An in Vivo Mouse Model to Investigate the Effect of Local Anesthetic Nanomedicines on Axonal Conduction and Excitability

Peripheral nerve blocks (PNBs) using local anesthetic (LA) are superior to systemic analgesia for management of post-operative pain. An insufficiently short PNB duration following single-shot LA can be optimized by development of extended release formulations among which liposomes have been shown to be the least toxic. In vivo rodent models for PNB have focused primarily on assessing behavioral responses following LA. In a previous study in human volunteers, we found that it is feasible to monitor the effect of LA in vivo by combining conventional conduction studies with nerve excitability studies. Here, we aimed to develop a mouse model where the same neurophysiological techniques can be used to investigate liposomal formulations of LA in vivo. To challenge the validity of the model, we tested the motor PNB following an unilamellar liposomal formulation, filled with the intermediate-duration LA lidocaine. Experiments were carried out in adult transgenic mice with fluorescent axons and with fluorescent tagged liposomes to allow in vivo imaging by probe-based confocal laser endomicroscopy. Recovery of conduction following LA injection at the ankle was monitored by stimulation of the tibial nerve fibers at the sciatic notch and recording of the plantar compound motor action potential (CMAP). We detected a delayed recovery in CMAP amplitude following liposomal lidocaine, without detrimental systemic effects. Furthermore, CMAP threshold-tracking studies of the distal tibial nerve showed that the increased rheobase was associated with a sequence of excitability changes similar to those found following non-encapsulated lidocaine PNB in humans, further supporting the translational value of the model

Benefit of pazopanib in advanced gastrointestinal stromal tumours : results from a phase II trial (SSG XXI, PAGIST)

Background: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. Patients and methods: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were >= 18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission thorn partial remission thorn stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. Results: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. Conclusion: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.Peer reviewe

A computational analysis of lower bounds for big bucket production planning problems

In this paper, we analyze a variety of approaches to obtain lower bounds for multi-level production planning problems with big bucket capacities, i.e., problems in which multiple items compete for the same resources. We give an extensive survey of both known and new methods, and also establish relationships between some of these methods that, to our knowledge, have not been presented before. As will be highlighted, understanding the substructures of difficult problems provide crucial insights on why these problems are hard to solve, and this is addressed by a thorough analysis in the paper. We conclude with computational results on a variety of widely used test sets, and a discussion of future research

Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study

<p>Abstract</p> <p>Background</p> <p>The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment.</p> <p>Methods</p> <p>We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis.</p> <p>Results</p> <p>The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≤ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin.</p> <p>Conclusions</p> <p>The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.</p

Evaluation of young smokers and non-smokers with Electrogustometry and Contact Endoscopy

<p>Abstract</p> <p>Background</p> <p>Smoking is the cause of inducing changes in taste functionality under conditions of chronic exposure. The objective of this study was to evaluate taste sensitivity in young smokers and non-smokers and identify any differences in the shape, density and vascularisation of the fungiform papillae (fPap) of their tongue.</p> <p>Methods</p> <p>Sixty-two male subjects who served in the Greek military forces were randomly chosen for this study. Thirty-four were non-smokers and 28 smokers. Smokers were chosen on the basis of their habit to hold the cigarette at the centre of their lips. Taste thresholds were measured with Electrogustometry (EGM). The morphology and density of the fungiform papillae (fPap) at the tip of the tongue were examined with Contact Endoscopy (CE).</p> <p>Results</p> <p>There was found statistically important difference (<it>p </it>< 0.05) between the taste thresholds of the two groups although not all smokers presented with elevated taste thresholds: Six of them (21%) had taste thresholds similar to those of non-smokers. Differences concerning the shape and the vessels of the fungiform papillae between the groups were also detected. Fewer and flatter fPap were found in 22 smokers (79%).</p> <p>Conclusion</p> <p>The majority of smokers shown elevated taste thresholds in comparison to non-smokers. Smoking is an important factor which can lead to decreased taste sensitivity. The combination of methods, such as EGM and CE, can provide useful information about the vascularisation of taste buds and their functional ability.</p

Mortality among Patients with Cleared Hepatitis C Virus Infection Compared to the General Population: A Danish Nationwide Cohort Study

BACKGROUND: The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity. METHODOLOGY/PRINCIPAL FINDINGS: Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20-39 years or 40-69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40-69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%-97%), MRR: 1.3 (95% CI: 0.8-2.3)), whereas those aged 20-39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3-14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40-69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1-30.6)). CONCLUSIONS: Mortality in patients aged 40-69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20-39 years without documented substance abuse or comorbidity

Determinação de função covariância local para a predição de anomalias da gravidade Bouguer e valores da gravidade visando à obtenção de números geopotenciais

Considerando as dimensões de um país como o Brasil, realizar observações gravimétricas sobre todas as linhas de nivelamento do país ainda constitui-se um problema pertinente quando o objetivo é a determinação de números geopotenciais e/ou quantidades relacionadas ao campo da gravidade (e.g. anomalias da gravidade). Funções de covariância locais foram construídas a partir de valores da gravidade disponibilizados pelo Instituto Brasileiro de Geografia e Estatística (IBGE). Estes valores foram digitalizados e anexados à base de dados do Laboratório de Referenciais Geodésicos e Altimetria por Satélites (LARAS) da UFPR, a qual já contém dados da rede gravimétrica argentina. Estas funções de covariância foram desenvolvidas para anomalias da gravidade Bouguer na região fronteiriça Brasil/Argentina. Estudos com funções polinomiais e de Fourier foram avaliadas utilizando dez por cento dos pontos originais para checagem. Os resultados obtidos em termos de Erro Médio Quadrático (RMS) para a função polinomial de quarta ordem e para a função de Fourier de terceira ordem foram do nível do mGal

Pancreatic β-cell signaling: toward better understanding of diabetes and its treatment

Pancreatic β-cells play a central role in the maintenance glucose homeostasis by secreting insulin, a key hormone that regulates blood glucose levels. Dysfunction of the β-cells and/or a decrease in the β-cell mass are associated closely with the pathogenesis and pathophysiology of diabetes mellitus, a major metabolic disease that is rapidly increasing worldwide. Clarification of the mechanisms of insulin secretion and β-cell fate provides a basis for the understanding of diabetes and its better treatment. In this review, we discuss cell signaling critical for the insulin secretory function based on our recent studies