Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences

Background: Gabapentin and pregabalin inhibit Ca2+ currents via high-voltage-activated channels containing the α2δ-1 subunit, reducing neurotransmitter release and attenuating the postsynaptic excitability. They are antiepileptic drugs successfully used also for the chronic pain treatment. A large number of clinical trials indicate that gabapentin and pregabalin could be effective as postoperative analgesics. This systematic-narrative review aims to analyse the most recent evidences regarding the effect of gabapentinoids on postoperative pain treatment. Methods: Medline, The Cochrane Library, EMBASE and CINHAL were searched for recent (2006-2009) randomized clinical trials (RCTs) of gabapentin-pregabalin for postoperative pain relief in adults. Quality of RCTs was evaluated according to Jadad method. Visual analogue scale (VAS), opioid consumption and side-effects (nausea, vomiting, dizziness and sedation) were considered the most important outcomes. Results: An overall of 22 gabapentin (1640 patients), 8 pregabalin (707 patients) RCTs and seven meta-analysis were involved in this review. Gabapentin provided better post-operative analgesia and rescue analgesics sparing than placebo in 6 of the 10 RCTs that administered only pre-emptive analgesia. Fourteen RCTs suggested that gabapentin did not reduce PONV when compared with placebo, clonidine or lornoxicam. Pregabalin provided better post-operative analgesia and rescue analgesics sparing than placebo in two of the three RCTs that evaluated the effects of pregabalin alone vs placebo. Four studies reported no pregabalin effects on preventing the PONV. Conclusion: Gabapentin and pregabalin reduce pain and opioid consumption after surgery in confront with placebo, but comparisons with other standard post-operative regimens are not sufficient. Gabapentin and pregabalin seem not to have any influence on the prevention of PONV

Thin-film composite forward osmosis membranes functionalized with graphene oxide–silver nanocomposites for biofouling control

© 2016 Elsevier B.V. Innovative approaches to prevent bacterial attachment and biofilm growth on membranes are critically needed to avoid decreasing membrane performance due to biofouling. In this study, we propose the fabrication of anti-biofouling thin-film composite membranes functionalized with graphene oxide–silver nanocomposites. In our membrane modification strategy, carboxyl groups on the graphene oxide–silver nanosheets are covalently bonded to carboxyl groups on the surface of thin-film composite membranes via a crosslinking reaction. Further characterization, such as scanning electron microscopy and Raman spectroscopy, revealed the immobilization of graphene oxide–silver nanocomposites on the membrane surface. Graphene oxide–silver modified membranes exhibited an 80% inactivation rate against attached Pseudomonas aeruginosa cells. In addition to a static antimicrobial assay, our study also provided insights on the anti-biofouling property of forward osmosis membranes during dynamic operation in a cross-flow test cell. Functionalization with graphene oxide–silver nanocomposites resulted in a promising anti-biofouling property without sacrificing the membrane intrinsic transport properties. Our results demonstrated that the use of graphene oxide–silver nanocomposites is a feasible and attractive approach for the development of anti-biofouling thin-film composite membranes

Leveraging vectored vaccine candidates manufacturing to GMP compatible bioprocesse

Background Vectored vaccines are very efficient in the in vivo delivery of antigens either in the form of antigen protein and peptides or genetic material. The bioprocess of vectored vaccines poses however several challenge since the viral particles to be effective must maintain their infectivity. Lentiviral and adenoviral vectors are among the particles more used in the treatment of cancer diseases modulating the immune system. Both viral vectors are currently produced in transient upstream process. While the adenoviral vectors are produced at high titers the lentiviral vector upstream process still requires further improvement. The non-lytic nature of lentivirus enables the design of stable cell lines which may improve its yields through perfusion and longer term productions, reducing costs. The application of novel methods for the downstream processing such as continuous purification will contribute to increase the yield and lower the overall cost of the manufacturing processes. Experimental approach At the upstream process, many of the challenges lentiviral bioproducts present in its manufacturing are related to the apoptosis-leading cytotoxicity of some of the vector components. Supported on our long track experience and enabling tools developed for gammaretrovirus manufacturing, we undertook the challenge of establishing a constitutive stable lentiviral producer cell line. To address this challenge we proposed to eliminate or reduce the cytotoxicity of the lentiviral vector expression components. At the downstream process lentiviral vectors face the challenges common to retroviridae family of vectors namely short half-lives at room temperature, sensitivity to pH variations and salt concentrations, and shear stress. The purification strategy developed was designed to be based on disposable and easily scalable technologies. A final concentration achieving 108 TU mL-1 was targeted since the concentration step itself allows to reduce the burden on process and improve the transduction efficiency. To address the high doses requirements we will report an improved oncolytic adenovirus purification process for phase I and II clinical trials and present a case on the use of Polysorb 20 as a replacement for Triton X-100 during cell lysis. Product recovery, potency, purity and the effect of manufacturing holding points will be discussed. Results and discussion A lentiviral producer cell line constitutively producing titers above 106 TU.mL-1.day-1 was established. The cell line showed to be stable, consistently maintaining vector productivity over one month in the absence of antibiotics. At the bioreaction process it was possible to maintain the cells continuously producing over 10 days. At downstream we implemented scalable protocols for lentiviral and adenoviral vectors that is easy to transfer to GMP environment, combining microfiltration, anion-exchange, and ultrafiltration membranes technologies toward maximization of infectious virus recovery, allowing generation of clinical-grade viral vectors without the need for cleaning validation in a cost-effective manner. Herein we will present and discuss the challenges on the biomanufacturing of lentiviral as well as adenoviral virus, the strategies and novel technologies to be adopted in order to enable a faster development of novel vectored vaccine candidates focusing on several case studies, supported by process technology innovation

Encapsulation of Blackberry Anthocyanins by Thermal Gelation of Curdlan

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Blackberry shows an attractive color due to the presence of anthocyanins; however the use of these pigments as natural colorant is difficult since some external agents, specially pH>3, cause their discoloration. On the other hand, encapsulation techniques have been widely used in the industry to protect active ingredients. The aims of this study were to establish the encapsulation conditions of anthocyanins from blackberry, to evaluate the capsules characteristics, as well as the anthocyanins release. Three polysaccharides (curdlan, pectin and sodium alginate) were evaluated as wall material to obtain capsules by gelation. Curdlan was chosen since it was the only gum capable to form hard gel under low pH value. The capsules showed spherical form and multinucleated appearance, and encapsulation efficiency ranged from 80.3 to 96.7%. The release curves followed first order kinetics, with a strong burst effect, 80 to 100% of the anthocyanins released in solution at pH 1 after 20 min.201019081915Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Impact of daily evaluation and spontaneous breathing test on the duration of pediatric mechanical ventilation: a randomized controlled trial

Objectives: To assess whether the combination of daily evaluation and use of a spontaneous breathing test could shorten the duration of mechanical ventilation as compared with weaning based on our standard of care. Secondary outcome measures included extubation failure rate and the need for noninvasive ventilation.Design: A prospective, randomized controlled trial.Setting: Two pediatric intensive care units at university hospitals in Brazil.Patients: the trial involved children between 28 days and 15 yrs of age who were receiving mechanical ventilation for at least 24 hrs.Interventions: Patients were randomly assigned to one of two weaning protocols. in the test group, the children underwent a daily evaluation to check readiness for weaning with a spontaneous breathing test with 10 cm H(2)O pressure support and a positive end-expiratory pressure of 5 cm H(2)O for 2 hrs. the spontaneous breathing test was repeated the next day for children who failed it. in the control group, weaning was performed according to standard care procedures.Measurements and Main Results: A total of 294 eligible children were randomized, with 155 to the test group and 139 to the control group. the time to extubation was shorter in the test group, where the median mechanical ventilation duration was 3.5 days (95% confidence interval, 3.0 to 4.0) as compared to 4.7 days (95% confidence interval, 4.1 to 5.3) in the control group (p = .0127). This significant reduction in the mechanical ventilation duration for the intervention group was not associated with increased rates of extubation failure or noninvasive ventilation. It represents a 30% reduction in the risk of remaining on mechanical ventilation (hazard ratio: 0.70).Conclusions: A daily evaluation to check readiness for weaning combined with a spontaneous breathing test reduced the mechanical ventilation duration for children on mechanical ventilation for > 24 hrs, without increasing the extubation failure rate or the need for noninvasive ventilation. (Crit Care Med 2011; 39: 2526-2533)Hosp Sirio Libanes, Intens Care Unit, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Pediat, Hosp Clin, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Pneumol, Hosp Clin, São Paulo, BrazilHosp Albert Einstein, Intens Care Unit, São Paulo, BrazilUniv Buenos Aires, Hosp Ninos R Gutierrez, Intens Care Unit, Buenos Aires, DF, ArgentinaUniv São Paulo, Sch Med, Intens Care Unit, Univ Hosp, São Paulo, BrazilWeb of Scienc

Activation profile of pro-inflammatory cytokines in acute cardiac overload

INTRODUCTION:Pro-inflammatory cytokines have been implicated in ventricular remodeling during heart failure progression. In the present study, we investigated the effects of acute volume and RV pressure overload on biventricular hemodynamics and myocardial gene expression of IL-6 and TNF-alpha.METHODS:Male Wistar rats (n = 45) instrumented with RV and LV tip micromanometers were randomly assigned to one of three protocols: i) acute RV pressure overload (PrOv) induced by pulmonary trunk banding in order to double RV peak systolic pressure, for 120 or 360 min; ii) acute volume overload (VolOv) induced by dextran40 infusion (5 ml/h), for 120 or 360 min; iii) Sham. Free wall samples from the RV and LV were collected for mRNA quantification.RESULTS:In the RV, acute overload induced IL-6 and TNF-alpha gene expression, higher in VolOv (IL-6: + 669.7 +/- 263.4%; TNF-alpha: + 5149.9 +/- 1099.0%; 360 min) than in PrOv (IL-6: + 64.9 +/- 44.2%; TNF-alpha: + 628.1 +/- 229.3%; 360 min). In PrOv, TNF-alpha mRNA levels in the LV were increased, in the absence of ventricular overload. IL-6 and TNF-alpha mRNA levels did not correlate in the LV, while in the RV a positive correlation was found (r = 0.574; p < 0.001).CONCLUSIONS:Acute cardiac overload induces overexpression of pro-inflammatory cytokines. This gene activation is not uniform, being higher in volume overload and involving both load-dependent and load-independent mechanisms

In vitro and in vivo characterization of PLLA-316L stainless steel electromechanical devices for bone tissue engineering—A preliminary study

Bone injuries represent a major social and financial impairment, commonly requiring surgical intervention due to a limited healing capacity of the tissue, particularly regarding critical-sized defects and non-union fractures. Regenerative medicine with the application of bone implants has been developing in the past decades towards the manufacturing of appropriate devices. This work intended to evaluate medical 316L stainless steel (SS)-based devices covered by a polymer poly (L-lactic acid) (PLLA) coating for bone lesion mechanical and functional support. SS316L devices were subjected to a previously described silanization process, following a three-layer PLLA film coating. Devices were further characterized and evaluated towards their cytocompatibility and osteogenic potential using human dental pulp stem cells, and biocompatibility via subcutaneous implantation in a rat animal model. Results demonstrated PLLA-SS316L devices to present superior in vitro and in vivo outcomes and suggested the PLLA coating to provide osteo-inductive properties to the device. Overall, this work represents a preliminary study on PLLA-SS316L devices’ potential towards bone tissue regenerative techniques, showing promising outcomes for bone lesion support.This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/50011/2019, financed by national funds through the FCT/MCTES and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. This work was also financed by Portugal 2020 through the European Regional Development Fund (ERDF), in the frame of Operational Competitiveness and Internationalization Programme (POCI), in the scope of the project “Advanced BioMEMs for tissue engineering: Applications in hard tissue (BioMEMs)”, POCI-01-0145-FEDER-032095. Mariana Vieira Branquinho (SFRH/BD/146172/2019), Ana Catarina Sousa (SFRH/BD/146689/2019), and Rui Damásio Alvites (SFRH/BD/116118/2016), acknowledge FCT, for financial support

SEASONAL VARIATIONS, METAL DISTRIBUTION AND WATER QUALITY IN THE TODOS OS SANTOS RIVER, SOUTHEASTERN BRAZIL: A MULTIVARIATE ANALYSIS

In aquatic habitats, metal contamination from natural and anthropogenic sources continues to pose a concern for human and environmental health. Thus, it is important to complete monitoring studies to assess patterns and the extent of metal contamination in these ecosystems. The objective of this study was to determine the concentrations of 31 chemical elements and water quality parameters of the Todos os Santos River located in the Mucuri Valley, Minas Gerais, Brazil and use multivariate statistical analyses to determine any seasonal and spatial patterns in the data. Results demonstrated that metals including Al, Fe, and Ni exceeded Brazilian and international guidelines for these elements with nutrients such as P also exceeding water quality standards. Principal components analysis indicated distinct geographical and seasonal patterns for multiple elements with hierarchical cluster analysis confirming the observed spatial patterns of contamination in the Todos os Santos River

ETB2 Receptor Subtype Stimulation Relaxes the Iris Sphincter Muscle

Effects of ETB receptor stimulation and its subcellular pathways were evaluated in carbachol pre-contracted rabbit iris sphincter muscles (n=51). ETB stimulation with sarafotoxin (SRTX-c; 10(-10)-10(-6) M) was tested in the absence (n=7) or presence of 10(-5) M of: BQ-788 (ETB2 receptor antagonist; n=6), L-NA (NOS inhibitor; n=7) or indomethacin (cyclooxygenase inhibitor; n=10). Effects of ETB stimulation by endothelin-1 (ET-1; 10-(10)-10(-7) M) in the presence of an ETA receptor antagonist (BQ-123; 10(-5) M; n=7) and of ETB1 stimulation by IRL-1620 (10-(10)-10(-7) M; n=7) were also tested. Finally, the effects of SRTX-c (10(-9)-10(-7) M) in electric field stimulation (EFS) contraction were evaluated (n=7). ETB receptor stimulation by SRTX-c or ET-1 in presence of BQ-123 promoted a concentration-dependent relaxation of the rabbit iris sphincter muscle by 10.8 +/- 2.0 % and 9.4 +/- 1.8 %, respectively. This effect was blocked by BQ-788 (-2.3 +/- 2.0 %), L-NA (4.5 +/- 2.3 %) or indomethacin (2.3 +/- 2.9 %). Selective ETB1 stimulation by IRL-1620 did not relax the iris sphincter muscle (0.9 +/- 5.4 %). EFS elicited contraction was not altered by SRTX-c. In conclusion, ETB receptor stimulation relaxes the carbachol precontracted iris sphincter muscle, an effect that is mediated by the ETB2 receptor subtype, through NO and the release of prostaglandins