Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD

The role of zirconium in microalloyed steels

Recently there has been a renewed interest in the addition of zirconium to microalloyed steels. It has been used since the early 1920's, but has never been universally employed, as have niobium, titanium or vanadium. The functions of zirconium in steelmaking are associated with a strong chemical affinity, in decreasing order, for oxygen, nitrogen, sulphur and carbon. Historically, the main use of additions of zirconium to steel was for combination preferentially with sulphur and so avoid the formation of manganese sulphide, known to have a deleterious influence of the impact toughness of wrought and welded steel. Modern steelmaking techniques have also raised the possibility that zirconium additions can reduce the austenite grain size and increase dispersion strengthening, due to precipitation of zirconium carbonitrides, or in high nitrogen vanadium-zirconium steels, vanadium nitride. This review gathers information on the compounds of zirconium identified in steels together with crystallographic data and solubility equations. Also brief accounts of the role of sulphides and particles in general on austenite grain size control and toughness are included

When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function

Emerging reports reveal that activating Toll-like receptor-2 (TLR2)–MyD88 signals in CD8 T lymphocytes enhances cytokine production and cytotoxicity; however, the signaling pathway remains undefined. In the present study, we examined the physiologic significance and molecular mechanisms involved in this process. We found that TLR2 engagement on T-cell receptor transgenic CD8 OT-1 T cells increased T-bet transcription factor levels consequently, augmenting effector transcript and protein levels both in vivo and in vitro. In contrast, TLR2 agonist did not costimulate TLR2−/−OT-1 or MyD88−/−OT-1 T cells. Elevated T-bet levels in TLR2-MyD88–activated T cells was a consequence of increased biosynthesis resulting from the enhanced acti- vation of the mammalian target of the rapamycin (mTOR) pathway. Inhibiting mTOR, Akt, or protein kinase C in T cells abolished the costimulatory effects of the TLR2 agonist. In vivo, activating TLR2–MyD88 signals in T cells increased effector-molecule levels and enhanced the clearance of Listeria monocytogenes-Ova. These results help define a signaling pathway linking the TLR-MyD88 and mTOR pathway in an Akt- and protein kinase C–dependent manner. These results highlight a critical role for MyD88 signaling in T-cell activation and cytotoxicity. Furthermore, these findings offer the opportunity for improving the efficacy of vaccines and T cell–based immunotherapies by targeting TLR-MyD88 signaling within T cells