Research Priorities in Pelvic Venous Disorders in Women: Recommendations from a Multidisciplinary Research Consensus Panel.

Pelvic venous disorders (PeVDs) in women can present with chronic pelvic pain, lower-extremity and vulvar varicosities, lower-extremity swelling and pain, and left-flank pain and hematuria. Multiple evidence gaps exist related to PeVDs with the consequence that nonvascular specialists rarely consider the diagnosis. Recognizing this, the Society of Interventional Radiology Foundation funded a Research Consensus Panel to prioritize a research agenda to address these gaps. This paper presents the proceedings and recommendations from that Panel.

Motor and behavioral changes in mice with cisplatin-induced acute renal failure.

We have previously shown that chronic renal failure in rats induces changes in motor activity and behavior. Similar work on the possible effects of acute renal failure (ARF) induced by cisplatin (CP) is lacking. This is the subject matter of the current work. CP was injected intraperitoneally (i.p.) at a single dose of 20 mg/kg to induce a state of ARF, and three days later, its effects on motor activity, thermal and chemical nociceptive tests, neuromuscular coordination, pentobarbitone-sleeping time, exploration activity and two depression models were investigated. The platinum concentration in the kidneys and brains of mice was also measured. The occurrence of CP-induced ARF was ascertained by standard physiological, biochemical and histo-pathological methods. CP induced all the classical biochemical, physiological and histopathological signs of ARF. The average renal platinum concentration of CP-treated mice was 5.16 ppm, but there was no measurable concentration of platinum in the whole brains. CP treatment significantly decreased motor and exploration activities, and increased immobility time in depression models, suggesting a possible depression-like state. There was also a significant decrease in neuromuscular coordination in CP-treated mice. CP, given at a nephrotoxic dose, induced several adverse motor and behavioral alterations in mice. Further behavioral tests and molecular and biochemical investigations in the brains of mice with CP-induced ARF are warranted.

Ellagic acid protects against cisplatin-induced nephrotoxicity in rats: a dose-dependent study.

BACKGROUND: The anticancerdrug cisplatin (CP) causes nephrotoxicity through different mechanisms, including generation of free radicals. Ellagic acid (EA) is a polyphenolic antioxidant found in fruits and nuts. AIM: This study aimed to investigate the ability of different doses of EA to ameliorate CP nephrotoxicity in rats. MATERIALS AND METHODS: Animals were randomly divided into six groups and treated with saline; CP alone (6 mg/kg); two doses of EA, both alone (10 and 30 mg/kg) or with CP. RESULTS: Treatment with CP alone reduced body weight, water intake, urine output, and renal total antioxidant and reduced glutathione (GSH) concentrations (p < 0.01). In addition, it increased relative kidney weight, plasma creatinine, and blood urea nitrogen (BUN) concentrations (p < 0.01). However, a dose of 30 mg/kg EA mitigated most of the CP-induced actions, but no effect was seen for the 10 mg/kg dose. Histopathologically, rats given CP+EA30 showed < 25% necrotic lesions in the renal cortical area compared with > 60% in rats treated with CP alone. Molecular analysis showed that clusterin (Clu) mRNA and protein were expressed in all treated groups, meanwhile kidney injury molecule-1 (Kim-1) mRNA and protein were only expressed in the CP and CP+EA treated rats. CONCLUSIONS: EA (30 mg/kg) ameliorated most of the physiological, histological, and biochemical markers of CP nephrotoxicity. The molecular findings in this work did not completely tally with the conventional method used. The overexpression of the molecular markers may be related to the EA induced repair mechanism.

Comparative efficacy of three brands of gum acacia on adenine-induced chronic renal failure in rats.

Gum acacia (GA) is used in pharmaceutical, cosmetic and food industries as an emulsifier and stabilizer, and in some countries in the traditional treatment of patients with chronic kidney disease (CKD). We have previously found that GA ameliorates adenine-induced chronic renal failure (CRF) in rats. Different brands of GA are commercially available, but their comparative efficacy against adenine-induced CKD is unknown. Here, we explored the effects of three different brands of GA (Sudanese GA, Supergum and GA from BDH) on some physiological, biochemical, and histological effects of adenine-induced CRF in rats. Adenine (0.75 %, w/w in feed, four weeks) reduced body weight, and increased urine output. It also induced significant increases in blood pressure, and in creatinine, urea, several inflammatory cytokines in plasma, and indices of oxidative stress, and caused histological damage in kidneys. Treatment of rats concomitantly with any of the three GA brands, significantly, and to a broadly similar extent, mitigated all the signs of CRF. The results suggested equivalent efficacy of these brands in antagonizing the CRF in this animal model. However, to enable standardization of different brands between laboratories, the use of the chemically well-characterized GA preparation (such as Supergum) is recommended.

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal.

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.

Protein kinase C regulates dopamine D4 receptor-mediated phospholipid methylation.

Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent phospholipid methylation. To investigate possible regulation of this multi-step D4 receptor-mediated phospholipid methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [14C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal phospholipid methylation and also shifted the dose-response curve for dopamine-stimulated phospholipid methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal phospholipid methylation but significantly inhibited dopamine-stimulated phospholipid methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated phospholipid methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated phospholipid methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated phospholipid methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N-nitro-L-arginine had any effect on basal or dopamine-stimulated phospholipid methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent phospholipid methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.

Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway.

In a previous study we demonstrated the ability of dopamine (DA) to stimulate phospholipid methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.

Syntheses of new 5,6,7,8-tetrahydropyrrolo [2,3-d]azepine ring system.

A first synthesis of pyrrolo[2,3-d]azepine ring system starting from pyrrole and perhydroazepine derivatives was reported. In addition, Lansbury's reaction is developed through the use of para-toluene sulphonic acid (p-TsOH) as a new catalyst for this reaction.

Synthesis and characterization of some novel substituted benzenesulphonamides of potential hypoglycemic activity.

Two series of substituted benzenesulphonamides (Va-e and VIa-e) have been synthesized from 4-methoxycarbonyl-1-[p-(acetylamino)benzenesulphonylimino]pyridini um ylide (II) with a view to investigate their pharmacological activity. The structure of the synthesized products was inferred from elemental and spectral data. The hypoglycemic effect, antimicrobial activity and toxicity of the possible chemotherapeutic agents were evaluated. Six of these products were effective, when administered at an oral dose of 100 mg/kg b. wt., inducing marked reduction in blood glucose level.