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BackgroundEndometriosis is regarded as a complex and heterogeneous disease in which genetic and environmental factors contribute to the phenotype. The Vascular Endothelial Growth Factor (VEGF) plays important roles in the pathogenesis of endometriosis. The present study was aimed at investigating the contribution of VEGF polymorphisms as risk factors for the development of endometriosis. This is the first study to evaluate the combined influence of the five most common VEGF polymorphisms.MethodsThis study was conducted at two hospitals from the Brazilian public health system, and comprised 294 women submitted to laparoscopic or laparotomy surgery: 182 patients had a histologically confirmed diagnosis of endometriosis (cases), whereas 112 had no evidence of the disease (controls). The VEGF polymorphisms were determined by TaqMan real-time polymerase chain reaction. The odds ratio (OR) with their 95% confidence intervals (CI) were calculated using an unconditional logistic regression model.ResultsEndometriosis patients and controls did not differ regarding age distribution, whereas the body mass index was significantly lower in endometriosis patients, when compared with controls (23.1 ± 3.9 versus 27.3 ± 5.9, P < 0.001). The evaluation of gynecological symptoms, including dysmenorrhea, non-cyclic chronic pelvic pain, dyspareunia and infertility, indicates significantly higher prevalences among endometriosis cases. The variant allele -1154A was significantly associated with endometriosis, either considering all cases (OR: 1.90, 95% CI: 1.23–2.97), deep infiltrating endometriosis (DIE) (OR: 1.83, 95% CI: 1.16-2.90) or moderate and severe endometriosis (stages III-IV) (OR: 1.97, 95% CI: 1.21-3.19). No significant differences were found in allele or genotype distributions of the –2578C > A, -460 T > C, +405G > C and +936C > T polymorphisms between endometriosis cases and controls. A total of six haplotypes were inferred derived from four polymorphisms (-2578C > A, -460 T > C, -1154G > A and +405G > C). There was a protective association between CCGG haplotype and endometriosis, either considering all cases (OR: 0.36, 95% CI: 0.15–0.86), DIE (OR: 0.37 95% CI: 0.15 – 0.90) or stages III-IV (OR: 0.35 95% CI: 0.13 – 0.95).ConclusionsThe present results indicate a positive association between VEGF -1154G > A and the risk of developing endometriosis, whereas the CCGG haplotype may be protective against the development of disease.

Crigler-Najjar type 1 disease (CN-1) is a genetic disorder characterized by high levels of unconjugated bilirubin due to the absence of hepatic UDPglucuronosyltransferase (UGT1) activity. Here we show that in vivo neonatal hepatocyte transduction with a lentiviral vector expressing the defective enzyme resulted in long-term correction in Gunn rats, a model of CN-1. Lentiviral vectors harboring the human UGT1 cDNA (approved symbol UGT1A1) under the control of a liver-specific transthyretin promoter were produced. Two-day-old Gunn rats were injected with 50 microl of vector. Bilirubinemia was monitored at 6 weeks and monthly thereafter. At 6 weeks, bilirubinemia was completely normalized in treated animals, whereas it remained around 100 microM in control rats. The level of correction remained stable for up to 42 weeks. Large amounts of bilirubin conjugates were present in the bile of corrected animals. PCR and Western blots confirmed the presence and expression of UGT1 in liver. The estimated proportion of transduced hepatocytes was 40% and transduced cells were not detected in extrahepatic tissues except bone marrow in some animals. This work represents the first demonstration of a complete and permanent correction of hyperbilirubinemia in Gunn rats using lentiviral vectors.

No predictor of NASH was found. Surgeons' evaluation could not identify NASH individuals. Routine liver biopsy during bariatric operations is mandatory to differentiate NASH and nonalcoholic fatty liver disease.

Purpose: Liver ischemia-reperfusion injury is a phenomenon presents in events like liver resections and transplantation. The restoration of blood flow may leads to local and systemic injury. Several techniques have been developed in order to avoid or ameliorate ischemia-reperfusion injury in clinical situations. The application of a sttuter reperfusion after the ischemic event (postconditioning) could alters the hydrodynamics and stimulates endogenous mechanisms that attenuate the reperfusion injury. The present study was designed to evaluate the potential protective effect of postconditioning in a model of ischemia-reperfusion in rats. Methods: Hepatic anterior pedicle of median and left anterolateral segments were exposed and clamped for 1 hour. Two hours later, clamp was released in two different ways: Control Group (n=7): clamp was release straightforward; Postconditioning Group (n=7): clamp was released intermittently. Lipid peroxidation (malondialdehyde) and expression of the glutathione-s-transferase--3 gene were studied. Results: Lipid peroxidation was significantly decreased in ischemic and non-ischemic liver by postconditioning. GST-3 gene was overexpressed in postconditioned group, but not significantly. Conclusion: Postconditioning induced hepatoprotection by reducing lipid peroxidation in the ischemic and non-ischemic liver. Key words: Liver. Ischemia. Reperfusion. Lipid Peroxidation. Rats. RESUMOObjetivo: A lesão de isquemia-reperfusão hepática é um fenômeno presente em eventos tais como ressecções hepáticas e transplante de fígado. A restauração do fluxo sangüíneo após a isquemia gera lesões locais e sistêmicas. Várias técnicas foram desenvolvidas com o objetivo de evitar ou diminuir a lesão de isquemia-reperfusão hepática em situações clínicas. A utilização da reperfusão intermitente após o evento isquêmico (pós-condicionamento) pode alterar a hidrodinâmica e estimular mecanismos endógenos que atenuam o dano da reperfusão. O presente estudo foi realizado para avaliar o potencial efeito protetor do pós-condicionamento em um modelo de isquemia-reperfusão em ratos. Métodos: O pedículo dos lobos mediano e ântero-lateral foi isolado e clampeado por 1 hora. Após 2 horas, o pedículo foi liberado de duas maneiras diferentes: Grupo Controle (n=7): clampe liberado de uma só vez; Grupo Pós-condicionamento (n=7): clampe liberado de maneira intermitente. Malondialdeído (MDA) e expressão do gene GST-3 foram estudadas nos grupos. Resultados: A peroxidação lipídica foi significativamente diminuída no fígado isquêmico e no fígado não isquêmico pelo pós-condicionamento. A expressão do gene GST-3 aumentou, porém não significativamente, no grupo pós-condicionamento. Conclusão: O pós-condicionamento induziu hepatoproteção pela redução da peroxidação lipídica nos fígados isquêmico e não isquêmico. Descritores: Fígado. Isquemia. Reperfusão. Peroxidação de Lipídeos. Ratos.

Survivin immunoexpression in NASH-related HCC is herein originally found substantially different than in HCC related to other causes, thus requiring further studies to elucidate the role of survivin in human NAFLD progression.

Crigler-Najjar type 1 disease (CN1) is a rare inherited metabolic disease characterized by complete absence of hepatic UDP-glucuronosyl transferase (UGT1), resulting in high levels of unconjugated bilirubin. CN1 is an attractive candidate disease for gene therapy. Here we show that in vivo neonatal hepatocyte transduction using recombinant oncoretroviral vectors results in long-term and complete phenotype correction in Gunn rats, a model for CN1. Two-day-old newborn Gunn rats were injected via the temporal vein with 200 L UGT1 or control ␤-galactosidase retroviral vectors. In UGT1-injected animals, bilirubinemia was normal at 6 weeks (3 mol/L) and remained in the normal range (i.e., <10 mol/L) for more than 34 weeks. In contrast, in ␤-galactosidase-injected animals as well as in noninjected controls, bilirubinemia remained at a high level (i.e., >100 mol/L) during the whole experimental follow-up. Large amounts of bilirubin monoglucuronides and diglucuronides were present in the bile of treated animals. Finally, polymerase chain reaction and reverse transcription polymerase chain reaction analysis as well as Western blot confirmed the presence and expression of UGT1 almost exclusively in the liver. The estimated proportion of transduced hepatocytes was in the range of 5% to 10%. In conclusion, complete and permanent correction of hyperbilirubinemia in newborn Gunn rats using retroviral vectors can be obtained, paving the way for future gene therapy for CN1. (HEPATOLOGY 2005;42: 431-438.) T he liver is an attractive target for gene therapy for several reasons. It is the site of many metabolic pathways and thus is involved in many inborn metabolism errors. It is a unique organ that is readily accessible via the bloodstream through a fenestrated endothelium. Finally, it is a large homogenous organ in which the effectiveness of in vivo liver transduction is easily monitored. Type 1 Crigler-Najjar disease (CN1) is a rare (1 in 1,000,000 births) recessive inherited genetic disorder that is an attractive candidate for gene replacement therapy. CN1 is characterized by marked accumulation of unconjugated bilirubin in the plasma. Bilirubin is a potentially toxic lipophilic waste, and hepatic conjugation to glucuronic acid (glucuronidation) is required for efficient excretion of bilirubin. Glucuronidation of bilirubin is catalyzed predominantly by 2 isoforms of the uridine diphospho-glucuronosyl transferase gene family (UGT1), the most potent isoform being UGT1A1, also known as bilirubin glucuronosyl transferase (B-UGT1; E.C. 2.4.1.17). These 2 isoforms, as well as 10 other isoforms responsible for the conjugation of various compounds, are expressed from a common locus on chromosome 2 spanning 500 kb. All 12 isoforms of the UGT1 locus are composed of 5 exons generated by alternative splicing. The four 3Ј exons encoding the C terminal part of the protein are identical between all isoforms. In contrast, each isoform has a unique 5Ј exon and hence a unique N terminus. 1,2 Genetic lesions in any of the four 3Ј exons that en...

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