Publications by authors named "Sergio Zucoloto"

89 Publications

Hepatic ballooning degeneration: a new feature of the refeeding syndrome in rats.

Clin Exp Hepatol 2020 Dec 30;6(4):327-334. Epub 2020 Dec 30.

Faculty of Medicine of Ribeirão Preto, University of Sao Paulo (USP), Brazil.

Aim Of The Study: Hepatic changes have been described during the refeeding syndrome due to increase in enzymes and hepatomegaly; however, they have not been properly described. Thus, the objective of this study was to investigate the hepatic histological characteristics and biochemical markers of hepatic steatosis in Wistar rats with refeeding syndrome.

Material And Methods: Thirty male Wistar rats were allocated to one of three groups: C, F or R. The animals from group C received an AIN-93 diet for 96 hours, and were then sacrificed. Animals allocated to group F were fasted for 48 hours and sacrificed. Animals from group R were also fasted for 48 hours, but were refed for another 48 hours, with AIN-93. The liver, blood and epididymal and retroperitoneal fats were collected.

Results: Data obtained in groups F and R show the changes observed in refeeding syndrome, during starvation and refeeding. The serum glucose, magnesium, potassium and phosphorus, in group F, decreased. There was no evidence of hepatic steatosis. Hypophosphatemia, hypomagnesemia and hypokalemia were also observed in group R, confirming refeeding syndrome. The main histological characteristic, in this group, was the extensive presence of ballooning degeneration. This is the first article that has detected such change in liver structure, due to refeeding syndrome. The possible causes are: retention of sodium, causing whole body edema; and/or dysfunction of the sodium/potassium pump of the hepatocytes, as a result of hypophosphatemia.

Conclusions: This is the first description of an animal model of hepatic severe ballooning degeneration induced due to refeeding syndrome.
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http://dx.doi.org/10.5114/ceh.2020.102151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816639PMC
December 2020

The HLA-G 14-base pair deletion allele and the deletion/deletion genotype are associated with persistent HBe antigenemia in chronic hepatis B infection.

Hum Immunol 2017 Feb 29;78(2):166-171. Epub 2016 Dec 29.

Division of Gastroenterology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Brazil.

Background And Aims: HLA-G has well-recognized immunomodulatory properties, and this molecule is frequently expressed in the livers of hepatitis B virus (HBV)-infected patients. Because the HLA-G 14 bp-insertion/deletion polymorphism (rs371194629) has been associated with the magnitude of HLA-G expression, we evaluated this polymorphism in the recognized evolutionary forms of chronic HBV infection.

Methods: We studied 196 chronic HBV-infected patients (118 HBeAg-negative chronic hepatitis, 53 HBeAg-positive chronic hepatitis and 25 inactive carriers exhibiting low levels of serum HBVDNA and persistently normal ALT levels), and 202 healthy individuals. Chronic hepatitis HLA-G typing was performed using PCR-amplified DNA hybridized with specific primers.

Results: The frequencies of the insertion/deletion alleles and genotypes were very similar in patients and controls. After patient stratification according to the evolutionary form of the chronic HBV infection, the frequencies of the deletion allele (P=0.0460; OR=1.26; 95%CI=1.01-1.45) and of the deletion/deletion genotype (P=0.0356; OR=2.08; 95%CI=1.05-4.09) were overrepresented in HBeAg-positive patients when compared to HBeAg-negative patients. No differences were observed when HBV inactive carriers were compared to HBeAg-negative chronic hepatitis patients.

Conclusions: Because the 14-bp deletion allele has been associated with increased HLA-G production and because HLA-G may down regulate the cytotoxic activity of TCD8 and NK cells, patients exhibiting the 14-bp deletion allele at single or double doses are at increased risk for developing chronic forms of HBV associated with persistent viremia and worse prognoses.
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http://dx.doi.org/10.1016/j.humimm.2016.12.011DOI Listing
February 2017

IL-18, TNF, and IFN-γ alleles and genotypes are associated with susceptibility to chronic hepatitis B infection and severity of liver injury.

J Med Virol 2015 Oct 7;87(10):1689-96. Epub 2015 May 7.

Gastroenterology Division, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.

This study evaluated the association of polymorphisms in the IL-18 (-607C/A and -137C/G), IFNγ (+874 A/T), and TNF (-238 A/G and -308 A/G) genes with susceptibility to HBV infection and severity of liver injury. A total of 259 chronic HBV-infected patients followed at the University Hospital, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil, and 202 healthy individuals were studied. Four Single Nucleotide Polymorphisms (SNPs) were amplified by Polymerase Chain Reaction (PCR). Liver biopsy was performed in 212 HBV-infected patients and classified according to severity of liver fibrosis (scores 0-4) and necroinflammatory activity (HAI scores 0-18). TNF-308*A allele (P < 0.001; OR = 2.16) and TNF -308 AA genotype (P = 0.026; OR = 5.43) were associated with susceptibility to HBV infection. An association was found between severe liver fibrosis when compared to mild fibrosis and the following polymorphisms: Alleles IL-18 -137*G (P = 0.004; OR = 3.45), TNF -308*A (P < 0.001; OR = 3.39), and IFNγ +874*T (P = 0.029; OR = 1.85) and IL-18 -137 GG genotype (P = 0.009; OR = 3.70). No significant association was found between IL-18 (-607 A/C) polymorphism and severity of liver fibrosis. Alleles IL-18 -137*G (P = 0.028; OR = 2.64) and TNF-308*A (P = 0.002; OR = 3.06) and IL-18 -137 GG genotype (P = 0.011; OR = 4.20) were associated with severe necroinflammatory activity (HAI>12) when compared to mild necroinflammatory activity (HAI 1-8). The results suggest that IL-18 -137C/G, TNF-308 G/A and IFNγ +874 A/T SNPs were associated to more severe liver injury in chronic HBV infection. TNF -308*A allele and TNF -308 AA genotype could play a role in the susceptibility to HBV infection.
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http://dx.doi.org/10.1002/jmv.24225DOI Listing
October 2015

BRCA1 and γH2AX as independent prognostic markers in oral squamous cell carcinoma.

Oncoscience 2014 1;1(5):383-91. Epub 2014 Jun 1.

Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.

Oral squamous cell carcinomas (OSCC) are believed to originate from sequential mutations that can develop as a consequence of genetic instability acquired over time. BRCA1 are linked to DNA recombination and repair processes, being of importance for its role in regulation of RAD51 and H2AX (γH2AX). The aim of this study was to investigate the relationship between BRCA1 expression status and evaluate its prognostic impact. We selected from 150 OSCC patients, and evaluated BRCA1 expression in OSCC by immunohistochemistry and qRT-PCR, comparing its expression with homologous recombination markers (RAD51, γH2AX and p53), clinicopathological and survival data. Expression of BRCA1 was observed in 61 cases (43.88%) and was related to tumor size (T stage) (p=0.001), and gender (p=0.017). mRNA from BRCA1 showed a borderline relationship with perineural invasion (p=0.053). BRCA1 [p=0.030; HR: 2.334 (C.I.: 1.087-5.012)], γH2AX [p=0.045; HR: 0.467 (C.I.: 0.222-0.628)] and gender [p=0.001; HR: 10.386 [(C.I.: 2.679-10.623)] were independent prognostic factors for DSS. BRCA1 and γH2AX expression by OSCC cells are associated with reduced overall survival time, independent of other variables in patients, as well as gender, and our findings shed some light about DSB markers in OSCC and its role as prognostic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278309PMC
http://dx.doi.org/10.18632/oncoscience.47DOI Listing
January 2015

Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital.

Ann Hepatol 2014 Nov-Dec;13(6):762-70

Division of Gastroenterology, Department of Internal Medicine.

Introduction: Few studies have evaluated the factors involved in the spontaneous HBsAg seroclearance in patients with chronic hepatitis B (HBV) followed up on a long-term basis from areas with a low prevalence of HBV infection. We aimed to determine the rate of spontaneous HBsAg seroclearance and the factors related to it in patients with chronic HBV infection followed up at the Hepatitis Outpatient Clinic of HCFMRP from 1992-2008.

Materials And Methods: A total of 548 patients with chronic HBV infection (366 with chronic hepatitis B and 182 inactive carriers) were followed for 15 years and 9 months with an annual measurement of HBV-DNA, ALT, AST and GGT (average of 4 annual determinations) and serology (HBsAg, HBeAg, Anti-HBeAg and Anti-HBsAg).

Results: Spontaneous HBsAg seroclearance occurred in 40 patients (7.3%) with a mean age of 46.0 ± 14.4 years, corresponding to an annual rate of 0.7%.The factors related to spontaneous HBsAg seroclearance were inactive carrier status (67.5 vs. 32.5%, p = 0.000191) and age of more than 40 years (p = 0.0007). There was no difference in the rate of spontaneous HBsAg seroclearance when comparing males and females (p = 0.383). Patients with spontaneous HBsAg seroclearance did not progress to more severe forms of the disease during follow-up.

Conclusion: Spontaneous HBsAg seroclearance has a favorable long-term prognosis in patients with chronic HBV infection. HBsAg seroclearance occurred at rates compatible with low prevalence areas and was associated with low serum HBV-DNA levels and an age older than 40 years.
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June 2015

CD44+/CD133+ immunophenotype and matrix metalloproteinase-9: Influence on prognosis in early-stage oral squamous cell carcinoma.

Head Neck 2014 Dec 29;36(12):1718-26. Epub 2014 Jan 29.

Vale do Rio Verde University (UninCor), Tres Coraçoes, Minas Gerais, Brazil.

Background: The purpose of this study was to investigate the expression of CD44 and/or CD133 immunophenotypes and the associated effects of matrix metalloproteinase-9 (MMP-9) in early-stage oral squamous cell carcinomas (SCC) to assess their influence on tumor prognosis.

Methods: The following data were derived from 150 patients: age, sex, primary anatomic site, smoking status, alcohol intake, recurrence, metastases, histological classification, treatment, disease-free survival (DFS), and overall survival (OS). Immunohistochemical study of CD44, CD133, and MMP-9 expression was performed on a tissue microarray of 150 paraffin blocks of oral SCCs.

Results: The predominant immunophenotype identified to exhibit a significant correlation with MMP-9 was the CD44+/CD133+. Multivariate analyses identified a significant correlation of OS with surgical treatment and with CD44+/CD133+ immunophenotype.

Conclusion: This investigation demonstrated the prognostic importance of CD44/CD133 expression, which can help improve the prognostic value of surgical treatment for oral SCCs when diagnosed in early stages.
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http://dx.doi.org/10.1002/hed.23527DOI Listing
December 2014

Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease.

Ann Nutr Metab 2013 19;63(3):193-9. Epub 2013 Sep 19.

Nutrology Division, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Background/aims: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by hepatic fat accumulation in the absence of alcohol consumption. Hyperhomocysteinemia is considered an independent risk factor for liver diseases, and the genetic polymorphisms C677T and A1298C in the MTHFR gene have been linked to hyperhomocysteinemia. The purpose of this study was to investigate serum homocysteine (Hcy) concentrations and the MTHFR C677T and A1298C polymorphisms as risk factors for the development of NAFLD.

Methods: One hundred and thirty-four Brazilian patients with biopsy-proven NAFLD and 134 healthy controls were recruited. The MTHFR C677T and A1298C polymorphisms were detected through polymerase chain reaction restriction fragment length polymorphism. Serum Hcy levels were determined by chemiluminescence.

Results: Serum Hcy levels were higher in NAFLD patients as compared to control subjects, but there were no differences between patients with steatosis and nonalcoholic steatohepatitis. The NAFLD and control groups did not differ in genotypic and allelic frequencies of the MTHFR C677T and A1298C polymorphisms, either. Elevated plasma Hcy levels were positively correlated with age in the NAFLD subjects.

Conclusion: The MTHFR C677T and A1298C polymorphisms are not genetic risk factors for the development of NAFLD. Higher Hcy levels exist in NAFLD subjects, but they are not associated with liver disease severity.
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http://dx.doi.org/10.1159/000353139DOI Listing
August 2014

Effects of α-tocopherol supplementation on liver of rats chronically exposed to ethanol.

J Nutrigenet Nutrigenomics 2013 10;6(3):125-36. Epub 2013 Aug 10.

Division of Nutrition, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Background/aims: Chronic alcoholism is characterized by hepatotoxicity associated with antioxidant and redox status imbalance. Continuous ethanol intake induces free radical synthesis, resulting in the depletion of antioxidants, especially α-tocopherol, which has an important role in lipid peroxidation. This study aimed to evaluate if α-tocopherol supplementation can restore liver phenotype in rats chronically exposed to ethanol.

Methods: α-Tocopherol levels were determined and histologic analysis of liver was performed. Hepatic gene expression was analyzed through oligonucleotide microarray and real-time PCR.

Results: Alcohol exposure for 6 weeks did not decrease hepatic α-tocopherol levels; however, both groups exposed to ethanol (supplemented or not with α-tocopherol) displayed fatty liver. The antioxidant supplementation prevented Mallory bodies and inflammatory infiltration, but not apoptosis, in liver of the rats exposed to ethanol. Gene expression analysis showed evidence of adaptive response to chronic alcohol consumption, where antioxidant components were not regulated. Nevertheless, differentially expressed genes reflected the change in cellular homeostasis.

Conclusion: The hepatic α-tocopherol content was coherent with the antioxidant gene expression in this study. Cells are likely to have adapted and restored their antioxidant status after long-term ethanol exposure, which might be the reason for such conflicting reports concerning α-tocopherol status in chronic alcoholism.
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http://dx.doi.org/10.1159/000354081DOI Listing
May 2014

Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients.

Gene 2013 Oct 24;529(2):326-31. Epub 2013 Jul 24.

Clinical Nutrition Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Pathology and Legal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD.

Methods: One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).

Results: NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP.

Conclusions: We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.
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http://dx.doi.org/10.1016/j.gene.2013.06.091DOI Listing
October 2013

Myenteric denervation in gastric carcinogenesis: differential modulation of nitric oxide and annexin-A1.

Int J Clin Exp Pathol 2013 20;6(1):13-23. Epub 2012 Nov 20.

Department of Anatomy, São José do Rio Preto School of Medicine-FAMERP São Paulo, SP, Brazil.

This study evaluated the properties of endogenous nitric oxide synthases (NOS) and annexin-A1 (ANXA1) and determined how they can be exploited in the N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and myenteric denervation model. Male Wistar rats were treated with MNNG and/or aminoguanidine (AG) for 20 weeks. In another set of experiments, rats with nondenervated and denervated stomachs were treated with MNNG or water for 28 weeks. Fragments of the pyloric region were processed for histopathology, NOS activity, and immunohistochemistry to explore the activity and expression of constitutive (cNOS) and inducible (iNOS) NO synthase and their relationship with annexin-A1 (ANXA1) expression. NO inhibition by AG increased the percentage of animals with adenocarcinomas (~29%) compared with the untreated MNNG group (~4%). Myenteric denervation did not alter NOS activity. cNOS activity was significantly greater in nondernervated and denervated stomachs with or without lesions (P<0.001) than iNOS activity (P<0.01), as confirmed by immunohistochemistry. Further, cNOS activity in normal stomachs and outside the lesion area was considerably higher than inside it (P<0.01). By densitometric analysis of nondenervated and denervated stomachs, ANXA1 expression was modulated in epithelial and inflammatory cells (mast cells and neutrophils), wherein significant alterations were induced by lesion development and myenteric denervation. In conclusion, NO protects against the development of gastric adenocarcinomas. The pattern of ANXA1 expression was not associated with NOS activity or expression, suggesting that NO and ANXA1 act in gastric tumors in disparate pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515986PMC
July 2013

Vitamin E alters inflammatory gene expression in alcoholic chronic pancreatitis.

J Nutrigenet Nutrigenomics 2012 8;5(2):94-105. Epub 2012 Aug 8.

Division of Nutrition, Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Objective: To evaluate the effect of vitamin E supplementation on pancreatic gene expression of inflammatory markers in rats with alcoholic chronic pancreatitis.

Methods: Wistar rats were divided into 3 groups: control (1), alcoholic chronic pancreatitis without (2) and with (3) vitamin E supplementation. Pancreatitis was induced by a liquid diet containing ethanol, cyclosporin A and cerulein. α-tocopherol content in plasma and liver and pancreas histopathology were analyzed. Gene expression of inflammatory biomarkers was analyzed by the quantitative real-time PCR technique.

Results: The animals that received vitamin E supplementation had higher α-tocopherol amounts in plasma and liver. The pancreas in Group 1 showed normal histology, whereas in Groups 2 and 3, mild to moderate tissue destruction foci and mononuclear cell infiltration were detected. Real-time PCR analysis showed an increased expression of all genes in Groups 2 and 3 compared to Group 1. Vitamin E supplementation decreased the transcript number of 5 genes (α-SMA, COX-2, IL-6, MIP-3α and TNF-α) and increased the transcript number of 1 gene (Pap).

Conclusion: Vitamin E supplementation had anti-inflammatory and beneficial effects on the pancreatic gene expression of some inflammatory biomarkers in rats with alcoholic chronic pancreatitis, confirming its participation in the inflammatory response mechanisms in the pancreas.
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http://dx.doi.org/10.1159/000336076DOI Listing
February 2013

Upregulation of soluble and membrane-bound human leukocyte antigen G expression is primarily observed in the milder histopathological stages of chronic hepatitis C virus infection.

Hum Immunol 2012 Mar 8;73(3):258-62. Epub 2011 Dec 8.

Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, CEP 59012-570, Brazil.

Chronic hepatitis C virus (HCV) infection is a worldwide health problem that may evolve to cirrhosis and hepatocellular carcinoma. Incompletely understood immune system mechanisms have been associated with impaired viral clearance. The nonclassical class I human leukocyte antigen G (HLA-G) molecule may downregulate immune system cell functions exhibiting well-recognized tolerogenic properties. HCV genotype was analyzed in chronic HCV-infected patients. Because HLA-G expression may be induced by certain viruses, we evaluated the presence of HLA-G in the liver microenvironment obtained from 89 biopsies of patients harboring chronic HCV infection and stratified according to clinical and histopathological features. Overall, data indicated that HCV genotype 1 was predominant, especially subgenotype 1a, with a prevalence of 87%. HLA-G expression was observed in 45 (51%) liver specimens, and it was more frequent in milder stages of chronic hepatitis (67.4%) than in moderate (27.8%; p = 0.009) and severe (36.0%; p = 0.021) stages of the disease. Altogether, these results suggest that the expression of HLA-G in the context of HCV is a complex process modulated by many factors, which may contribute to an immunologic environment favoring viral persistence. However, because the milder forms predominantly expressed HLA-G, a protective role of this molecule may not be excluded.
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http://dx.doi.org/10.1016/j.humimm.2011.12.004DOI Listing
March 2012

Fructose and NAFLD: metabolic implications and models of induction in rats.

Acta Cir Bras 2011 ;26 Suppl 2:45-50

FMRP, USP, Ribeirao Preto, SP, Brazil.

Purpose: The increase in fructose consumption is paralleled by a higher incidence of obesity worldwide. This monosaccharide is linked to metabolic syndrome, being associated with hypertriglyceridemia, hypertension, insulin resistance and diabetes mellitus. It is metabolized principally in the liver, where it can be converted into fatty acids, which are stored in the form of triglycerides leading to NAFLD. Several models of NAFLD use diets high in simple carbohydrates. Thus, this study aimed to describe the major metabolic changes caused by excessive consumption of fructose in humans and animals and to present liver abnormalities resulting from high intakes of fructose in different periods of consumption and experimental designs in Wistar rats.

Methods: Two groups of rats were fasted for 48 hours and refed for 24 or 48 hours with a diet containing 63% fructose. Another group of rats was fed an diet with 63% fructose for 90 days.

Results: Refeeding for 24 hours caused accumulation of large amounts of fat, compromising 100% of the hepatocytes. The amount of liver fat in animals refed for 48 hours decreased, remaining mostly in zone 2 (medium-zonal). In liver plates of Wistar rats fed 63% fructose for 45, 60 and 90 days it's possible to see that there is an increase in hepatocytes with fat accumulation according to the increased time; hepatic steatosis, however, is mild, compromising about 20% of the hepatocytes.

Conclusions: Fructose is highly lipogenic, however the induction of chronic models in NAFLD requires long periods of treatment. The acute supply for 24 or 48 hours, fasted rats can cause big changes, liver steatosis with macrovesicular in all lobular zones.
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http://dx.doi.org/10.1590/s0102-86502011000800009DOI Listing
June 2012

The role of tumor hypoxia in MUC1-positive breast carcinomas.

Virchows Arch 2011 Oct 3;459(4):367-75. Epub 2011 Sep 3.

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1α) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1α and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1α (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-κB (IκBα), driving NF-κB to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-κB expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-κB to the nucleus. Our data also support the notion that activation of HIF-1α in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.
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http://dx.doi.org/10.1007/s00428-011-1142-6DOI Listing
October 2011

Light and moderate doses of ethanol in chemical carcinogenesis of the colon in rats.

Nutr Cancer 2011 29;63(7):1029-35. Epub 2011 Aug 29.

Department of Pathology and Legal Medicine, Cell Proliferation Laboratory, Medicine School of Ribeirão Preto, University of São Paulo, Brazil.

The aberrant crypt foci (ACF), cyclooxygenase 2 (COX-2), and the proliferating cell nuclear antigen (PCNA) are putative biomarkers for colon cancer. To study the association between light (1 g of ethanol/kg bw) and moderate (3 g of ethanol/kg bw) doses of ethanol with the chemical carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), Wistar rats were divided into 6 groups. The colon fragments were collected for histochemical and immunohistochemical analyses, and the liver samples were collected for oxidative stress analysis, with products of lipid peroxidation (malondialdehyde), antioxidant enzymes (glutathione), and vitamin E. The association of light and moderate doses of ethanol with MNNG did not present differences in the oxidative parameters. However, a reduction in vitamin E levels in the carcinogen groups was observed. The association induced a reduction of the COX-2 and PCNA expression. The number of ACF in the group that received a light dose of ethanol had lower rates, while the group that received a moderate dose had the highest rates compared to the control MNNG, demonstrating that the light dose of ethanol could have a protective effect, while the moderate dose could represent a risk during chemical carcinogenesis in rats.
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http://dx.doi.org/10.1080/01635581.2011.596647DOI Listing
February 2012

Differential expression of HIF-1α in CD44+CD24-/low breast ductal carcinomas.

Diagn Pathol 2011 Aug 8;6:73. Epub 2011 Aug 8.

Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.

Background: Cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of tumor. Stem cells renewal and differentiation can be directly influenced by the oxygen levels of determined tissues, probably by the reduction of oxidative DNA damage in hypoxic regions, thus leading to a friendlier microenvironment, regarding to clonal expansion and for resistance to chemotherapeutic regimens. Furthermore, there have been strong data indicating a pivotal role of hypoxic niche in cancer stem cells development. There are evidence that hypoxia could drive the maintenance of CSC, via HIF-1α expression, but it still to be determined whether hypoxia markers are expressed in breast tumors presenting CD44+CD24-/low immunophenotype.

Methods: Immunohistochemical analysis of CD44+CD24-/low expression and its relationship with hypoxia markers and clinical outcome were evaluated in 253 samples of breast ductal carcinomas. Double-immunolabeling was performed using EnVision Doublestain System (Dako, Carpinteria, CA, USA). Slides were then scanned into high-resolution images using Aperio ScanScope XT and then, visualized in the software Image Scope (Aperio, Vista, CA, USA).

Results: In univariate analysis, CD44+CD24-/low expression showed association with death due to breast cancer (p = 0.035). Breast tumors expressing CD44+CD24-/low immunophenotype showed relationship with HIF-1α (p = 0.039) and negativity for HER-2 (p = 0.013).

Conclusion: Considering that there are strong evidences that the fraction of a tumour considered to be cancer stem cells is plastic depending upon microenvironmental signals, our findings provide further evidence that hypoxia might be related to the worse prognosis found in CD44+CD24-/low positive breast tumors.
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http://dx.doi.org/10.1186/1746-1596-6-73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170242PMC
August 2011

Clinical, demographic and epidemiological characteristics of patients with hepatitis B followed at a university hospital in southeastern Brazil: predominance of HBeAg negative cases.

Rev Soc Bras Med Trop 2011 Jan-Feb;44(1):13-7

Department of Medicine, Federal University of São Carlos, São Carlos, SP, Brazil.

Introduction: Hepatitis B is common in Brazil, although there are regional differences regarding the degree of endemicity, the most frequent forms of transmission and the presence of different evolutive stages of chronic disease. The present study aimed to determine the clinical, demographic and epidemiological characteristics of patients chronically infected with hepatitis B virus (HBV) residing in the Ribeirão Preto region, southeastern Brazil.

Methods: A total of 529 medical records of individuals with HBV monoinfection were reviewed.

Results: More than 60% of the subjects were males, with a mean age of 38 years-old. The HBeAg-negative serological pattern was verified in 84.4% of the patients, among whom the risk of vertical/intrafamily transmission was 43.2% (p = 0.02). The consumption of alcohol in amounts exceeding 20 g a day was observed in 21.3% of the subjects and was more frequent among men (33%) (p < 0.001). Among patients with cirrhosis, 54.1% were alcohol abusers (p = 0.04), all of them males. The presence of cirrhosis was more frequent in the HBeAg-positive group (24.4%) than in the HBeAg-negative group (10.2%) (p < 0.001).

Conclusions: High proportions of HBV-infected subjects with an HBeAg-negative pattern were observed, with a higher risk of vertical/intrafamily transmission. Alcohol abuse was associated with male subjects and with cirrhosis of the liver in this group. A tendency toward an increase in the number of HBeAg-negative cases was observed over time.
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http://dx.doi.org/10.1590/s0037-86822011000100004DOI Listing
September 2011

Experimental induction of steatosis in different tissues after the ingestion of a carbohydrate-rich diet: effect on the liver, on the heart and on indicators of oxidation.

Arq Gastroenterol 2010 Oct-Dec;47(4):388-92

Departamento de Clínica Médica/Nutrologia, Universidade de São Paulo – SP, Brazil.

Context: The western dietary pattern is characterized by a high calorie intake with a high proportion of simple sugars. This diet is associated with comorbidities such as hepatic fat deposition and is possibly related to non-alcoholic fatty liver disease.

Objective: To evaluate the capacity of a hyperglucidic diet to induce steatosis in adult male Wistar rats. After the administration of a carbohydrate-rich diet, we also evaluated the presence of hepatic and cardiac steatosis and the levels of intrinsic antioxidants in the liver.

Methods: Forty-six eutrophic adult male Wistar rats were used and 10 of them were chosen, at random, to serve as controls, while the remaining ones formed the experimental group. Control animals received the standard ration offered by the animal house and the experimental group received the hyperglucidic diet. The diets were offered for 21 days and, at the end of this period, tissue samples were collected for analysis of indicators of oxidative stress (malondialdehyde, and reduced glutathione) and of vitamin E. The animals were then sacrificed by decapitation and their viscera were removed for analysis of liver and heart fat.

Results: The hyperglucidic diet used induced hepatic fat deposition, with lipid vacuoles being detected in 83% of the livers analyzed by histology. No lipid vacuoles were observed in the heart. Malondialdehyde and reduced glutathione levels remained unchanged when the animals were submitted to the hyperglucidic diet, probably because there was no liver development of fibrosis or inflammation. In contrast, the levels of vitamin E (antioxidant) were reduced, as confirmed in the literature for steatotic animals.

Conclusion: The hyperglucidic diet induced hepatic steatosis. In the heart there was an increase in fat content, although no histological changes were observed. These alterations cannot be explained by the presence of malondialdehyde or reduced glutathione (indicators of oxidation), since the values were similar in the groups studied. However, a significant reduction of vitamin E was observed in the experimental group.
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http://dx.doi.org/10.1590/s0004-28032010000400013DOI Listing
August 2011

Myenteric denervation downregulates galectin-1 and -3 expression in gastric carcinogenesis.

Dig Dis Sci 2011 Jun 29;56(6):1637-44. Epub 2010 Dec 29.

Department of Anatomy, São José do Rio Preto School of Medicine, FAMERP, Avenida Brigadeiro Faria Lima 5416, São José do Rio Preto, 15090-000 São Paulo, Brazil.

Background: This study evaluated the galectin-1 and -3 expression during N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis in denervated rat stomachs using benzalkonium chloride.

Method: Four experimental situations were evaluated: nondenervated and denervated stomachs without lesions and nondenervated and denervated stomachs with lesions. Sections of the pyloric region were stained with toluidine blue and incubated with mouse monoclonal anti-Gal-1 and rabbit polyclonal anti-Gal-3 for histopathological and immunohistochemical analysis, respectively.

Result: MNNG caused the development of benign and malignant epithelial lesions, which were more pronounced in nondenervated stomachs with lesions and accompanied by inflammatory cell-enriched stroma. By immunostaining, the epithelial cells, blood vessels, muscle layer, and myenteric plexus were Gal-1 and -3 positive. Gal-3 was also detected in the gastric crypts, mucus secretion, and fibroblasts of pyloric fragments. Development of lesions in denervated stomachs was associated with a significant decrease in Gal-1 and -3 expression in epithelial cells, mast cells, and neutrophil cytoplasm, compared with that of nondenervated stomach lesions (P < 0.01; P < 0.001; P < 0.001, respectively).

Conclusion: These results demonstrate that myenteric denervation downregulates endogenous Gal-1 and -3 expression, which might inhibit tumor development in this experimental model.
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http://dx.doi.org/10.1007/s10620-010-1516-7DOI Listing
June 2011

Cancer stem cell immunophenotypes in oral squamous cell carcinoma.

J Oral Pathol Med 2011 Feb 15;40(2):135-42. Epub 2010 Nov 15.

Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Background: The presence of cancer stem cell (CSC) antigens can be evidenced in some human tumors by phenotypic analysis through immunostaining. This study aims to identify a putative CSC immunophenotype in oral squamous cell carcinoma (OSCC) and determine its influence on prognosis.

Methods: The following data were retrieved from 157 patents: age, gender, primary anatomic site, smoking and alcohol intake, recurrence, metastases, histologic classification, treatment, disease-free survival (DFS), and overall survival (OS). An immunohistochemical study for CD44 and CD24 was performed in a tissue microarray of 157 paraffin blocks of OSCCs.

Results: In univariate analysis, the immunostaining pattern showed significant influences in relation to OS for alcohol intake and treatment, as well as for the CD44(+) and CD44(-) /CD24(-) immunophenotypes. The multivariate test confirmed these associations.

Conclusions: Based on our results, the CD44 immunostaining and the absence of immunoexpression of these two investigated markers can be used in combination with other clinicopathologic information to improve the assessment of prognosis in OSCC.
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http://dx.doi.org/10.1111/j.1600-0714.2010.00967.xDOI Listing
February 2011

Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon.

Braz J Infect Dis 2010 Jul-Aug;14(4):330-4

Department of Medicine, Ribeirão Preto University Hospital, Universidade de São Paulo, SP, Brazil.

Background And Aim: The durability of the sustained virologic response (SVR) in patients with chronic hepatitis C after treatment and the ideal follow-up time for these patients remains undefined. The objective of the study was to evaluate the durability of the virologic response in patients with chronic hepatitis C followed up for at least 12 months after SVR at HCFMRP-USP.

Methods: The study was conducted on 174 patients with chronic hepatitis C treated with different antiviral regimens who had achieved SVR. Qualitative serum HCV-RNA was determined by the commercial kit (COBAS AMPLICOR HCV, v2.0).

Results: There was predominance of male (73%) with a mean age of 45.6 ± 10 years. Liver cirrhosis was present in 16.1% of the study subjects. Mean follow-up time after SVR was 47 months (12-156 months). Twenty-two patients received monotherapy with interferon; 94 received interferon plus ribavirin, and 58 received pegylated interferon plus ribavirin. A total of 134 patients (77.0%) received one treatment course, 29 (16.7%) received two courses, and 11 (6.3%) received three courses. The distribution of HCV genotypes was: genotype 1 (40.2%), genotype 3 (40.8%) and genotype 2 (10.3%). Genotype was undetermined in 8.7% of cases. None of the 174 patients had recurrence of HCV infection. Two cirrhotic patients developed hepatocellular carcinoma (HCC) during follow-up.

Conclusions: Among patients with SVR there was no recurrence of HCV infection or evidence of liver disease progression in any patient followed up for a mean of 47 months after SVR, except for patients with advanced hepatic disease before treatment, who may develop HCC despite SVR. Therefore, one can assume that SVR is associated with long term good prognosis.
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http://dx.doi.org/10.1590/s1413-86702010000400003DOI Listing
March 2011

Relationship between plasma cells and hepatic stellate cells in autoimmune hepatitis.

Pathol Res Pract 2010 Dec;206(12):800-4

Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

Autoimmune hepatitis is an inflammatory chronic disease of the liver, which frequently results in cirrhosis. The present study aimed to verify the relationship between plasma cells and stellate cells in autoimmune hepatitis. Thirty-three pre-treatment, 11 post-treatment, and 10 normal liver biopsies were reviewed. Sirius Red staining (for semi-quantitative analysis of hepatic fibrosis) and immunohistochemistry were carried out: double staining for smooth muscle α-actin and plasma cell marker (for detection and localization of activated hepatic stellate cells and plasma cells, respectively); and single staining for glial fibrillary acid protein (for detection of hepatic stellate cells). We found an increase in the stellate cell population, mainly with an activated phenotype in autoimmune hepatitis, compared to the control group (liver specimens with no histological evidence of liver disease, obtained from patients undergoing hepatic resection for benign liver mass). A positive significant correlation was observed between stellate cells and scores of fibrosis (measured by Sirius Red) and the number of plasma cells. Additionally, there was a co-localization of plasma cells and activated stellate cells. We also observed a reduction in the number of plasma cells, hepatic stellate cells, and fibrosis in patients who had successfully been treated and had a second liver biopsy post-treatment. Our findings support that the number of plasma cells can be a surrogate marker for the severity of liver disease, reflecting the number of hepatic stellate cells and the amount of fibrosis. It remains to be seen if this is a result of a direct interaction between the plasma cells and hepatic stellate cells or the response to the same stimulus that affects both cellular types.
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http://dx.doi.org/10.1016/j.prp.2010.08.002DOI Listing
December 2010

A BALB/c mouse model shows that liver involvement in dengue disease is immune-mediated.

Exp Mol Pathol 2010 Dec 29;89(3):321-6. Epub 2010 Jul 29.

Program of Graduate Studies on Applied and Basic Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

In the present study, BALB/c mice were used to develop a model for the hepatic injury associated to dengue infection. Histological analysis after subcutaneous inoculation with a low viral dose of dengue-2 virus showed Kupffer cell hyperplasia and an increased inflammatory cellular infiltrate next to the bile ducts on days 5, 7 and 14 post-inoculation, mainly characterized by the presence of mononuclear cells. The liver mRNA transcription level of IL-1β was highest on the 5th day post-infection (p.i.) and decreased by the 21st day, TNF-α showed a peak of mRNA transcription after 14 days p.i. coinciding with the regression of cellular infiltrates and elevated expression of TGF-β mRNA. Serum AST and ALT levels were slightly elevated at 7 and 14 days post-infection. Dengue-2 RNA levels were undetectable in the liver on any of the days following inoculation. Our observations suggest that, as it is true for humans, the animals undergo a transient and slight liver inflammation, probably due to local cytokine production and cellular infiltration in the liver.
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http://dx.doi.org/10.1016/j.yexmp.2010.07.007DOI Listing
December 2010

Effects of myenteric denervation on extracellular matrix fibers and mast cell distribution in normal stomach and gastric lesions.

Cancer Cell Int 2010 Jun 22;10:18. Epub 2010 Jun 22.

Department of Anatomy, School of Medicine - FAMERP, Avenida Brigadeiro Faria Lima 5416, CEP 15090-000, São José do Rio Preto, SP, Brazil.

Background: In this study the effect of myenteric denervation induced by benzalconium chloride (BAC) on distribution of fibrillar components of extracellular matrix (ECM) and inflammatory cells was investigated in gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Rats were divided in four experimental groups: non-denervated (I) and denervated stomach (II) without MNNG treatment; non-denervated (III) and denervated stomachs (IV) treated with MNNG. For histopathological, histochemical and stereological analysis, sections of gastric fragments were stained with Hematoxylin-Eosin, Picrosirius-Hematoxylin, Gomori reticulin, Weigert's Resorcin-Fuchsin, Toluidine Blue and Alcian-Blue/Safranin (AB-SAF).

Results: BAC denervation causes an increase in the frequency of reticular and elastic fibers in the denervated (group II) compared to the non-denervated stomachs (group I). The treatment of the animals with MNNG induced the development of adenocarcinomas in non-denervated and denervated stomachs (groups III and IV, respectively) with a notable increase in the relative volume of the stroma, the frequency of reticular fibers and the inflammatory infiltrate that was more intense in group IV. An increase in the frequency of elastic fibers was observed in adenocarcinomas of denervated (group IV) compared to the non-denervated stomachs (group III) that showed degradation of these fibers. The development of lesions (groups III and IV) was also associated with an increase in the mast cell population, especially AB and AB-SAF positives, the latter mainly in the denervated group IV.

Conclusions: The results show a strong association in the morphological alteration of the ECM fibrillar components, the increased density of mast cells and the development of tumors induced by MNNG in the non-denervated rat stomach or denervated by BAC. This suggests that the study of extracellular and intracellular components of tumor microenvironment contributes to understanding of tumor biology by action of myenteric denervation.
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http://dx.doi.org/10.1186/1475-2867-10-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908609PMC
June 2010

The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C.

Eur J Gastroenterol Hepatol 2010 Oct;22(10):1204-10

Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Background: Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients.

Aim: To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C.

Methods: Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations.

Results: Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. CONCLUSION THE: H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits.
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http://dx.doi.org/10.1097/MEG.0b013e32833bec1eDOI Listing
October 2010

Co-infection with paracoccidioidomycosis and human immunodeficiency virus: report of a case with esophageal involvement.

Am J Trop Med Hyg 2010 Jun;82(6):1099-101

Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Paracoccidioiodomycosis (PCM) is a systemic and deep mycosis endemic in Latin America, especially in Brazil. In patients infected with human immunodeficiency virus (HIV), PCM can manifest with prominent involvement of the reticuloendothelial system. There are no reports in the literature of esophageal involvement by PCM in that population. We report a case of PCM with pulmonary and esophageal involvement without radiologic evidence of an esophageal-bronchial fistula in an HIV-infected patient.
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http://dx.doi.org/10.4269/ajtmh.2010.09-0751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877417PMC
June 2010

Esophageal ulcer in Brazilian patients with HIV: prevalence and comparative analysis among diagnostic methods.

AIDS Patient Care STDS 2010 May;24(5):311-6

Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Esophageal ulcer (EU) represents an important comorbidity in AIDS. We evaluated the prevalence of EU, the accuracy of the endoscopic and histologic methods used to investigate viral EU in HIV-positive Brazilian patients and the numerical relevance of tissue sampling. A total of 399 HIV-positive patients underwent upper gastrointestinal (UGI) endoscopy. HIV-positive patients with EU determined by UGI endoscopy followed by biopsies were analyzed by the hematoxylin-eosin (HE) and immunohistochemical (IH) methods. EU was detected in 41 patients (mean age, 39.2 years; 23 males), with a prevalence of 10.27%. The median CD4 count was 49 cells/mm(3) (range, 1-361 cells/mm(3)) and the viral load was 58,869 copies per milliliter (range, 50-77,3290 copies per milliliter). UGI endoscopy detected 29 of 41 EU suggestive of cytomegalovirus (CMV) infection and 7 of 41 indicating herpes simplex virus (HSV) infection. HE histology confirmed 4 of 29 ulcers induced by CMV, 2 of 7 induced by HSV, and 1 of 7 induced by HSV plus CMV. IH for CMV and HSV confirmed the HE findings and detected one additional CMV-induced case. UGI endoscopy showed 100% sensitivity and 15% specificity for the diagnosis of EU due to CMV or HSV compared to HE and IH. HE proved to be an adequate method for etiologic evaluation, with 87% sensitivity and 100% specificity compared to IH. The number of samples did not influence the etiologic evaluation. The data support the importance of IH as a complementary method for HE in the diagnosis of EU of viral etiology.
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http://dx.doi.org/10.1089/apc.2009.0299DOI Listing
May 2010

Slight activation of nuclear factor kappa-B is associated with increased hepatic stellate cell apoptosis in human schistosomal fibrosis.

Acta Trop 2010 Jan 23;113(1):66-71. Epub 2009 Sep 23.

Department of Pathology and Legal Medicine of Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil.

To investigate the relationship between NF-kappaB activation and hepatic stellate cell (HSC) apoptosis in hepatosplenic schistosomiasis, hepatic biopsies from patients with Schistosoma mansoni-induced periportal fibrosis, hepatitis C virus-induced cirrhosis, and normal liver were submitted to alpha-smooth muscle actin (alpha-SMA) and NF-kappaB p65 immunohistochemistry, as well as to NF-kappaB Southwestern histochemistry and TUNEL assay. The numbers of alpha-SMA-positive cells and NF-kappaB- and NF-kappaB p65-positive HSC nuclei were reduced in schistosomal fibrosis relative to liver cirrhosis. In addition, increased HSC NF-kappaB p65 and TUNEL labeling was observed in schistosomiasis when compared to cirrhosis.These results suggest a possible relationship between the slight activation of the NF-kappaB complex and the increase of apoptotic HSC number in schistosome-induced fibrosis, taking place to a reduced HSC number in schistosomiasis in relation to liver cirrhosis. Therefore, the NF-kappaB pathway may constitute an important down-regulatory mechanism in the pathogenesis of human schistosomiasis mansoni, although further studies are needed to refine the understanding of this process.
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http://dx.doi.org/10.1016/j.actatropica.2009.09.008DOI Listing
January 2010

Progression of lipid peroxidation measured as thiobarbituric acid reactive substances, damage to DNA and histopathological changes in the liver of rats subjected to a methionine-choline-deficient diet.

Basic Clin Pharmacol Toxicol 2009 Sep 10;105(3):150-5. Epub 2009 Jun 10.

Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Methionine-choline-deficient diet represents a model for the study of the pathogenesis of steatohepatitis. Male rats were divided into three groups, the first group receiving a control diet and the other two groups receiving a methionine-choline-deficient diet for 1 month (MCD1) and for 2 months (MCD2), respectively. The livers of the animals were collected for the determination of vitamin E, thiobarbituric acid reactive substances (TBARS), GSH concentration, DNA damages, and for histopathological evaluation. The hepatic TBARS and GSH content was higher (P < 0.05) in the groups receiving the experimental diet (MCD1 and MCD2) compared to control diet, and hepatic vitamin E concentration differed (P < 0.05) between the MCD1 and MCD2 groups, with the MCD2 group presenting a lower concentration. Damage to hepatocyte DNA was greater (P < 0.05) in the MCD2 group (262.80 DNA injuries/100 hepatocytes) compared to MCD1 (136.4 DNA injuries/100 hepatocytes) and control diet (115.83 DNA injuries/100 hepatocytes). Liver histopathological evaluation showed that steatosis, present in experimental groups was micro- and macro-vesicular and concentrated around the centrolobular vein, zone 3, with preservation of the portal space. The inflammatory infiltrate was predominantly periductal and the steatosis and inflammatory infiltrate was similar in the MCD1 and MCD2 groups, although the presence of Mallory bodies was greater in the MCD2 group. The study describes the contribution of a methionine-choline-deficient diet to the progression of steatosis, lipid peroxidation and hepatic DNA damage in rats, serving as a point of reflection about the role of these nutrients in the western diet and the elevated non-alcoholic steatohepatitis rates in humans.
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http://dx.doi.org/10.1111/j.1742-7843.2009.00394.xDOI Listing
September 2009