Spigelian Hernia

We report on the evolution in concept and techniques that allowed us to improve the treatment of spigelian hernia, operable in day surgery in 90% of cases and through a preperitoneal and recently a preperitoneal and subfascial prosthetic repair (PHS). Background data. We propose an innovative use of the PHS mesh for spigelian hernia repair. With this new implementation, we confront the standard surgical technique and its postoperative period. Methods. From January 1992 to March 2004, we performed 2,500 hernia surgical operations, including 32 spigelian hernia repairs (1.3% of total case series). The first surgical approach used for 20 of these 32 patients (62.5% of total spigelian hernias), all electively operated on, was a classical preperitoneal repair (Wantz), performed when possible by size of defect and weight (Body Mass Index) of the patient, under local anesthesia and on a day-surgery basis. Our new modified technique takes place through the insertion of a PHS large-type mesh, whose bottom underlay portion lies flat in the preperitoneal space with the connector obliterating the hernial orifice and with the overlay portion lying on the internal oblique muscle, covered by the aponeurosis of the external oblique muscle. Results. Our modification to the classical technique consisted only in the application of a product, such as the PHS, in a hernia defect, which presented with an orifice of the size of the connector and, therefore, was easily repairable with the use of the PHS device. This approach is easier than the preperitoneal approach, its always suitable for local anaesthesia, and it gives a more comfortable postoperative period. The surgical approach may be performed completely in day surgery. Conclusions. We believe that spigelian hernia surgical repair should always be performed by means of a preperitoneal prosthesis under local anaesthesia when the patients clinical and physical conditions allow for it, always in day surgery, and using the PHS mesh when the hernia defect size fits with the connector diameter. This last possibility seems to be easier and more comfortable for the patient in the postoperative period.     

Design, synthesis, and biological evaluation of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 1) and related compounds [for example, CDDO-Me (2) and CDDO-Im (3)] are potential anti-inflammatory, cancer chemopreventive, and chemotherapeutic agents. However, the mechanisms responsible for the multiple effects of CDDO are still unclear. Clarification of these mechanisms and particularly isolation of the protein targets are essential for the development of CDDO and its analogues as clinically useful drugs. Such knowledge would provide superior opportunities for designing new compounds with improved potency and selectivity. Therefore, to isolate protein targets using affinity chromatography with immobilized streptavidin as a carrier, we have designed and synthesized C-17 and C-23 biotin conjugates of CDDO (4, 5, and 6) on the basis of our established structure-activity relationships. For the synthesis of 6, a new important precursor, 23-hydroxy-CDDO-Me (29) was synthesized from 20 by a C-23 oxidation protocol, which involves cyclopalladation of the C-4 methyl group from a 3-one oxime. The inhibitory activity of C-23 conjugate 6 is only about 3 times less potent than the mother compound, CDDO, against the proliferation of MCF-7 breast cancer cells. Consequently, 6 may be a very promising tool for the isolation of the protein targets of CDDO.     

The antimalarial agent mefloquine inhibits ATP-sensitive K-channels

The aim of this study was to determine whether antimalarial agents inhibit ATP-sensitive potassium (K(ATP)) channels and thereby contribute to the observed side-effects of these drugs. Mefloquine (10 - 100 microM), but not artenusate (100 microM), stimulated insulin release from pancreatic islets in vitro. Macroscopic K(ATP) currents were studied in inside-out patches excised from XENOPUS: oocytes expressing cloned K(ATP) channels. Mefloquine (IC(50) approximately 3 microM), quinine (IC(50) approximately 3 microM), and chloroquine inhibited the pancreatic beta-cell type of K(ATP) channel Kir6.2/SUR1. Artenusate (100 microM) was without effect. Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6. 2DeltaC36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents. Our results suggest that inhibition of the beta-cell K(ATP) channel accounts for the ability of quinoline-based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia. The results also indicate that quinoline-based antimalarial agents inhibit K(ATP) channels by interaction with the Kir6.2 subunit. This subunit is common to beta-cell, neuronal, cardiac, skeletal muscle, and some smooth muscle K(ATP) channels suggesting that K(ATP) channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.     

Spermicidal activity of chelated complexes of bis(cyclopentadienyl)vanadium(IV)

Transition metal complexes containing vanadium IV have been shown to modulate the cellular redox potential and catalyse the generation of reactive oxygen intermediates (ROI). Since sperm function is exquisitely susceptible to ROI, we examined the effects of stable chelate complexes of vanadocenes on human sperm motility. We synthesized seven structurally distinct chelate complexes of bis(cyclopentadienyl)vanadium(IV) with bidentate ligands [i.e. vanadocene acetylacetonato monotriflate (VDacac), vanadocene hexafluoro acetylacetonato monotriflate (VDHfacac), vanadocene N-phenyl benzohydroxamato monotriflate (VDPH), vanadocene acethydroxamato monotriflate (VDH), vanadocene catecholate (VDCAT), vanadocene bipyridino ditriflate (VDBPY), and vanadocene dithiocarbamate monotriflate (VDDTC)], and evaluated their spermicidal activity using computer-assisted sperm analysis (CASA; Hamilton-Thorne). All seven chelate complexes of vanadocene elicited potent spermicidal activity at micromolar concentrations (EC50 values: 3.9-106 microM) without affecting the sperm acrosome integrity. The catecholate and acetylacetonate complexes of vanadocene were the most active and the bipyridyl complex the least active with an order of efficacy VDCAT > VDacac > VDDTC > VDPH > VDH > VDHfacac > VDBPY. The spermicidal activity of chelate complexes of vanadocenes was rapid and irreversible since the treated spermatozoa underwent apoptosis, as determined by the flow cytometric analysis of mitochondrial membrane potential, surface annexin V binding assay, in-situ nick-end labelling of sperm nuclei, and confocal laser scanning microscopy. These results provide unprecedented evidence that chelate complexes of vanadocene with bidentate ligands have spermicidal and apoptosis inducing properties. These vanadocene complexes, especially VDacac, may be useful as contraceptive agents.      

Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure

Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase (AS3MT). Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena, including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for AS3MT, is differentially methylated as a function of arsenic exposure. In this study, we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989 to 1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean  % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation, and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene.     

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

相似文献   

Creating options in family planning for the private sector in Latin America.

The countries of Latin America and the Caribbean are facing the gradual phase-out of international-donor support of contraceptive commodities and technical and management assistance, as well as an increased reliance on limited public sector resources and a limited private sector role in providing contraceptives to the public. Therefore, those nations must develop multisectoral strategies to achieve contraceptive security. The countries need to consider information about the market for family planning commodities and services in order to define and promote complementary roles for the public sector, the commercial sector, and the nongovernmental-organization sector, as well as to better identify which segments of the population each of those sectors should serve. While it is unable to mandate private sector participation, the public sector can create conditions that support and promote a greater role for the private sector in meeting the growing needs of family planning users. Taking steps to actively involve and expand the private sector's market share is a critical strategy for achieving a more equitable distribution of available resources, addressing unmet need, and creating a more sustainable future for family planning commodities and services. This paper also discusses in detail the experiences of two countries, Paraguay and Peru. Paraguay's family planning market illustrates a vibrant private sector, but with limited access to family planning commodities and services for those who cannot afford private sector prices. In Peru a 1995 policy change that sought to increase family planning coverage had the effect of restricting access for the poor and leaving the Ministry of Health unable to pay for the growing need for family planning commodities and services.