Effects of morphine and alcohol on functional brain connectivity during "resting state": a placebo-controlled crossover study in healthy young men

A major challenge in central nervous system (CNS) drug research is to develop a generally applicable methodology for repeated measurements of drug effects on the entire CNS, without task-related interactions and a priori models. For this reason, data-driven resting-state fMRI methods are promising for pharmacological research. This study aimed to investigate whether different psychoactive substances cause drug-specific effects in functional brain connectivity during resting-state. In this double blind placebo-controlled (double dummy) crossover study, seven resting-state fMRI scans were obtained in 12 healthy young men in three different drug sessions (placebo, morphine and alcohol; randomized). Drugs were administered intravenously based on validated pharmacokinetic protocols to minimize the inter- and intra-subject variance in plasma drug concentrations. Dual-regression was used to estimate whole-brain resting-state connectivity in relation to eight well-characterized resting-state networks, for each data set. A mixed effects analysis of drug by time interactions revealed dissociable changes in both pharmacodynamics and functional connectivity resulting from alcohol and morphine. Post hoc analysis of regions of interest revealed adaptive network interactions in relation to pharmacokinetic and pharmacodynamic curves. Our results illustrate the applicability of resting-state functional brain connectivity in CNS drug research.     

Psychometric Evaluation of the Brunei-Malay SF-36 version 2 Health Survey

Objectives: To culturally adapt the Short Form Health-36 version 2 (SF-36v2) into the Brunei-Malay context anddetermine its reliability and validity for measuring health-related quality of life (HRQOL) in healthy individuals andpatients with chronic kidney disease in Brunei Darussalam. Methods: An iterative multistep strategy involving setting upa bilingual expert panel, pretesting, text revision and back translation was used to prepare the Brunei-Malay SF-36v2 asan adaptation from the Malaysian-Malay SF-36v2. The Brunei-Malay SF-36v2 was then self-administered to a sample ofhealthy individuals (n=95) and predialysis chronic kidney disease outpatients (n=95) resident in Brunei. The mean(SD) age of the participants was 46.6 (17.8) years. Results: Data completion rate was 100% with minimal floor effects(≤0.21) in all the 8 domains and >15% ceiling effects in 3 of the 8 domain scales. Cronbach’s alpha was >0.70 for allthe 8 domain scales. Scaling success was 100% for convergent validity, with 100% item discriminant validity for alldomain scales except Social Functioning (94%), Mental Health (85%) and General Health (85%). Principal componentanalysis of the two-factor dimension explained 68% overall variance and accounted for 81% reliable variance, but theexact SF-36 two-factor summary constructs in the standard algorithm were not replicated in the Bruneian population.Conclusions: The Brunei-Malay SF-36v2 is a valid and reliable instrument for measuring HRQOL in healthy individualsand patients with chronic kidney disease in Brunei. The summary scales should, however, be interpreted with caution.Further studies should be carried out to assess additional psychometric properties of the Brunei-Malay SF-36v2.     

Eating practices and behavior in the urban environment: a study in downtown São Paulo

This study focuses on the implications of urban life style on eating habits and the related symbolic representations. Theoretical references used to approach the food experience are the concepts of social representation and habitus. The methodology consisted of a qualitative analysis of interviews with 21 administrative employees and field observations made at commercial establishments in downtown S?o Paulo, such as snack bars and restaurants. Study of eating behavior and practices was developed along two planes: food actually eaten and food desired. Results were classified into three segments: "ingesting and digesting affection", "determinants of social representations of eating practices", and "rituals in eating practices". Due to their origin in a domestic universe, symbolic aspects associated with food have a strong affective matrix. Concrete conditions of the urban environment associated with the subject's financial limits establish a structure of values and feelings compatible with the subject's possibilities. The study addresses both the abbreviation of food rituals and its implications on food behavior as well as features of the present urban food pattern.     

Does a single control mechanism exist for both forward and backward walking?

It has been proposed that the highly reproducible forward walking (FW) locomotor pattern is generated by a central neuronal program or central pattern generator (CPG) which provides the underlying mechanism which produces the coordinated walking movement. The purpose of this study was to quantify the differences in the muscular activation patterns during FW and backward walking (BW) at a constant step frequency and to determine if common features exist across both locomotor conditions. The hypothesis was that FW and BW are both mediated by the same CPG; therefore, only small modifications in the CPG are required in order to produce the different characteristics of each walking mode. The results noted kinematically reversed patterns at the hip and ankle joints between FW and BW. The knee joint movement pattern was similar between conditions, however, a phase shift of 14.3% of the gait cycle occurred. An approximately 25% phase shift in the muscle activation patterns existed between FW and BW in four of the six muscles studied. Additionally, a pattern recognition technique was applied to the combined EMG signals to determine the minimum number of features required to generate the measured muscular output. Only two main features were necessary to produce the EMG patterns for both the FW and BW condition. The main features in FW were more consistent than noted in BW. The results support the notion that a single spinal mechanism such as a CPG with two main features appears to be in control during both FW and BW.     

Prediction of response to antiretroviral therapy by human experts and by the EuResist data‐driven expert system (the EVE study)

Objectives

The EuResist expert system is a novel data‐driven online system for computing the probability of 8‐week success for any given pair of HIV‐1 genotype and combination antiretroviral therapy regimen plus optional patient information. The objective of this study was to compare the EuResist system vs. human experts (EVE) for the ability to predict response to treatment.

Methods

The EuResist system was compared with 10 HIV‐1 drug resistance experts for the ability to predict 8‐week response to 25 treatment cases derived from the EuResist database validation data set. All current and past patient data were made available to simulate clinical practice. The experts were asked to provide a qualitative and quantitative estimate of the probability of treatment success.

Results

There were 15 treatment successes and 10 treatment failures. In the classification task, the number of mislabelled cases was six for EuResist and 6–13 for the human experts [mean±standard deviation (SD) 9.1±1.9]. The accuracy of EuResist was higher than the average for the experts (0.76 vs. 0.64, respectively). The quantitative estimates computed by EuResist were significantly correlated (Pearson r=0.695, P<0.0001) with the mean quantitative estimates provided by the experts. However, the agreement among experts was only moderate (for the classification task, inter‐rater κ=0.355; for the quantitative estimation, mean±SD coefficient of variation=55.9±22.4%).

Conclusions

With this limited data set, the EuResist engine performed comparably to or better than human experts. The system warrants further investigation as a treatment‐decision support tool in clinical practice.     

Membrane expression of platelet calpain

Platelet calpain has many platelet substrates, including external membrane proteins. We thus investigated whether platelet calpain II was associated with platelet membranes in unstimulated and thrombin- activated platelets. A monospecific, goat polyclonal antibody was reared to purified platelet calpain II. Sixteen whole platelet lysates were found to contain 4.5 +/- 0.7 micrograms calpain antigen II per 10(8) platelets (mean +/- SEM) as determined by a competitive enzyme- linked immunosorbent assay. Using the dipeptide fluorogenic substrate, Suc-Leu-Tyr-MCA, 17 human platelet lysates contained 3.6 +/- 0.4 micrograms calpain activity per 10(8) platelets. Platelet calpain II was associated with the Triton X-100 insoluble platelet cytoskeletons from both unstimulated and thrombin-activated platelets. When compared with the total cell content of platelet calpain II, calpain antigen (10% to 13%) and calpain activity (24% to 28%) was associated with platelet cytoskeletons in unstimulated and thrombin-activated platelets, respectively. On immunoblot, the heavy chain (80 Kd) of calpain II was detected in platelet cytoskeletons. Subcellular fractionation studies on both unstimulated and thrombin-activated platelets, revealed that half of the total platelet calpain II antigen was associated with cytosol, and the other half was associated with the membrane fraction. Platelet calpain II was not seen on the surface of unstimulated, paraformaldehyde fixed platelets by immunofluorescence. However, on thrombin-activated platelets, rim immunofluorescence was seen, indicating that activated platelets externalize their calpain. This observation was confirmed by the finding that about 2,000 molecules per platelet of an 125I-anti-calpain II Fab' specifically bound to thrombin-activated but not unstimulated platelets. Both dibucaine (1 mmol/L) and platelet activating factor (1.86 mumol/L) in the absence of external Ca++, but not collagen (5 micrograms/mL) or ionophore A23187 (2.5 mumol/L) in the absence of external Ca++, were also able to externalize platelet calpain II antigen, as indicated by a similar level of specific 125I-anti-calpain II Fab'-platelet binding. These combined studies indicate that platelet calpain II is a major protein, comprising 2% of total platelet protein, a substantial portion of which is membrane-associated. When platelets are activated by thrombin and platelet activating factor, calpain II antigen also becomes present on the external platelet surface.