A series of seton techniques involving “top-down therapy” for patients with Crohn's disease who initially presented with perianal fistulas

Objectives: We determined the outcomes of seton treatment through a series of techniques using biological agents (BIOs) in 18 patients with Crohn's disease (CD) who initially presented with perianal fistulas. Methods: The patients underwent seton drainage using three seton types: a Penrose tube for fistulas with massive purulent discharge, a vessel loop for a small amount of discharge, and a rubber band for unproductive fistulas. If the distal end of the fistula extended more than 4 cm from the anal orifice, the skin and subcutaneous tissue were dissected along the outer edge of the anal sphincter to divide the fistulous tract into two portions. One seton encircled the sphincter from the primary opening throughout the anal canal (medial seton), and the other was inserted through the distal tract outside the sphincter (lateral seton). A BIO was then introduced immediately. When discharge ceased, the Penrose tube or vessel loop was replaced sequentially with a rubber band, which was tied fittingly and subsequently removed in medial to lateral order. Results: The mean interval between fistula onset and CD diagnosis was 2.1 years, and that between CD diagnosis and introduction of BIOs was 0.5 years. The mean follow-up duration was 4 years. The BIOs currently used were infliximab in 10 patients, adalimumab in 7, and ustekinumab in 1. The overall success rate was 94.4%, including unproductive fistulas in 10 (55.6%) patients and fistula disappearance in 7 (38.9%). Conclusions: Our seton drainage techniques via the “top-down” approach represent a promising avenue for treating perianal fistulas in patients with CD

Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS

Working mechanism underlying the reduction of the behavioral and accumbal dopamine response to cocaine by alpha-1-adrenoceptor antagonists

Item does not contain fulltex

Adolescence as a critical period for nandrolone-induced muscular strength in relation to abuse liability, alone and in conjunction with morphine, using accumbal dopamine efflux in freely moving rats

Nandrolone, an anabolic androgenic steroid, is included in the prohibited list of the World Anti-Doping Agency. Drugs of abuse activate brain dopamine neurons and nandrolone has been suspected of inducing dependence. Accordingly, possible critical periods for the effects of nandrolone on muscular strength and dopaminergic activity have been investigated, including the effects of chronically administered nandrolone alone and on morphine-induced increases in dopamine efflux in the nucleus accumbens. Six- or 10-week-old male Sprague-Dawley rats were used. Treatment with nandrolone was initiated in adolescent (6-week-old) and young adult (10-week-old) rats. Nandrolone (5.0 mg/kg s.c.) or sesame oil vehicle was given once daily, on six consecutive days per week, for 3 weeks and then once per day for 4 consecutive days. Nandrolone enhanced the developmental increase in grip strength of 6- but not 10-week-old rats, without altering the developmental increase in body weight of either age group. Using in vivo microdialysis in freely moving 6-week-old rats given nandrolone for 4 weeks, basal accumbal dopamine efflux was unaltered, while the increase in dopamine efflux induced by acute administration of morphine (1.0 mg/kg s.c.) was reduced. The present study provides in vivo evidence that adolescence constitutes a critical period during which repeated administration of nandrolone enhances increases in muscular strength without influencing increases in body weight. Though repeated administration of nandrolone during this period of adolescence did not stimulate in vivo mesolimbic dopaminergic activity, it disrupted stimulation by an opioid, the drug class that is most commonly coabused with nandrolone. </p

Highly Efficient Conversion of Motor Neuron-Like NSC-34 Cells into Functional Motor Neurons by Prostaglandin E2

Motor neuron diseases are a group of progressive neurological disorders that degenerate motor neurons. The neuroblastoma &times; spinal cord hybrid cell line NSC-34 is widely used as an experimental model in studies of motor neuron diseases. However, the differentiation efficiency of NSC-34 cells to neurons is not always sufficient. We have found that prostaglandin E2 (PGE2) induces morphological differentiation in NSC-34 cells. The present study investigated the functional properties of PGE2-differentiated NSC-34 cells. Retinoic acid (RA), a widely-used agent inducing cell differentiation, facilitated neuritogenesis, which peaked on day 7, whereas PGE2-induced neuritogenesis took only 2 days to reach the same level. Whole-cell patch-clamp recordings showed that the current threshold of PGE2-treated cell action potentials was lower than that of RA-treated cells. PGE2 and RA increased the protein expression levels of neuronal differentiation markers, microtubule-associated protein 2c and synaptophysin, and to the same extent, motor neuron-specific markers HB9 and Islet-1. On the other hand, protein levels of choline acetyltransferase and basal release of acetylcholine in PGE2-treated cells were higher than in RA-treated cells. These results suggest that PGE2 is a rapid and efficient differentiation-inducing factor for the preparation of functionally mature motor neurons from NSC-34 cells