Epidemiology of mental disorders in children and adolescents

This article provides a review of the magnitude of mental disorders in children and adolescents from recent community surveys across the world. Although there is substantial variation in the results depending upon the methodological characteristics of the studies, the findings converge in demonstrating that approximately one fourth of youth experience a mental disorder during the past year, and about one third across their lifetimes. Anxiety disorders are the most frequent conditions in children, followed by behavior disorders, mood disorders, and substance use disorders. Fewer than half of youth with current mental disorders receive mental health specialty treatment. However, those with the most severe disorders tend to receive mental health services. Current issues that are now being identified in the field of child psychiatric epidemiology include: refinement of classification and assessment, inclusion of young children in epidemiologic surveys, integration of child and adult psychiatric epidemiology, and evaluation of both mental and physical disorders in children.     

Regulation of CTLA‐4 recycling by LRBA and Rab11

CTLA‐4 is an essential regulator of T‐cell immune responses whose intracellular trafficking is a hallmark of its expression. Defects in CTLA‐4 trafficking due to LRBA deficiency cause profound autoimmunity in humans. CTLA‐4 rapidly internalizes via a clathrin‐dependent pathway followed by poorly characterized recycling and degradation fates. Here, we explore the impact of manipulating Rab GTPases and LRBA on CTLA‐4 expression to determine how these proteins affect CTLA‐4 trafficking. We observe that CTLA‐4 is distributed across several compartments marked by Rab5, Rab7 and Rab11 in both HeLa and Jurkat cells. Dominant negative (DN) inhibition of Rab5 resulted in increased surface CTLA‐4 expression and reduced internalization and degradation. We also observed that constitutively active (CA) Rab11 increased, whereas DN Rab11 decreased CTLA‐4 surface expression via an impact on CTLA‐4 recycling, indicating CTLA‐4 shares similarities with other recycling receptors such as EGFR. Additionally, we studied the impact of manipulating both LRBA and Rab11 on CTLA‐4 trafficking. In Jurkat cells, LRBA deficiency was associated with markedly impaired CTLA‐4 recycling and increased degradation that could not be corrected by expressing CA Rab11. Moreover LRBA deficiency reduced CTLA‐4 colocalization with Rab11, suggesting that LRBA is upstream of Rab11. These results show that LRBA is required for effective CTLA‐4 recycling by delivering CTLA‐4 to Rab11 recycling compartments, and in its absence, CTLA‐4 fails to recycle and undergoes degradation.     

Transgenerational effects of fetal and neonatal exposure to nicotine

A wide variety of in utero insults are associated with an increased incidence of metabolic disorders in the offspring and in subsequent generations. We have shown that fetal and neonatal exposure to nicotine results in endocrine and metabolic changes in the offspring that are consistent with those observed in type 2 diabetes. This study examines whether fetal and neonatal exposure to nicotine has transgenerational effects in the F2 offspring. Female Wistar rats were given either saline or nicotine (1 mg/kg/d) during pregnancy and lactation to create saline- and nicotine-exposed female F1 progeny. These F1 females were then bred to produce F2 offspring. We examined glucose homeostasis, serum lipids and fat pad weights, mitochondrial enzyme activity in skeletal muscle and blood pressure in these F2 offspring between 13 and 15 weeks of age. Offspring of nicotine- versus saline-exposed mothers had elevated fasting serum insulin concentrations and an enhanced total insulin response to the glucose challenge. This apparent insulin resistance was unrelated to changes in skeletal muscle mitochondrial volume or activity. The offspring of nicotine-exposed mothers also had elevated blood pressure. These data demonstrate that adverse effects of fetal and neonatal exposure to nicotine can influence aspects of metabolic risk in subsequent generations.     

Effect of acute unloaded leg cycling on spasticity in individuals with multiple sclerosis using anti-spastic medications

This article examines the effect of a bout of unloaded leg cycling on the soleus H-reflex and modified Ashworth scale (MAS) in 6 individuals with multiple sclerosis (MS) who had spasticity of the leg muscles and were currently taking anti-spastic medications. H-reflex and MAS data were collected before and 10, 30, and 60 min after 20 min of unloaded leg cycling and a control condition. The unloaded leg cycling resulted in concomitant reductions in soleus H-reflex and MAS scores compared with the control condition. This provides a basis for incorporating exercise along with anti-spastic medications into a multifaceted plan for spasticity management in individuals with MS.     

Patterns of white matter atrophy in frontotemporal lobar degeneration

BACKGROUND: Structural magnetic resonance imaging (MRI) has been used to investigate the in vivo pathology of frontotemporal lobar degeneration. However, few neuroimaging studies have focused on white matter (WM) alterations in this disease. OBJECTIVES: To use volumetric MRI techniques to identify the patterns of WM atrophy in vivo in 2 clinical variants of frontotemporal lobar degeneration-frontotemporal dementia (FTD) and semantic dementia-and to compare the patterns of WM atrophy with those of gray matter (GM) atrophy in these diseases. DESIGN: Structural MRIs were obtained from patients with FTD (n = 12) and semantic dementia (n = 13) and in cognitively healthy age-matched controls (n = 24). Regional GM and WM were classified automatically from high-resolution T1-, T2-, and proton density-weighted MRIs with Expectation-Maximization Segmentation and compared between the groups using a multivariate analysis of covariance model that included age and WM lesion volumes as covariates. RESULTS: Patients with FTD had frontal WM atrophy and frontal, parietal, and temporal GM atrophy compared with controls, who had none. Patients with semantic dementia had temporal WM and GM atrophy and patients with FTD had frontal GM atrophy. Adding temporal WM volume to temporal GM volume significantly improved the discrimination between semantic dementia and FTD. CONCLUSIONS: These results show that patients with frontotemporal lobar degeneration who are in relatively early stages of the disease (Clinical Dementia Rating score, 1.0-1.2) have WM atrophy that largely parallels the pattern of GM atrophy typically associated with these disorders.     

Hippocampus, amygdala, and basal ganglia morphometrics in children after moderate-to-severe traumatic brain injury

While closed head injury frequently results in damage to the frontal and temporal lobes, damage to deep cortical structures, such as the hippocampus, amygdala, and basal ganglia, has also been reported. Five deep central structures (hippocampus, amygdala, globus pallidus, putamen, and caudate) were examined in 16 children (eight males, eight females; aged 9-16y), imaged 1 to 10 years after moderate-to-severe traumatic brain injury (TBI), and in 16 individually-matched uninjured children. Analysis revealed significant volume loss in the hippocampus, amydala, and globus pallidus of the TBI group. Investigation of relative volume loss between these structures and against five cortical areas (ventromedial frontal, superomedial frontal, lateral frontal, temporal, and parieto-occipital) revealed the hippocampus to be the most vulnerable structure following TBI (i.e. greatest relative difference between the groups). In a separate analysis excluding children with focal hippocampal abnormalities (e.g. lesions), group differences in hippocampal volume were still evident, suggesting that hippocampal damage may be diffuse rather than focal.     

Brain structure correlates of component reading processes: implications for reading disability

Brain structures implicated in developmental dyslexia (reading disability - RD) vary greatly across structural magnetic resonance imaging (MRI) studies due to methodological differences regarding the definition of RD and the exact measurements of a specific brain structure. The current study attempts to resolve some of those methodological concerns by examining brain volume as it relates to components of proposed RD subtypes. We performed individual regression analyses on total cerebral volume, neocortical volume, subcortical volume, 9 neo-cortical structures and 2 sub-cortical structures. These analyses used three dimensions of reading, phonemic ability (PA), orthographic ability, and rapid naming (RN) ability, while accounting for total cerebral volume, age, and performance IQ (PIQ). Primary analyses included membership to a group (poor reader vs. good reader) in the analysis. The result was a significant interaction between PA and reading ability as it predicts total cerebral volume. Analyses revealed that poor readers lacked a relationship between PA and brain size, but that good readers had a significant positive relationship. This pattern of interaction was not present for the other two reading component factors. These findings bring into question the general belief that individuals with RD are at the low end of a reading ability distribution and do not have a unique disorder. Additional analyses revealed only a few significant relationships between brain size and task performance, most notably a positive correlation between orthographic ability and the angular gyrus (AG), as well as a negative correlation between RN ability and the parietal operculum (PO).     

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.     

Mechanisms of fatigue differ after low- and high-force fatiguing contractions in men and women

The magnitude of failure in voluntary drive after fatiguing contractions of different intensities in men and women is not known. The purpose of this study was to compare the time to task failure and voluntary activation of men and women for a sustained isometric contraction performed at a low and high intensity with the elbow flexor muscles. Nine men and nine women sustained an isometric contraction at 20% and 80% of maximal voluntary contraction (MVC) force until task failure during separate sessions. The men had a shorter time to failure than women for the 20% but not the 80% MVC task. Voluntary activation was reduced to similar levels for the men and women at the end of the fatiguing contractions but was reduced less after the 80% MVC task than the 20% MVC contraction. Twitch amplitude was reduced similarly at task failure for both sexes and to similar levels at termination of the 20% and 80% MVC tasks. The rate of change in mean arterial pressure was the main predictor of time to failure for the low-force sustained contraction. These results suggest that women experienced greater muscle perfusion, less peripheral fatigue, and a longer time to task failure than men during the low-force fatiguing contraction. However, the low-force task induced greater central fatigue than the high-force contraction for both men and women. Thus, low-force, long-duration fatiguing contractions can be used in rehabilitation to induce significant fatigue within the central nervous system and potentially greater neural adaptations in men and women.