Background The multimodality addition of preoperative gabapentin, acetaminophen, and celecoxib (GAC) and postoperative TENS has been recommended to diminish narcotics. We predict that GAC-TENS implementation will reduce recovery room time, improve pain control, reduce narcotic refills, and demonstrate usefulness of TENS treatment. Methods A prospective study compared a control group of patients not utilizing the GAC-TENS protocol during 2015 to patients using the GAC-TENS protocol during 2016. Results There was less recovery room time in the control group compared to the protocol group. Postoperative day one pain control was similar between the groups. Less refills were noted. TENS unit satisfaction level was rated "very helpful" by 63% of patients. Conclusion The results call into question the efficacy of the American Pain Society recommendations as they increase time in recovery room but do not decrease the quantity of narcotics used in the recovery room, nor do they improve pain satisfaction responses.

It is well known that exercise training can deeply affect redox homeostasis by enhancing antioxidant defenses. However, exhaustive exercise can induce excessive reactive oxygen species (ROS) production, leading to oxidative stress-related tissue injury and impaired muscle contractility. Hence, ROS represent important signaling molecules whose level has to be maintained to preserve normal cellular function, but which can also accumulate in response to repetitive muscle contraction. In fact, low levels of oxidants have been suggested to be essential for muscle contraction. Both aerobic and anaerobic exercise induce ROS production from several sources (mitochondria, NADPH oxidases and xanthine oxidases); however, the exact mechanisms underlying exercise-induced oxidative stress remain undefined. Professional athletes show a high risk for oxidative stress, and consequently muscle injury or decreased performance. Based on this background, we investigated leukocyte redox homeostasis alterations during the soccer season in élite soccer players. Overall blood redox status was investigated in twenty-seven male soccer players from primary division (Italian "Serie A" team) at four critical time points during the soccer season: T0: just before the first team training session; T1: at the beginning of the season; T2: in the middle of the season and T3: at the end of the season. The main markers of muscular damage (CK, myoglobin, LDH), assessed by standard routine methods, are significantly altered at the considered time points (T0 vs T1 P < 0.01). In peripheral leukocyte subpopulations, ROS production shows significant alterations at the considered time points during the soccer season, and strictly and significantly correlates with CK values at every considered time point. Our experimental data indicate that deep redox homeostasis alterations are evident during the soccer season in élite soccer players, and that oxidative stress can be easily monitored, besides using the standard plasma biochemical parameters, by leukocyte ROS production analysis.

PURPOSE:The purpose of this study is to describe the known soft tissue neuro-histology factors associated with compression neuropathy in relation to the incidence of preoperative pain in primary inguinal hernia. Enlargement of the ilioinguinal nerve occurs in 63% of patients with primary inguinal hernia; compression neuropathy has similar gross features. METHODS:Patients completed pain questionnaires pertaining to preoperative pain and the quality of pain experienced. During routine inguinal hernia repair, nerve segments were sampled for histologic evaluation. RESULTS:Twenty-two thickened nerve segments (63% of total) with proximal and distal specimens were resected for examination and comparison. We quantified various histologic indicators including nerve diameter, fascicle count, myxoid content within the epineurium, perineurium and endoneurium. Increased preoperative patient pain scores correlate with increased nerve diameter, increased fascicle count and increased myxoid material both within the perineurium and endoneurium. CONCLUSION:These findings support the concept that preoperative hernia pain is associated with compression neuropathy.

PURPOSE:Enlargement of the ilioinguinal nerve at the external inguinal ring is observed in 34% of patients undergoing primary open inguinal herniorrhaphy; in 88% of patients it occurs at the fascial edge where the hernia mushrooms with abdominal pressure. Compression neuropathy occurs near many anatomical nerve constriction sites and is associated with enlargement of the peripheral nerve accompanied by sensory changes.METHODS:In this prospective study, Carolina Comfort Scale (CCS) questionnaire data was collected for 35 primary hernia repairs. Each patient underwent primary inguinal herniorrhaphy that included ilioinguinal neurectomy. All nerves were sampled proximal to the external inguinal ring. Any nerves with grossly increased overall diameter to any degree distal to the external ring were additionally sampled in the thickened portions. A neuropathologist performed histologic evaluation of the H&E-stained cross sections.RESULTS:Paired comparison of proximal and distal nerves revealed a greater overall diameter and greater measured nerve-specific diameter in distal nerve segments. Nerves with increased overall diameter were also found to have a statistically significant positive correlation with four of eight pain measures. Additionally, increased nerve-specific diameter correlates with increased pain on four of eight pain values, but age effect on nerve diameter blunts this finding.CONCLUSIONS:Increased preoperative CCS pain values in primary open inguinal hernia are significantly correlated with gross enlargement of the overall diameter and nerve-specific diameter of the ilioinguinal nerve beyond the external inguinal ring. This is consistent with a compression neuropathy.

AimIsolation by distance (IBD) analyses are an effective tool for determining genetic connectivity among populations, providing a basis for estimating dispersal and thus contributing to spatial biodiversity planning. Here, we use an IBD approach to determine patterns of connectivity to infer dispersal distances for a phylogenetically diverse range of marine species.LocationTwo thousand and eight hundred kilometre of South African coastline.MethodsmtDNA data sets for 11 rocky shore and reef-dwelling marine species with diverse life history strategies (broadcast spawning, brooding and live-bearing) were used to quantify intraspecific genetic connectivity by means of global and pairwise (st). Mantel tests were used to assess the significance of genetic structure with geographic distance. Significant, positive slopes were used to estimate dispersal distances. For all species, we also plotted genetic diversity along the coast and compared this to patterns of species richness.ResultsFor seven of the 11 species tested, we report positive IBD relationships, with patterns of IBD of similar magnitude in broadcast spawners and live-bearers. Dispersal estimates were low, with effective distances of <10km per generation. We find discordance between pelagic larval development and population structure and that genetic structure and the physio-geographic features of the coastline considered to be important biogeographic barriers do not overlap. Genetic diversity and species richness show congruent patterns, with both variables lowest on the west coast, and increasing towards the east.Main conclusionsOur study highlights the complexity of marine systems and the clear need for regional assessments of connectivity, rather than more general management plans which may not otherwise effectively encompass area-specific conservation needs. Importantly, we show that the current marine protected area (MPA) network in South Africa is not effective in protecting evolutionary processes and strongly recommend a network of more closely spaced MPAs in the region that reflects the low average connectivity between distant marine populations.

The prion protein (PrP) has been implicated both in prion diseases such as Creutzfeldt-Jakob disease, where its monomeric cellular isoform (PrPC) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer disease, where PrPC may act as a receptor for synaptotoxic oligomeric forms of amyloid-beta (A beta). There has been considerable interest in identification of compounds that bind to PrPC, stabilizing its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrPC could also inhibit the binding of toxic A beta species and may have a role in treating Alzheimer disease, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of A beta oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen that utilizes site-specifically fluorescently labeled protein to identify compounds that bind to PrP and inhibit both A beta binding and prion propagation. Following a screen of 1,200 approved drugs, we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting A beta binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterized by isothermal titration calorimetry, and its ability to inhibit A beta binding and reduce prion levels was established in cell-based assays.

Background: The cellular form of the prion protein (PrP C ) is implicated in Alzheimer’s disease as a receptor for amyloid-beta (Aβ) Results: An assay was developed capable of identifying inhibitors of Aβ binding to PrP C Conclusion: Chicago Sky Blue inhibits Aβ binding to PrP C Significance: This is the first small molecule shown to disrupt the binding of Aβ to PrP C Abstract The prion protein (PrP) 4 has been implicated both in prion diseases such as Creutzfeldt-Jakob disease (CJD), where its monomeric cellular isoform (PrP C ) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer’s disease (AD) where PrP C may act as a receptor for synaptotoxic oligomeric forms of amyloid beta (Aβ). There has been considerable interest in identification of compounds which bind to PrP C , stabilising its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrP C could also inhibit the binding of toxic Aβ species and may have a role in treating AD, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen which utilises site-specifically fluorescently labelled protein to identify compounds which bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterised by isothermal titration calorimetry and its ability to inhibit Aβ binding and reduce prion levels established in cell-based assays .

Several lines of evidence suggest that the initial events of amyloid-β peptide (Aβ) oligomerization and deposition in Alzheimer's disease (AD) involve the interaction of soluble oligomers with neuronal membranes. In this study, we show that Aβ42 oligomers are recruited to lipid rafts, which are ordered membrane microdomains rich in cholesterol and gangliosides, resulting in lipid peroxidation, Ca(2+) dyshomeostasis and membrane permeabilization in primary fibroblasts from familial AD patients (FAD) bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations. Moreover, the presence of significantly higher levels of lipid peroxidation correlated with greater structural modification in detergent resistant domains (DRMs) isolated from APP and PS-1 fibroblasts, compared to WT fibroblasts from healthy subjects. Modulation of raft GM1, including modest depletion of GM1 content and interference with GM1 exposure or negative charge, precluded the interaction of amyloid aggregates with the plasma membrane and the resulting cell damage in FAD fibroblasts and rat brains cortical neurons. These findings suggest a specific role for raft domains as primary mediators of amyloid toxicity in AD neurons.

Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer's disease with toxicities mimicked by synthetic Aβ(1-42). However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ(1-42) after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer's disease.

Oxidative stress-mediated neuronal death may be initiated by a decrease in glutathione (GSH), whose levels are reduced in mitochondrial and synaptosomal fractions of specific CNS regions in Alzheimer disease (AD) patients. Currently, the use of GSH as a therapeutic agent is limited by its unfavorable pharmacokinetic properties. In this study, we designed the synthesis of new S-acyl glutathione (acyl-SG) thioesters of fatty acids via N-acyl benzotriazole-intermediate production and investigated their potential for targeted delivery of the parent GSH and free fatty acid to amyloid-exposed fibroblasts from familial AD patients and human SH-SY5Y neuroblastoma cells. Cell culture supplementation with acyl-SG derivatives triggers a significant decrease in lipid peroxidation and mitochondrial dysfunction in a fatty acid unsaturation degree-dependent fashion. Acyl-SG thioesters also protect cholinergic neurons against Aβ-induced damage and reduce glial reaction in rat brains. Collectively, these findings suggest that acyl-SG thioesters could prove useful as a tool for controlling AD-induced cerebral deterioration.

Post-mortem analyses of human brain tissue samples from patients suffering from neurodegenerative disorders have demonstrated dysfunction of the endoplasmic reticulum (ER). A common characteristic of the aforementioned disorders is the intracellular accumulation and aggregation of proteins due to genetic mutations or exogenous factors, leading to the activation of a stress mechanism known as the unfolded protein response (UPR). This mechanism aims to restore cellular homeostasis, however, if prolonged, can trigger pro-apoptotic signals, which are thought to contribute to neuronal cell death. The authors present evidence to support the role of ER stress-induced apoptosis in Alzheimer's, Parkinson's and Huntington's diseases, and further examine the interplay between ER dyshomeostasis and mitochondrial dysfunction, and the function of reactive oxygen species (ROS) and calcium ions (Ca2+) in the intricate relationship between the two organelles. Possible treatments for neurodegenerative diseases that are based on combating ER stress are finally presented.

UV-induced toxicity is characterized by marked oxidative stress, accompanied by the depletion of key cellular antioxidants, particularly glutathione (GSH). Replenishing cellular GSH may represent a means of counteracting UV-induced toxicity: however, treatment with free GSH is not therapeutically effective due to its unfavorable pharmacokinetic properties. In this study, we show that S-acyl-glutathione (acyl-SG) derivatives, which consist of an acyl chain (of variable length and saturation) linked via a thioester bond to GSH, increase intracellular levels of reduced GSH in primary skin fibroblasts, adenocarcinoma HeLa and neuroblastoma SH-SY5Y cells. Consistent with this, acyl-SG derivatives protect against UV-induced reactive oxygen species (ROS) production and UV-B/C-mediated lipid peroxidation and caspase-3 activation in the analyzed cell lines, with unsaturated thioesters displaying a significantly greater protective effect. Taken together, our findings suggest that acyl-SG thioesters may be therapeutically effective in the treatment of UV-related skin disorders and oxidative stress-mediated conditions in general.

Cell therapy is a promising approach for the treatment of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. However, the presence of toxic aggregates in tissue raises the question of whether grafted stem cells are susceptible to amyloid toxicity before they differentiate into mature neurons. To address this question, we investigated the relative vulnerability of human mesenchymal stromal cells and their neuronally differentiated counterparts to Aβ(42) oligomers and whether susceptibility correlates with membrane GM1 content, a key player in oligomer toxicity. We found that our cell model was highly susceptible to aggregate toxicity, whereas neuronal differentiation induced resistance to amyloid species. This data correlated well with the content of membrane GM1, levels of which decreased considerably in differentiated cells. These findings extend our knowledge of stem cell vulnerability to amyloid species, which remains a controversial issue, and confirm that amyloid-GM1 interactions play an important role in cell impairment.

Peptides and proteins can convert from their soluble forms into highly ordered fibrillar aggregates, giving rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. It is increasingly recognized that protein oligomers forming early in the process of fibril aggregation represent the pathogenic species in protein deposition diseases. The N‐terminal domain of the HypF protein from Escherichia coli (HypF‐N) has previously been shown to form, under distinct conditions, two types of HypF‐N oligomers with indistinguishable morphologies but distinct structural features at the molecular level. Only the oligomer type exposing hydrophobic surfaces and possessing sufficient structural plasticity is toxic (type A), whereas the other type is benign to cultured cells (type B). Here we show that only type A oligomers are able to induce a Ca2+ influx from the cell medium to the cytosol, to penetrate the plasma membrane, to increase intracellular reactive oxygen species production, lipid peroxidation and release of intracellular calcein, resulting in the activation of the apoptotic pathway. Remarkably, these oligomers can also induce a loss of cholinergic neurons when injected into rat brains. By contrast, markers of cellular stress and viability were unaffected in cultured and rat neuronal cells exposed to type B oligomers. The analysis of the time scales of such effects indicates that the difference of toxicity between the two oligomer types involve the early events of the toxicity cascade, shedding new light on the mechanism of action of protein oligomers and on the molecular targets for the therapeutic intervention against protein deposition diseases.

At the time of writing (1Q06) most countries have a small number (2-6) of major cellular operators offering competing 2.5G and 3G cellular services. In addition, there is a much larger number of operators of WiFi networks. In some cases, a major cellular operator, for example, Deutsche Telekomm and British Telecom, also offers a WiFi service. In other cases, WiFi services are provided by a proliferation of smaller network operators, such as restaurants, laundromats, airports, railways, community associations and municipal governments. Many organizations offer WiFi free of charge as a hospitality service, for example, restaurants. Cellular services offer ubiquitous, low data rate communications for mobile computing and commerce, whereas WiFi offers higher data rates, but less ubiquitous coverage, with limitations on mobility due to business as opposed to technology reasons. Emerging networks for mobile computing and commerce include WiMAX and WiMobile (Wright, 2006), which offer higher data rates, lower costs and city-wide coverage with handoff of calls among multiple base stations. These new technologies may be deployed by the organizations that currently deploy cellular and WiFi networks, and also may give rise to a new group of competitive wireless network operators. This article identifies the capabilities needed for mobile computing and commerce and assesses their technology and business implications. It identifies developments in the wireless networks that can be used for mobile computing and commerce, together with the services that can be provided over such networks. It provides a business analysis indicating which network operators can profitably deploy new networks, and which network operators need to establish business and technology links with each other so as to better serve their customers. The resulting range of next generation service, technologies and network operators available for mobile computing and commerce is identified.

This paper identifies 8 wireless access technologies that can be expected to be deployed for e-commerce applications in the next 1-3 years and shows that they have sufficiently diverse characteristics that users and network operators need to interconnect among them. The paper analyzes the role of those interconnections under three scenarios for the evolution of the industry structure: the status quo, and oligopolies of either network operators or portal operators.

Efficient supply chain management relies on knowing where products in the supply chain are located. The ability to track items from manufacturing plant to warehouse to distribution center to wholesaler to retailer is currently provided by RFID, radio frequency identification (Weinstein, 2005). Case examples of commercial applications of RFID in supply chain management are evaluated by Jones et al. (2004). A recent development, low power wireless personal area networking, WPAN, can offer advantages over RFID in certain circumstances. It is the purpose of this article to evaluate RFID and wireless personal area networks with respect to each other and to identify the features that give one an advantage over the other. We first describe the two technologies.