Lower strontium in two different body matrices in neurodevelopmental disorders: A preliminary report

BackgroundEnvironmental factors, including elemental homeostasis, have not been studied sufficiently in neurodevelopmental disorders (NDD). This study aims to compare the status of 13 elements in blood and deciduous teeth dentine of children having an autism spectrum disorder or attention deficit hyperactivity disorder with typically developing controls.MethodsElements including calcium, phosphorus, magnesium, iron, zinc, copper, chromium, manganese, mercury, lead, cadmium, molybdenum, and strontium in both deciduous teeth and blood were analyzed by inductively coupled plasma mass spectrometry.ResultsStrontium levels in both blood and teeth samples were found to be significantly lower in the NDD group. Additionally, blood cadmium and mercury levels, and copper/zinc ratio were higher in the NDD group.ConclusionsOur results warrant further investigation in a large series of NDD examining symptom levels and genetic variations associated with elemental homeostasis.     

Endoplasmic reticulum proteostasis impairment in aging

Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one‐third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.     

Melatonin Shifts Human Orcadian Rhythms According to a Phase-Response Curve

A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.     

Mesenchymal stem cells as carrier of the therapeutic agent in the gene therapy of blood disorders

Nonhematopoietic stem cells as a delivery platform of therapeutic useful genes have attracted widespread attention in recent years, owing to gained a long lifespan, easy separation, high proliferation, and high transfection capacity. Mesenchymal stem/stromal cells (MSCs) are the choice of the cells for gene and cell therapy due to high self-renewal capacity, high migration rate to the site of the tumor, and with immune suppressive and anti-inflammatory properties. Hence, it has a high potential of safety genetic modification of MSCs for antitumor gene expression and has paved the way for the clinical application of these cells to target the therapy of cancers and other diseases. The aim of gene therapy is targeted treatment of cancers and diseases through recovery, change, or enhancement cell performance to the sustained secretion of useful therapeutic proteins and induction expression of the functional gene in intended tissue. Recent developments in the vectors designing leading to the increase and durability of expression and improvement of the safety of the vectors that overcome a lot of problems, such as durability of expression and the host immune response. Nowadays, gene therapy approach is used by MSCs as a delivery vehicle in the preclinical and the clinical trials for the secretion of erythropoietin, recombinant antibodies, coagulation factors, cytokines, as well as angiogenic inhibitors in many blood disorders like anemia, hemophilia, and malignancies. In this study, we critically discuss the status of gene therapy by MSCs as a delivery vehicle for the treatment of blood disorders. Finally, the results of clinical trial studies are assessed, highlighting promising advantages of this emerging technology in the clinical setting.     

某医院儿童抽动障碍发病因素调查分析

目的:调查儿童抽动障碍发病情况,对其进行研究,了解抽动障碍发病特点及其相关危险因素,为制定预防措施提供来源依据。方法:选取2013年1月至2013年12月上海新华医院中医科就诊的抽动障碍儿童122例,发放问卷调查患儿的一般资料、家族史、既往史、母孕史、发病情况包括发病年龄、就诊年龄、病程进行分析。结果:122例患儿中发病年龄大多集中在10岁以前,为总发病儿童的93.4%,4~6岁的占45.9%,7~9岁的占39.3%。就诊年龄中6岁的占27.9%,6~8岁占39.3%,9~11岁占24.6%。病程6月的占13.1%,6~12月的占27.9%,1~2年的占19.7%,≥2年的占39.3%。其中36.1%有反复呼吸道感染史(OR1,P0.05);29.5%在生产中有轻度窒息(OR1,P0.05);11.5%有流产史(OR1,P0.05);13.1%有家族抽动障碍史(OR1,P(0.05);其中反复呼吸道感染、生产中轻度窒息、家族抽动障碍史是抽动障碍发病的危险因素。结论:儿童抽动障碍发病年龄较早,其起病可能是由多因素相互作用的结果,其中反复呼吸道感染、生产中轻度窒息、家族抽动障碍史是抽动障碍发病的危险因素。     

Peripherally restricted CB1 receptor blockers

Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).     

Mast cell activation and autism

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with “allergic-like” problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut-blood-brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.