Investigation of the antinociceptive efficacy and relative potency of extended duration injectable 3-acylmorphine-6-sulfate prodrugs in rats

This investigation was designed to examine the antinociceptive activity in rats of 3-O-acyl prodrugs of M6S relative to the parent drug, after intravenous and intramuscular injection, using the tail flick latency test of antinociception. M6S, 3-acetylmorphine-6-sulfate (3AcM6S), 3-propionylmorphine-6-sulfate (3PrM6S), 3-butanoylmorphine-6-sulfate (3BuM6S) and 3-heptanoylmorphine-6-sulfate (3HpM6S) were administered by the IV route in a dose of 4.10 mu mol/kg. Relatively high levels of antinociception (>40% Maximum Possible Effect) were achieved following administration of M6S, 3AcM6S and 3PrM6S, whereas insignificant antinociception (<20%MPE) was achieved following administration of 3BuM6S or 3HpM6S. Although the mean duration of action for 3AcM6S (6 h) was longer than for M6S or 3PrM6S (4 h), the mean area (+/- S.E.M.) under the degree of antinociception versus time curve (AUG) for 3AcM6S (151.6 +/- 6.9%MPE h) was not significantly different (p <0.05) from that for M6S (120.8 +/- 32.7%MPE h) or for 3PrM6S (106.0 +/- 21.3%MPE h). The mean ED50 (range) doses for M6S, 3AcM6S and 3PrM6S were calculated to be 4.16 (3.61-4.48), 4.32 (3.55-5.09) and 4.54 (4.21-4.79) mu mol/kg, respectively. Preliminary studies were conducted on potential long-acting formulations containing 8 x ED50 doses of M6S and the 3-acetyl and 3-propionyl esters suspended in soybean oil. These showed that 3PrM6S gave a greater AUC (mean + S.E.M.) (1087.4 +/- 97.4%MPE h) and longer duration of action (20 h) than did M6S (613.1 +/- 155.9%MPE h; 10 h duration) or 3AcM6S (379.3 + 114.2%MPE h: 8 h duration). Further studies are needed to more fully investigate these findings. (C) 1998 Elsevier Science B.V. All rights reserved.

Gender differences in drinking restraint

Objective: This study examines the factor structure and the predictive power of drinking restraint for men and women as measured by the Temptation and Restraint Inventory (TRI). The TRI assesses two factors: Cognitive-Emotional Preoccupation (CEP) and Cognitive-Behavioral Control (CBC). Method: A group of 418 drinkers was drawn from a university sample and divided by gender into two groups. Men (n = 122) were of a mean age (+/-SD) of 23 +/- 7 years; women (n = 296) were of a mean age of 22.5 +/- 8 years. Subjects completed the TRI and the Alcohol Dependence Scale (ADS) and validated quantity and frequency of drinking indices. Results: Drinking restraint for the men was found to better predict alcohol dependence, quantity of drinking and frequency of drinking. Moreover, two factors confirming the TRI's CEP and CBC model were extracted for the men, but only one factor was extracted for the women. Conclusions: It was proposed that, as men tend to drink greater amounts of alcohol more often, they have learned to distinguish more clearly the conflicts in their personal control over drinking. If the TRI is to be used as a diagnostic and treatment tool, it is recommended that clinicians be cognizant of possible gender differences in restrained drinking behavior.

Interability interactions: Impact of type and visibility of disability on perceptions

Research on perceptions of people with disabilities has in general focussed on a single disability or on unspecified 'disability.' The aim of this study was to compare perceptions of several acquired disabilities from an intergroup perspective. It was hypothesised that the type (sensory or motor) and visibility of the disability would influence perceptions, and that prior contact would increase the positivity of perceptions. Participants were 155 students who gave their own, other, perceived self, and communication perceptions of male and female targets (with deafness, blindness, aphasia, or paraplegia) in vignettes. Results indicated that for most measures, people with motor disabilities were perceived more negatively than those with sensory ones, visible sensory disabilities more negatively than invisible sensory, but contrary to predictions, invisible motor more negatively than visible motor. There was some support for the association between prior contact and more positive perceptions.

Neighborhood and Efficiency in Manufacturing in Brazilian Regions: A Spatial Markov Chain Analysis

This paper analyzes the geography of regional competitiveness in manufacturing in Brazil. The authors estimate stochastic frontiers to calculate regional efficiency of representative firms in 137 regions in the period 2000-2006, in four sectors defined by technological intensity. The efficiency results are analyzed using Markov Spatial Transition Matrices to provide insights into the transition of regions between efficiency levels, considering their local spatial context. The results indicate that geography plays an important role in manufacturing competitiveness. In particular, regions with more competitive neighbors are more likely to improve their relative efficiency (pull effect) over time, and regions with less competitive neighbors are more likely to lose relative efficiency (drag effect). The authors find that the pull effect is stronger than the drag effect.

Hierarchical risk scale of agribusiness activities

This study aims to elaborate a hierarchical risk scale (HRS) of agricultural and cattle breeding activities and to classify the main agricultural crops and cattle breeding activities according to their risk levels. The research is characterized as exploratory and quantitative and was based on previous risk assessment (MARKOWITZ, 1952) and capital cost calculation (SHARPE, 1964) work for other business segments. The calculations on agricultural and cattle breeding data were processed for the period from 2000 to 2006. The used methods considers simplifications and adaptations needed to achieve the proposed objective. The final result, pioneering and embryonic, provides support to improve the management of these activities that are so essential to produce food for society.

Risk Categories Disclosed in the Administration Reports of Brazilian Companies with ADRs

The study aims to find the categories of risks disclosed in the Administration Reports of Brazilian companies with the issuance of ADR`s. The research is characterized as descriptive, accomplished through doucmentary analysis. The sample includes 28 Brazilian companies with the issuance of American Depository Receipt (ADR`s) in the Stock Exchange of New York (USA). We have tried to identify the categories of risk, presented by the companies surveyed in the Administration Reports (AR) of 2007. Seven categories of corporate risks were considered, identified through COSO (2004) methodology strategic risks, operational risks, legal risks and image risks,. The survey results show that in general there is no standaardization of the types sof risks disclosed by the companies. A total of 14 types of risks havd been identified. The predominant category in the disclosure was the operational risk, with 20.72% of the observations. There was no disclosre of image risk in the AR of the companies surveyed. It was found that 19 companies, 67.86% of the surveyed companies, demonstrate some kind of risk to which they are exposed. On the other hand, nine companies (32.14%) did not show any kind of risk.

An analysis of US greenhouse gas cap-and-trade proposals using a forward-looking economic model

We develop a forward-looking version of the recursive dynamic MIT Emissions Prediction and Policy Analysis (EPPA) model, and apply it to examine the economic implications of proposals in the US Congress to limit greenhouse gas (GHG) emissions. We find that shocks in the consumption path are smoothed out in the forward-looking model and that the lifetime welfare cost of GHG policy is lower than in the recursive model, since the forward-looking model can fully optimize over time. The forward-looking model allows us to explore issues for which it is uniquely well suited, including revenue-recycling and early action crediting. We find capital tax recycling to be more welfare-cost reducing than labor tax recycling because of its long-term effect on economic growth. Also, there are substantial incentives for early action credits; however, when spread over the full horizon of the policy they do not have a substantial effect on lifetime welfare costs.

Production of xylanase by Aspergilli using alternative carbon sources: application of the crude extract on cellulose pulp biobleaching

The ability of xylanolytic enzymes produced by Aspergillus fumigatus RP04 and Aspergillus niveus RP05 to promote the biobleaching of cellulose pulp was investigated. Both fungi grew for 4-5 days in liquid medium at 40A degrees C, under static conditions. Xylanase production was tested using different carbon sources, including some types of xylans. A. fumigatus produced high levels of xylanase on agricultural residues (corncob or wheat bran), whereas A. niveus produced more xylanase on birchwood xylan. The optimum temperature of the xylanases from A. fumigatus and A. niveus was around 60-70A degrees C. The enzymes were stable for 30 min at 60A degrees C, maintaining 95-98% of the initial activity. After 1 h at this temperature, the xylanase from A. niveus still retained 85% of initial activity, while the xylanase from A. fumigatus was only 40% active. The pH optimum of the xylanases was acidic (4.5-5.5). The pH stability for the xylanase from A. fumigatus was higher at pH 6.0-8.0, while the enzyme from A. niveus was more stable at pH 4.5-6.5. Crude enzymatic extracts were used to clarify cellulose pulp and the best result was obtained with the A. niveus preparation, showing kappa efficiency around 39.6% as compared to only 11.7% for that of A. fumigatus.

Five-Year Follow-Up of a Randomized Comparison Between Off-Pump and On-Pump Stable Multivessel Coronary Artery Bypass Grafting. The MASS III Trial

Background-Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body`s response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. Methods and Results-In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P=0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240 +/- 65 versus 300 +/- 87.5 minutes; P<0.001), in the length of ICU stay (19.5 +/- 17.8 versus 43 +/- 17.0 hours; P<0.001), time to extubation (4.6 +/- 6.8 versus 9.3 +/- 5.7 hours; P<0.001), hospital stay (6 +/- 2 versus 9 +/- 2 days; P<0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P<0.001), and blood requirements (31 versus 61% of patients; P<0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P<0.001). Conclusions-No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes.

Human breast tumor slices: A model for identification of vitamin D regulated genes in the tumor microenvironment

While many studies have addressed the direct effects of 1 alpha,25(OH)(2)D(3) on breast cancer (BC) cells, stromal-epithelial interactions, which are important for the tumor development, have been largely ignored. In addition, high concentrations of the hormone, which cannot be attained in vivo, have been used. Our aim was to establish a more physiological breast cancer model, represented by BC tissue slices, which maintain epithelial-mesenchymal interactions, cultured with a relatively low 1 alpha,25(OH)(2)D(3) concentration, in order to evaluate the vitamin D pathway. Freshly excised human BC samples were sliced and cultured in complete culture media containing vehicle, 0.5 nM or 100 nM 1 alpha,25(OH)(2)D(3) for 24 h. BC slices remained viable for at least 24 h, as evaluated by preserved tissue morphology in hematoxylin and eosin (HE) stained sections and bromodeoxyuridine (BrdU) incorporation by 10% of tumor cells. VDR mRNA expression was detected in all samples and CYP24A1 mRNA expression was induced by 1 alpha,25(OH)(2)D(3) in both concentrations (but mainly with 100 nM). Our results indicate that the vitamin D signaling pathway is functional in BC slices, a model which preserves stromal-epithelial interactions and mimics in vivo conditions. (C) 2010 Elsevier Ltd. All rights reserved.

A Dynamic Model of Hand-and-Foot Syndrome in Patients Receiving Capecitabine

For the purpose of developing a longitudinal model to predict hand-and-foot syndrome (HFS) dynamics in patients receiving capecitabine, data from two large phase III studies were used. Of 595 patients in the capecitabine arms, 400 patients were randomly selected to build the model, and the other 195 were assigned for model validation. A score for risk of developing HFS was modeled using the proportional odds model, a sigmoidal maximum effect model driven by capecitabine accumulation as estimated through a kinetic-pharmacodynamic model and a Markov process. The lower the calculated creatinine clearance value at inclusion, the higher was the risk of HFS. Model validation was performed by visual and statistical predictive checks. The predictive dynamic model of HFS in patients receiving capecitabine allows the prediction of toxicity risk based on cumulative capecitabine dose and previous HFS grade. This dose-toxicity model will be useful in developing Bayesian individual treatment adaptations and may be of use in the clinic.

Baseline hippocampal theta oscillation speeds correlate with rate of operant task acquisition

Many lines of evidence indicate that theta rhythm, a prominent neural oscillatory mode found in the mammalian hippocampus, plays a key role in the acquisition, processing, and retrieval of memories. However, a predictive neurophysiological feature of the baseline theta rhythm that correlates with the learning rate across different animals has yet to be identified. Here we show that the mean theta rhythm speed observed during baseline periods of immobility has a strong positive correlation with the rate at which rats learn an operant task. This relationship is observed across rats, during both quiet waking (r=0.82; p<0.01) and paradoxical sleep (r=0.83; p<0.01), suggesting that the basal theta frequency relates to basic neurological processes that are important in the acquisition of operant behavior. (c) 2008 Elsevier B.V. All rights reserved.

Better CD4+T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3`A, CCR2-V64I, CCR5-D32 and CCR5-Promoter 59029A/G Polymorphisms

Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3`A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3`A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/mu l/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure.

Maternal smoking during pregnancy: Impact on otoacoustic emissions in neonates

Objectives: To determine the effect of maternal smoking during pregnancy on transient evoked otoacoustic emissions levels in neonates. Methods: This was a cross-sectional study investigating neonates in the maternity ward of a university hospital in the city of Sao Paulo, Brazil. A total of 418 term neonates without prenatal or perinatal complications were evaluated. The neonates were divided into two groups: a study group, which comprised 98 neonates born to mothers who had smoked during pregnancy; and a control group, which comprised 320 neonates born to mothers who had not. In order to compare the two ears and the two groups in terms of the mean overall response and the mean transient evoked otoacoustic emissions in response to acoustic stimuli delivered at different frequencies, we used analysis of variance with repeated measures. Results: The mean overall response and the mean frequency-specific response levels were lower in the neonates in the study group (p < 0.001). The mean difference between the groups was 2.47 dB sound pressure level (95% confidence interval: 1.47-3.48). Conclusions: Maternal smoking during pregnancy had a negative effect on cochlear function, as determined by otoacoustic emissions testing. Therefore, pregnant women should be warned of this additional hazard of smoking. It is important that smoking control be viewed as a public health priority and that strategies for treating tobacco dependence be devised. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

In-shoe plantar pressure distribution during running on natural grass and asphalt in recreational runners

The type of surface used for running can influence the load that the locomotor apparatus will absorb and the load distribution could be related to the incidence of chronic injuries. As there is no consensus on how the locomotor apparatus adapts to loads originating from running Surfaces with different compliance, the objective of this study was to investigate how loads are distributed over the plantar surface while running on natural grass and on a rigid surface-asphalt. Forty-four adult runners with 4 3 years of running experience were evaluated while running at 12 km/h for 40 m wearing standardised running shoes and Pedar insoles (Novel). Peak pressure, contact time and contact area were measured in six regions: lateral, central and medial rearfoot, midfoot, lateral and media] forefoot. The Surfaces and regions were compared by three ANOVAS (2 x 6). Asphalt and natural grass were statistically different in all variables. Higher peak pressures were observed on asphalt at the central (p < 0.001) [grass: 303.8(66.7) kPa; asphalt: 342.3(76.3) kPa] and lateral rearfoot (p < 0.001) [grass: 312.7(75.8) kPa: asphalt: 350.9(98.3) kPa] and lateral forefoot (p < 0.001) [grass: 221.5(42.9) kPa asphalt: 245.3(55.5) kPa]. For natural grass, contact time and contact area were significantly greater at the central rearfoot (p < 0.001). These results suggest that natural grass may be a Surface that provokes lighter loads on the rearfoot and forefoot in recreational runners. (C) 2008 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.