Digital symbol-digit modalities test with modified flexible protocols in patients with CNS demyelinating diseases.

Cognitive impairment (CI) is prevalent in central nervous system demyelinating diseases, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We developed a novel tablet-based modified digital Symbol Digit Modalities Test (MD-SDMT) with adjustable protocols that feature alternating symbol-digit combinations in each trial, lasting one or two minutes. We assessed 144 patients (99 with MS and 45 with NMOSD) using both MD-SDMT protocols and the traditional paper-based SDMT. We also gathered participants' feedback through a questionnaire regarding their preferences and perceived reliability. The results showed strong correlations between MD-SDMT and paper-based SDMT scores (Pearsons correlation: 0.88 for 2 min; 0.85 for 1 min, both p < 0.001). Among the 120 respondents, the majority preferred the digitalized SDMT (55% for the 2 min, 39% for the 1 min) over the paper-based version (6%), with the 2 min MD-SDMT reported as the most reliable test. Notably, patients with NMOSD and older individuals exhibited a preference for the paper-based test, as compared to those with MS and younger patients. In summary, even with short test durations, the digitalized SDMT effectively evaluates cognitive function in MS and NMOSD patients, and is generally preferred over the paper-based method, although preferences may vary with patient characteristics.

Disease characteristics of idiopathic transverse myelitis with serum neuronal and astroglial damage biomarkers.

Despite its close association with CNS inflammatory demyelinating disorders (CIDDs), pathogenic characteristics of idiopathic transverse myelitis (ITM) remain largely unknown. Here, we investigated serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) in patients with ITM to unravel the disease characteristics of ITM. We prospectively recruited 70 patients with ITM, 62 with AQP4 + NMOSD and 85 with RRMS-including 31 patients with acute TM attacks-along with 30 HCs. We measured sNfL and sGFAP levels using single-molecular arrays and compared these levels per lesion volume between the disease groups during attacks. Compared to HCs, ITM patients showed higher sNfL and sGFAP during acute attacks (sNfL: p < 0.001, sGFAP: p = 0.024), while those in remission (sNfL: p = 0.944, sGFAP: p > 0.999) did not, regardless of lesion extents and presence of multiple attacks. ITM patients demonstrated lower sGFAP/volume (p = 0.011) during acute attacks and lower sGFAP (p < 0.001) in remission compared to AQP4 + NMOSD patients. These findings suggest that both neuronal and astroglial damages occur in patients with acute ITM attacks at a similar level to those with RRMS, distinct from AQP4 + NMOSD. However, active neuroinflammatory process was not remarkable during remission in this cohort.

Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway.

Our knowledge of the immunomodulatory role of mesenchymal stem cells (MSCs) in both the innate and adaptive immune systems has dramatically expanded, providing great promise for treating various autoimmune diseases. However, the contribution of MSCs to Th17-dominant immune disease, such as psoriasis and its underlying mechanism remains elusive. In this study, we demonstrated that human palatine tonsil-derived MSCs (T-MSCs) constitutively express both the membrane-bound and soluble forms of programmed death-ligand 1 (PD-L1), which enables T-MSCs to be distinguished from MSCs originating from other organs (i.e. bone marrow or adipose tissue). We also found that T-MSC-derived PD-L1 effectively represses Th17 differentiation via both cell-to-cell contact and a paracrine effect. Further, T-MSCs increase programmed death-1 (PD-1) expression on T-cells by secreting IFN-ß, which may enhance engagement with PD-L1. Finally, transplantation of T-MSCs into imiquimod-induced psoriatic skin inflammation in mice significantly abrogated disease symptoms, mainly by blunting the Th17 response in a PD-L1-dependent manner. This study suggests that T-MSCs might be a promising cell source to treat autoimmune diseases such as psoriasis, via its unique immunoregulatory features. Copyright © 2017 John Wiley & Sons, Ltd.

Heat shock protein 90 is involved in IL-17-mediated skin inflammation following thermal stimulation.

The pathogenesis of inflammatory skin diseases involves interactions between immune cells and keratinocytes, including the T helper 17 (Th17)-mediated immune response. Several chemokines [chemokine (C-X-C motif) ligand (CXCL)1, CXCL5 and CXCL8] and antimicrobial peptides [ß-defensin 1 (BD1), LL-37, S100A8 and S100A9] were transcriptionally upregulated in the keratinocyte cell line HaCaT upon stimulation with interleukin (IL)-17. Balneotherapy, the treatment of disease by bathing, is an alternative therapy that has frequently been used for the treatment of inflammatory skin diseases. Immersion in pools of thermal mineral water is often considered to have chemical, thermal, mechanical and immunomodulatory benefits. We examined the effect of thermal treatment on IL-17-mediated inflammation in a model of skin disease. As Act1 is required for IL-17 signaling and is a client protein of heat shock protein 90 (HSP90), we evaluated the effect of HSP90 inhibition on IL-17-mediated cytokine and antimicrobial peptide expression in keratinocytes following heat treatment. We found that after thermal stimulation, Act1 binding to HSP90α was significantly increased in the presence of IL-17 (100 ng/ml) and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG, 1 µM). Antimicrobial peptide and chemokine expression generally increased after heat treatment; Act1 knockdown and 17­AAG reversed this effect. These observations demonstrate the possible immunomodulatory effect of heat on keratinocytes during the progression of IL-17-mediated inflammatory skin diseases.

HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation.

The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

Increased error-related brain activity in six-year-old children with clinical anxiety.

Anxiety disorders are the most frequently diagnosed form of psychopathology in children and often result in chronic impairment that persists into adulthood. Identifying neurobehavioral correlates of anxiety that appear relatively early in life would inform etiological models of development and allow intervention and prevention strategies to be implemented more effectively. The error-related negativity (ERN), a negative deflection in the event-related potential at fronto-central sites approximately 50 ms following the commission of errors, has been consistently found to be larger among anxious adults. The current study sought to extend these findings to even younger individuals: the ERN was elicited by a Go/NoGo task in 48 six year-old children with a clinical anxiety disorder assessed by diagnostic interview and 48 age-matched controls. In addition to child anxiety disorder, the ERN was examined in relation to maternal history of anxiety disorder, which was previously related to a smaller ERN. Anxious children were characterized by a larger (i.e., more negative) ERN and maternal history of anxiety disorder was associated with a smaller ERN. Thus, the relationship between an increased ERN and clinical anxiety is evident by age 6, and this effect appears independent from an opposing influence of maternal anxiety history on the ERN. These findings support the ERN as a promising neurobehavioral marker of anxiety, and implications are discussed.

Child dopamine active transporter 1 genotype and parenting: evidence for evocative gene-environment correlations.

The dopamine active transporter 1 (DAT1) gene is implicated in psychopathology risk. Although the processes by which this gene exerts its effects on risk are poorly understood, a small body of research suggests that the DAT1 gene influences early emerging negative emotionality, a marker of children's psychopathology risk. As child negative emotionality evokes negative parenting practices, the DAT1 gene may also play a role in gene-environment correlations. To test this model, children (N = 365) were genotyped for the DAT1 gene and participated in standardized parent-child interaction tasks with their primary caregiver. The DAT1 gene 9-repeat variant was associated with child negative affect expressed toward the parent during parent-child interactions, and parents of children with a 9-repeat allele exhibited more hostility and lower guidance/engagement than parents of children without a 9-repeat allele. These gene-environment associations were partially mediated by child negative affect toward the parent. The findings implicate a specific polymorphism in eliciting negative parenting, suggesting that evocative associations play a role in elevating children's risk for emotional trajectories toward psychopathology risk.

Error-related brain activity in young children: associations with parental anxiety and child temperamental negative emotionality.

BACKGROUND: There is increasing interest in error-related brain activity in anxiety disorders. The error-related negativity (ERN) is a negative deflection in the event-related potential approximately 50 ms after errors compared to correct responses. Recent studies suggest that the ERN may be a biomarker for anxiety, as it is positively associated with anxiety disorders and traits in adults and older youth. However, it is not known if the ERN in young children is related to risk for anxiety disorders. We addressed this by examining the association of six-year olds' ERNs with two established risk factors for anxiety: parental anxiety disorder and child temperamental negative emotionality (NE). METHOD: The ERN was assessed using a Go/No-Go task in a community sample of 413 six-year olds. In a prior assessment at age 3, child temperament was evaluated using a laboratory observational measure and parental psychopathology was assessed using semi-structured diagnostic interviews. RESULTS: Children of mothers with anxiety disorders and children with greater temperamental NE (particularly fearfulness) exhibited significantly smaller ERNs than their peers. Paternal psychopathology, maternal mood and substance use disorders, and child positive emotionality were not associated with children's ERNs. CONCLUSION: Both maternal anxiety disorders and child NE (particularly fearfulness) were significantly associated with children's ERNs. However, the direction of these associations was opposite to the relations between ERNs and anxiety in older youth and adults. These results suggest that there may be a difference between risk and disorder status in the relation of error-related brain activity to anxiety between early childhood and late childhood/ early adolescence.

Tonsil-derived mesenchymal stromal cells: evaluation of biologic, immunologic and genetic factors for successful banking.

BACKGROUND AIMS: Although mesenchymal stromal cells (MSC) from human palatine tonsils (tonsillar MSC, T-MSC) have been isolated, whether T-MSC isolated from multiple donors are feasible for cell banking has not been studied. METHODS: T-MSC before and after a standard protocol of cryopreservation and thawing were assessed regarding several basic characteristics, including colony-forming unit-fibroblast features, MSC-specific surface antigen profiles, and inhibition of alloreactive T-cell proliferation. In vitro mesodermal differentiation potentials to adipocytes, osteocytes and chondrocytes were detected by staining with either cell-specific dyes or antibody after incubation with each appropriate differentiation medium. Expression of mesoderm-specific genes was also quantified by real-time polymerase chain reaction (PCR) assay. Expression profiles of endoderm-specific genes were identified by reverse transcription PCR assay. The feasibility of T-MSC in future engraftment was tested by short tandem repeat (STR) analysis using genomic DNA isolated randomly from three independent subjects. RESULTS: Both fresh and cryopreserved-thawed T-MSC showed a similar high proliferation capacity and expressed primitive cell-surface markers. Hematopoietic cell markers, HLA-DR, co-stimulatory molecules and follicular dendritic cell markers were not detected. In addition to mesodermal differentiation, fresh and cryopreserved-thawed cells also underwent endodermal differentiation, as evidenced by the expression of endoderm-specific genes including forkhead box A2 (FoxA2), SIX homeobox 1 (Six1) and chemokine (C-C motif) ligand 21 (CCL21). Both cells significantly decreased phorbol 12- myristate 13-acetate (PMA)-induced T-cell proliferation. T-MSC from three independent donors formed chimerism in STR analysis. CONCLUSIONS: Our results demonstrate for the first time that T-MSC are a potentially good source for MSC banking.

Tonsil-derived mesenchymal progenitor cells acquire a follicular dendritic cell phenotype under cytokine stimulation.

Tonsils comprise part of the mucosal immune system and contain lymphocytes, macrophages, and follicular dendritic cells (FDCs). FDCs are located in the B cell area of the follicles of secondary lymphoid organs, such as the spleen, tonsils, or lymph nodes, and they trap and retain immune complexes on their surfaces to regulate B cell activation and maturation. Stromal cells from the palatine tonsils are often used for FDC in vitro studies, and it has been reported that human palatine tonsils may be a good source of multipotent mesenchymal cells. Therefore, we assessed whether tonsil-derived mesenchymal stromal cells could differentiate into a FDC-like phenotype. We discovered that stromal cells isolated from human tonsils not only had the potential to differentiate into various cell types of mesenchymal origin, but they also could differentiate into FDC-like cells under cytokine stimulation in vitro.

Correlates of the CBCL-dysregulation profile in preschool-aged children.

BACKGROUND: A growing literature indicates that the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) identifies youths with heightened risk for severe psychopathology, comorbidity, and impairment. However, this work has focused on school-age children and adolescents; no studies have examined whether preschool-aged children with the CBCL-DP exhibit a similar constellation of problems. METHOD: Using a community sample of preschoolers, we compared children with (N = 61) and without (N = 488) the CBCL-DP on a broad range of variables assessed using multiple methods. RESULTS: Univariate analyses revealed numerous differences between children with the CBCL-DP and their peers on psychiatric symptomatology, temperament, parenting behavior, and parental personality, psychopathology, and marital functioning. In multivariate analyses, children with the CBCL-DP exhibited greater temperamental negative affectivity and lower effortful control. They also had more depressive and oppositional defiant symptoms, as well as greater functional impairment. Parents of CBCL-DP children reported engaging in more punitive, controlling parenting behavior than parents of non-profile children. CONCLUSIONS: In a non-clinical sample of preschoolers, the CBCL-DP is associated with extensive emotional and behavioral dysregulation and maladaptive parenting.

Electrocortical reactivity to emotional faces in young children and associations with maternal and paternal depression.

BACKGROUND: The late positive potential (LPP) is an event-related potential component that indexes selective attention toward motivationally salient information and is sensitive to emotional stimuli. Few studies have examined the LPP in children. Depression has been associated with reduced reactivity to negative and positive emotional stimuli, including reduced LPPs in response to emotional faces. The current study sought to identify the time course and scalp distribution of the LPP in response to emotional faces in young children and to determine whether reduced reactivity is observed among children at risk for depression. METHODS: Electrocortical reactivity to emotional faces was examined in a large sample of young children and as a function of maternal and paternal depression. RESULTS: In the overall sample, emotional faces were associated with increased positivities compared to neutral faces at occipital sites 200-600 ms after stimulus onset and at parietal sites 600-1,000 ms after stimulus onset. Children of mothers with a history of depressive disorders exhibited reduced differentiation in the early occipital LPP for emotional compared to neutral faces. CONCLUSIONS: Results suggest that children as young as 6 years exhibit LPPs to emotional faces, and patterns of electrocortical reactivity to emotional stimuli may be associated with vulnerability to depressive disorders.

Electrocortical and behavioral measures of response monitoring in young children during a Go/No-Go task.

The current study examined behavioral measures and response-locked event-related brain potentials (ERPs) derived from a Go/No-Go task in a large (N = 328) sample of 5- to 7-year-olds in order to better understand the early development of response monitoring and the impact of child age and sex. In particular, the error-related negativity (ERN, defined on both error trials alone and the difference between error and correct trials, or ΔERN), correct response negativity (CRN), and error positivity (P(e)) were examined. Overall, the ERN, CRN, and the P(e) were spatially and temporally similar to those measured in adults and older children. Even within our narrow age range, older children were faster and more accurate; a more negative ΔERN and a more positive P(e) were associated with: increasing age, increased accuracy, and faster reaction times on errors, suggesting these enhanced components reflected more efficient response monitoring of errors over development. Girls were slower and more accurate than boys, although both genders exhibited comparable ERPs. Younger children and girls were characterized by increased posterror slowing, although they did not demonstrate improved posterror accuracy. Posterror slowing was also related to a larger P(e) and reduced posterror accuracy. Collectively, these data suggest that posterror slowing may be unrelated to cognitive control and may, like the P(e), reflect an orienting response to errors.

Psychometric properties of the Behavioral Inhibition Questionnaire in preschool children.

We examined the psychometric properties of the Behavioral Inhibition Questionnaire (BIQ; Bishop, Spence, & McDonald, 2003), a rating scale for children's behavioral inhibition. Parent and teacher ratings, parent interviews, and laboratory observations were obtained for 495 preschoolers. Confirmatory factor analysis yielded 6 factors, each reflecting the BIQ's subscales, and all loading onto a second-order general dimension. Model fit was acceptable for parent ratings, but only marginal for teacher ratings. The convergent and discriminant validity of the BIQ was examined by using a multitrait-multimethod approach. Results indicate that the BIQ displays evidence of reliability and validity that can complement observational paradigms.

Attentional biases for emotional faces in young children of mothers with chronic or recurrent depression.

Attentional biases for negative stimuli have been observed in school-age and adolescent children of depressed mothers and may reflect a vulnerability to depression. The direction of these biases and whether they can be identified in early childhood remains unclear. The current study examined attentional biases in 5-7-year-old children of depressed and non-depressed mothers. Following a mood induction, children participated in a dot-probe task assessing biases for sad and happy faces. There was a significant interaction of group and sex: daughters of depressed mothers attended selectively to sad faces, while children of controls and sons of depressed mothers did not exhibit biases. No effects were found for happy stimuli. These findings suggest that attentional biases are discernible in early childhood and may be vulnerability markers for depression. The results also raise the possibility that sex differences in cognitive biases are evident before the emergence of sex differences in the prevalence of depression.

Do positive and negative temperament traits interact in predicting risk for depression? A resting EEG study of 329 preschoolers.

Researchers have long been interested in whether particular temperamental traits in childhood connote risk for depressive disorders. For example, children characterized as having high negative emotionality (NE; sadness, fear, anger) and low positive emotionality (PE; anhedonia, listlessness, and lack of enthusiasm) are hypothesized to be at risk for depression. Few studies, however, have examined whether (and how) these two temperamental dimensions interact to confer risk. In a sample of 329 preschoolers, the present study addressed this question by examining the relation between PE and NE and asymmetry in resting EEG activity in frontal and posterior regions, which are putative biomarkers for depression. Using a laboratory battery to define temperament, we found an interaction of PE and NE on posterior asymmetry. Specifically, when PE was high, NE was associated with greater relative right activity. When PE was low, NE was not related to posterior asymmetry. These results were driven by differences in EEG activity in right posterior regions, an area associated with emotional processing and arousal, and were specific to girls. We found no relation between temperament and frontal asymmetry. These findings suggest that, at least for girls, PE and NE may have an interactive effect on risk for depression.