Reduced expression of uncoupling proteins-2 and -3 in adipose tissue in post-obese patients submitted to biliopancreatic diversion

OBJECTIVE: Little is known about the physiological role and the regulation of uncoupling proteins-2 and -3 (UCP-2 and -3) in adipose tissue. We investigated whether the expression of UCP-2 and -3 in adipose tissue was affected by weight loss due to a biliopancreatic diversion (BPD) and related to the daily energy expenditure (24-h EE). DESIGN: Ten morbidly obese subjects (mean body mass index +/- s.e.m.=49.80 +/- 2.51 kg/m(2)) were studied before and 18+/-2 Months after BPD. METHODS: We determined body composition using tritiated water and 24-h EE in a respiratory chamber. Adipose tissue UCP-2 and -3 mRNA, plasma insulin, glucose, free fatty acids (NEFA), free triiodothyronine (FT3), free thyroxine (FT4) and leptin were assayed before and after BPD. RESULTS: BPD treatment resulted in a marked weight loss (P<0.001) mainly due to a fat mass reduction. A significant decrease in 24-h EE/fat-free mass (FFM) (P<0.05) and in UCP-2 (P<0.05) and UCP-3 (P<0.05) mRNA was observed. A significant reduction in plasma insulin, glucose, NEFA, FT3, FT4 and leptin was seen after BPD. The decline in plasma leptin and FFA was tightly correlated with the decrease in both UCP-2 and -3. A significant correlation was found between changes in FT3 and variations in 24-h EE (r=0.64, P<0.05). In a multiple-regression analysis changes in 24-h EE/FFM after BPD were significantly correlated with changes in UCP-3 expression (P<0.05). CONCLUSION: These findings suggest that UCPs in adipose tissue may play a role in the reduction in 24-h EE observed in post-obese individuals.     

The Correlation of Il28B Genotype With Sustained Virologic Response In Romanian patients With Chronic Hepatitis C

Background

Multiple variables influencing the sustained virologic response (SVR) in chronic hepatitis C have been evaluated. One of them is genetic polymorphism near the IL28B gene.

Objectives

The aim of this study was to evaluate the influence of IL28B genotypes on SVR rates in a group of patients with chronic hepatitis C from the western part of Romania.

Patients and Methods

A retrospective study was performed in 107 consecutive patients, previously treated with standard-of-care medication for chronic hepatitis C, identified from the databases of 2 centers. Patient demographics, viral load before treatment and at 12, 24, and 72 weeks from the treatment start, and IL28B genotype were evaluated.

Results

Among the 107 patents in the study group, 54 patients had SVR (50.5%), and 62 (57.9%) showed a complete early virologic response (cEVR). The SVR rates according to IL28B genotype were as follows: 73.1% in patients with genotype C/C, 40.9% in those with genotype C/T, and 57.1% in those with genotype T/T (i.e., 73.1% among patients with the C/C genotype vs. 43.7% among those with non-C/C genotypes; P = 0.0126). The cEVR rates were 80.8% in patients with the C/C genotype vs. 51.2% in those with non-C/C genotypes (P = 0.011).

Conclusions

In our cohort of 107 Caucasian HCV patients, the SVR rate was 50.5% with standard-of-care treatment. The SVR rate was directly related to the IL28B genotype: 73.1% in the C/C genotype vs. 43.7% in non-C/C genotypes (P = 0.0126).     

Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial

No proven treatment exists for nonalcoholic fatty liver disease (NAFLD) in children and adolescents. We sought to determine the efficacy of lifestyle intervention with or without antioxidant therapy in pediatric NAFLD. A total of 53 patients (age 5.7-18.8 years, 37 boys) were included. Lifestyle intervention consisting of a diet tailored to the patient's calorie needs, and increased physical activity was prescribed in all. Patients were concomitantly randomized to alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day (n = 25) or placebo (n = 28), and treated for 24 months. The study was an extension of a previous study aimed at evaluating the effect of 12-month lifestyle intervention and antioxidant therapy on serum levels of aminotransferases. The primary end point of the present study was change in liver histology on repeated biopsy at 24 months. Secondary end points were changes in body weight, liver enzymes, and insulin sensitivity indices on 2-hour oral glucose tolerance test. The amount of weight lost at 24 months was similar in the placebo and antioxidant groups (-4.75 [range, -16-4.0] versus -5.5 [range, -12.2-0.4] kg, respectively, P = 0.9). A significant improvement occurred in the grade of steatosis, lobular inflammation, and hepatocyte ballooning, and in the NAFLD activity score in both groups. Levels of aminotransferases, triglycerides, cholesterol, fasting glucose, and insulin, and insulin sensitivity indices improved significantly as well. The improvement in all these parameters was not significantly different between the two groups. CONCLUSION: Lifestyle intervention with diet and increased physical activity induces weight loss and is associated with a significant improvement in liver histology and laboratory abnormalities in pediatric NAFLD. Alpha-tocopherol plus ascorbic acid does not seem to increase the efficacy of lifestyle intervention alone.     

Impact of female sex on long-term outcomes in patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention

Background

Conflicting information exists about whether sex differences affect long-term outcomes in patients undergoing primary percutaneous coronary intervention (PCI).

Methods

This retrospective study enrolled consecutive patients with ST-elevation myocardial infarction undergoing primary PCI within 24 hours from symptom onset. Hazard ratios (HRs) of events with 95% confidence interval (CI) were calculated in the overall population and in a propensity score matched cohort of women and men.

Results

Among 481 patients, median age 66 years old, 138 (28.7%) were women. Women were older than men (72 vs 63 years, P < 0.001), had a higher prevalence of hypertension (68% vs 54%, P = 0.006), diabetes (27% vs 19%, P = 0.04), and Killip class ≥ 3 at admission (19% vs 10%, P = 0.007). After a median follow-up of 1041 days women experienced a significant higher incidence of the composite of death, nonfatal myocardial infarction, and hospitalization for heart failure (31.9% vs 18.4%, unadjusted HR 1.86; 95% CI, 1.26-2.74; P = 0.002), driven mainly by heart failure (unadjusted HR 2.47; 95% CI, 1.12-5.41; P = 0.024), without significant differences in death (unadjusted HR 1.49; 95% CI, 0.88-2.53; P = 0.13), or nonfatal myocardial infarction (unadjusted HR 1.59; 95% CI, 0.78-3.27; P = 0.19) and no increase in target lesion revascularization (9.4% vs 12.5%, unadjusted HR 0.77; 95% CI, 0.42-1.44; P = 0.42). After propensity score matching the hazard of the composite endpoint was largely attenuated (HR 1.32; 95% CI, 0.84-2.06; P = 0.23).

Conclusions

Women undergoing primary PCI experience worse long-term outcomes than men, but this difference is largely explained by their more adverse baseline cardiovascular profile.     

Effects of celecoxib on prostanoid biosynthesis and circulating angiogenesis proteins in familial adenomatous polyposis

Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI(2)) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet α-granules. Thus, a profound inhibition of COX-2-dependent PGI(2) might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI(2), thromboxane (TX) A(2), and prostaglandin (PG) E(2), assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF(1α) (PGI-M), 11-dehydro-TXB(2) (TX-M), and 11-α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA(2) generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE(2) and PGI(2) biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE(2) by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI(2), in a context of enhanced TXA(2) biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.     

Molecular bases of endometrial cancer: new roles for new actors in the diagnosis and the therapy of the disease

Endometrial carcinoma (EC) is the most commonly diagnosed gynecologic malignancy in the western world. The majority of these cancers are curable, but a subset about 15-20% of endometrial tumors exhibits an aggressive phenotype. Based on clinic-pathological and molecular characteristics, EC has been classified into two groups: Type I estrogen-dependent adenocarcinomas, which have a good prognosis and an endometrioid histology, and Type II or non-estrogen-dependent EC associated with poor prognosis and non-endometrioid histology. EC develops as a result of a stepwise accumulation of alterations that seem to be specific of each histological type. However, more knowledge is needed to better understand the differences in the biology and the clinical outcome of EC. We would like to highlight the need to explore new potential biomarkers of EC as a tool for the detection and monitoring of aggressive endometrial tumors that, at the same time, will allow us to develop novel and more selective molecular targeted therapies against EC.     

The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy

Background

Telomerase, encoded by TERT, is the ribonucleoprotein polymerase that maintains telomere ends and it plays a crucial role in cellular senescence. TERT single nucleotide polymorphisms (SNPs) have been associated both with various malignancies and telomere length (TL). The association of TERT SNPs with longevity remains uncertain and varies with ethnicity. The aim of this study was to investigate whether the functional variable number of tandem repeat (VNTR) MNS16A of TERT is associated with longevity.

Methods

MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18–106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals < 66 years old (< 73 years old), the second class of individuals 66–88 years old (73–91 years old), and the third class of individuals > 88 years old (> 91 years old). TL was assessed using genomic DNA from whole blood of 72 selected individuals by a multiplex real-time PCR assay.

Results

MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3 vs. Age Class 2) under both additive (odds ratio [O.R.] 0.749; p = 0.019) and dominant (O.R. 0.579; p = 0.011) models. The MNS16A*L allele is significantly underrepresented in Age Class 3 (O.R. 0.759; p = 0.020) compared to Age Class 2. A significant telomere attrition is reported along the three age classes (p = 0.0001), that remains significant only in L*/L* genotype carriers (p = 0.002) when the analysis was conducted according to MNS16A genotype.

Conclusions

The TERT MNS16A*L allele appears negatively associated with longevity. The concomitant significant telomere cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influence human longevity by affecting TL.