- Under-immunization of pediatric transplant recipients: a call to action for the pediatric community. [Review]
- PRPediatr Res 2019 Jul 22
- Vaccine-preventable infections (VPIs) are a common and serious complication following transplantation. One in six pediatric solid organ transplant recipients is hospitalized with a VPI in the first 5…
Vaccine-preventable infections (VPIs) are a common and serious complication following transplantation. One in six pediatric solid organ transplant recipients is hospitalized with a VPI in the first 5 years following transplant and these hospitalizations result in significant morbidity, mortality, graft injury, and cost. Immunizations are a minimally invasive, cost-effective approach to reducing the incidence of VPIs. Despite published recommendations for transplant candidates to receive all age-appropriate immunizations, under-immunization remains a significant problem, with the majority of transplant recipients not up-to-date on age-appropriate immunizations at the time of transplant. This is extremely concerning as the rate for non-medical vaccine exemptions in the United States (US) is increasing, decreasing the reliability of herd immunity to protect patients undergoing transplant from VPIs. There is an urgent need to better understand barriers to vaccinating this population of high-risk children and to develop effective interventions to overcome these barriers and improve immunization rates. Strengthened national policies requiring complete age-appropriate immunization for non-emergent transplant candidates, along with improved multi-disciplinary immunization practices and tools to facilitate and ensure complete immunization delivery to this high-risk population, are needed to ensure that we do everything possible to prevent infectious complications in pediatric transplant recipients.
- Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro. [Journal Article]
- TOTransl Oncol 2019 Jul 19; 12(10):1296-1304
- Off-target activities of drug candidates observed during in vitro pharmacological profiling frequently do not translate to adverse events (AEs) in human. This could be because off-target activities d…
Off-target activities of drug candidates observed during in vitro pharmacological profiling frequently do not translate to adverse events (AEs) in human. This could be because off-target activities do not have functional consequences, are not observed at exposures achieved during clinical testing, or may not translate into clinical outcomes. We report clinical consequences of an off-target activity observed during profiling of AMG 337, a selective inhibitor of the mesenchymal-epithelial transition factor being evaluated for treatment of solid tumors. In our screen of 151 potential off-targets, AMG 337 inhibited only adenosine transporter (AT). During clinical trials, headache emerged as the dose-limiting AE in the first-in-human trial. It was thought that headache was caused by extracellular accumulation of adenosine from inhibition of AT by AMG 337 and subsequent adenosine-mediated vasodilation through adenosine receptors (ARs). Further nonclinical studies were performed to evaluate this hypothesis. AMG 337 inhibited AT function in dog and human cells in vitro and dog and human arteries ex vivo. In a dog telemetry study, AMG 337 caused hypotension, which was reduced by pretreatment with theophylline, an AR antagonist. Overall, nonclinical and clinical data suggested that headache was due to cerebral vasorelaxation caused by AMG 337-mediated inhibition of AT. When subjects were advised to drink coffee, an AR antagonist, prior to AMG 337, the severity of headaches was reduced, allowing them to continue treatment. These findings demonstrate the importance of carefully evaluating clinical observations during early drug development and the value of translational nonclinical studies to investigate the mechanism of action driving clinical observations.
- Pharmacological characterization of the seven human NOX isoforms and their inhibitors. [Journal Article]
- RBRedox Biol 2019 Jul 11; 26:101272
- CONCLUSIONS: Our findings indicate that experimental results obtained with widely used NOX inhibitors must be carefully interpreted and highlight the challenge of developing reliable pharmacological inhibitors of these key molecular targets.
- Telmisartan, an angiotensin II receptor blocker, attenuates Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1β in murine macrophages. [Journal Article]
- IIInt Immunopharmacol 2019 Jul 19; 75:105750
- Telmisartan, widely prescribed for the treatment of hypertension, has an anti-inflammatory property in addition to being an angiotensin II type 1 receptor antagonist. This study was carried out to ex…
Telmisartan, widely prescribed for the treatment of hypertension, has an anti-inflammatory property in addition to being an angiotensin II type 1 receptor antagonist. This study was carried out to explore the influence of telmisartan upon the elaboration of inflammatory mediators in murine macrophages stimulated with lipopolysaccharide (LPS) prepared from Prevotella intermedia, a periodontal pathogen, as well as its molecular mechanisms. Telmisartan significantly inhibited LPS-induced generation of inducible nitric oxide (NO) synthase-derived NO and interleukin-1β (IL-1β) as well as their gene expressions in RAW264.7 cells. Telmisartan treatment of LPS-activated cells significantly up-regulated arginase 1 (Arg-1) and chitinase-like 3 (Ym-1), which are specific markers of M2 macrophages. Telmisartan caused a significant increase in heme oxygenase-1 (HO-1) expression in cells stimulated with LPS, and its inhibitory action against NO production was reversed by treatment with SnPP, an HO-1 inhibitor. Phosphorylation of STAT1 and STAT3 induced by LPS was attenuated by telmisartan. Telmisartan inhibited LPS-induced generation of NO and IL-1β independently of PPAR-γ activation. In addition, activation of NF-κB as well as JNK and p38 signaling induced by LPS was not modulated by telmisartan. In summary, telmisartan is a potent inhibitor of P. intermedia LPS-induced generation of NO and IL-1β in RAW264.7 cells and promotes macrophage phenotype switching toward the M2 phenotype. Telmisartan may have potential to be developed into host modulatory agent for inflammatory periodontal disease, although additional studies are needed to confirm the therapeutic effect.
- Strengthening child and youth programs: A look at inter-organizational mentoring strategies. [Journal Article]
- EPEval Program Plann 2019 Jul 10; 76:101679
- Community-based non-profit organizations rarely have access to research or evaluation evidence to inform their programs and often lack the capacity to gather or use this information independently. In…
Community-based non-profit organizations rarely have access to research or evaluation evidence to inform their programs and often lack the capacity to gather or use this information independently. In 2016, Wisdom2Action-a network of knowledge mobilization (KMb) experts, policy makers and service providers across Canada-launched an inter-organizational mentorship program to facilitate the implementation and sharing of best and promising practices within community-based programs for young people. This article outlines the findings from a developmental evaluation of eight mentoring relationships. Drawing on the Promoting Action on Research in Health Sciences (PARiHS) model of KMb, we look at mentoring as a type of facilitation that supports the increased use of evidence and evaluation information by non-profit organizations and identify key themes that support effective organizational mentorship in this sector. Findings reinforce the importance of establishing connected relationships and understanding context in mentoring relationships, creating adaptive and responsive work plans, ensuring consistent communication, and maintaining a focus on capacity-building if knowledge mobilization is to occur.
- SAFE@HOME - Feasibility study of a telemonitoring platform combining blood pressure and preeclampsia symptoms in pregnancy care. [Journal Article]
- EJEur J Obstet Gynecol Reprod Biol 2019 Jul 15; 240:226-231
- CONCLUSIONS: This is the first feasibility study of a telemonitoring platform, combining remote monitoring of BP with preeclampsia symptoms in pregnancy care. Action from health care providers during telemonitoring is only needed in case of alarming combinations of results. This system is potentially very useful in care for women at risk for hypertensive disorders during pregnancy.
- UV Spectrophotometric method for characterization of curcumin loaded nanostructured lipid nanocarriers in simulated conditions: Method development, in-vitro and ex-vivo applications in topical delivery. [Journal Article]
- SASpectrochim Acta A Mol Biomol Spectrosc 2019 Jul 15; 224:117392
- Curcumin the extract obtained from the dried rhizome of turmeric, Curcuma longa is a hydrophobic phenol that delivers numerous pharmacological actions like anti-inflammatory, anti-microbial and anti-…
Curcumin the extract obtained from the dried rhizome of turmeric, Curcuma longa is a hydrophobic phenol that delivers numerous pharmacological actions like anti-inflammatory, anti-microbial and anti-oxidant, anti-psoriasis, antidiabetic, anticancer. But curcumin has low bioavailability issues that accompany low aqueous solubility, further, when administered orally, >90% of the drug degrades rapidly in the alkaline medium. Administering the drug topically can bypass the problem as well as first-pass metabolism and therefore delivering the drug at the targeted site of action. Encapsulating curcumin in nanostructured lipid nanocarriers (NLC) is an excellent novel strategy. Further, these NLC provides both the controlled release and helps in the enhanced permeation of the drug through the skin's physiological barrier, stratum corneum. For the NLC characterization, a reliable method must be developed that can accurately and precisely determine the drug content in the formulation and also for its in-vitro and ex-vivo characterization. This experiment describes the analytical validation parameters described as per International Conference of Harmonization guidelines to develop a method using the UV-Visible spectroscopy. The method was developed in two solvent systems i.e. methanol and 6.4 pH phosphate buffer with 1.5% polysorbate 80. Methanol solvent was used for the determination of curcumin in the NLC formulation via determining the encapsulation efficiency and 6.4 pH phosphate buffer with 1.5% polysorbate 80 solvent was used for in-vitro and ex-vivo characterization of the developed NLC formulation (cream and gel). These methods were validated in response to linearity, the limit of detection, the limit of quantification, precision, accuracy, repeatability, and specificity.
- More Transporters, More Substrates: The Arabidopsis Major Facilitator Superfamily Revisited. [Review]
- MPMol Plant 2019 Jul 19
- The Major Facilitator Superfamily (MFS) is ubiquitous in living organisms and represents the largest group of secondary active membrane transporters. In plants, significant research efforts have focu…
The Major Facilitator Superfamily (MFS) is ubiquitous in living organisms and represents the largest group of secondary active membrane transporters. In plants, significant research efforts have focused on the role of specific families within the MFS, particularly those transporting macronutrients (C, N and P) that comprise the vast majority of the members of this superfamily. Other MFS families remain less explored, though a plethora of additional substrates and physiological functions have been uncovered. Nevertheless, the lack of a systematic approach to the analysis of the MFS as a whole has obscured the high diversity and versatility of these transporters. Here, we present a phylogenetic analysis of all annotated MFS domain-containing proteins encoded in the Arabidopsis thaliana genome and propose that this superfamily of transporters consists of 218 members, clustered in 22 families. In reviewing the available information regarding the diversity in biological functions and substrates of arabidopsis MFS members, we provide arguments for intensified research on these membrane transporters to unveil the breadth of their physiological relevance, disclose the molecular mechanisms underlying their mode of action, and explore their biotechnological potential.
- Effects of crustacean hyperglycemic hormone (CHH) on regulation of hemocyte intracellular signaling pathway and phagocytosis in white shrimp Litopenaeus vannamei. [Journal Article]
- FSFish Shellfish Immunol 2019 Jul 19
- Shrimps like other arthropods rely on innate immune system, and may have some form of adaptive immunity in defending against pathogens. Phagocytosis is one of the oldest cellular processes, serving a…
Shrimps like other arthropods rely on innate immune system, and may have some form of adaptive immunity in defending against pathogens. Phagocytosis is one of the oldest cellular processes, serving as a development process, a feeding mechanism and especially as a key defense reaction in innate immunity of all multicellular organisms. It is confirmed that crustacean hyperglycemic hormone (CHH) is one of the most important neuropeptides produced by Neuro-endocrine Immune (NEI) regulatory network, which undertake important roles in various biological processes, especially in immune function and stress response. In this study, the recombinant Litopenaeus vannamei CHH (rLvCHH) was obtained from a bacterial expression system and the intracellular signaling pathways involved in the mechanism of phagocytosis after rLvCHH injection was investigated. The results showed that the contents of adenylyl cyclase (AC), phospholipase C (PLC) and calmodulin (CaM) was increased significantly after rLvCHH injection. Furthermore, the mRNA expression levels of NF-kB family members (relish and dorsal) and phagocytosis-related proteins were basically overexpressed after rLvCHH stimulation, while the expression level of NF-kB repressing factor (NKRF) gene was down-regulated significantly. Eventually, the total hemocyte count and phagocytic activity of hemocyte were dramatically enhanced within 3 h. Collectively, these results indicate that shrimps L. vannamei could carry out a simple but 'smart' NEI regulation through the action of neuroendocrine factors, which could couple with their receptors and trigger the downstream signaling pathways during the phagocytic responses of hemocytes.
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- Administration of branched-chain amino acids increases the susceptibility to lipopolysaccharide-induced inflammation in young Wistar rats. [Journal Article]
- IJInt J Dev Neurosci 2019 Jul 19
- Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a-ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino a…
Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a-ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine and valine). Patients with MSUD present a series of neurological dysfunction. Recent studies have been associated the brain damage in the MSUD with inflammation and immune system activation. MSUD patients die within a few months of life due to recurrent metabolic crises and neurologic deterioration, often precipitated by infection or other stresses. In this regard, our previous results showed that the inflammatory process, induced by lipopolysaccharide (LPS), associated with high levels of BCAAs causes blood-brain barrier (BBB) breakdown due to hyperactivation of MMPs. Thus, we hypothesize that the synergistic action between high concentrations of BCAAs (H-BCAAs) and LPS on BBB permeability and hyperactivation of MMPs could be through an increase in the production of cytokines and RAGE protein levels. We observed that high levels of BCAA in infant rats are related to increased brain inflammation induced by LPS administration. In addition, BCAA exposure led to an increase on brain RAGE expression of young rats. The brain inflammation was characterized by enhanced levels of interleukin 1 β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and Interferon- γ (IFN-γ), and decreased content of interleukin-10 (IL-10). Therefore, MSUD is associated with a more intense neuroinflammation induced by LPS infection.