Adenosine actions are preserved in corpus cavernosum from obese and type II diabetic db/db mouse

Introduction. Erectile dysfunction (ED) in diabetes is associated with autonomic neuropathy and endothelial dysfunction. Whereas the nonadrenergic-noncholinergic (NANC)/neurogenic nitric oxide pathway has received great attention in diabetes-associated ED, few studies have addressed sympathetic overactivity. Aim. To test the hypothesis that adenosine-induced inhibition of adrenergic-mediated contractile responses in mouse corpus cavernosum is impaired in the presence of diabetes. Methods. The db/db (obesity and type II diabetes caused by a leptin receptor mutation) mouse strain was used as a model of obesity and type II diabetes, and standard procedures were performed to evaluate functional cavernosal responses. Main Outcome Measures. Increased cavernosal responses to sympathetic stimulation in db/db mice are not associated with impaired prejunctional actions of adenosine. Results. Electrical field stimulation (EFS)-, but not phenylephrine (PE)-, induced contractions are enhanced in cavernosal strips from db/db mice in comparison with those from lean littermates. Direct effects of adenosine, 2-chloro-adenosine, A(1) receptor agonist C-8031 (N6 cyclopentyladenosine), and sodium nitroprusside are similar between the strips from lean and db/db mice, whereas relaxant responses to acetylcholine and NANC stimulation are significantly impaired in the cavernosal strips from db/db mice. 5`-Iodotubercidin (adenosine kinase inhibitor) and dipyridamole (inhibitor of adenosine transport), as well as the A(1) agonist C-8031, significantly and similarly inhibit contractions induced by stimulation of adrenergic nerves in the cavernosal strips from lean and db/db mice. Conclusions. Results from this study suggest that corpora cavernosa from obese and diabetic db/db mice display altered neural-mediated responses that would favor penile detumescence, i.e., increased contractile response to adrenergic nerve stimulation and decreased relaxant responses upon activation of NANC nerves. However, increased cavernosal responses to adrenergic nerve stimulation are not due to impaired negative modulation of sympathetic neurotransmission by adenosine in this diabetic model.

Transcorneal Electrical Stimulation for Patients with Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Exploratory Study

PURPOSE. To assess the safety of transcorneal electrical stimulation (TES) and explore its efficacy in various subjective and objective parameters of visual function in patients with retinitis pigmentosa (RP). METHODS. Twenty-four patients in this prospective, randomized, partially blinded, good-clinical-practice study underwent TES (5-ms biphasic pulses; 20 Hz; DTL electrodes) 30 minutes per week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical phosphene threshold (EPT). Visual acuity (VA), visual field (VF; kinetic, static), electroretinography (Ganzfeld, multifocal), dark-adaptation (DA), color discrimination, and EPTs were assessed at all visits or four times, according to the study plan. RESULTS. TES using DTL electrodes was tolerated well; all patients finished the study. Two adverse (foreign body sensation), but no serious adverse events were encountered. There was a tendency for most functional parameters to improve (8/18) or to remain constant (8/18) in the 150% group. VF area and scotopic b-wave amplitude reached statistical significance (P < 0.027 and P < 0.001, respectively). Only desaturated color discrimination and VF mean sensitivity decreased. There was no obvious trend in the 66% group. CONCLUSIONS. TES was found to be safe in RP patients. Positive trends were discovered, but due to the small sample size of this exploratory study, statistical significance was reached only for VF area and scotopic b-wave amplitude. Further studies with larger sample sizes and longer duration are needed to confirm the findings and to define optimal stimulation parameters. (ClinicalTrials.gov number, NCT00804102.) (Invest Ophthalmol Vis Sci. 2011;52:4485-4496) DOI:10.1167/iovs.10-6932

Histology of the regenerate and docking site in bone transport

Bone transport is based on the principle of distraction osteogenesis described by Ilizarov and is a consecrated method for the treatment of segmental bone defects. One of its most problematic and, paradoxically, least studied aspects is the consolidation of the docking site. We studied histologically the ossification of the docking site and regenerate to determine any difference between them. Nine adult sheep were submitted to correction of a 1-cm tibial diaphyseal defect using a system of plate-fixed bone transport, with latency period of 1 week and 0.2 mm distraction of the transported segment four times a day. The sheep were divided into three groups of three animals each, according to the observation period of 3, 6 or 12 weeks between the fixation of the transported fragment and the euthanasia. The docking site and the regenerate were studied histologically on sections stained with Masson trichrome. The main mode of docking site ossification was the endochondral one and although intramembranous ossification was also observed simultaneously, it was limited to rare and small foci. In contrast, intramembranous ossification played the major role in the regenerate, with bone formation evolving from the base segment to the target segment. The experimental bone transport model proposed in the present study permits us to conclude that there is a clear difference between the ossification of the docking site and of the regenerate.

Hypoalgesic effect of the transcutaneous electrical nerve stimulation following inguinal herniorrhaphy: A randomized, controlled trial

We investigated the effect of transcutaneous electrical nerve stimulation (TENS) for inguinal herniorrhaphy postoperative pain control in a prospective, randomized, double-blinded, placebo-controlled study. Forty patients undergoing unilateral inguinal herniorrhaphy with an epidural anesthetic technique were randomly allocated to receive either active TENS or placebo TENS. Postoperative pain was evaluated using a standard 10-point numeric rating scale (NRS). Analgesic requirements were also recorded. TENS (100 Hz, strong but comfortable sensory intensity) was applied for 30 minutes through 4 electrodes placed around the incision twice, 2 and 4 hours after surgery. Pain was assessed before and after each application of TENS and 8 and 24 hours after surgery. In the group treated with active TENS, pain intensity was significantly lower 2 hours (P = .028), 4 hours (P = .022), 8 hours (P = .006), and 24 hours (P = .001) after the surgery when compared with the group that received placebo TENS. Active TENS also decreased analgesic requirements in the postoperative period when compared with placebo TENS (P = .001). TENS is thus beneficial for postoperative pain relief, after inguinal herniorrhaphy; it has no observable side effects, and the pain-reducing effect continued for at least 24 hours. Consequently, the routine use of TENS after inguinal herniorrhaphy is recommended. Perspective: This study presents the hypoalgesic effect of high-frequency TENS for postoperative pain after inguinal herniorrhaphy. This may reinforce findings from basic science showing an opioid-like effect provided by TENS, given that high-frequency TENS has been shown to activate delta-opioid receptors. (C) 2008 by the American Pain Society.

An investigation of the microstructure/electrical conductivity relationship in In2O3-substituted LSGM

The effect of controlled In3+ substitution on to the B-site in the perovskite oxygen ion conductor La0.9Sr0.1Ga0.8Mg0.2O2.85 (LSGM) has been examined with a view to exploring the influence on oxygen ion conductivity. In combination with the electrical conductivity study, detailed microstructural analysis was used to verify the location of the substituting cation and to determine the nature of secondary phase formation. The indium species clearly substituted for Ga3+ on the B-site of the lattice and the electrical conductivity showed a gradual decrease as the In+3 content increased. The interpretation of this data was complicated by the formation of the secondary phases LaInO3 and LaSrGaO4. (C) 2001 Elsevier Science Ltd. All rights reserved.

Improvement of the electrolytic properties of Y2O3-based materials using a crystallographic index

Y2O3 is a c-type rare earth oxide with a fluorite-related structure. This material has been used to refractory because of its high thermal stability and excellent resistance to hydration. In this study, the effective index was suggested in order to improve the electrolytic properties of Y2O3-based oxide. (CexY1-x)(2)O3+delta (x = 0.25 and 0.3) and [LaaSrbCe0.25Y(1-a-b)](2)O3+delta (a = 0.05, 0.1 and 0.15, b = 0, 0.006 and 0.0125) were prepared as the examples with intermediate and high index, respectively. The specimens with high index value such as (La0.15Ce0.25Y0.60)(2)O-3.25 and (La0.1Sr0.0125Ce0.25Y0.6375)(2)O-3.24 consisted of two phases such as c-type and fluorite, although (Ce0.25Y0.75)(2)O-3.25 with intermediate index value had a single phase of c-type rare earth oxide. Microanalysis indicates that a grain in the (La0.1Sr0.0125Ce0.25Y0.6375)(2)O-3.23(7) sintered body consists of c-type and fluorite phases. An interface between c-type and fluorite phases is coherent in a grain. This suggests that this effective index guides the crystal structure in the specimen to fluorite and the examined composition introduces the interface between c-type and fluorite in the microstructure. The electrochemical properties of specimens including Y2O3 were characterized on the basis of the suggested index. The electrical conductivity of Y2O3-based materials increased with an increase of the index. The apparent activation energy of Y2O3-based materials decreased with increasing index. The ionic transport number of oxygen of the specimens was improved by enhancement of the index, confirming validity of the index. The oxide ionic conductive region of (La0.1Sr0.0125Ce0.25Y0.(6375))(2)O-3.23(7) with high effective index extended up to P-O2 = 10(-18) atm at 800 degreesC, although the specimens with low or intermediate index showed p- or n-type semi-conduction in the same P-O2 region at 800 and 1000 degreesC. These results suggest that the interface between c-type and fluorite phases also contributes to improve the electrolytic properties in the grain. It is concluded that the improvement of electrolytic properties in Y2O3-based materials is attributable to the microstructure with interface between two phases in a grain and the fluorite structure guided by the suggested index. (C) 2001 Published by Elsevier Science B.V.

Glycosphingolipids modulate renal phosphate transport in potassium deficiency

Background. Potassium (K) deficiency (KD) and/or hypokalemia have been associated with disturbances of phosphate metabolism The purpose of the present study was to determine the cellular mechanisms that mediate the impairment of renal proximal tubular Na/Pi cotransport in a model of K deficiency in the rat. Methods. K deficiency in the rat was achieved by feeding rats a K-deficient diet for seven days. which resulted in a marked decrease in serum and tissue K content. Results. K deficiency resulted in a marked increase in urinary Pi excretion and a decrease in the V-max of brush-border membrane (BBM) Na/Pi cotransport activity (1943 95 in control vs. 1183 +/- 99 pmol/5 sec/mg BBM protein in K deficiency. P < 0.02). Surprisingly. the decrease in Na/Pi cotransport activity was associated with increases in the abundance of type I (NaPi-1). and type II (NaPi-2) and type III (Glvr-1) Na/Pi protein. The decrease in Na/Pi transport was associated with significant alterations in BBM lipid composition, including increases in sphingomyelin. glucosylceramide. and ganglioside GM, content and a decrease in BBM lipid fluidity. Inhibition of glucosylceramide synthesis resulted in increases in BBM Na/Pi cotransport activity in control and K-deficient rats. The resultant Na/Pi cotransport activity in K-deficit nt rats was the same as in control rats (1148 +/- 52 in control + PDMP vs. 11.52 +/- 61 pmol/5 sec/mg BBM protein in K deficiency + PDMP). These changes in transport activity occurred independent of further changes in BBM NaPi-2 protein or renal cortical NaPi-2 mRNA abundance. Conclusion. K deficiency in the rat causes inhibition of renal Na/Pi cotransport activity by post-translational mechanisms that are mediated in part through alterations in glucosylceramide content and membrane lipid dynamics.

Pharmacotherapy of the ion transport defect in cystic fibrosis

1. More than 1300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), a disease characterized by deficient epithelial Cl- secretion and enhanced Na+ absorption. The clinical course of the disease is determined by the progressive lung disease. Thus, novel approaches in pharmacotherapy are based primarily on correction of the ion transport defect in the airways. 2. The current therapeutic strategies try to counteract the deficiency in Cl- secretion and the enhanced Na+ absorption. A number of compounds have been identified, such as genistein and xanthine derivatives, which directly activate mutant CFTR. Other compounds may activate alternative Ca2+-activated Cl- channels or basolateral K+ channels, which supply the driving force for Cl- secretion. Apart from that, Na+ channel blockers, such as phenamil and benzamil, are being explored, which counteract the hyperabsorption of NaCl in CF airways. 3. Clinical trials are under way using purinergic compounds such as the P2Y(2) receptor agonist INS365. Activation of P2Y(2) receptors has been found to both activate Cl- secretion and inhibit Na+ absorption. 4. The ultimate goal is to recover Cl- channel activity of mutant CFTR by either enhancing synthesis and expression of the protein or by activating silent CFTR Cl- channels. Strategies combining these drugs with compounds facilitating Cl- secretion and inhibiting Na+ absorption in vivo may have the best chance to counteract the ion transport defect in cystic fibrosis.

Differential perturbation of neuronal and glial glutamate transport systems in retinal ischaemia

Glutamate is the major excitatory neurotransmitter in the retina and is removed from the extracellular space by an energy-dependent process involving neuronal and glial cell transporters. The radial glial Muller cells express the glutamate transporter, GLAST, and preferentially accumulate glutamate. However, during an ischaemic episode, extracellular glutamate concentrations may rise to excitotoxic levels. Is this catastrophic rise in extracellular glutamate due to a failure of GLAST? Using immunocytochemistry, we monitored the transport of the glutamate transporter substrate, D-aspartate, in the retina under normal and ischaemic conditions. Two models of compromised retinal perfusion were compared: (1) Anaesthetised rats had their carotid arteries occluded for 7 days to produce a chronic reduction in retinal blood flow. Retinal function was assessed by electroretinography. D-aspartate was injected into the eye for 45 min, Following euthanasia, the retina was processed for D-aspartate. GLAST and glutamate immunocytochemistry. Although reduced retinal perfusion suppresses the electroretinogram b-wave, neither retinal histology, GLAST expression, nor the ability of Muller cells to uptake D-aspartate is affected. As this insult does not appear to cause excitotoxic neuronal damage, these data suggest that GLAST function and glutamate clearance are maintained during periods of reduced retinal perfusion. (2) Occlusion of the central retinal artery for 60 min abolishes retinal perfusion, inducing histological damage and electroretinogram suppression. Although GLAST expression appears to be normal. its ability to transport D-aspartate into Muller cells is greatly reduced. Interestingly, D-aspartate is transported into neuronal cells, i.e. photoreceptors, bipolar and ganglion cells. This suggests that while GLAST is vitally important for the clearance of excess extracellular glutamate, its capability to sustain inward transport is particularly susceptible to an acute ischaemic attack. Manipulation of GLAST function could alleviate the degeneration and blindness that result from ischaemic retinal disease. (C) 2001 Elsevier Science Ltd, All rights reserved.