Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients.

SUMMARY: Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Comparison of [3H]tamsulosin and [3H]prazosin binding to wild-type and constitutively active alpha1B-adrenoceptors.

We have tested the hypothesis that smaller alpha1B-adrenoceptor labeling by [3H]tamsulosin compared to [3H]prazosin is related to differential recognition of agonist low affinity states. Paired saturation binding experiments with [3H]prazosin and [3H]tamsulosin were performed in membrane preparations from rat liver and Rat- fibroblasts stably transfected with wild-type hamster alpha1B-adrenoceptors or a constitutively active mutant thereof. In all three settings [3H]tamsulosin labeled significantly fewer alpha1B-adrenoceptors than [3H]prazosin. In noradrenaline competition binding experiments, the percentage of agonist low affinity sites was smallest for the constitutively active alpha1B-adrenoceptor but the percentage of agonist low affinity sites recognized by [3H]tamsulosin and [3H]prazosin did not differ significantly. We conclude that [3H]tamsulosin labels fewer alpha1B-adrenoceptors than [3H]prazosin but this is not fully explained by a poorer labeling of agonist low affinity sites.

Health education of diabetes as a chronic disease : transmission of information or active appropriation ?

Résumé du poster : Diabetes is both an important chronic disease and a real public health problem. It requires a great control over the body and a great mastery of the tools used in the daily struggle to reach a physiological balance. It is therefore a disease in which health education plays an important role, since patients are expected to reach a certain autonomy in the management of their disease. But how can the patients' autonomy be promoted? This is the question to which this study tried to answer from the perspective of socio-cultural psychology. The study was launched by the Cantonal Diabetes Program Vaud and aimed at evaluating a health education setting located in the east region of the Canton Vaud. It was based on both quantitative and qualitative methodological approaches. The results showed that there is a correlation between the number of hospitalizations and the quality of support provided by this particular health education setting. Moreover, the acquisition of expertise appears to be a distributed and collective process based upon the actors' active participation in various types of activities and involving and extended network. Further research is now required in order to examine how health education might be grasped through the lens of social-cultural psychology.

Long-term outcome after cognitive and behavioral regression in non-lesional epilepsy with CSWS

Purpose: To present the long-term outcome (LTO) of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to non-lesional focal, mainly frontal epilepsy with continuous spike-waves during slow wave sleep (CSWS). Method: Past medical and EEG data of all patients were reviewed and neuropsychological tests exploring main cognitive functions were administered. Result: After a mean duration of follow-up of 15.6 years (range 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders that were so disturbing during the active period (AP) resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the AP disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. LTO correlated best with duration of CSWS. Conclusion: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence as reported in adults with destructive lesions of the frontal lobes during childhood. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation.

Site-directed mutagenesis and molecular dynamics simulations of the alpha 1B-adrenergic receptor (AR) were combined to explore the potential molecular changes correlated with the transition from R (inactive state) to R (active state). Using molecular dynamics analysis we compared the structural/dynamic features of constitutively active mutants with those of the wild type and of an inactive alpha 1B-AR to build a theoretical model which defines the essential features of R and R. The results of site-directed mutagenesis were in striking agreement with the predictions of the model supporting the following hypothesis. (i) The equilibrium between R and R depends on the equilibrium between the deprotonated and protonated forms, respectively, of D142 of the DRY motif. In fact, replacement of D142 with alanine confers high constitutive activity to the alpha 1B-AR. (ii) The shift of R143 of the DRY sequence out of a conserved 'polar pocket' formed by N63, D91, N344 and Y348 is a feature common to all the active structures, suggesting that the role of R143 is fundamental for mediating receptor activation. Disruption of these intramolecular interactions by replacing N63 with alanine constitutively activates the alpha 1B-AR. Our findings might provide interesting generalities about the activation process of G protein-coupled receptors.

Differential DNA extraction of challenging simulated sexual assault samples: a Swiss collaborative study.

ABSTRACT: In sexual assault cases, autosomal DNA analysis of gynecological swabs is a challenge, as the presence of a large quantity of female material may prevent the detection of the male DNA. A solution to this problem is differential DNA extraction, but as there are different protocols, it was decided to test their efficiency on simulated casework samples. Four difficult samples were sent to the nine Swiss laboratories active in the forensic genetics. They used their routine protocols to separate the epithelial cell fraction, enriched with the non-sperm DNA, from the sperm fraction. DNA extracts were then sent to the organizing laboratory for analysis. Estimates of male to female DNA ratio without differential DNA extraction ranged from 1:38 to 1:339, depending on the semen used to prepare the samples. After differential DNA extraction, most of the ratios ranged from 1:12 to 9:1, allowing the detection of the male DNA. Compared to direct DNA extraction, cell separation resulted in losses of 94-98% of the male DNA. As expected, more male DNA was generally present in the sperm than in the epithelial cell fraction. However, for about 30% of the samples, the reverse trend was observed. The recovery of male and female DNA was highly variable depending on the laboratories. Experimental design similar to the one used in this study may help for local protocol testing and improvement.

Guidelines for Perioperative Care in Elective Colonic Surgery: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations.

BACKGROUND: This review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced-based enhanced perioperative protocol. METHODS: Studies were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English-language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. RESULTS: For most of the protocol items, recommendations are based on good-quality trials or meta-analyses of good-quality trials (quality of evidence and recommendations according to the GRADE system). CONCLUSIONS: Based on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence-based consensus review of perioperative care for colonic surgery.

Performance comparison of an active matrix flat panel imager, computed radiography system, and a screen-film system at four standard radiation qualities.

Four standard radiation qualities (from RQA 3 to RQA 9) were used to compare the imaging performance of a computed radiography (CR) system (general purpose and high resolution phosphor plates of a Kodak CR 9000 system), a selenium-based direct flat panel detector (Kodak Direct View DR 9000), and a conventional screen-film system (Kodak T-MAT L/RA film with a 3M Trimax Regular screen of speed 400) in conventional radiography. Reference exposure levels were chosen according to the manufacturer's recommendations to be representative of clinical practice (exposure index of 1700 for digital systems and a film optical density of 1.4). With the exception of the RQA 3 beam quality, the exposure levels needed to produce a mean digital signal of 1700 were higher than those needed to obtain a mean film optical density of 1.4. In spite of intense developments in the field of digital detectors, screen-film systems are still very efficient detectors for most of the beam qualities used in radiology. An important outcome of this study is the behavior of the detective quantum efficiency of the digital radiography (DR) system as a function of beam energy. The practice of users to increase beam energy when switching from a screen-film system to a CR system, in order to improve the compromise between patient dose and image quality, might not be appropriate when switching from screen-film to selenium-based DR systems.

Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.

Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease.

Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8(+) T cells is controversial. Here we performed a broad phenotypic and functional characterization of Mtb-specific CD8(+) T cells in 326 subjects with latent Mtb infection (LTBI) or active TB disease (TB). Mtb-specific CD8(+) T cells were detected in most (60%) TB patients and few (15%) LTBI subjects but were of similar magnitude. Mtb-specific CD8(+) T cells in LTBI subjects were mostly T EMRA cells (CD45RA(+) CCR7(-)), coexpressing 2B4 and CD160, and in TB patients were mostly TEM cells (CD45RA(-) CCR7(-)), expressing 2B4 but lacking PD-1 and CD160. The cytokine profile was not significantly different in both groups. Furthermore, Mtb-specific CD8(+) T cells expressed low levels of perforin and granulysin but contained granzymes A and B. However, in vitro-expanded Mtb-specific CD8(+) T cells expressed perforin and granulysin. Finally, Mtb-specific CD8(+) T-cell responses were less frequently detected in extrapulmonary TB compared with pulmonary TB patients. Mtb-specific CD8(+) T-cell proliferation was also greater in patients with extrapulmonary compared with pulmonary TB. Thus, the activity of Mtb infection and clinical presentation are associated with distinct profiles of Mtb-specific CD8(+) T-cell responses. These results provide new insights in the interaction between Mtb and the host immune response.

Longitudinal and cross-sectional changes in active commuting to school among Brazilian schoolchildren.

OBJECTIVE: The objective of the study is to evaluate cross-sectional and longitudinal changes in children's commuting to school in a representative sample of a Brazilian city. METHODS: Two school-based studies were carried out in 2002 (n=2936; 7-10years old) and 2007 (n=1232; 7-15years old) in Florianopolis, Brazil. Cross-sectional data were collected from children aged 7 to 10years in 2002 and 2007. Longitudinal analyses were performed with data from 733 children participating in both surveys. Children self-reported their mode of transportation to school using a validated illustrated questionnaire. Changes were tested with chi square statistics and McNemar's test. RESULTS: Cross-sectional data showed a 17% decline in active commuting; a decrease from 49% in 2002 to 41% in 2007. On the other hand, active commuting among the 733 children increased as they entered adolescence 5years later, rising from 40% to 49%. CONCLUSION: Active commuting to school decreased in Brazilian children aged 7-10years over a five year period; whereas, it increased among children entering adolescence. Policies should focus on safety and environmental determinants to increase active commuting.

Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with ON-resonant water suppression (IRON)

In proton magnetic resonance imaging (MRI) metallic substances lead to magnetic field distortions that often result in signal voids in the adjacent anatomic structures. Thus, metallic objects and superparamagnetic iron oxide (SPIO)-labeled cells appear as hypointense artifacts that obscure the underlying anatomy. The ability to illuminate these structures with positive contrast would enhance noninvasive MR tracking of cellular therapeutics. Therefore, an MRI methodology that selectively highlights areas of metallic objects has been developed. Inversion-recovery with ON-resonant water suppression (IRON) employs inversion of the magnetization in conjunction with a spectrally-selective on-resonant saturation prepulse. If imaging is performed after these prepulses, positive signal is obtained from off-resonant protons in close proximity to the metallic objects. The first successful use of IRON to produce positive contrast in areas of metallic spheres and SPIO-labeled stem cells in vitro and in vivo is presented.

Changes in spring-mass model characteristics during repeated running sprints.

This study investigated fatigue-induced changes in spring-mass model characteristics during repeated running sprints. Sixteen active subjects performed 12 × 40 m sprints interspersed with 30 s of passive recovery. Vertical and anterior-posterior ground reaction forces were measured at 5-10 m and 30-35 m and used to determine spring-mass model characteristics. Contact (P < 0.001), flight (P < 0.05) and swing times (P < 0.001) together with braking, push-off and total stride durations (P < 0.001) lengthened across repetitions. Stride frequency (P < 0.001) and push-off forces (P < 0.05) decreased with fatigue, whereas stride length (P = 0.06), braking (P = 0.08) and peak vertical forces (P = 0.17) changes approached significance. Center of mass vertical displacement (P < 0.001) but not leg compression (P > 0.05) increased with time. As a result, vertical stiffness decreased (P < 0.001) from the first to the last repetition, whereas leg stiffness changes across sprint trials were not significant (P > 0.05). Changes in vertical stiffness were correlated (r > 0.7; P < 0.001) with changes in stride frequency. When compared to 5-10 m, most of ground reaction force-related parameters were higher (P < 0.05) at 30-35 m, whereas contact time, stride frequency, vertical and leg stiffness were lower (P < 0.05). Vertical stiffness deteriorates when 40 m run-based sprints are repeated, which alters impact parameters. Maintaining faster stride frequencies through retaining higher vertical stiffness is a prerequisite to improve performance during repeated sprinting.

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.