Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids

Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.     

Tumor Necrosis Factor‐Related Apoptosis‐Inducing Ligand (TRAIL) and Its Death Receptor (DR5) in Peyronie's Disease. A Biomolecular Study of Apoptosis Activation

IntroductionPeyronie's disease (PD) is a connective tissue disorder of tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis. Relatively, little is known about the disease itself.AimTo investigate whether the apoptosis cascade in degenerated and macroscopically deformed TA from men with PD is activated through the extrinsic pathway, by assessing the immunoexpression of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and its death receptor, DR5.MethodsTA plaques from 15 men with PD and from four unaffected men were processed for TRAIL and DR5 immunohistochemistry and Western blot analysis.Main Outcome MeasuresA greater understanding of the pathophysiology of PD through a molecular approach, to gain insights that may lead to novel forms of treatment.ResultsActivation of the apoptosis mechanisms through the extrinsic pathway was demonstrated by TRAIL and DR5 overexpression in fibroblasts and myofibroblasts from affected TA.ConclusionThe finding that apoptosis activation in TA plaques occurs, at least in part, via the extrinsic pathway may help devise novel therapeutic options for these patients. Loreto C, Barbagli G, Djinovic R, Vespasiani G, Carnazza ML, Miano R, Musumeci G, Sansalone S. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and its death receptor (DR5) in Peyronie's disease. A biomolecular study of apoptosis activation. J Sex Med 2011;8:109–115.     

The use of lingual mucosal graft in adult anterior urethroplasty: surgical steps and short-term outcome

OBJECTIVES: Investigate the tolerability, safety, and efficacy of using the lingual mucosal graft (LMG) for anterior urethroplasty. METHODS: Ten patients (average age, 41 yr) underwent substitution urethroplasty LMG. Harvesting the graft from the tongue was performed by either the oral surgeon or the urologist. In five patients with penile urethral strictures, the grafts were placed on the dorsal urethral surface as a "dorsal inlay." In five patients with bulbar urethral strictures, the grafts were used as a "dorsal inlay" (3 cases) or "ventral onlay" (2 cases). The average follow-up was 5 mo (range: 3-12 mo). RESULTS: Nine cases (90%) were successful and one (10%) was a failure. Three patients who underwent bulbar urethroplasty showed prior failed repair using buccal mucosal grafts harvested from a single cheek (1 case), from both cheeks (1 case), or from the lip (1 case). The length of the lingual grafts was 4-6cm (mean: 4.5cm) with a width of 2.5cm. No patient developed early or late postoperative complications on the harvest site related to the tongue surgery. No difference was observed in patients in whom the graft harvesting was performed by the oral surgeon compared to the patients in whom the procedure was performed by the urologist. CONCLUSIONS: The surgical technique for harvesting a graft from the tongue is simple and safe. The tongue may be the best alternative donor site to the lip when a thin graft is required for urethroplasty or when the cheek harvesting is not possible.     

5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: a versatile scaffold to obtain potent and selective A3 adenosine receptor antagonists

Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a Ki of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.     

Migraine pain: reflections against vasodilatation

The original Wolff’s vascular theory of migraine was supported by the discovery of a class of drugs, the triptans, developed as a selective cephalic vasoconstrictor agents. Even in the neurovascular hypothesis of Moskowitz, that is the neurogenic inflammation of meningeal vessels provoked by peptides released from trigeminal sensory neurons, the vasodilatation provoked by calcitonin gene-related peptide (CGRP) is considered today much more important than oedema. The role of cephalic vasodilatation as a cause of migraine pain was recently sustained by studies showing the therapeutic effect of CGRP receptor antagonists. We discuss the evidence against vasodilatation as migraine pain generator and some findings which we suggest in support of a central (brain) origin of pain.     

Secondary aldosteronism documented by plasma renin and aldosterone circadian rhythm in subjects with kidney or heart transplantation.

The circadian rhythm (CR) of plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (PC) was investigated in 8 patients with kidney transplantation, and in 10 patients with heart transplantation. Ten clinically healthy subjects were studied as controls. The transplanted patients were all under cyclosporine treatment associated with prednisone (PDN). Time-qualified levels of PRA and PA were seen to be higher than normal in both groups of transplanted patients. The analysis of PRA and PA circadian rhythm provided evidence for a systematically higher level of within-day concentrations. The higher level of oscillation suggests the occurrence of a condition of hyperreninemic hyperaldosteronism. The higher levels of PRA and PA 24-h values show no periodicity. The finding suggests the abrogation of the rhythmic function for renin-aldosterone system. The disappearance of PRA-PA circadian rhythm seems to be attributable to a side effect of immunosuppressive therapy.     

Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study

OBJECTIVE: To evaluate in a 12-month, prospective, randomized, double-blind, placebo-controlled study whether pure administration of the phytoestrogen genistein (54 mg/d) might reduce the number and severity of hot flushes in postmenopausal women with no adverse effect on the endometrium. DESIGN: A total of 389 participants met the main study criteria and were randomly assigned to receive the phytoestrogen genistein (n=198) or placebo (n=191). About 40% of participants in both groups did not suffer from hot flushes, and the evaluation was performed in a subgroup of 247 participants (genistein, n=125; placebo, n=122). Reductions from baseline in the frequency and severity of hot flushes were the principal criteria of efficacy. Endometrial thickness was evaluated by ultrasonography. The maturation value was also used to determine hormonal action on the vaginal cells. RESULTS: There were no significant differences in age, time since menopause, body mass index, and vasomotor symptoms between groups at baseline (4.4 +/- 0.33 hot flushes per day in the genistein group and 4.2 +/- 0.35 hot flushes per day in the control group). The effect was already evident in the first month and reached its peak after 12 months of genistein therapy (-56.4% reduction in the mean number of hot flushes). Furthermore, there was a significant difference between the two groups at each evaluation time (1, 3, 6, and 12 months). No significant difference was found in mean endometrial thickness and maturation value score between the two groups, either at baseline or after 12 months. CONCLUSIONS: The phytoestrogen genistein has been shown to be effective on vasomotor symptoms without an adverse effect on endometrium.