Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics.

Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins.

Up-regulation of FXR isoforms is not required for stimulation of the expression of genes involved in the lack of response of colon cancer to chemotherapy.

Several mechanisms are involved in the poor response of colorectal adenocarcinoma (CRAC) to pharmacological treatment. Since preliminary evidences have suggested that the enhanced expression of farnesoid X receptor (FXR) results in the stimulation of chemoresistance, we investigated whether FXR up-regulation is required for the expression of genes that characterize the multidrug resistance (MDR) phenotype of CRAC. Samples of tumours and adjacent healthy tissues were collected from naive patients. Using Taqman Low-Density Arrays, the abundance of mRNA of 87 genes involved in MDR was determined. Relevant changes were re-evaluated by conventional RT-QPCR. In healthy tissue the major FXR isoforms were FXRα2(+/-) (80%). In tumours this predominance persisted (91%) but was accompanied by a consistent reduction (3-fold) in total FXR mRNA. A lower FXR expression was confirmed by immunostaining, in spite of which there was a significant change in the expression of MDR genes. Pharmacological challenge was simulated "in vitro" using human CRAC cells (LS174T cells). Short-term (72h) treatment with cisplatin slightly increased the almost negligible expression of FXR in wild-type LS174T cells, whereas long-term (months) treatment induced a cisplatin-resistant phenotype (LS174T/R cells), which was accompanied by a 350-fold up-regulation of FXR, mainly FXRα1(+/-). However, the changed expression of MDR genes in LS174T/R cells was not markedly affected by incubation with the FXR antagonist Z-guggulsterone. In conclusion, although the enhanced expression of FXR may be involved in the stimulation of chemoresistance that occurs during pharmacological treatment, FXR up-regulation is not required for the presence of the MDR phenotype characteristic of CRAC.

[Preoperative platelet count as index of the grading in endometrial carcinoma]. / Conta piastrinica preoperatoria come indice del grading nel carcinoma endometriale.

AIM: To investigate a possible relationship between preoperative platelet count and following clinicopathological variables of the endometrial carcinoma: age, stage, histological type, histological grading (G), myometrial invasion, lymphovascular space involvement, cervical involvement, lymph node metastasis. In particular the existence of a possible relationship between elevated preoperative platelet count (=or>300 000 microL) and negative prognostic factors. METHODS: The authors analyzed retrospectively 120 patients with endometrial carcinoma underwent to surgery as the initial treatment. All the patients were subjected to radical surgical procedure: peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymphadenectomy and omentectomy. Blood platelet count was taken from the patients three days prior to the surgery. RESULTS: The patients with platelet count<300000/microL whom they had a G1, G2, G3 they were respectively the 23.1%, 44.2% and 32.7% versus the 0%, 12.5% and 87.5%, respectively for G1, G2, G3, of the patients with platelet count>300000/microL (P=0.024). Only considering the patients to the stage I of the Federazione Internazionale dei Ginecologi ed Ostetrici (FIGO). The patients with platelet count<300000/microL whom they had a G1, G2, G3 they were respectively the 27.3%, 43.2% and 29.5% versus the 0%, 0% and 100%, respectively for G1, G2, G3, of the patients with platelet count=or>300000/microL (P=0.008). There were no differences respect to age, stage, histological type, myometrial invasion, lymphovascular space involvement and cervical involvement. CONCLUSION: Elevated preoperative platelet count, in the patients with endometrial carcinoma, may reflect poor prognostic factor such as higher histological grade. This study allowed to observe: a significant correlation between elevated preoperative platelet count (=or>300000/microL) and tumoral grading (G3) of general population submitted to study; for the patients to the stage I FIGO a more significant correlation between elevated preoperative platelet count (=or>300000/microL) and tumoral grading: the 100% of the patients with platelet count=or>300 000/microL had a histological grading G3.

The usefulness of clinical indexes in the evaluation of cardiovascular risk in non cardiac surgery.

AIM: The preoperative cardiac evaluation of a patient who undergoes noncardiac surgery is a very important problem, particularly for diagnostic tools used. Aim of this study is to test the usefulness of 4 most used clinical indexes for the evaluation of cardiovascular risk in the management of patients who undergo noncardiac surgery. METHODS: The study is based on a retrospective analysis of a group of 45 patients, who underwent extracardiac surgery in biennium 2002-2004. The cardiovascular risk scores of Goldman, Detsky, Lee and Eagle were used; a comparison among the different scores was done. RESULTS: Six out of our 45 patients had perioperative cardiovascular complications, and 4 of them died. The Eagle and Lee scores were more predictive than Goldman and Detsky ones. About the 13 echocardiographic tests recorded, no one of them modified the patient preoperative risk. CONCLUSIONS: In the preoperative assessment of risk, the Eagle score was more useful than the others ones and improved the negative predictive value of the Goldman and Detsky scores. The preventive application of the clinical indexes allows optimizing the preoperative stratification of the risk, limiting the request of useless examinations and offering to the patient a well appropriated preoperative management, reducing the incidence of complications.

The inflammatory abdominal aortic aneurysm and coronary artery disease. Case report and review.

Inflammatory abdominal aortic aneurysm (IAAA) is defined as an unusually thickened aneurysmatic wall, encircled by a wide dense perianeurysmal and/or retroperitoneal fibrosis with adjacent tissues adhesion, and is now considered as an extreme shape of the common phlogistic process involved in atherosclerotic plaque formation. Latest studies demonstrated that inflammation plays an important role in coronary disease and in other atherosclerosis manifestations. We introduce the clinical case of a patient with IAAA who developed an acute myocardial infarction 6 months after the surgical procedure on the aorta. Through a literature review about IAAA we stress the clinical usefulness of the inflammatory markers as independent predictors in management of patients with coronary disease and we present the hypothesis, related to the introduced case, of an advanced coronary disease, aggravated or clinically revealed after the cytokine storm related to important localized inflammatory engagements or great vascular surgery treatments.

Sonographic biometrical range of external genitalia differentiation in the first trimester of pregnancy: analysis of 2593 cases.

OBJECTIVES: The aim of this study was to establish the accuracy of fetal gender assignment by sonography in the biometrical range of 18 to 29 mm of biparietal diameter (BPD). METHODS: Transvaginal and/or transabdominal sonography was used to detect the sagittal sign as a marker of fetal gender in 2593 fetuses with BPD between 18 and 29 mm. The results of sonographic examination were compared with the gender at birth or with karyotype obtained from amniotic fluid cells or chorionic villus sampling. RESULTS: Fetal gender assignment was feasible in 2374 of 2593 cases (91%). Of the 2188 fetuses with known fetal sex outcome, 1025 were males and 1157 were females, and 6 had genital anomalies. In fetuses without genital anomalies, an accuracy rate of 100% was achieved at a BPD of >/=24 mm. The results of the six cases with genital malformations were considered separately. CONCLUSION: Sonography is a reliable method for the study of the morphological development of the external genitalia in fetuses 'in vivo'; it is possible to assign fetal gender in 95 to 99% starting at a BPD of 20 mm and to achieve an accuracy rate of 99 to 100% from a BPD of 22 mm, but fetal sex assignment should not be undertaken below a BPD of 22 mm, and especially not in cases where fetal sexing affects pregnancy management.

Prenatal diagnosis of female pseudohermaphroditism associated with bilateral luteoma of pregnancy: case report.

Female pseudohermaphroditism associated with luteoma of pregnancy (LP) is a rare condition characterized by varying degrees of masculinization of a female fetus. We describe a case, diagnosed at 13 weeks gestation. Transvaginal ultrasound at 5 weeks of gestation revealed a normal intrauterine gestational sac and an enlarged maternal right ovary. Re-examination at 13 weeks showed a fetus with male external genitalia. Cytogenetic investigation on amniotic fluid revealed a normal female karyotype 46,XX. Follow-up sonography confirmed the previous assignment of male external genitalia and a second amniocentesis was negative for the SRY gene. High levels of androgens were found in the maternal blood. A diagnosis of female pseudohermaphroditism associated with bilateral LP was made. A healthy girl was born by Caesarean section with complete masculinization of external genitalia (Prader V). Histology confirmed a bilateral LP. To the best of our knowledge this represents the first case of prenatal diagnosis of female pseudohermaphroditism associated with LP and demonstrates the feasibility of diagnosis by sonography from 13 weeks gestation. This is also the first case described of Prader V masculinization associated with LP.