral glucocorticoids underwent bone biopsies after double tetracycline labeling. Biopsies were analyzed by histomorphometry and mu CT and compared with age-matched controls. Distribution of the patients according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was: Type I (15%), Type II (40%), Type III (30%), and Type IV (15%). Mean (+/-SD) cancellous bone volume (15.20 +/- 5.91 versus 21.34 +/- 5.53%, p = .01), trabecular number (1.31 +/- 0.26 versus 1.77 +/- 0.51/mm, p = .003), and trabecular thickness (141 +/- 23 versus 174 +/- 36 mu m, p = .006) were lower in patients than in controls. Connectivity density was lower in COPD (5.56 +/- 2.78 versus 7.94 +/- 3.08 mu m, p = .04), and correlated negatively with smoking (r = -0.67; p = .0005). Trabecular separation (785 +/- 183 versus 614 +/- 136 mu m, p = .01) and cortical porosity (4.11 +/- 1.02 versus 2.32 +/- 0.94 voids/mm(2); p < .0001) were higher in COPD while cortical width (458 +/- 214 versus 762 +/- 240 mu m; p < .0001) was lower. Dynamic parameters showed significantly lower mineral apposition rate in COPD (0.56 +/- 0.16 versus 0.66 +/- 0.12 mu m/day; p = .01). Patients with more severe disease, GOLD III and IV, presented lower bone formation rate than GOLDI and II (0.028 +/- 0.009 versus 0.016 +/- 0.011 mu m(3)/mu m(2)/day;p = 04). This is the first evaluation of bone microstructure and remodeling in COPD. The skeletal abnormalities seen in cancellous and cortical bone provide an explanation for the high prevalence of vertebral fractures in this disease. (C) 2010 American Society for Bone and Mineral Research.

Interstitial expression of angiotensin II and AT1 receptor are increased in patients with progressive glomerulopathies

In animal models, interstitial angiotensin II (ang II) and AT1 receptor (AT1R) are key mediators of renal inflammation and fibrosis in progressive chronic nephropathies. We hypothesized that these molecules were overexpressed in patients with progressive glomerulopathies. In this observational retrospective study, we described the expression of ang II and AT1R by immunohistochemistry in kidney biopsies of 7 patients with minimal change disease (MCD) and in 25 patients with progressive glomerulopathies (PGPs). Proteinuria, serum albumin, and serum creatinine were not statistically different between MCD and PGP patients. Total expression of ang II and AT1R was not statistically different between MCD (108.7 +/- 11.5 and 73.2 +/- 13.6 cells/mm(2), respectively) and PGN patients (100.7 +/- 9.0 and 157.7 +/- 13.8 cells/mm(2), respectively; p>0.05). Yet, interstitial expression of ang II and AT1R (91.6 +/- 16.0 and 45.6 +/- 5.4 cells/mm(2), respectively) was higher in patients with PGN than in those with MCD (22.0 +/- 4.1 and 17.9 +/- 2.9 cells/mm(2), respectively, p<0.05), as was the proportion of interstitial fibrosis (11.0 +/- 0.7% versus 6.1 +/- 1.2%, p<005). In patients with MCD, ang II and AT1R expressions predominate in the tubular compartment (52% and 36% of the positive cells, respectively). In those with PGP, the interstitial expression of ang II and AT1R predominates (58% and 45%, respectively). In conclusion, interstitial expression of ang II and AT1R is increased in patients with progressive glomerulopathies. The relationship of these results and interstitial fibrosis and disease progression in humans warrants further investigations.

Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia

Background: Percutaneous transluminal angioplasty has been used with increasing frequency in the treatment of infrainguinal arterial occlusive disease. This meta-analysis aimed to assess the middle-term outcomes after crural angioplasty in patients with chronic critical limb ischemia and compare results with a meta-analysis of popliteal-to-distal vein bypass graft. Methods: Data were retrieved from 30 articles published from 1990 through 2006 (63% of articles published between 2000 and 2006). All studies used survival analysis, reported a 12-month cumulative rate of patency or limb salvage, and included at least 15 infrapopliteal angioplasties. The outcome measures were immediate technical success, primary and secondary patency, limb salvage, and patient survival. Data from life-tables, survival curves, and texts were used. Results. The pooled estimate of success was 89.0% +/- 2.2% for immediate technical result. Results at 1 and 36 months were 77.4% +/- 4.1% and 48.6% +/- 8.0% for primary patency, 83.3% +/- 1.4% and 62.9% +/- 11.0% for secondary patency, 93.4% +/- 2.3% and 82.4% +/- 3.4% for limb salvage, and 98.3% +/- 0.7% and 68.4% +/- 5.5% for patient survival, respectively. Studies with >75% of the limbs with tissue loss fared worse than their respective comparative subgroup for technical success and patency but not for limb salvage or survival. No publication bias was detected. Conclusion: The technical success and subsequent durability of crural angioplasty are limited compared with bypass surgery, but the clinical benefit is acceptable because limb salvage rates are equivalent to bypass surgery. Further studies are necessary to determine the proper role of infrapopliteal angioplasty.

PROWESS-SHOCK TRIAL: A PROTOCOL OVERVIEW AND PERSPECTIVES

Sepsis remains a challenge for intensive care physicians, as it keeps up with high mortality rate in spite of the high costs associated with its treatment. Several studies indicate that the infusion of Drotrecogin-alpha activated (DrotAA) reduce mortality in patients at high risk of death when administered early and secured the appropriate initial treatment of sepsis as recommended by Surviving Sepsis Campaign. Europe and United States of America differ regarding the criteria of high risk of death in sepsis, two or more organ dysfunctions and Acute Physiology and Chronic Health Evaluation 25 or more, respectively. In addition to varied definitions of high risk of death for inclusion of patients in sepsis studies, the possibility of bleeding related to drug use and intrinsic limitations related to study design led the Company to develop a new randomized, multinational, placebo-controlled, double-blind study to assess the effectiveness of drug in patients with septic shock in adults.

Endovascular Treatment for Chronic Arteriovenous Fistula Between Renal Artery and Inferior Vena Cava: Image in Vascular Surgery

Arteriovenous fistula involving renal artery and inferior vena cava are rare. We report the case of a 47-year-old woman with a chronic arteriovenous fistula between right renal artery and inferior vena cava due to a penetrating trauma. Another finding was a vena cava aneurysm caused by the fistula. The patient was successfully treated with a covered stent in the renal artery. Diagnosis and postoperative control have been documented with CT scan. Endovascular techniques may be effective and minimally invasive option for treatment and renal preservation in renal-cava arteriovenous fistulae.

Congenital intrahepatic arterioportal fistula presenting as severe undernutrition and chronic watery diarrhea in a 2-year-old girl

Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension in young children. We report the case of a 2-year-old girl with severe undernutrition, chronic watery diarrhea, and gastrointestinal bleeding because of a congenital intrahepatic arterioportal fistula. Radiographic embolization and surgical ligation of the left hepatic artery were attempted, with no resolution of the symptoms. So, a left lobectomy was performed, with excellent results and prompt disappearance of the diarrhea. Hepatectomy should be considered as a definitive and reliable. therapy for congenital IAPF. (C) 2009 Elsevier Inc. All rights reserved.

Arteriovenous fistula for chronic hemodialysis in pediatric candidates for renal transplantation: Technical details and refinements

AVFs may be considered the best type of venous access for chronic hemodialysis in pediatric patients with more than 20 kg who are not likely to receive a kidney transplant or be transitioned to peritoneal dialysis within one yr. The aim of the study was to report the experience in the creation of AVFs in pediatric candidates for renal transplantation using microsurgical vascular techniques, with emphasis on the details of the surgical technique. Forty children underwent 50 fistula creations - 31 radial-cephalic, 11 brachial-cephalic, five brachial-basilic and three saphenous-femoral. The vein was anastomosed to the artery in an end-to-lateral fashion by using two separate 8/0 prolene running sutures. The overall patency rate was 76.0%:22 (70.9%) of the radial-cephalic fistulas, nine (81.8%) of the brachial-cephalic, five (100.0%) of the brachial-basilic and two (66.6%) of the saphenous-femoral. There was no significant difference in patency rates between the brachial-cephalic, brachial-basilic and radial-cephalic fistulas. The incidences of fistula patency were not different for patients weighing < 20 kg compared with patients weighing > 20 kg. AVF remains as a satisfactory method for providing hemodialysis in children. The utilization of microsurgical techniques with some technical refinements described herein permits the achievement of high fistula patency rates.

Urine is necessary to provoke bladder inflammation in protamine sulfate induced urothelial injury

Purpose: The bladder is normally impermeable to possible hostile environmental factors and toxic urinary wastes. Any disruption of the permeability barrier would permit the leakage of urine constituents into the underlying cells layers and subsequent inflammation. Protamine sulfate, which increases urothelial permeability, is used in experimental models of cystitis. We examined whether protamine sulfate alone could cause bladder inflammation or if the association of protamine sulfate and urine is needed for this condition. Materials and Methods: Female Wistar rats (Center for the Development of Experimental Models for Medicine and Biology, Federal University of Sao Paulo, Sao Paulo, Brazil) had the bladder catheterized and instilled with protamine sulfate (10 mg) or sterile saline for 30 minutes. To exclude urine other groups of rats underwent bilateral nephrectomy and the same procedure was used. One day after instillation the bladders were removed for histopathology. Edema and vascular congestion were graded from 0-none to 3-severe. Polymorphonuclear and mast cells were counted. The Kruskal-Wallis test was performed for statistical analysis. Results: Intravesical instillation of protamine sulfate in nonnephrectomized rats led to inflammation, in contrast to findings in rats instilled with saline. On the other hand, nephrectomized rats showed no inflammatory changes following the instillation of protamine sulfate or saline. The mast cell count was similar in all groups. Conclusions: Bladder inflammation in this experimental model of urothelial injury was not due to protamine sulfate alone. The association of protamine sulfate and urine was necessary to trigger the inflammatory cascade. Thus, urine indeed has an important role in the development of bladder inflammation in an environment of higher urothelial permeability.

Heterozygosity for the S180L Variant of MAL/TIRAP, a Gene Expressing an Adaptor Protein in the Toll-Like Receptor Pathway, Is Associated with Lower Risk of Developing Chronic Chagas Cardiomyopathy

Background. Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Among T. cruzi-infected individuals, only a subgroup develops severe chronic Chagas cardiomyopathy (CCC); the majority remain asymptomatic. T. cruzi displays numerous ligands for the Toll-like receptors (TLRs), which are an important component of innate immunity that lead to the transcription of proinflammatory cytokines by nuclear factor-kappa B. Because proinflammatory cytokines play an important role in CCC, we hypothesized that single-nucleotide polymorphisms (SNPs) in the genes that encode proteins in the TLR pathway could explain differential susceptibility to CCC among T. cruzi-infected individuals. Methods. For 169 patients with CCC and 76 T. cruzi-infected, asymptomatic individuals, we analyzed SNPs by use of polymerase chain reaction-restriction fragment length polymorphism analysis for the genes TLR1, TLR2, TLR4, TLR5, TLR9, and MAL/TIRAP, which encodes an adaptor protein. Results. Heterozygous carriers of the MAL/TIRAP variant S180L were more prevalent in the asymptomatic group (24 [32%] of 76 subjects) than in the CCC group (21 [12%] of 169) (chi(2) = 12.6; P = .0004 [adjusted P (P(c)) = .0084]; odds ratio [OR], 0.31 [95% confidence interval {CI}, 0.16-0.60]). Subgroup analysis showed a stronger association when asymptomatic patients were compared with patients who had severe CCC (i.e., patients with left-ventricular ejection fraction <= 40%) (chi(2) = 11.3; P = .0008 [P(c) = .017]; OR, 0.22 [95% CI, 0.09-0.56]) than when asymptomatic patients were compared with patients who had mild CCC (i.e., patients with left-ventricular ejection fraction >40%) (chi(2) = 7.7; P = .005 [P(c) = .11]; OR, 0.33 [95% CI, 0.15-0.73]). Conclusion. T. cruzi-infected individuals who are heterozygous for the MAL/TIRAP S180L variant that leads to a decrease in signal transduction upon ligation of TLR2 or TLR4 to their respective ligand may have a lower risk of developing CCC.

Effects of Chronic Exposure to Air Pollution from Sao Paulo City on Coronary of Swiss Mice, from Birth to Adulthood

To explore the hypothesis that air pollution promotes cardiovascular changes, Swiss mice were continuously exposed, since birth, in two open-top chambers (filtered and nonfiltered for airborne particles <= 0.3 mu m) placed 20 m from a street with heavy traffic in downtown Sao Paulo, twenty-four hours per day for four months. Fine particle (PM(2.5)) concentration was determined gravimetrically; hearts were analyzed by morphometry. There was a reduction of the PM(2.5) inside the filtered chamber (filtered = 8.61 +/- 0.79 mu g/m(3), nonfiltered = 18.05 +/- 1.25 mu g/m(3), p < .001). Coronary arteries showed no evidence of luminal narrowing in the exposed group but presented higher collagen content in the adventitia of LV large-sized and RV midsized vessels (p = .001) and elastic fibers in both tunicae adventitia and intima-media of almost all sized arterioles from both ventricles (p = .03 and p = .001, respectively). We concluded that chronic exposure to urban air since birth induces mild but significant vascular structural alterations in normal individuals, presented as coronary arteriolar fibrosis and elastosis. These results might contribute to altered vascular response and ischemic events in the adulthood.

The possible role of physical exercise on the treatment of idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases that share some symptoms such as muscular weakness and inflammation of skeletal muscle. Complete recovery of muscle function with pharmacological treatment does not always occur, suggesting that physical inability is a great concern for these patients. In this context, it has been speculated that physical exercise could result in functional benefits to patients with IIM, leading to an improvement in quality of life. In fact, recent studies of polymyositis (PM) and dermatomyositis (DM) support the notion that exercise training improves or at least stabilizes muscle strength and functional ability without inducing disease flares. Importantly, these benefits were observed not only during the chronic phase, but also in the course of active disease. This positive effect was found to be long term, as demonstrated by a six-month significant improvement in exercise capacity and strength. Together, these findings indicate that a well controlled exercise program can be recommended for patients with DM and PM. The optimal exercise modality training and the underlying mechanism for this encouraging response remain to be determined in future studies. (C) 2008 Elsevier B.V. All rights reserved.

HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN EXPRESSION ENHANCES THE MOUSE SURVIVAL RATE IN AN EXPERIMENTAL SYSTEMIC INFLAMMATION MODEL: A NOVEL ROLE FOR CETP

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LIPS because death rates 5 days after intraperitoneal inoculation of LIPS were higher in wild-type than in huCETP(+/-) mice, whereas all huCETP(+/+) mice remained alive. After LIPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP(+/+) than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LIPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused C-14-LPS from Salmonella typhimurium was greater in huCETP(+/+) than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.