Novel injectable urethral bulking agents for the treatment of urinary incontinence

Stress urinary incontinence is a highly prevalent disorder resulting from weak urethral closure mechanisms. Endoscopic injection of a urethral bulking agent (UBA) under the urethral mucosa increases coaptation, which improves continence. Collagen is an efficient agent, although its effects are limited in time. Other materials still suffer either from a short-lasting effect or migration in distant organs. We evaluated here novel UBAs using an ex vivo model, with respect to criteria of ease of injection, ability to form a high and stable tissue bulking, implant elasticity and tissue reaction. One approach involves solutions of polymers in water-miscible organic solvents that precipitates in situ. In this manner, high and stable bulks were routinely obtained using various commercial polymers. Selected solvents reduced the tissue reaction to the implant. Microsphere suspensions in hydrogels also proved to be efficient UBA, although less stable bulks were obtained. Thermosetting chitosan hydrogels showed promising results with respect to bulk stability and isoelasticity with surrounding tissues. Different strategies have thus been compared and optimised ex vivo. Further experiments are required to compare the ability of these materials to induce a sustained in vivo bulking effec

Management of risk of breast carcinoma in postmenopausal women.

Breast carcinoma is the most frequent tumor in the female population. Many factors can influence the risk of breast cancer; some of them, such as old age and breast cancer 1/2 (BRCA1/BRCA2) gene mutations, are associated with a fourfold increase in risk. A previous diagnosis of atypical ductal or lobular hyperplasia or having a first-degree relative with a carcinoma are factors associated with a two- to fourfold increase in risk. A relative risk between 1 and 2 is associated with longer exposure to endogenous hormones as a result of early menarche, late menopause and obesity, or with recent and prolonged use of hormone replacement therapy (HRT) or with behavioural factors such as high alcohol and fat intake. Is it possible to modify breast cancer risk in postmenopausal women? Risk factors related to lifestyle can be changed, even if it is not clear whether modifying these behavioural factors during the postmenopausal period will influence the overall breast cancer risk. For instance, the influence of exogenous hormones throughout life (both oral contraceptives and HRT) should be evaluated according to the individual risk-benefit ratio. The problem is even more complex for women who carry genetic mutations and for those who have close relatives with breast cancer, who may be candidates for risk reduction strategies. Prophylactic bilateral mastectomy is still controversial, but is frequently offered to or requested by this group of women and may be indicated in BRCA1/BRCA2 carriers. Chemoprevention with tamoxifen and with the new selective estrogen receptor modulators, namely raloxifene, is very promising and deserves a thorough discussion for all high-risk women

Minced Umbilical Cord Fragments as a Source of Cells for Orthopaedic Tissue Engineering: An In Vitro Study

A promising approach for musculoskeletal repair and regeneration is mesenchymal-stem-cell- (MSC-)based tissue engineering. The aim of the study was to apply a simple protocol based on mincing the umbilical cord (UC), without removing any blood vessels or using any enzymatic digestion, to rapidly obtain an adequate number of multipotent UC-MSCs. We obtained, at passage 1 (P1), a mean value of 4, 2 × 106 cells (SD 0,4) from each UC. At immunophenotypic characterization, cells were positive for CD73, CD90, CD105, CD44, CD29, and HLA-I and negative for CD34 and HLA-class II, with a subpopulation negative for both HLA-I and HLA-II. Newborn origin and multilineage potential toward bone, fat, cartilage, and muscle was demonstrated. Telomere length was similar to that of bone-marrow (BM) MSCs from young donors. The results suggest that simply collecting UC-MSCs at P1 from minced umbilical cord fragments allows to achieve a valuable population of cells suitable for orthopaedic tissue engineering

Caratteristiche chimiche e compositive di un salame tipico, il \u201csalam d\u2019la d\uf6ja\u201d

Cison di Valmarin

ALTERATIONS IN HIGH-DENSITY LIPOPROTEIN SUBFRACTIONS DURING POSTPRANDIAL LIPIDEMIA INDUCED BY FAT WITH AND WITHOUT ETHANOL

1. Serum lipid and apolipoprotein levels, distribution and composition of high-density lipoprotein (HDL) subfractions and lecithin:cholesterol acryltransferase activity were analysed in nine normolipidaemic subjects, in whom a hypertriglyceridaemic state was induced by the acute administration of ethanol (40 g) plus fat (70 g) or of fat only. 2. Triglyceride (TG) levels increased by 180% 4-6 h after fat plus ethanol intake, the hypertriglyceridaemic response being inversely correlated with the basal HDL 2 mass (r = -0.82). Serum apolipoprotein (apo) B levels rose by 8%, HDL-cholesterol decreased by 10% and HDL-TG increased by 57% at 6-8 h. 3. When ethanol was omitted, serum cholesterol and TG rose by 6% and 70%, respectively; both apo AI and apo B levels went up by 8%, whereas HDL-cholesterol rose progressively (15%) at 12 h. 4. The flotation rates of both HDL 2 and HDL 3 increased, reaching a maximum 6-8 h after ethanol plus fat intake. These changes were due to an increase in TG and phospholipid contents, whereas cholesteryl esters and proteins decreased. 5. The alterations in HDL are attributable to the increase in TG-rich lipoproteins, to the stimulated cholesterol esterification (+15%) and to an enhanced transfer of newly formed cholesteryl esters to apo-B-containing lipoproteins in exchange for TG. 6. Changes in HDL properties were evident only when ethanol was given concomitantly with fat. 7. These findings suggest that in the postprandial phase lipoprotein changes may occur, which facilitate an improved removal of cholesterol from tissues

HEPATIC NUCLEAR RECEPTOR EXPRESSION AND REGULATION OF BILE ACID SYNTHESIS IN HUMANS

Bile acid synthesis plays a crucial role in cholesterol homeostasis. Recent evidence has highlighted the role of nuclear receptors in the regulation of the expression and activity of cholesterol 7alpha-hydroxylase (CYP7A1), the limiting enzyme, in cellular and animal models. Understanding the regulatory role of nuclear receptors in humans might help to define molecular targets for pharmacological intervention aimed to enhance hepatic cholesterol degradation. AIM of the present study was to analyze the expression of CYP7A1 and a number of related nuclear receptors in human liver. METHODS. Surgical liver biopsies were obtained in 40 patients; 30 of them were untreated, presenting gallbladder stones (12), non-metastatic abdominal cancer (10) or obstructive cholestasis (8); 10 subjects were receiving standard dose of CDCA (3), UDCA (5) or cholestyramine (2). mRNA levels of CYP7A1 and of the main nuclear receptors involved in its regulation (FXR, SHP, LRH-CPF-1, HNF-4, PGC-1) were assayed by real-time RT-PCR, using custom-designed primers and with sybr-green as an intercalator of double-stranded DNA. RESULTS. CYP7A1 mRNA showed a high degree of variability. No difference was detected between untreated gallstone and gallstone-free subjects regarding the expression of CYP7A1 and other genes, with the exception of PGC-1 which was significantly (p < 0.05 on a log scale) less expressed in gallstone subjects. In untreated, non-cholestatic subjects no correlation could be detected between CYP7A1 or other genes and age. Stepwise regression analysis of data from all non-cholestatic subjects, with CYP7A1 mRNA levels as the dependent variable, showed the strongest correlation with HNF-4 as the independent variable (r = 0.471 on a log scale, p < 0.05), all other genes (including SHP) bringing non-significant further contribution to the correlation. A very strong direct correlation (r = 0.880 on a log scale, p< 0.05) was detected between HNF-4 and LRH-CPF-1 expression. Finally, no difference was observed between cholestatic and non-cholestatic patients.CONCLUSIONS. Our data suggest that HNF-4 might play a relevant role in the regulation of CYP7A1 transcription in humans; on the other hand no evidence for a suppressive role of SHP, which was well documented in cellular models, was observed. As a whole, the interrelationships between the different nuclear receptors, and their physiological role, have still to be defined. Data on CYP7A1 expression support the view that post-transcriptional, and possibly post-translational levels of regulation may also play a critical role in the control of bile acid synthesis

Paclitaxel administration on days 1 and 8 every 21 days in anthracycline-pretreated metastatic breast cancer patients. A multicenter phase II trial.

14noPaclitaxel is now included in second- and even first-line regimens in advanced breast cancer. The optimal dose and schedule of this drug, however, still remain a matter of investigation. A group of 57 consecutive patients with advanced breast cancer previously treated with anthracycline-containing regimens were submitted to treatment with single-agent paclitaxel administered at 130 mg/m2 on days 1 and 8 every 21 days. Of the 57 patients, 56 were fully evaluable, and of these 25 had an absolute anthracycline resistance, 14 a relative resistance and 17 were potentially sensitive. The median age of the patients was 57 years (range 33-71 years), their median performance status was 1 (0-3), and 27 (47%) had liver involvement, 17 (30%) lung involvement, 30 (53%) bone involvement and 15 (26%) skin/lymph node involvement. Toxicity was recorded in 295 cycles. This scheme was well tolerated, the dose-limiting toxicities being hematological and neurological. Grade 3/4 leukopenia was observed in 20% of patients at nadir, while grade 3 leukopenia was observed in 3% of patients at recycle. Only one patient experienced febrile neutropenia. Grade 2/3 neurotoxicity was observed in 26% of patients, leading to drug withdrawal in three. The treatment was given on an outpatient basis in all patients and the median relative dose intensity of 86.6 mg/m2 per week was 100% of the planned dose (range 75-100%). Three patients (5%) attained a complete clinical response and 12 (21%) a partial response for an overall response rate of 26% (95% confidence interval 18-38%), while 30 (53%) attained disease stabilization and 11 progressed (19%). Time to progression in responding patients was 10.3 months, and the median overall survival of the entire population was 15.4 months. To conclude, paclitaxel administration on days 1 and 8 every 21 days was active and manageable in advanced breast cancer patients previously treated with anthracyclines. The response obtained was durable.nonenoneDONADIO M; MANZIN E; A. BERRUTI; BOTTINI A; GORZEGNO G; DANESE S; DEFABIANI E; SAROBBA MG; LORUSSO V; CASTIGLIONE F; MORO G; BERTETTO O; BUMMA C; DOGLIOTTI LDonadio, M; Manzin, E; Berruti, Alfredo; Bottini, A; Gorzegno, G; Danese, S; Defabiani, E; Sarobba, Mg; Lorusso, V; Castiglione, F; Moro, G; Bertetto, O; Bumma, C; Dogliotti, L