ESSENCE-Q – used as a screening tool for neurodevelopmental problems in public health checkups for young children in south Japan

Background: Screening for developmental disorders is an important task for Child Health Care. The concept of ESSENCE (early symptomatic syndromes eliciting neurodevelopmental clinical examinations) was created to cover all types of early developmental disorders and the ESSENCE-Questionnaire (ESSENCE-Q containing 12 questions with possible total scores ranging from 0 to 22) was developed as a tool for early detection of these disorders. The aim of this study was to perform a validation study in a public health situation in Japan. Methods: The psychometric properties of the ESSENCE-Q, completed by mothers, public health nurses (PHNs), and psychologists at 18-month (n=143 children) and 36-month (n=149 children) checkups were evaluated in a small city of Japan. Results were validated against clinical ESSENCE diagnoses. Receiver operating characteristic curves were generated and compared by using the area under the curve (AUC). Optimal cutoff values were explored. Results: At the 18-month checkup, AUC by mothers was 0.72, by PHNs 0.86, and by psychologists 0.82. An optimal cutoff was 3 with a high negative predictive value (NPV). At the 36-month checkup, AUC by mothers was 0.57, by PHNs 0.82, and by psychologists 0.87. Optimal cutoff was 2 with high NPV. Conclusion: The ESSENCE-Q completed by PHNs and psychologists had good diagnostic validity. The results suggested that almost all children scoring under cutoff would not have any ESSENCE problems/diagnoses

ESSENCE-Q- used as a screening tool for neurodevelopmental problems in public health checkups for young children in south Japan

Background: Screening for developmental disorders is an important task for Child Health Care. The concept of ESSENCE (early symptomatic syndromes eliciting neurodevelopmental clinical examinations) was created to cover all types of early developmental disorders and the ESSENCE-Questionnaire (ESSENCE-Q containing 12 questions with possible total scores ranging from 0 to 22) was developed as a tool for early detection of these disorders. The aim of this study was to perform a validation study in a public health situation in Japan. Methods: The psychometric properties of the ESSENCE-Q, completed by mothers, public health nurses (PHNs), and psychologists at 18-month (n=143 children) and 36-month (n=149 children) checkups were evaluated in a small city of Japan. Results were validated against clinical ESSENCE diagnoses. Receiver operating characteristic curves were generated and compared by using the area under the curve (AUC). Optimal cutoff values were explored. Results: At the 18-month checkup, AUC by mothers was 0.72, by PHNs 0.86, and by psychologists 0.82. An optimal cutoff was 3 with a high negative predictive value (NPV). At the 36-month checkup, AUC by mothers was 0.57, by PHNs 0.82, and by psychologists 0.87. Optimal cutoff was 2 with high NPV. Conclusion: The ESSENCE-Q completed by PHNs and psychologists had good diagnostic validity. The results suggested that almost all children scoring under cutoff would not have any ESSENCE problems/diagnoses

ESSENCE-Q - dash; a first clinical validation study of a new screening questionnaire for young children with suspected neurodevelopmental problems in south Japan

Background: Early identification of autism spectrum disorder, intellectual developmental disorder, attention-deficit/hyperactivity disorder, and other neurodevelopmental disorders/problems is crucial, yet diagnosis is often delayed for years under the often misguided “wait-and-see” paradigm. The early symptomatic syndromes eliciting neurodevelopmental clinical examinations-questionnaire (ESSENCE-Q) is a brief (12-item) screening questionnaire developed specifically for the purpose of speeding up the identification process of a wide variety of neurodevelopmental problems. The aims were to 1) estimate the reliability of the ESSENCE-Q, 2) evaluate the clinical cutoff levels suggested by the author of the ESSENCE-Q, and 3) propose optimal cutoff levels based on receiver operating characteristic analysis. Methods: The ESSENCE-Q was used for 1 year by a psychiatrist in Kochi, Japan, assessing children under the age of 6 years referred for developmental problems. The children were also clinically assessed with regard to whether or not they met criteria for a developmental disorder (diagnosis positive and diagnosis negative groups). We contrasted the results of the ESSENCE-Q and those of clinical diagnostic assessments in 130 cases. Results: Cronbach’s alpha was 0.82, sensitivity was 0.94 (95% confidence interval [CI]: [0.88, 0.98]), and specificity 0.53 (95% CI: [0.28, 0.77]), which are reasonable psychometrics for a first-step screening tool. Based on receiver operating characteristic analysis, we recommended an optimal cutoff level of yes ≥2 or maybe/a little ≥3 on the ESSENCE-Q (0.87 (95% CI: [0.79, 0.92]) sensitivity and 0.77 (95% CI: [0.50, 0.93]) specificity). Conclusion and implication: The ESSENCE-Q can be a good instrument for use as a screening tool for aiding in the process of early identification of neurodevelopmental disorders in clinical settings. To establish the broader validity and reliability of the ESSENCE-Q, case–control studies and general population studies of children in different age groups are needed

ESSENCE-Q – a first clinical validation study of a new screening questionnaire for young children with suspected neurodevelopmental problems in south Japan

BACKGROUND: Early identification of autism spectrum disorder, intellectual developmental disorder, attention-deficit/hyperactivity disorder, and other neurodevelopmental disorders/problems is crucial, yet diagnosis is often delayed for years under the often misguided “wait-and-see” paradigm. The early symptomatic syndromes eliciting neurodevelopmental clinical examinations-questionnaire (ESSENCE-Q) is a brief (12-item) screening questionnaire developed specifically for the purpose of speeding up the identification process of a wide variety of neurodevelopmental problems. The aims were to 1) estimate the reliability of the ESSENCE-Q, 2) evaluate the clinical cutoff levels suggested by the author of the ESSENCE-Q, and 3) propose optimal cutoff levels based on receiver operating characteristic analysis. METHODS: The ESSENCE-Q was used for 1 year by a psychiatrist in Kochi, Japan, assessing children under the age of 6 years referred for developmental problems. The children were also clinically assessed with regard to whether or not they met criteria for a developmental disorder (diagnosis positive and diagnosis negative groups). We contrasted the results of the ESSENCE-Q and those of clinical diagnostic assessments in 130 cases. RESULTS: Cronbach’s alpha was 0.82, sensitivity was 0.94 (95% confidence interval [CI]: [0.88, 0.98]), and specificity 0.53 (95% CI: [0.28, 0.77]), which are reasonable psychometrics for a first-step screening tool. Based on receiver operating characteristic analysis, we recommended an optimal cutoff level of yes ≥2 or maybe/a little ≥3 on the ESSENCE-Q (0.87 (95% CI: [0.79, 0.92]) sensitivity and 0.77 (95% CI: [0.50, 0.93]) specificity). CONCLUSION AND IMPLICATION: The ESSENCE-Q can be a good instrument for use as a screening tool for aiding in the process of early identification of neurodevelopmental disorders in clinical settings. To establish the broader validity and reliability of the ESSENCE-Q, case–control studies and general population studies of children in different age groups are needed

ESSENCE‐Q obtained in routine Japanese public child health check‐ups may be a valuable tool in neurodevelopmental screening

Aim: Our aim was to extend the validity of a questionnaire developed for screening and identifying early symptomatic syndromes eliciting neurodevelopmental clinical examinations‐questionnaire (ESSENCE‐Q) in young children. Methods: Early symptomatic syndromes eliciting neurodevelopmental clinical examinations‐questionnaire data for 207 children, living in Aki City, Japan, in 2014‐2015, were obtained from mothers, public health nurses and psychologists at 20‐ and 40‐month routine check‐ups at child healthcare centres. These were checked against subsequent ESSENCE diagnoses made by physicians. Receiver operating characteristic curves were constructed, and the area under the curves was compared. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values were calculated at optimal cut‐off values. The clinical utility index was also calculated. Results: When the ESSENCE‐Q was used by public health nurses, it demonstrated good validity, in terms of high sensitivity and high NPVs, at the 20‐month check‐up, but not at 40 months. Psychologists demonstrated good validity at both ages, but mothers did not. Good negative utility indexes, indicating screening accuracy, were obtained from the psychologists at both check‐ups and from nurses at 20 months. Conclusion: The ESSENCE‐Q results used by nurses and psychologists showed good validity. Future studies should confirm the effectiveness of this tool to identify children in need of clinical detailed neurodevelopmental assessment

Effects of Perfluorooctane Sulfonate on Cerebellar Cells via Inhibition of Type 2 Iodothyronine Deiodinase Activity

Perfluorooctane sulfonate (PFOS) has been used in a wide variety of industrial and commercial products. The adverse effects of PFOS on the developing brain are becoming of a great concern. However, the molecular mechanisms of PFOS on brain development have not yet been clarified. We investigated the effect of early-life exposure to PFOS on brain development and the mechanism involved. We investigated the change in thyroid hormone (TH)-induced dendrite arborization of Purkinje cells in the primary culture of newborn rat cerebellum. We further examined the mechanism of PFOS on TH signaling by reporter gene assay, quantitative RT-PCR, and type 2 iodothyronine deiodinase (D2) assay. As low as 10−7 M PFOS suppressed thyroxine (T4)-, but not triiodothyronine (T3)-induced dendrite arborization of Purkinje cells. Reporter gene assay showed that PFOS did not affect TRα1- and TRβ1-mediated transcription in CV-1 cells. RT-PCR showed that PFOS suppressed D2 mRNA expression in the absence of T4 in primary cerebellar cells. D2 activity was also suppressed by PFOS in C6 glioma-derived cells. These results indicate that early-life exposure of PFOS disrupts TH-mediated cerebellar development possibly through the disruption of D2 activity and/or mRNA expression, which may cause cerebellar dysfunction

Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes

Introduction: Human induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called “iCell cardiomyocytes” under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na+ and Ca2+ currents. Methods: iCell cardiomyocytes were cultured for 8–14 days (38–44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na+ channel current (INa) and L-type Ca2+ channel current (ICaL) were evaluated by the whole-cell patch clamp. Results: iCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of INa, ICaL, and rapidly-activating delayed-rectifier K+ channel current were −62.7 ± 13.7, −8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K+ channel currents were observed, whereas the T-type Ca2+ channel or slowly-activating delayed-rectifier K+ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked INa in a concentration-dependent manner with IC50 of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak INa block with a higher IC50 of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked ICaL with IC50 of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively. Conclusions: In iCell cardiomyocytes, INa was blocked by the class Ia and Ic antiarrhythmic agents and ICaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity. Keywords: iCell cardiomyocytes, class I antiarrhythmic agents, Na+ channel current, L-type Ca2+ channel curren

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer

The serum L-kynurenine/L-tryptophan ratio and tissue gene expression of IDO and TDO.

<p><b>A,</b> The serum L-kynurenine/L-tryptophan ratio (Kyn/Trp) was determined at 32 weeks by measuring the concentrations of L-kynurenine and L-tryptophan using HPLC. (B, C) Liver tissues were separated into hepatic tumors and non-tumorous tissues. Total RNA was then extracted and the expression levels of IDO and TDO mRNA were measured using quantitative RT-PCR. Data points represent the mean ± SD. * p<0.05, ** p<0.01, N.S.: not significant</p

Representative immunohistochemical expression (IHC) of IDO and kynurenine (KYN).

<p>Representative images of normal tissue (top panel) of a saline treated WT mouse, of HCC (second panels) and adenoma (third panels) of a WT mouse, and of adenoma of an IDO-/- mouse (bottom panels), at 32 weeks of DEN treatment that were stained with H&E (a-d), or were immunohistochemically stained for the IDO protein (e-h) or for L-KYN (i-l). The black line in the HCC tissues demarcates HCC from non-HCC tissue. (Bar = 50 μm)</p