Κυριακή 21 Αυγούστου 2016
Annexins A2 and A8 in endothelial cell exocytosis and the control of vascular homeostasis
Journal Name: Biological Chemistry
Issue: Ahead of print
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Inducing a Site Specific Replication Blockage in E. coli Using a Fluorescent Repressor Operator System
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Preparation of Formalin-fixed Paraffin-embedded Tissue Cores for both RNA and DNA Extraction
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Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay (EMSA) and DNA-affinity Precipitation Assay (DAPA)
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Altered EMG patterns in diabetic neuropathic and not neuropathic patients during step ascending and descending
Publication date: Available online 20 August 2016
Source:Journal of Electromyography and Kinesiology
Author(s): Fabiola Spolaor, Zimi Sawacha, Gabriella Guarneri, Silvia Del Din, Angelo Avogaro, Claudio Cobelli
Diabetic peripheral neuropathy (DPN) causes motor control alterations during daily life activities. Tripping during walking or stair climbing is the predominant cause of falls in the elderly subjects with DPN and without (NoDPN). Surface Electromyography (sEMG) has been shown to be a valid tool for detecting alterations of motor functions in subjects with DPN. This study aims at investigating the presence of functional alterations in diabetic subjects during stair climbing and at exploring the relationship between altered muscle activation and temporal parameter. Lower limb muscle activities, temporal parameters and speed were evaluated in 50 subjects (10 controls, 20 with DPN, 20 without DPN), while climbing up and down a stair, using sEMG, three-dimentional motion capture system and force plates. Magnitude and timing of sEMG linear envelopes peaks were extracted. Level walking was used as reference condition for the comparison with step negotiation. sEMG, speed and temporal parameters revealed significant differences among all groups of patients. Results showed an association between earlier activation of lower limb muscles and reduced speed in subjects with DPN. Speed and temporal parameters significantly correlated with sEMG (p< 0.05). The findings of this study are encouraging and could be used to improve rehabilitation programs aiming at reducing falls risk in diabetic subjects.
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Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress
Publication date: Available online 20 August 2016
Source:Free Radical Biology and Medicine
Author(s): Juha J. hulmi, Jaakko Hentilä, Keith C. DeRuisseau, Bernardo M. Oliveira, Konstantinos G. Papaioannou, Reija Autio, Urho M. Kujala, Olli Ritvos, Heikki Kainulainen, Ayhan Korkmaz, Mustafa Atalay
Protein homeostasis in cells, proteostasis, is maintained through several integrated processes and pathways and its dysregulation may mediate pathology in many diseases including Duchenne muscular dystrophy (DMD). Oxidative stress, heat shock proteins, endoplasmic reticulum (ER) stress and its response, i.e. unfolded protein response (UPR), play key roles in proteostasis but their involvement in the pathology of DMD are largely unknown. Moreover, exercise and activin receptor IIB blocking are two strategies that may be beneficial to DMD muscle, but studies to examine their effects on these proteostasis pathways are lacking. Therefore, these pathways were examined in the muscle of mdx mice, a model of DMD, under basal conditions and in response to seven weeks of voluntary exercise and/or activin receptor IIB ligand blocking using soluble activin receptor-Fc (sAcvR2B-Fc) administration. In conjunction with reduced muscle strength, mdx muscle displayed greater levels of UPR/ER-pathway indicators including greater protein levels of IRE1α, PERK and Atf6b mRNA. Downstream to IRE1α and PERK, spliced Xbp1 mRNA and phosphorylation of eIF2α, were also increased. Most of the cytoplasmic and ER chaperones and mitochondrial UPR markers were unchanged in mdx muscle. Oxidized glutathione was greater in mdx and was associated with increases in lysine acetylated proteome and phosphorylated sirtuin 1. Exercise increased oxidative stress when performed independently or combined with sAcvR2B-Fc administration. Although neither exercise nor sAcvR2B-Fc administration imparted a clear effect on ER stress/UPR pathways or heat shock proteins, sAcvR2B-Fc administration increased protein expression levels of GRP78/BiP, a triggering factor for ER stress/UPR activation and TxNIP, a redox-regulator of ER stress-induced inflammation. In conclusion, the ER stress and UPR are increased in mdx muscle. However, these processes are not distinctly improved by voluntary exercise or blocking activin receptor IIB ligands and thus do not appear to be optimal therapeutic choices for improving proteostasis in DMD.
Graphical abstract
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Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-κB pathway in Nrf2 deficient mice
Publication date: Available online 20 August 2016
Source:Free Radical Biology and Medicine
Author(s): Min-xuan Xu, Yan-fang Zhu, Hsiao-feng Chang, Ying Liang
Increasing studies demonstrated that air pollution (PM2.5) plays a significant role in metabolic and neurological diseases. Unfortunately, there is no direct testimony of this, and yet the molecular mechanism by which the occurrence remains unclear. In this regard, we investigated the role of NF-κB and Nrf2 signaling in PM2.5-induced metabolic disorders and neuroinflammation, and further confirmed whether Nrf2 deficiency promoted PM2.5-induced inflammatory response by up regulating astrocytes activation and nerve injur via modulating NF-κB signaling pathways. Present results found that, indeed, PM2.5 challenges results in glucose tolerance, insulin resistance, dysarteriotony, peripheral inflammation, nerve injury and hypothalamus oxidative stress through astrocytes activation related NF-κB pathway in Nrf2 deficient mice. Moreover, in vitro study, we confirmed that activated astrocytes induced by PM2.5 were involved in pathogenesis of hypothalamic inflammation, which were significantly associated with NF-κB signaling. Nanoceria as potential anti-inflammatory and anti-oxidant stress biomaterial has gained increasing attention. Moderate nanoceria treatment is able to restrain PM2.5-induced metabolic syndrome and inflammation. Inhibition of astrocytes activation related NF-κB and enhancement of Nrf2 by cerium oxide were observed in vivo and in vitro, suggesting cerium oxide inhibited hypothalamic inflammation and nerve injury by alterring hypothalamic neuroendocrine alterations and decreasing glial cells activation. In addition, NF-κB inhibitor pyrollidine dithiocarbamate (PDTC) treated primary astrocytes directly determined Nrf2 pathway could be up regulated by dose-dependent nanoceria. These results suggest a new therapeutic approach or target to protect against air pollution related diseases by cerium oxide treatment.
Graphical abstract
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Serum free sulfhydryl status is associated with patient and graft survival in renal transplant recipients
Source:Free Radical Biology and Medicine
Author(s): Anne-Roos S. Frenay, Martin H. de Borst, Matthias Bachtler, Nadine Tschopp, Charlotte A. Keyzer, Else van den Berg, Stephan J.L. Bakker, Martin Feelisch, Andreas Pasch, Harry van goor
Oxidative stress contributes significantly to graft failure, morbidity and mortality in renal transplant recipients (RTR). In cells, free sulfhydryl groups (reduced thiols, R-SH) are the transducers of redox-regulated events; their oxidation status is modulated by interaction with reactive oxygen and nitrogen oxide species and thought to be in equilibrium with the circulating pool. We hypothesized that high levels of serum free thiols are a reflection of a favorable redox status and therefore positively associated with cardiovascular risk parameters, patient and graft survival in RTR.To test this, reactive free thiol groups (R-SH; corrected for total protein) were quantified in serum of 695 RTR (57% male, 53±13yr, functioning graft ≥1yr) using Ellman's Reagent, and R-SH determinants were evaluated with multivariable linear regression models. Associations between R-SH and mortality or graft failure were assessed using multivariable Cox regression analyses.In multivariable models, male gender, estimated glomerular filtration rate and serum thiosulfate positively associated with R-SH while BMI, HbA1c, corrected calcium and NT-pro-BNP inversely associated with R-SH (model R2=0.26). During follow-up (3.1 [2.7-3.9] yrs), 79 (11%) patients died and 45 (7%) patients developed graft failure. R-SH correlated inversely with all-cause mortality (HR 0.58 [95% CI 0.45 – 0.75] per SD increase) and graft failure (HR 0.42 [0.30 – 0.59]; both P<0.001), independent of parameters with which R-SH significantly associated in the multivariable regression analyses, except for NT-pro-BNP.Serum R-SH are associated with a beneficial cardiovascular risk profile and better patient and graft survival in RTR, suggesting potential usefulness as low-cost, high-throughput screening tool for whole-body redox status in translational studies. Whether R-SH modification improves long-term outcome of RTR warrants further exploration.
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Loss of C/EBPδ enhances IR-induced cell death by promoting oxidative stress and mitochondrial dysfunction
Publication date: Available online 20 August 2016
Source:Free Radical Biology and Medicine
Author(s): Sudip Banerjee, Nukhet Aykin-Burns, Kimberly J. Krager, Sumit K. Shah, Stepan B. Melnyk, Martin Hauer-Jensen, Snehalata A. Pawar
Exposure of cells to ionizing radiation (IR) generates reactive oxygen species (ROS). This results in increased oxidative stress and DNA double strand breaks (DSBs) which are the two underlying mechanisms by which IR causes cell/tissue injury. Cells that are deficient or impaired in the cellular antioxidant response are susceptible to IR-induced apoptosis. The transcription factor CCAAT enhancer binding protein delta (Cebpd, C/EBPδ) has been implicated in the regulation of oxidative stress, DNA damage response, genomic stability and inflammation. We previously reported that Cebpd-deficient mice are sensitive to IR and display intestinal and hematopoietic injury, however the underlying mechanism is not known. In this study, we investigated whether an impaired ability to detoxify IR-induced ROS was the underlying cause of the increased radiosensitivity of Cebpd-deficient cells.We found that Cebpd-knockout (KO) mouse embryonic fibroblasts (MEFs) expressed elevated levels of ROS, both at basal levels and after exposure to gamma radiation which correlated with increased apoptosis, and decreased clonogenic survival. Pre-treatment of wild type (WT) and KO MEFs with polyethylene glycol-conjugated Cu-Zn superoxide dismutase and catalase combination prior to irradiation showed a partial rescue of clonogenic survival, thus demonstrating a role for increased intracellular oxidants in promoting IR-induced cell death. Analysis of mitochondrial bioenergetics revealed that irradiated KO MEFs showed significant reductions in basal, ATP-linked, maximal respiration and reserved respiratory capacity and decrease in intracellular ATP levels compared to wild type (WT) MEFs indicating they display mitochondrial dysfunction. KO MEFs expressed significantly lower levels of the cellular antioxidant glutathione (GSH) and its precursor- cysteine as well as methionine. In addition to its antioxidant function, GSH plays an important role in detoxification of lipid peroxidation products such as 4-hydroxynonenal (4-HNE). The reduced GSH levels observed in KO MEFs correlated with elevated levels of 4-HNE protein adducts in irradiated KO MEFs compared to respective WT MEFs.We further showed that pre-treatment with the GSH precursor, N-acetyl L-cysteine (NAC) prior to irradiation showed a significant reduction of IR-induced cell death and increases in GSH levels, which contributed to the overall increase in clonogenic survival of KO MEFs. In contrast, pre-treatment with the GSH synthesis inhibitor- buthionine sulfoximine (BSO) further reduced the clonogenic survival of KO MEFs.This study demonstrates a novel role for C/EBPδ in protection from basal as well as IR-induced oxidative stress and mitochondrial dysfunction thus promoting post-radiation survival.
Graphical abstract
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Suppression of StarD7 promotes endoplasmic reticulum stress and induces ROS production
Publication date: Available online 20 August 2016
Source:Free Radical Biology and Medicine
Author(s): Jésica Flores-Martín, Luciana Reyna, Magali E. Ridano, Graciela M. Panzetta-Dutari, Susana Genti-Raimondi
StarD7 is an intracellular lipid transport protein identified as up-regulated in the choriocarcinoma JEG-3 cell line. StarD7 facilitates the delivery of phosphatidylcholine (PC) to the mitochondria, and StarD7 knockdown causes a reduction in phospholipid synthesis. Since inhibition of PC synthesis may lead to endoplasmic reticulum (ER) stress we hypothesized that StarD7 may be involved in maintaining cell homeostasis. Here, we examined the effect of StarD7 silencing on ER stress response and on the levels of reactive oxygen species (ROS) in the human hepatoma cell line HepG2. StarD7 knockdown induced alterations in mitochondria and ER morphology. These changes were accompanied with an ER stress response as determined by increased expression of inositol−requiring enzyme 1α (IRE1α), calnexin, glucose regulated protein 78/immunoglobulin heavy chain-binding protein (Grp78/BiP), protein kinase-like ER kinase (PERK) as well as the phosphorylated eukaryotic translation initiation factor 2, subunit 1α (p-eIF2α). Additionally, a downregulation of the tumor suppressor p53 by a degradation mechanism was observed in StarD7 siRNA cells. Furthermore, StarD7 silencing induced ROS generation and reduced cell viability after H2O2 exposure. Decreased expression of StarD7 was associated to increased levels of the heme oxygenase-1 (HO-1) and catalase enzymes as well as in catalase enzymatic activity. Finally, no changes in levels of autophagy and apoptosis markers were observed in StarD7 siRNA treated cells respect to control cells. Taken together, these results indicate that StarD7 contributes to modulate cellular redox homeostasis.
Graphical abstract
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Different Vancomycin Immunoassays Contribute to the Variability in Vancomycin Trough Measurements in Neonates
Substantial interassay variability (up to 20%) has been described for vancomycin immunoassays in adults, but the impact of neonatal matrix is difficult to quantify because of blood volume constraints in neonates. However, we provide circumstantial evidence for a similar extent of variability. Using the same vancomycin dosing regimens and confirming similarity in clinical characteristics, vancomycin trough concentrations measured by PETINIA (2011-2012, ) were 20% lower and the mean difference was 1.93 mg/L compared to COBAS (2012–2014, ) measurements. The impact of vancomycin immunoassays in neonatal matrix was hereby suggested, supporting a switch to more advanced techniques (LC-MS/MS).
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Promoting Authentic Learning for Our Students
Probably more than any other profession, nursing has recognized that "learning by doing" is one of the most effective ways to learn. Historically, educating nurses was accomplished through highly structured apprenticeship models at training schools. Fortunately, we have moved away from that model, and nursing education is now appropriately situated in colleges and graduate schools. Yet we have not lost sight of the value of learning by doing, and largely thanks to the Internet, we now have at our disposal a variety of communication, visualization, and simulation technologies that provide students with authentic learning experiences that promote creativity, experimentation, and real-world problem solving.
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You Hold the Key to Improving the Well-Being of Children
The challenges of providing comprehensive, family-centered care to all children in a rapidly changing health care delivery system continue to grow. The scope of practice of pediatric advanced practice nurses and the diversity of settings in which our practitioners are employed continue to evolve to meet the ever-changing health care needs of children and families (American Nurses Association, National Association of Pediatric Nurse Practitioners, & Society of Pediatric Nurses, 2015). In my opinion, our expert pediatric knowledge coupled with the application of both the art and science of nursing make us uniquely qualified to lead in devising solutions for these challenges.
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Open Mouth, Open Mind: Expanding the Role of Primary Care Nurse Practitioners
Oral health is essential to overall health at any age, although in children it is particularly important because poor oral health can have a deleterious effect on deciduous and permanent dentition. For decades, oral health providers have urged primary care providers to incorporate oral health assessment, risk factor identification, parent education, and preventive therapy into routine well-child visits. Despite recommendations from various professional associations and governmental organizations, the incidence of dental disease in young children remains relatively unchanged.
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NAPNAP Position Statement on Child Maltreatment
A goal of the National Association of Pediatric Nurse Practitioners (NAPNAP) is to enhance the quality of health care for infants, children, and adolescents. To achieve this purpose, NAPNAP promotes the provision of a safe, caring, and healthy environment that contributes to optimal growth and development of children from infancy to adulthood.
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A randomized non-inferiority clinical study to assess post-exposure prophylaxis by a new purified vero cell rabies vaccine (Rabivax-S) administered by intramuscular and intradermal routes
Source:Vaccine
Author(s): Anuradha Bose, Renuka Munshi, Radha Madhab Tripathy, Shampur N. Madhusudana, B.R. Harish, Saket Thaker, B.J. Mahendra, Bhagwat Gunale, Nithya Gogtay, Urmila Thatte, Reeta Subramaniam Mani, K. Manjunath, Kuryan George, Ashwin Belludi Yajaman, Ashish Sahai, Rajeev M. Dhere, Reginald G. Alex, Debasis Das Adhikari, Abhilash, Venkata Raghava, Dipti Kumbhar, Tapas Ranjan Behera, Prasad S. Kulkarni
BackgroundRabies is a 100% fatal disease but preventable with vaccines and immunoglobulins. We have developed a new purified vero cell rabies vaccine (Rabivax-S) and evaluated its safety and immunogenicity in post-exposure prophylaxis by intramuscular (IM) and intradermal (ID) routes.MethodsThis was a randomized active-controlled non-inferiority study in 180 individuals (age 5years and above) with suspected rabies exposure (90 each with WHO Category II and Category III exposures). The participants received either Rabivax-S (1mL IM; five doses), Rabivax-S (0.1mL ID; eight doses) or purified chick embryo cell vaccine (PCEC, Rabipur®) (1mL IM; five doses). The IM doses were given on Day 0, 3, 7, 14 and 28 while the ID doses were given on days 0, 3, 7 and 28. Category III patients also received a human rabies immunoglobulin (HRIG) on Day 0. Adverse events (AEs) were recorded with diary cards till day 42. Rabies neutralizing antibody levels were measured on day 0, 7, 14, 28 and 42.ResultsIn both the category II and III patients, the geometric mean concentration (GMC) ratios of Rabivax-S IM and Rabivax-S ID groups to PCEC IM were more than 1, thus proving the non-inferiority. GMCs were similar or higher in Rabivax-S groups at all the time points. Seroresponse against rabies (RFFIT titre⩾0.5IU/mL) was achieved in all participants. Mostly mild local and systemic adverse events were reported across the three groups and all resolved without sequelae.ConclusionsRabivax-S was well tolerated and showed immunogenicity comparable to a licensed rabies vaccine by both IM and ID routes in post-exposure prophylaxis.Registry No.: CTRI/2012/11/003135
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Assessing dengue vaccination impact: Model challenges and future directions
Publication date: 31 August 2016
Source:Vaccine, Volume 34, Issue 38
Author(s): Mario Recker, Kirsten Vannice, Joachim Hombach, Mark Jit, Cameron P. Simmons
In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk–benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making.
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PCV13 vaccination for older adults: Another view
Source:Vaccine, Volume 34, Issue 38
Author(s): David S. Fedson
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Decrease in circulating CD25hiFoxp3+ regulatory T cells following vaccination with the candidate malaria vaccine RTS,S
Source:Vaccine, Volume 34, Issue 38
Author(s): Emily Parsons, Judith Epstein, Martha Sedegah, Eileen Villasante, Ann Stewart
Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine.We found that the frequency of CD25hiFoxp3+ Treg cells decreased following administration of RTS,S (p=0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25hiFoxp3+ Treg cells (p=0.0093) and PD-1 levels on CD8+ T cells (p=0.0002). Additionally, the frequency of anergic CTLA-4+CCR7+ T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design.
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Response to Letter to the Editor regarding: Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 18–49 years of age, naive to 23-valent pneumococcal polysaccharide vaccine
Source:Vaccine, Volume 34, Issue 38
Author(s): Kristina Bryant, Robert W. Frenck
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Human papilloma virus vaccination and dysautonomia: Considerations for autoantibody evaluation and HLA typing
Source:Vaccine, Volume 34, Issue 38
Author(s): Jeanne E. Hendrickson, Christopher A. Tormey
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Response to letter to the editor
Source:Vaccine, Volume 34, Issue 38
Author(s): Louise Schouborg Brinth, Jesper Mehlsen
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 34, Issue 38
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Assessment of outer membrane vesicles of periodontopathic bacterium Porphyromonas gingivalis as possible mucosal immunogen
Source:Vaccine, Volume 34, Issue 38
Author(s): Ryoma Nakao, Hideki Hasegawa, Bai Dongying, Makoto Ohnishi, Hidenobu Senpuku
Periodontitis is the most prevalent infectious disease and related to oral and systemic health, therefore novel prophylaxis to prevent the disease is highly desirable. Here, we assessed the outer membrane vesicles (OMVs) of a keystone periodontal pathogen, Porphyromonas gingivalis, as a candidate mucosal immunogen and adjuvant for a periodontitis vaccine. The structural and functional stability of OMVs, demonstrated by proteinase K resistance and ability to withstand long-term storage, are considered advantageous for carrying the OMV components into the host immune system. Intranasal vaccination of OMVs in mice elicited production of P. gingivalis-specific antibodies in blood and saliva by OMVs in a dose-dependent manner, which was dramatically enhanced by addition of a TLR3 agonist, Poly(I:C). Serum samples from mice immunized with OMVs plus Poly(I:C) adjuvant [OMV+Poly(I:C)] showed significant inhibition of gingipain proteolytic activity of not only the vaccine strain, but also heterologous strains. The viability of P. gingivalis was also decreased by preincubation with OMV+Poly(I:C)-immunized sera, while the killing effect was partially blocked by heat-inactivation of the sera. Saliva samples from mice immunized with OMV+Poly(I:C) enhanced bacterial agglutination of both the vaccine and heterologous strains. In an oral infection mouse model, the numbers of P. gingivalis in the oral cavity were significantly decreased in mice intranasally immunized with OMV+Poly(I:C) as compared to mock (only Poly[I:C])-immunized mice. The high levels of serum IgG (including IgG1 and IgG2a) and salivary S-IgA were elicited in mice intranasally immunized with OMV+Poly(I:C), which were maintained for at least 28 and 18weeks, respectively, after immunization. An experiment examining the accumulation of OMVs after intranasal immunization in proximal organs and an intracerebral injection experiment confirmed the safety of OMVs. Based on our results, we propose that intranasal immunization with OMV+Poly(I:C) is a feasible vaccine strategy in the context of bacterial clearance and safety.
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Retraction notice to “Development of live attenuated Streptococcus agalactiae as potential vaccines by selecting for resistance to sparfloxacin” [Vaccine 31 (2013) 2705–2712]
Source:Vaccine, Volume 34, Issue 38
Author(s): Julia W. Pridgeon, Phillip H. Klesius
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A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children
Source:Vaccine, Volume 34, Issue 38
Author(s): Sodiomon B. Sirima, Benjamin Mordmüller, Paul Milligan, Ulysse Ateba Ngoa, Fred Kironde, Frank Atuguba, Alfred B. Tiono, Saadou Issifou, Mark Kaddumukasa, Oscar Bangre, Clare Flach, Michael Christiansen, Peter Bang, Roma Chilengi, Søren Jepsen, Peter G. Kremsner, Michael Theisen
BackgroundGMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda.MethodsChildren 12–60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL.ResultsA cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI −44%, 63%).ConclusionsGMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role.
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Obstetrical and neonatal case definitions for immunization safety data
Source:Vaccine
Author(s): Pedro L. Moro, Robert T. Chen
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Immunogenicity and safety of the inactivated Japanese encephalitis vaccine IXIARO® in elderly subjects: Open-label, uncontrolled, multi-center, phase 4 study
Source:Vaccine, Volume 34, Issue 38
Author(s): Jakob P. Cramer, Katrin Dubischar, Susanne Eder, Gerd D. Burchard, Tomas Jelinek, Bernd Jilma, Herwig Kollaritsch, Emil Reisinger, Kerstin Westritschnig
BackgroundIXIARO® is a Vero cell-derived, inactivated Japanese encephalitis (JE) vaccine licensed mainly in western countries for children and adults traveling to JE endemic areas. Limited immunogenicity and safety data in elderly travelers have been available.ObjectivesTo evaluate safety and immunogenicity of IXIARO in elderly subjects.MethodsOpen-label, single arm, multi-centered study. Two-hundred subjects with good general health, including adequately controlled chronic conditions, received two doses of IXIARO®, 28days apart. Protective levels of antibodies were tested 42days after the second dose. Systemic and local adverse events (AEs) were solicited for 7days after each dose, unsolicited AEs were collected up to day 70 and in a phone call at month 7.Summary of resultsSubjects were aged 64–83years (median 69.0years). Nineteen percent of subjects had serious or medically attended AEs up to Day 70 (primary endpoint), none of them causally linked to IXIARO. Solicited local AEs were reported by 33.5% (most common: local tenderness) and solicited systemic AEs by 27% (most common: headache) of subjects. The seroprotection rate was 65% with a geometric mean titre (GMT) of 37. Subjects with tick borne encephalitis (TBE) vaccinations in the past 5years (N=29) had a SCR of 90% and GMT of 65.ConclusionsIXIARO is generally well tolerated in the elderly, and the safety profile is largely comparable with younger adults. SCR and GMT are lower compared to younger adults, but SCR is in the range reported in elderly for other vaccines e.g. against TBE, hepatitis-A virus (HAV)/hepatitis-B virus (HBV), influenza. The differences in SCR and GMT from younger to elderly adults were in the range of other vaccines.Duration of protection is uncertain in older persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus.
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The Effects of Tai Chi Chuan on Improving Mind-Body Health for Knee Osteoarthritis Patients: A Systematic Review and Meta-Analysis
Purpose. To conduct a meta-analysis and systematic review examining whether Tai Chi Chuan could have mental and physical benefits for patients with knee osteoarthritis. Methods. MEDLINE, PUBMED, EMBASE, and CINAHL databases were searched for relevant studies. Data of the studies were collected, and outcomes were classified using the International Classification of Functioning, Disability, and Health model. Effect sizes of the mental and physical components were determined, along with the recommendation grades of Philadelphia Panel Classification System for Tai Chi Chuan on knee osteoarthritis. Results. Eleven studies were selected and retrieved from the databases. The results of meta-analysis revealed that the effects of Tai Chi Chuan were observed for physical components in the body functions and structures domain. The effects favoring Tai Chi Chuan were observed in the physical component in the activities and participation domain. Insufficient data was included in the meta-analysis of the mental component. Conclusions. The review revealed that Tai Chi Chuan had beneficial outcomes for patients with knee osteoarthritis. The evidence-based results represented that it had small-to-moderate effects on body functions and structures, activities, and participation of physical component. However, there was insufficient evidence to support that Tai Chi Chuan had beneficial mental effect.
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What you get from what you see: Parametric assessment of visual processing capacity in multiple sclerosis and its relation to cognitive fatigue
Source:Cortex, Volume 83
Author(s): Steffen W. Kluckow, Jan-Gerrit Rehbein, Matthias Schwab, Otto W. Witte, Peter Bublak
Multiple sclerosis (MS1) is a diffusely disseminated inflammatory disease affecting widespread cerebral networks. Major cognitive impairments are a reduction of processing capacity and mental fatigue, i.e., an "abnormal sense of tiredness or lack of energy". Here, the present study provides the first assessment of the distinct components of visual processing capacity based on a 'theory of visual attention' (TVA2) in MS patients and relates it to measures of subjective as well as (more) objective fatigue. The performance of 36 relapsing-remitting MS patients in a whole report task of brief letter arrays was compared to healthy control subjects matched for gender, age and education. Additionally, the sustained attention test PASAT-33 served as a measure of objective fatigue, and the self-report questionnaire MFIS4 as a measure of subjective fatigue. Results indicate generally diminished processing speed as well as iconic memory buffers, and increased perceptual thresholds in MS patients compared to healthy controls. Block-wise analysis of attentional parameters shows that the processing speed performance of MS patients declines in the second half of the TVA-based test compared to healthy controls and in particular for patients with high versus low objective fatigue. These findings describe which aspects of processing capacity are impaired in MS, and show that fatigue mainly affects speed of processing. Thus, TVA-based assessment provides a novel approach in the determination of cognitive impairments and fatigue in MS. However, further research is required to elucidate the complex relations of processing capacity and cognitive functions in MS.
http://ift.tt/2b7lWZM
Evaluation of an Integrated Group Cognitive-Behavioral Treatment for Comorbid Mood, Anxiety, and Substance Use Disorders: A Pilot Study
Source:Journal of Anxiety Disorders
Author(s): Irena Milosevic, Susan M. Chudzik, Susan Boyd, Randi E. McCabe
This paper presents the development and preliminary evaluation of an integrated group cognitive-behavioral treatment for comorbid mood, anxiety, and substance use disorders. The 12-session, manualized treatment was developed collaboratively by a mental health program in a teaching hospital and a community-based addictions service and administered in both settings. Results from an uncontrolled effectiveness trial of 29 treatment completers suggest that integrated group CBT may reduce stress and alcohol use symptoms and improve substance refusal self-efficacy. Changes in symptoms of anxiety, depression, and drug use were not significant, although the effect size for anxiety reduction was in the medium range. Nonetheless, the clinical significance of treatment effects on mood, anxiety, and substance use symptoms was modest. Changes in coping skills and quality of life were not significant, although medium-to-large effects were observed for changes in several coping skills. Participants reported being highly satisfied with treatment, found the treatment strategies to be useful, and noted an improvement in their functioning, particularly socially. Methodological and sample size limitations warrant more rigorous follow-up investigations of this treatment. Results are considered in the context of the current literature on integrated psychological treatments for these common comorbidities.
http://ift.tt/2bGHqJo
Discovery of Potential Orthosteric and Allosteric Antagonists of P2Y1R from Chinese Herbs by Molecular Simulation Methods
P2Y1 receptor (P2Y1R), which belongs to G protein-coupled receptors (GPCRs), is an important target in ADP-induced platelet aggregation. The crystal structure of P2Y1R has been solved recently, which revealed orthosteric and allosteric ligand-binding sites with the details of ligand-protein binding modes. And it suggests that P2Y1R antagonists, which recognize two distinct sites, could potentially provide an efficacious and safe antithrombotic profile. In present paper, 2D similarity search, pharmacophore based screening, and molecular docking were used to explore the potential natural P2Y1R antagonists. 2D similarity search was used to classify orthosteric and allosteric antagonists of P2Y1R. Based on the result, pharmacophore models were constructed and validated by the test set. Optimal models were selected to discover potential P2Y1R antagonists of orthosteric and allosteric sites from Traditional Chinese Medicine (TCM). And the hits were filtered by Lipinski's rule. Then molecular docking was used to refine the results of pharmacophore based screening and analyze the binding mode of the hits and P2Y1R. Finally, two orthosteric and one allosteric potential compounds were obtained, which might be used in future P2Y1R antagonists design. This work provides a reliable guide for discovering natural P2Y1R antagonists acting on two distinct sites from TCM.
http://ift.tt/2bLDDN8
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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