Neurobehavioral Profiles in Individuals with Hyperimmunoglobulin E Syndrome (HIES) and Brain White Matter Hyperintensities

Purpose

Individuals with hyperimmunoglobulin E Syndrome (HIES) have central nervous system abnormalities, including focal white matter hyperintensities (WMH), or unidentified bright objects. This cross-sectional study aimed to describe the cognitive and emotional functioning and quality of life of people with HIES. We also sought to explore the relationship between cognitive functioning and WMHs in this population.

Methods

Twenty-nine individuals (13 males) with autosomal-dominant HIES (mean age?=?35.1 years, range 16–55) were administered a comprehensive psychological assessment as part of a natural history protocol. The assessment included measures of global cognitive functioning (Wechsler Adult Intelligence Scale-III), memory (California Verbal Learning Test-II, Wechsler Memory Scale-III), executive skills (Delis Kaplan Executive Function System), and attention (Test of Everyday Attention). Emotional symptoms and quality of life also were assessed.

Results

All mean cognitive scores were within normal limits. Mean scores on memory and executive functioning measures were significantly lower than Full Scale IQ scores (ps?<?.05). Substantial percentages of patients self-reported executive skills to be in the clinical range. Patients with fewer (1–20) versus more (21+) WMHs scored significantly better on measures of global cognitive skills, visual-perceptual skills, and working memory. Mean scores on emotional symptom and quality of life measures were in the average range and unrelated to WMHs.

Conclusions

Global cognitive functioning was average to high average in our sample of individuals with HIES. However, focal brain lesions were associated with lower scores in specific domains. Emotional functioning and quality of life are within normal limits in this sample.     

Specificity of psychological treatments for bulimia nervosa and binge eating disorder? A meta-analysis of direct comparisons

Treatment guidelines state that cognitive–behavioral therapy (CBT) and interpersonal therapy are the best-supported psychotherapies for bulimia nervosa (BN) and that CBT is the preferred psychological treatment for binge eating disorder (BED). However, no meta-analysis which both examined direct comparisons between psychological treatments for BN and BED and considered the role of moderating variables, such as the degree to which psychotherapy was bona fide, has previously been conducted Thus, such an analysis was undertaken. We included 77 comparisons reported in 53 studies. The results indicated that: (a) bona fide therapies outperformed non-bona fide treatments, (b) bona fide CBT outperformed bona fide non-CBT interventions by a statistically significant margin (only approaching statistical significance for BN and BED when examined individually), but many of these trials had confounds which limited their internal validity, (c) full CBT treatments offered no benefit over their components, and (d) the distribution of effect size differences between bona fide CBT treatments was homogeneously distributed around zero. These findings provide little support for treatment specificity in psychotherapy for BN and BED.     

Inhibition of Fas-mediated Apoptosis by Antigen: Implications for Lymphomagenesis

Apoptotic deletion of expanded B cell populations is essential in avoidance of autoimmune disease and immune regulation of some B cell malignancies. The role of CD4+ T cells in B cell apoptosis is evident from the high incidence of B cell tumors and autoimmunity in patients with T cell diseases such as the acquired immune deficiency syndrome (AIDS). We have previously demonstrated that in Epstein-Barr Virus (EBV) negative Burkitt's lymphoma (BL), a tumor derived from proliferating centroblasts of the germinal center, the malignant lymphocytes can be induced to express Fas (CD95) by ligation of CD40 at the B cell surface. Upon CD40 engagement, BL cells are sensitized to T-cell derived death signals provided by Fas ligand (FasL, CD95L). HBL-3 is a cell line derived from an AIDS-related BL in which the tumor IgM binds the human erythrocyte "i" antigen. To determine whether Fas-mediated apoptosis of BL cells is reduced in the context of antigen to which the tumor IgM binds, we stimulated HBL-3 cells with CD40 ligand (CD40L, CD154) in the presence and absence of human erythrocytes expressing the "i" antigen, and measured Fas-mediated apoptosis upon exposure to an agonistic anti-Fas antibody. We observed that HBL-3 cells were sensitized to Fas-mediated death by exposure to CD40L. When i+ RBCs were present, Fas-mediated apoptosis in HBL-3 cells was reduced by greater than 30%. In contrast, there was no reduction in Fas-mediated apoptosis in the presence of i &#109 (I+) RBCs. These findings demonstrate that Fas-mediated deletion of BL cells is inhibited upon surface IgM engagement by antigen for which the malignant clone has affinity.     

Adolescent Mothers,Stress, and Prevention

Abstract

Adolescent mothers face problems that can lead to psychological stress. Based on prospective data from the present study, these problems point toward the need for a coping skills prevention approach to help adolescent mothers manage stress. This paper reports data from outcome research on such an approach with adolescent mothers. Subjects were 79 adolescent mothers who were tested before, immediately after, and three months following the provision of coping skills intervention in an experimental condition. Subjects in a test-only control condition received no special intervention. At posttest, experimental condition subjects showed more positive outcomes on measures of social support, cognitive performance, conflict management, and interpersonal competence. At three-month follow-up, experimental condition subjects had more positive outcomes on social support, cognitive performance, parenting ability, child care self-efficacy, and measures of psychological well-being.     

UMMPerfusion: an Open Source Software Tool Towards Quantitative MRI Perfusion Analysis in Clinical Routine

To develop a generic Open Source MRI perfusion analysis tool for quantitative parameter mapping to be used in a clinical workflow and methods for quality management of perfusion data. We implemented a classic, pixel-by-pixel deconvolution approach to quantify T1-weighted contrast-enhanced dynamic MR imaging (DCE-MRI) perfusion data as an OsiriX plug-in. It features parallel computing capabilities and an automated reporting scheme for quality management. Furthermore, by our implementation design, it could be easily extendable to other perfusion algorithms. Obtained results are saved as DICOM objects and directly added to the patient study. The plug-in was evaluated on ten MR perfusion data sets of the prostate and a calibration data set by comparing obtained parametric maps (plasma flow, volume of distribution, and mean transit time) to a widely used reference implementation in IDL. For all data, parametric maps could be calculated and the plug-in worked correctly and stable. On average, a deviation of 0.032 ± 0.02 ml/100 ml/min for the plasma flow, 0.004 ± 0.0007 ml/100 ml for the volume of distribution, and 0.037 ± 0.03 s for the mean transit time between our implementation and a reference implementation was observed. By using computer hardware with eight CPU cores, calculation time could be reduced by a factor of 2.5. We developed successfully an Open Source OsiriX plug-in for T1-DCE-MRI perfusion analysis in a routine quality managed clinical environment. Using model-free deconvolution, it allows for perfusion analysis in various clinical applications. By our plug-in, information about measured physiological processes can be obtained and transferred into clinical practice.     

Neural modelling of the semantic predictability gain under challenging listening conditions

When speech intelligibility is reduced, listeners exploit constraints posed by semantic context to facilitate comprehension. The left angular gyrus (AG) has been argued to drive this semantic predictability gain. Taking a network perspective, we ask how the connectivity within language‐specific and domain‐general networks flexibly adapts to the predictability and intelligibility of speech. During continuous functional magnetic resonance imaging (fMRI), participants repeated sentences, which varied in semantic predictability of the final word and in acoustic intelligibility. At the neural level, highly predictable sentences led to stronger activation of left‐hemispheric semantic regions including subregions of the AG (PGa, PGp) and posterior middle temporal gyrus when speech became more intelligible. The behavioural predictability gain of single participants mapped onto the same regions but was complemented by increased activity in frontal and medial regions. Effective connectivity from PGa to PGp increased for more intelligible sentences. In contrast, inhibitory influence from pre‐supplementary motor area to left insula was strongest when predictability and intelligibility of sentences were either lowest or highest. This interactive effect was negatively correlated with the behavioural predictability gain. Together, these results suggest that successful comprehension in noisy listening conditions relies on an interplay of semantic regions and concurrent inhibition of cognitive control regions when semantic cues are available.     

Unique deficit in embodied simulation in autism: An fMRI study comparing autism and developmental coordination disorder

A deficit in pre‐cognitively mirroring other people''s actions and experiences may be related to the social impairments observed in autism spectrum disorder (ASD). However, it is unclear whether such embodied simulation deficits are unique to ASD or instead are related to motor impairment, which is commonly comorbid with ASD. Here we aim to disentangle how, neurologically, motor impairments contribute to simulation deficits and identify unique neural signatures of ASD. We compare children with ASD (N = 30) to children with Developmental Coordination Disorder (DCD; N = 23) as well as a typically developing group (N = 33) during fMRI tasks in which children observe, imitate, and mentalize about other people''s actions. Results indicate a unique neural signature in ASD: during action observation, only the ASD group shows hypoactivity in a region important for simulation (inferior frontal gyrus, pars opercularis, IFGop). However, during a motor production task (imitation), the IFGop is hypoactive for both ASD and DCD groups. For all tasks, we find correlations across groups with motor ability, even after controlling for age, IQ, and social impairment. Conversely, across groups, mentalizing ability is correlated with activity in the dorsomedial prefrontal cortex when controlling for motor ability. These findings help identify the unique neurobiological basis of ASD for aspects of social processing. Furthermore, as no previous fMRI studies correlated brain activity with motor impairment in ASD, these findings help explain prior conflicting reports in these simulation networks.     

VEGF-A165b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in?Vivo and in?Vitro

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A₁₆₅a and VEGF-A₁₆₅b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A₁₆₅a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A₁₆₅b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A₁₆₅b was detected in hippocampal and cortical neurons. VEGF-A₁₆₅b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A₁₆₅b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3–kinase activation. Recombinant human VEGF-A₁₆₅b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A₁₆₅b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A₁₆₅b expression suggests that non–isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.Vascular endothelial growth factor (VEGF) A, originally described as a potent vascular permeability and growth factor for endothelial cells, is up-regulated in the brain during stroke and ischemic episodes¹ and has been linked with many neuronal diseases. The most widely studied isoform of VEGF-A, VEGF-A₁₆₅a, is up-regulated in hypoxia, induces increased vascular permeability in neuronal vasculature, and can stimulate angiogenesis after ischemic episodes. The resulting edema and hyperemia can be damaging, but VEGF-A₁₆₅a has also been found to have direct anticytotoxic effects on neurons, raising the possibility that it may act as an endogenous neuroprotective agent in neurodegenerative pathologies. VEGF-A exerts neurotrophic (survival) and neurotropic (neurogenesis and axon outgrowth) actions, which, although initially thought to be a function of increased angiogenesis and perfusion after neuronal injury,² are now appreciated as direct effects of VEGF-A on neurons.The vegfa gene encodes numerous products by differential splicing, but not all isoforms exert the same effects.³ Alternative splicing of exon 8 leads to two functionally distinct families: the proangiogenic VEGF-A_xxxa family and the counteracting VEGF-A_xxxb family.^4,5 VEGF-A₁₆₅b prevents the VEGF-A₁₆₅a effects on increased vascular permeability, blood vessel growth, and vasodilatation.^4–7The therapeutic potential of VEGF-A and anti–VEGF-A treatments are now widely recognized, and effective anti–VEGF-A treatments are available in ophthalmology⁸ and oncology.⁹ The finding that VEGF-A is implicated in neuronal disorders (eg, Alzheimer disease, Parkinson disease, Huntington disease, diabetic neuropathy, and amyotrophic lateral sclerosis¹⁰) provides a rationale for the use of VEGF-A as a therapeutic agent in neurodegenerative conditions. Although this rationale is supported by preclinical evidence,¹¹ the identification of the VEGF-A_xxxb family requires reexamination of VEGF-A isoforms in these contexts to allow for the clear evidence that VEGF-A splicing variants are not functionally equivalent³ and to determine whether augmentation of the proangiogenic isoform family (VEGF-A_xxxa) alone may have deleterious effects (eg, in occult malignancy and carcinoma in situ).The neuroprotective profile of the exon 8 alternatively spliced isoforms VEGF-A_xxxb remains unexplored. Interestingly, VEGF-A_xxxb isoforms do not exhibit the vascular effects seen with VEGF-A_xxxa isoforms, such as a sustained increase in capillary permeability or hypotension.^5,12 The lack of these potential adverse effects may make VEGF-A_xxxb isoforms more amenable as therapeutic agents in neurodegenerative diseases.We therefore tested the hypothesis that VEGF-A₁₆₅b is neuroprotective for central and peripheral neurons. We found that VEGF-A₁₆₅b is expressed in central neurons and is neuroprotective in vitro and in vivo. This finding indicates that VEGF-A₁₆₅b may prove to be a suitable therapeutic agent in neurodegenerative disorders, exhibiting fewer adverse effects than VEGF-A₁₆₅a.