Maria Teresa Vietri

The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: A prospective, randomized, double-blind, placebo-controlled trial

We investigated whether intervention with antioxidant vitamins C and E in enteral feeding influenced oxidative stress and clinical outcome in critically ill patients. Two-hundred-sixteen patients expected to require at least 10 days of enteral feeding completed the study. One-hundred-five patients received enteral feeding supplemented with antioxidants, and 111 control patients received an isocaloric formula. Plasma lipoper-oxidation (by thiobarbituric acid reactive substances [TBARS] and prostaglandin F2&agr; isoprostane levels), low-density lipoprotein (LDL) oxidizability, and LDL tocopherol content were determined at baseline and at the end of the 10-day period. The clinical 28-day outcome was also assessed. Plasma TBARS and isoprostanes were 5.33 ± 1.26 nM/mL and 312 ± 68 pg/mL, respectively, before treatment and 2.42 ± 0.61 nM/mL and 198 ± 42 pg/mL after intervention (P < 0.01 for both comparisons). Antioxidants improved LDL resistance to oxidative stress by approximately 30% (the lag time before treatment was 87 ±23 min and was 118 ±20 min after treatment; P <0.04). There was a significantly reduced 28-day mortality after antioxidant intervention (45.7% in the antioxidant group and 67.5% in the regular-feeding group; P < 0.05). Isoprostanes may provide a sensitive biochemical marker for dose selection in studies involving antioxidants.

Cytokine pattern in postmenopause.

OBJECTIVE The present study was undertaken to evaluate the pattern of serum cytokine production in postmenopausal women and the relationship with the hormonal status. A group of fertile women served as controls. METHODS Eighty-two women in apparent good health, non-smokers and without a history of hormone replacement therapy, were enrolled for the study. The women were divided in two groups according to their hormonal status: fertile women (n=34, age 32 +/- 7 years) and postmenopausal women (n=48, age 54 +/- 8 years). Blood samples were withdrawn in the morning, after an overnight fast. RESULTS Sex hormones (LH, FSH, Estradiol, Progesterone, DHEA, DHEA-S), as well as GH and IGF-1 levels, were significantly higher in the serum of fertile women as compared with their postmenopausal counterparts. Unlike IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, significant differences were observed in serum IL-6, IL-18, TNFalpha and TNFbeta between groups: both IL-6 and IL-18 were higher in postmenopausal women, while TNFalpha and TNFbeta were significantly lower. There was an inverse relationship between serum DHEA and DHEA-S levels and both IL-6 (r= -0.46, P<0.02) or IL-18 (r= -0.38, P<0.05) serum concentrations. CONCLUSIONS Compared with fertile counterparts, women in postmenopause present an alteration in serum cytokine profile suggesting a prevalence of Th2 lymphocytes.

Serum anti-p53 antibodies in lung cancer: comparison with established tumor markers

As reported earlier, p53 antibodies are detected in the sera of patients with different types of cancer, including lung cancer. In contrast, in the serum of healthy subjects the presence of anti-p53 antibodies is extremely rare. We collected the venous blood samples of 109 patients affected with lung cancer (LC): 57 patients (46 M, 11 F) with non-small-cell carcinoma (NSCLC), 52 others (40 M, 12 F) with small-cell carcinoma (SCLC). Serum p53 antibodies were assayed using ELISA method and all positive sera were confirmed by Western-blot method. In addition, using IRMA methods we assayed serum CEA, TPA, CYFRA21-1 and NSE. Serum p53Ab are detectable (p53Ab-positive) in 35/109 (32.1%) patients with lung cancer. About 17/57 (29.8%) patients affected with NSCLC and 18/52 (34.6%) with SCLC were p53Ab-positive. CEA, TPA, CYFRA21-1 and NSE sensitivity in LC patients (NSCLC+SCLC) is 50.5%, 58.7%, 42.2%, 35.8%, respectively. The lower sensitivity (32.1%) of serum p53Ab is connected with the higher specificity and diagnostic accuracy (100% and 69%, respectively). Out of 35 patients p53Ab-positive, five (14.3%) exhibit only serum p53Ab, while serum values of the established tumor markers were lower than cut-off. Serum p53Ab assessment is a simple and a low-cost assay with a good specificity and diagnostic accuracy that in LC patients can be used at least in association with established tumor markers.

Epigenetic-related therapeutic challenges in cardiovascular disease

Progress in human genetic and genomic research has led to the identification of genetic variants associated with specific cardiovascular diseases (CVDs), but the pathogenic mechanisms remain unclear. Recent studies have analyzed the involvement of epigenetic mechanisms such as DNA methylation and histone modifications in the development and progression of CVD. Preliminary work has investigated the correlations between DNA methylation, histone modifications, and RNA-based mechanisms with CVDs including atherosclerosis, heart failure (HF), myocardial infarction (MI), and cardiac hypertrophy. Remarkably, both in utero programming and postnatal hypercholesterolemia may affect the epigenetic signature in the human cardiovascular system, thereby providing novel early epigenetic-related pharmacological insights. Interestingly, some dietary compounds, including polyphenols, cocoa, and folic acid, can modulate DNA methylation status, whereas statins may promote epigenetic-based control in CVD prevention through histone modifications. We review recent findings on the epigenetic control of cardiovascular system and new challenges for therapeutic strategies in CVDs.

CYP17 and CYP19 gene polymorphisms in women affected with endometriosis

OBJECTIVE To investigate whether CYP17 T>C polymorphism and polymorphisms C1558T and Val80 of CYP19 are related to endometriosis. DESIGN Clinical study. PATIENT(S) Women affected with endometriosis (n = 104) and control group (n = 86). The diagnosis of endometriosis was confirmed by the histologic examination of the endometriotic lesions. RESULT(S) In patients affected with endometriosis, we observed that AA and CC genotypes were significantly represented in Val80 and C1558T polymorphisms of CYP19. CONCLUSION(S) The molecular mechanisms that underlie the development of endometriosis are unclear. Both environmental and genetic factors are involved in the pathogenesis of the disease. The inheritable susceptibility to endometriosis justifies the growing interest in identifying genes and/or genetic polymorphisms that predispose women to an increased risk of developing endometriosis. The identification of single-nucleotide polymorphism (SNP), probably linked to endometriosis, could help to explain its pathogenesis.

Laboratory markers in ulcerative colitis: Current insights and future advances

Ulcerative colitis (UC) and Crohns disease (CD) are the major forms of inflammatory bowel diseases (IBD) in man. Despite some common features, these forms can be distinguished by different genetic predisposition, risk factors and clinical, endoscopic and histological characteristics. The aetiology of both CD and UC remains unknown, but several evidences suggest that CD and perhaps UC are due to an excessive immune response directed against normal constituents of the intestinal bacterial flora. Tests sometimes invasive are routine for the diagnosis and care of patients with IBD. Diagnosis of UC is based on clinical symptoms combined with radiological and endoscopic investigations. The employment of non-invasive biomarkers is needed. These biomarkers have the potential to avoid invasive diagnostic tests that may result in discomfort and potential complications. The ability to determine the type, severity, prognosis and response to therapy of UC, using biomarkers has long been a goal of clinical researchers. We describe the biomarkers assessed in UC, with special reference to acute-phase proteins and serologic markers and thereafter, we describe the new biological markers and the biological markers could be developed in the future: (1) serum markers of acute phase response: The laboratory tests most used to measure the acute-phase proteins in clinical practice are the serum concentration of C-reactive protein and the erythrocyte sedimentation rate. Other biomarkers of inflammation in UC include platelet count, leukocyte count, and serum albumin and serum orosomucoid concentrations; (2) serologic markers/antibodies: In the last decades serological and immunologic biomarkers have been studied extensively in immunology and have been used in clinical practice to detect specific pathologies. In UC, the presence of these antibodies can aid as surrogate markers for the aberrant host immune response; and (3) future biomarkers: The development of biomarkers in UC will be very important in the future. The progress of molecular biology tools (microarrays, proteomics and nanotechnology) have revolutionised the field of the biomarker discovery. The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve, characterize and analyse large amounts of data generated by the technological advances. The techniques available for biomarkers development are genomics (single nucleotide polymorphism genotyping, pharmacogenetics and gene expression analyses) and proteomics. In the future, the addition of new serological markers will add significant benefit. Correlating serologic markers with genotypes and clinical phenotypes should enhance our understanding of pathophysiology of UC.

The roles of Mediator complex in cardiovascular diseases

Despite recent treatment advances, an increase in cardiovascular diseases (CVD) mortality is expected for the next years. Mediator (MED) complex plays key roles in eukaryotic gene transcription. Currently, while numerous studies have correlated MED alterations with several diseases, like cancer or neurological disorders, fewer studies have investigated MED role in CVD initiation and progression. The first finding of MED involvement in these pathologies was the correlation of missense mutations in MED13L gene with transposition of the great arteries. Nowadays, also MED13 and MED15 have been associated with human congenital heart diseases and others could be added, like MED12 that is involved in early mouse development and heart formation. Interestingly, a missense mutation in MED30 gene causes a progressive cardiomyopathy in homozygous mice suggesting a potential role for this subunit also in human CVDs. Moreover, several subunits like MED1, MED13, MED14, MED15, MED23, MED25 and CDK8 exert important roles in glucose and lipid metabolism. Although these evidences derive from in vitro and animal model studies, they indicate that their deregulation may have a significant role in human CVD-related metabolic disorders. Finally, alternative transcripts of MED12, MED19 and MED30 are differently expressed in circulating endothelial progenitor cells thus suggesting they can play a role in the field of regenerative medicine. Overall, further functional studies exploring MED role in human CVD are warranted. The results could allow identifying novel biomarkers to use in combination with imaging techniques for early diagnosis; otherwise, they could be useful to develop targets for novel therapeutic approaches.

Epigenetic Reprogramming in Atherosclerosis

Recent data support the involvement of epigenetic alterations in the pathogenesis of atherosclerosis. The most widely investigated epigenetic mechanism is DNA methylation although also histone code changes occur during the diverse steps of atherosclerosis, such as endothelial cell proliferation, vascular smooth muscle cell (SMC) differentiation, and inflammatory pathway activation. In this review, we focus on the main genes that are epigenetically modified during the atherogenic process, particularly nitric oxide synthase (NOS), estrogen receptors (ERs), collagen type XV alpha 1 (COL15A1), vascular endothelial growth factor receptor (VEGFR), and ten-eleven translocation (TET), which are involved in endothelial dysfunction; gamma interferon (IFN-γ), forkhead box p3 (FOXP3), and tumor necrosis factor-α (TNF-α), associated with atherosclerotic inflammatory process; and p66shc, lectin-like oxLDL receptor (LOX1), and apolipoprotein E (APOE) genes, which are regulated by high cholesterol and homocysteine (Hcy) levels. Furthermore, we also discuss the role of non-coding RNAs (ncRNA) in atherosclerosis. NcRNAs are involved in epigenetic regulation of endothelial function, SMC proliferation, cholesterol synthesis, lipid metabolism, and inflammatory response.

Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells

Background:BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound.Methods:Cell cycle, apoptosis and differentiation analyses; western blots.Results:BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA.Conclusion:BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis.

Serum p53 antibodies in patients affected with ulcerative colitis

During tumor progression, theaccumulation in genetic alterations is a fundamental characteristic of malignant cells. p53 gene is frequently mutated in human tumor. Cellular accumulation of p53 protein can initiate an immune response with generation of circulating anti-p53 antibodies. Patients with ulcerative colitis have an increased risk of developing colorectal neoplasm and, among the different genes involved in carcinogenesis, p53 may play a key role. Sera and tissues from 97 patients (M = 53, F = 44) affected with ulcerative colitis (UC) were collected. Serum anti-p53 antibodies (p53Abs) were detected in duplicate with ELISA method. Serum p53Abs were detectable in 9.3% (9/97) of patients affected with UC. In these patients, the titer of p53Ab ranged between 3.1 and 14.9 U/mL (mean, 6.6 U/mL; SD, 4.64). Serum p53Abs were undetectable in control group. With an immunoluminometric assay for the quantitative determination of p53, we found 9/97 positive samples (≥0.69 mg/mg of total proteins). In contrast, the samples of the remaining 89 patients were found negative (≤0.30 mg/mg of total proteins). All patients that were positive for anti-p53 antibodies were also positive with p53 protein accumulation in the tissue of colonic biopsies. In UC, follow-up with colonoscopy has several advantages. The colonoscopy is not well accepted by patients, and poor patient observance has the potential to seriously devalue the technique as a screening tool, despite practical considerations of competence within endoscopy service. Serological detection of p53Abs by enzyme-linked immunosorbent assay (ELISA) is easy to perform, does not require tumor specimen, can be performed in a routine diagnostic procedure, may be used in clinical practice, and could facilitate physicians in patient monitoring. We suggest that serum p53Abs assessment, indirect marker for p53 gene mutations, and abnormally high p53 protein levels could be considered to have a potential for use as a complementary test to improve surveillance program performance.