Age-related differences in white matter diffusion measures in autism spectrum condition.

BACKGROUND: Autism spectrum condition (ASC) is accompanied by developmental differences in brain anatomy and connectivity. White matter differences in ASC have been widely studied with diffusion imaging but results are heterogeneous and vary across the age range of study participants and varying methodological approaches. To characterize the neurodevelopmental trajectory of white matter maturation, it is necessary to examine a broad age range of individuals on the autism spectrum and typically developing controls, and investigate age × group interactions. METHODS: Here, we employed a spatially unbiased tract-based spatial statistics (TBSS) approach to examine age-related differences in white matter connectivity in a sample of 41 individuals with ASC, and 41 matched controls between 7-17 years of age. RESULTS: We found significant age-related differences between the ASC and control group in widespread brain regions. This included age-related differences in the uncinate fasciculus, corticospinal tract, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior longitudinal fasciculus and forceps major. Measures of fractional anisotropy (FA) were significantly positively associated with age in both groups. However, this relationship was significantly stronger in the ASC group relative to controls. Measures of radial diffusivity (RD) were significantly negatively associated with age in both groups, but this relationship was significantly stronger in the ASC group relative to controls. LIMITATIONS: The generalisability of our findings is limited by the restriction of the sample to right-handed males with an IQ > 70. Furthermore, a longitudinal design would be required to fully investigate maturational processes across this age group. CONCLUSIONS: Taken together, our findings suggest that autistic males have an altered trajectory of white matter maturation relative to controls. Future longitudinal analyses are required to further characterize the extent and time course of these differences.

Effects of comorbidity on Tourette's tic severity and quality of life.

OBJECTIVE: The aim of this study is to gain more insight in the differential contributions of anxiety, depression and obsessive-compulsive (OC) symptom severity to quality of life (QoL) and tic severity in adults with Tourette Disorder (TD). METHODS: Self-reported OC symptom, anxiety and depression severity measures were used to investigate their predictive value on QoL and Tic severity in adult TD patients (N = 187), using correlation, regression, and mediation analyses. RESULTS: Tic severity has no effect on QoL. Depression severity directly reduces QoL, whereas anxiety and OC symptom severity have an indirect effect on QoL, mediated by depression severity. OC symptom severity directly affects tic severity, whereas depression and anxiety severity do not have a direct effect on tic or OC severity. Finally, anxiety severity indirectly impacts tic severity, with OC symptom severity functioning as a mediator. CONCLUSION: In line with and extending previous studies, these findings indicate that OC symptom severity directly influences tic symptom severity whereas depression severity directly influences QoL in TD. Results imply that to improve QoL in TD patients, treatment should primarily focus on diminishing OC and depressive symptom severity rather than focusing on tic reduction.

Overlaps and distinctions between attention deficit/hyperactivity disorder and autism spectrum disorder in young adulthood: Systematic review and guiding framework for EEG-imaging research.

Attention deficit/hyperactivity disorders (ADHD) and autism spectrum disorders (ASD) frequently co-occur. However, we know little about the neural basis of the overlaps and distinctions between these disorders, particularly in young adulthood - a critical time window for brain plasticity across executive and socioemotional domains. Here, we systematically review 75 articles investigating ADHD and ASD in young adult samples (mean ages 16-26) using cognitive tasks, with neural activity concurrently measured via electroencephalography (EEG) - the most accessible neuroimaging technology. The majority of studies focused on event-related potentials (ERPs), with some beginning to capitalise on oscillatory approaches. Overlapping and specific profiles for ASD and ADHD were found mainly for four neurocognitive domains: attention processing, performance monitoring, face processing and sensory processing. No studies in this age group directly compared both disorders or considered dual diagnosis with both disorders. Moving forward, understanding of ADHD, ASD and their overlap in young adulthood would benefit from an increased focus on cross-disorder comparisons, using similar paradigms and in well-powered samples and longitudinal cohorts.

A longitudinal study of cortical EEG activity in adolescents.

BACKGROUND: The objective of this study is to test Davidson's, and Heller and Nitschke's models stating cortical activity in adolescents to be a marker for increased risk for depression. METHODS: Alpha activity was measured in 80 adolescents from medial-frontal (F3/4), lateral-frontal (F7/8), and medial-parietal (P3/4) electrodes, as well as self-reported depression and anxiety twice within 12 months. Step-wise hierarchical regression analyses with anxiety as covariate were calculated with alpha asymmetry as predicting variable and depression as target variable and vice versa. RESULTS: Independent of whether anxiety was used as covariate or not, frontal and parietal alpha asymmetry predict depression, but depression did not predict alpha activity. CONCLUSIONS: The results partially support both models and conclusions drawn by studies with remitted depressed subjects. However, it remains unclear if anxious arousal has a partial influence on the predictive association between alpha activity and depression.

A new dihydroxanthenone from a plant-associated strain of the fungus Chaetomium globosum demonstrates anticancer activity.

Bioassay-guided fractionation of a cytotoxic EtOAc extract of the fungal strain, Chaetomium globosum, inhabiting the rhizosphere of the Christmas cactus, Opuntia leptocaulis, of the Sonoran desert afforded a new dihydroxanthenone, globosuxanthone A (1), a new tetrahydroxanthenone, globosuxanthone B (2), two new xanthones, globosuxanthone C (3) and D (4), 2-hydroxyvertixanthone (5), and two known anthraquinones (6 and 7). The structures of the new compounds 1-4 were elucidated by NMR and MS techniques, and the relative stereochemistry of 1 was determined by X-ray crystallographic analysis. Of the compounds encountered, 1 was found to exhibit strong cytotoxicity against a panel of seven human solid tumor cell lines, disrupt the cell cycle leading to the accumulation of cells in either G2/M or S phase, and induce classic signs of apoptosis.

Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation.

MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that functions upstream of the MAP kinases and IkappaB kinase. Phosphorylation is believed to be a critical component for MEKK3-dependent signal transduction, but little is known about the phosphorylation sites of this MAP3K. To address this question, point mutations were introduced in the activation loop (T-loop), substituting alanine for serine or threonine, and the mutants were transfected into HEK293 Epstein-Barr virus nuclear antigen cells. MEKK3-dependent activation of an NF-kappaB reporter gene as well as ERK, JNK, and p38 MAP kinases correlated with a requirement for serine at position 526. Constitutively active mutants of MEKK3, consisting of S526D and S526E, were capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK, suggesting that a negative charge at Ser526 was necessary for MEKK3 activity and implicating Ser526 as a phosphorylation site. An antibody was developed that specifically recognized phospho-Ser526 of MEKK3 but did not recognize the S526A point mutant. The catalytically inactive (K391M) mutant of MEKK3 was not phosphorylated at Ser526, indicating that phosphorylation of Ser526 occurs via autophosphorylation. Endogenous MEKK3 was phosphorylated on Ser526 in response to osmotic stress. In addition, phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro, whereas dephosphorylation of Ser526 was mediated by protein phosphatase 2A and sensitive to okadaic acid and sodium fluoride. Finally, the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526. In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins.

Effect of moderate hypercapnic hypoxia on cerebral dopaminergic activity and brain O2 uptake in intrauterine growth-restricted newborn piglets.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434 g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p <0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p <0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.

Ponicidin and oridonin are responsible for the antiangiogenic activity of Rabdosia rubescens, a constituent of the herbal supplement PC SPES.

Antiangiogenic activity has been identified in an aqueous EtOH extract of Rabdosia rubescens, a component of the dietary supplement PC SPES. Bioassay-guided fractionation using a novel in vitro human endothelial cell-based assay for angiogenesis afforded the diterpenoids ponicidin (1) and oridonin (2), with significant antiangiogenic activity at subcytotoxic concentrations, suggesting that these constituents may strongly contribute to the demonstrated clinical efficacy of PC SPES as a treatment for advanced prostate cancer.

Effect of hypoxia/hypercapnia on metabolism of 6-[(18)F]fluoro-L-DOPA in newborn piglets.

There is evidence that the dopaminergic system is sensitive to altered p(O(2)) in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of fifteen newborn piglets (2-5 days old). Two PET scans were performed in each piglet. Eleven animals underwent a period of normoxia and moderate hypoxia/hypercapnia (H/H). The remaining four animals were used as an untreated control group. Simultaneously, the brain tissue p(O(2)) was recorded, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rate of oxygen (CMRO(2)) was determined. In addition, in four untreated and six H/H treated piglets the relative amounts of fluorodopamine and the respective metabolites were determined in brain tissue samples using HPLC analysis. H/H conditions were induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding CO(2) to the inspired gas resulting in an arterial p(CO(2)) between 74 and 79 mmHg. H/H elicited a more than 3-fold increase of the CBF (P<0.05) so that the CMRO(2) remained unchanged throughout the H/H period. Despite this, the brain tissue p(O(2)) was reduced from 19+/-4 to 6+/-3 mmHg (P<0.05). The permeability-surface area product of FDOPA (PS(FDOPA)) was unchanged. However, the transfer rate of FDOPA (k(3)(FDOPA)) of the nigrostriatal dopaminergic system and the relative amounts of fluorodopamine and the respective metabolites were significantly increased (P<0.05). It is suggested that H/H induces an increase of AADC activity. However, an H/H-induced CBF increase maintains bulk O(2) delivery and preserves CMRO(2).