Neurological and Neurocognitive Impairments in Adults with a History of Prenatal Methylmercury Poisoning: Minamata Disease.

Minamata disease, which happened during the 1950s and 1960s in Minamata, Japan, is a well-known case of food poisoning caused by methylmercury-contaminated fish. Although many children were born, in the affected areas, with severe neurological signs after birth (known as congenital Minamata disease (CMD)), few studies have explored the possible effects of low-to-moderate methylmercury exposure in utero, probably at lower levels than in CMD patients, in Minamata. We, therefore, recruited 52 participants in 2020: 10 patients with known CMD; 15 moderately exposed residents; and 27 non-exposed controls. The average umbilical cord methylmercury concentrations were 1.67 parts per million (ppm) for CMD patients and 0.77 ppm for moderately exposed participants. After conducting four neuropsychological tests, we compared the functions among the groups. Compared with the non-exposed controls, both the CMD patients and moderately exposed residents had worse scores in the neuropsychological tests, although the score decline was more severe in the CMD patients. For example, even after adjusting for age and sex, the CMD patients and moderately exposed residents had 16.77 (95% CI: 13.46 to 20.08) and 4.11 (95% CI: 1.43 to 6.78) lower scores in the Montreal Cognitive Assessment, respectively, than the non-exposed controls. The present study indicates that residents of Minamata who experienced low-to-moderate prenatal methylmercury exposure also have neurological or neurocognitive impairments.

Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

Children with autism spectrum disorder comorbid with attention-deficit/hyperactivity disorder examined by the Wisconsin card sorting test: Analysis by age-related differences.

The DSM-5 confirmed that autism spectrum disorder (ASD) might be comorbid with attention-deficit/hyperactivity disorder (ADHD). This study investigated the executive function of ASD comorbid with ADHD (ASD + ADHD), ASD, and typically developed (TD) children using the Keio version of the modified Wisconsin card sorting test (KWCST). Children with ASD + ADHD (n = 43), ASD (n = 69), and TD (n = 69) were examined in two age groups: 5-9 years and 10-15 years. Both of the younger clinical groups showed significantly unfavorable scores for many indices in the second step compared to the TD group. As for the older groups, the ASD children showed significantly unfavorable scores in total errors in the second step, while the ASD + ADHD children did not show significant differences in either step. However, some index scores of the two older clinical groups were comparable to the older TD group in the second step. For the cognitive differences between clinical groups, the younger ASD + ADHD showed unfavorable scores in numbers of response cards until the first category achieved in the second step, while the older ASD showed unfavorable scores in categories achieved and perseverative errors of Nelson in the first step. For the degree of improvements in the second step, the older groups did not show significant group differences, while the younger ASD group showed significantly fewer improvements compared to the TD group. Based on these results, it is presumed that younger ASD + ADHD individuals are not sufficiently able to sustain attention and/or memory, and that the older ASD patients have difficulty in terms of flexibility.

Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

Combination of lenalidomide and low-dose dexamethasone therapy promotes the anticoagulant activity of warfarin in patients with immunoglobulin light-chain amyloidosis.

The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1.7-fold during treatment. The median time to reach maximum values was 17 days. Horn's drug Interaction Probability Scale indicated a possible interaction between lenalidomide and warfarin. These patients exhibited no marked alterations in hepatic function or serum albumin concentrations prior to and following combination chemotherapy and no additional administration of CYP2C9 inhibitors or vitamin K supplements was conducted. In addition, no patient experienced chemotherapy-induced nausea or appetite loss. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Therefore, the combination of warfarin and lenalidomide may cause a pharmacodynamic interaction, more likely by inhibiting the production of interleukin-6. In conclusion, clinically important interactions between warfarin and lenalidomide and low-dose dexamethasone therapy were observed in AL amyloidosis patients, where INR values signi ficantly increased. Therefore, close and regular monitoring of patients during the course of treatment is important, and the dose of warfarin should be reduced if required.

Prenatal exposure to outdoor air pollution and child behavioral problems at school age in Japan.

INTRODUCTION: Recent studies suggest positive associations between prenatal exposure to ambient air pollution and neurodevelopment of children, but evidence on the adverse effects of exposure to air pollution on child neurobehavioral development remains limited. We thus examined associations between prenatal exposure to outdoor air pollution and child behavioral problems at school age, using data from a nationwide population-based longitudinal survey in Japan, where participants were recruited in 2001 and are continuously followed. METHODS: Suspended particulate matter (SPM), nitrogen dioxide, and sulfur dioxide concentrations during the 9months before birth were obtained at municipality level and assigned to those participants born in the corresponding municipality. We analyzed data from singleton births with linked pollution data available (e.g., n=33,911 for SPM). We used responses to survey questions about behavioral problems at age 8years. We conducted multilevel logistic regression analysis, adjusting for individual and municipality-level variables. RESULTS: Air pollution exposure during gestation was positively associated with risk for behavioral problems related to attention and delinquent or aggressive behavior. In the fully adjusted models, odds ratios following a one-interquartile-range increase in SPM were 1.06 (95% confidence interval: 1.01, 1.11) for interrupting others, 1.09 (1.03, 1.15) for failure to pay attention when crossing a street, 1.06 (1.01, 1.11) for lying, and 1.07 (1.02, 1.13) for causing public disturbance. CONCLUSIONS: Prenatal exposure to outdoor air pollution was associated with behavioral problems related to attention and delinquent or aggressive behavior at age 8years in a nationally representative sample in Japan.

The interaction between oral melphalan and gastric antisecretory drugs: Impact on clinical efficacy and toxicity.

The aim of the present study was to clarify whether gastric antisecretory drugs affect the clinical efficacy and toxicity of orally administered melphalan in patients with multiple myeloma. A total of 10 patients receiving bortezomib plus oral melphalan and prednisolone (VMP) therapy between December 2011 and November 2014 were analyzed retrospectively. The patients were divided into a control group (seven patients) and a concomitant group (three patients, who were also administered with gastric antisecretory drugs). The gastric antisecretory drugs included rabeprazole sodium (two patients) and famotidine (one patient). No significant differences between the groups were observed in either the characteristics of the patients or the VMP regimen. The levels of monoclonal protein (M protein) in the control group tended to decrease (with a VMP cycle-dependency), although they were primarily stable in the concomitant group. During the second and third VMP cycles, the levels of M protein were markedly lower in the control group compared with the concomitant group. All the patients in the control group achieved a partial response, whereas those in the concomitant group exhibited stable disease. Hematological toxicity levels were revealed to be comparable between the two groups, whereas gastrointestinal toxicity was more prevalent in the control group. In conclusion, the results of the present study suggested that the clinical efficacy of melphalan may be reduced by the co-administration of gastric antisecretory drugs. This interaction may result in decreased toxicity and clinical efficacy of melphalan.

Preterm birth and behavioural outcomes at 8†years of age: a nationwide survey in Japan.

OBJECTIVE: To analyse the effect of different preterm birth categories on behavioural outcomes. DESIGN: Prospective cohort design. SETTINGS: The Japanese Longitudinal Survey of Babies in the 21st Century was used for the study. SUBJECTS: Neonates born in 2001 in Japan (n=34,163) and followed up at the age of 8 years. Post-term births were excluded and the sample was divided into four groups according to gestational age: <34 weeks, 34-36 weeks, 37-38 weeks and 39-41 weeks. OUTCOME MEASURES: Seven behavioural outcomes were examined: three attention problems and four delinquent/aggressive behaviours. RESULTS: Logistic regression was used to estimate adjusted ORs and 95% CIs for each outcome. Positive associations were found between preterm birth (<37 weeks) and adverse behavioural outcomes compared with full-term birth (39-41 weeks). For attention problems, the OR for 'inability to wait his/her turn' was increased by 1.72 (95% CI 1.22 to 2.43) for gestational age <34 weeks and by 1.28 (95% CI 1.03 to 1.59) for 34-36 weeks' gestation. For delinquent/aggressive behaviour, the OR for the outcome 'destroying books/toys' was increased by 1.46 (95% CI 1.07 to 1.99) for gestational age <34 weeks, while the outcome 'disturbance in public' was increased by 1.20 (95% CI 1.04 to 1.38) for 34-36 weeks' gestation. CONCLUSIONS: Children who are born <34 weeks, but also between 34 and 36 weeks, are at increased risk of behavioural problems related to attention and delinquent/aggressive behaviour when 8 years old.

Prenatal Exposure to Traffic-related Air Pollution and Child Behavioral Development Milestone Delays in Japan.

BACKGROUND: Recent studies suggest that prenatal exposure to outdoor air pollution is associated with unfavorable neurodevelopment in children. We examined associations between prenatal exposure to traffic-related air pollution and child behavioral development milestone delays, using data from a nationwide population-based longitudinal survey in Japan, where the participants were recruited in 2001 and followed. METHODS: Particulate matter, nitrogen dioxide, and sulfur dioxide concentrations during the 9 months before birth were obtained at the municipality level and assigned to the participants who were born in the corresponding municipality. We analyzed data from singleton births with linked pollution data available (N = 33,911 at the maximum). We used responses to survey questions about age-appropriate behaviors at ages 2.5 and 5.5 years as indicators of behavioral development. We conducted multilevel logistic regression analysis, adjusting for individual and municipality-level variables. RESULTS: Air pollution exposure during gestation was positively associated with the risk of some developmental milestone delays at both ages. Specifically, air pollution was associated with verbal and fine motor development at age 2.5 years, and with behaviors related to inhibition and impulsivity at 5.5 years. In the fully-adjusted models, odds ratios following one-interquartile-range increase in nitrogen dioxide and suspended particulate matter were 1.24 (95% confidence interval: 1.07, 1.43) for inability to compose a two-phrase sentence at ages 2.5 and 1.10 (1.05, 1.16) for inability to express emotions at age 5.5 years, respectively. CONCLUSIONS: Prenatal exposure to traffic-related air pollution was associated with behavioral development milestone delays of children in a nationally representative sample in Japan.

Neurological and neurocognitive functions from intrauterine methylmercury exposure.

In the 1950s, large-scale food poisoning caused by methylmercury was identified in Minamata, Japan. Although severe intrauterine exposure cases (ie, congenital Minamata disease patients) are well known, possible impacts of methylmercury exposure in utero among residents, which is likely at lower levels than in congenital Minamata disease patients, are rarely explored. In 2014, the authors examined neurological and neurocognitive functions among 18 exposed participants in Minamata, focusing on fine motor, visuospatial construction, and executive functions. More than half of the participants had some fine motor and coordination difficulties. In addition, several participants had lower performance for neurocognitive function tests (the Rey-Osterrieth Complex Figure test and Keio version of the Wisconsin card sorting test). These deficits imply diffuse brain damage. This study suggests possible neurological and neurocognitive impacts of prenatal exposure to methylmercury among exposed residents of Minamata.

Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease.

A large-scale food poisoning caused by methylmercury was identified in Minamata, Japan, in the 1950s. The severe intrauterine exposure cases are well known, although the possible impact of low-to-moderate methylmercury exposure in utero are rarely investigated. We examined neurocognitive functions among 22 participants in Minamata, mainly using an intelligence quotient test (Wechsler Adults Intelligent Scale III), in 2012/2013. The participants tended to score low on the Index score of processing speed (PS) relative to full-scale IQ, and discrepancies between PS and other scores within each participant were observed. The lower score on PS was due to deficits in digit symbol-coding and symbol search and was associated with methylmercury concentration in umbilical cords. The residents who experienced low-to-moderate methylmercury exposure including prenatal one in Minamata manifested deficits in their cognitive functions, processing speed in particular.

Executive function in children with pervasive developmental disorder and attention-deficit/hyperactivity disorder assessed by the Keio version of the Wisconsin card sorting test.

The Wisconsin card sorting test (WCST) comprehensively examines executive function (EF). The Keio version of the WCST (KWCST) uses fewer cards and presents them in two steps, separated by a short pause during which an instruction is given. Being of short duration, this test is suitable for children with pervasive developmental disorder (PDD) and attention-deficit/hyperactivity disorder (AD/HD), yet few studies have examined the performance of children with such developmental disorders in the second step of a two-step test such as the KWCST. Using the KWCST, this study compares EF in children with PDD (n=52), or AD/HD (n=46) to that in typically developing (TD) children (n=52). Scores for the six indices of this test, including numbers of response cards until the first category achieved (NUCA), total errors (TE), and non-perseverative errors of Nelson (NPEN), were analyzed using ANOVA. Compared to the TD group, scores in the PDD and/or AD/HD groups were significantly lower for all indices except NUCA and NPEN for the first step, and lower for all indices except NUCA for the second step. Moreover, significantly fewer improvements in TE were seen in the PDD group, and significantly fewer improvements in NPEN were seen in the AD/HD group, compared with TD. This study suggests that both PDD and AD/HD make it difficult for children to utilize their experience in the first step and to effectively apply the instruction given before the second step. It also suggests that the two-step nature of the KWCST is clinically important.

[Clinical application of the modified Stroop test to children with attention deficit/hyperactivity disorder].

The Stroop test has been already applied to many children with attention deficit/hyperactivity disorder (AD/HD). There are, however, differences in the measurement of the Stroop test, and also in the background conditions of the patients, such as the status of comorbidity with learning disorder (LD), medication and the level of Intelligence Quotient (IQ), and presumably as a result, the outcome of the Stroop test shows a diversity. This study was undertaken to compare the performances of children with AD/HD to normal controls using the modified Stroop test according to the subtypes of AD/HD. Subjects in this study were 23 unmedicated children with AD/HD, ranging from 6 to 14 years of age, and 69 normal controls who were matched on sex and age. Children with AD/HD whose verbal IQ and performance IQ were above 80 showed significant differences in such indices as Incongruent Color Naming time (ICN) and the resulting index of subtracting Color Naming time (CN) from ICN (ICN-CN). As to the analysis according to the subtypes excluding 8 cases with comorbid LD, both the predominantly inattentive type and the group putting together the predominantly hyperactive-impulsive type and the combined type showed significant differences in ICN--CN compared with the normal controls. These results suggest that the inattentiveness relevant factor affects the performance of the interference task in children with AD/HD.

[Standard value and developmental changes in the indices of interference effect in the modified Stroop test].

The Stroop test was originally invented by Stroop to measure selective attention and cognitive flexibility and various versions of this test have been developed by many other researchers. Since the Stroop test requires the examinee's sustained efforts, it is not readily applicable to children with developmental disorders. In order to overcome this weakness, a modified Stroop test by reducing the total number of stimulations from 300 to 72 was proposed for clinical use. This study was performed to obtain the standard value of the modified Stroop test, and also to clarify the developmental changes in indices of interference effect. Two hundred eighty one normal children and adults, ranging from 6 to 20 years of age were examined. A simple regression analysis was performed to examine the relation between age and the score of indices such as Incongruent Color Naming (ICN), ICN--Color Naming (CN), ICN/CN. The results from this analysis showed significant age-related changes. Subjects between sixteen and seventeen showed the best score in each index. These findings suggest that a brain region and/or functional system of late maturation might participate in the execution of the interference task.

Predicting executive function task scores with the Rey-Osterrieth Complex Figure.

The Boston Qualitative Scoring System (BQSS) is one of the scoring methods of the Rey-Osterrieth Complex Figure Test (ROCF). With BQSS, 17 qualitative ratings are generated, and subsequently 6 summary scores are calculated by combining several qualitative scores. Previously we showed that 5 of 6 BQSS summary scores were correlated with the scores of the several executive function tests in children. The objective of this study was to develop a new summary score which correlates with the executive function test scores more strongly than the existing summary scores. For this purpose, we conducted multiple regression analysis to predict PEN, CA, DSM of the Wisconsin Card Sorting Test Keio Version, and the Mazes scores from WISC-III, by the BQSS qualitative scores derived from ROCF drawings in copy condition. The subjects were 78 children with various neuropsychological disorders (5 years 5 months-14 years 11 months; mean: 9 years 2 months; F 22, M 56). Significant predictive models were generated for PEN, CA, and Mazes scores. Among them the models for the Mazes scores were the most accurate. The second model for the Mazes scores was most suitable for a new summary score. Its degree-of-freedom-adjusted coefficient of multiple determination and multiple correlation coefficient reached 0.467 and 0.695, respectively. A new summary score should be applied in future studies to evaluate its clinical usefulness.

Japanese version of the Frontal Assessment Battery for dementia.

The Frontal Assessment Battery (FAB) was developed as a short bedside cognitive and behavioral battery to assess frontal lobe functions. The purpose of this study was to evaluate the validity and reliability of a Japanese version of the FAB to measure cognitive dysfunction in patients with dementia. We studied 25 normal subjects and 105 patients with Alzheimer's disease, n=58, vascular dementia, n=24, and frontotemporal dementia, n=23. The neuropsychological test battery included the FAB, the Mini Mental State Examination (MMSE), a memory test, and the Wisconsin Card Sorting Test (Keio version: KWCST). Patients with dementia performed significantly more poorly than controls on all tests. The FAB showed a good correlation with other cognitive measures: MMSE (r=0.725), KWCST number of categories completed (r=0.654), KWCST number of perseveration errors (r=-0.484), and memory test (r=0.643). Patients with more severe Clinical Dementia Rating scores showed lower scores on the FAB. There was good inter-rater reliability (r=0.972), test-retest reliability (r=0.769), and internal consistency (Cronbach's coefficient alpha=0.715). The FAB is a valid and reliable screening test to evaluate cognitive dysfunction among patients with dementia.

The Rey-Osterrieth Complex Figure as a measure of executive function in childhood.

In adults, the Rey-Osterrieth Complex Figure (ROCF) can be used for the assessment of not only visuoconstructional ability and visual memory, but also executive function in adults. We studied whether ROCF scores also correlated with executive function in childhood. The subjects consisted of 56 patients with various neurological diseases (5 years 7 months-14 years 11 months; mean: 8 years 8 months; M 42, F 14) whose full-scale IQs were 70 or higher (mean: 93.3). All subjects underwent the Wechsler Intelligence Scale for children third edition (WISC-III) and various psychological tests focusing on executive function. We evaluated the ROCF with the Boston Qualitative Scoring System (BQSS). We calculated the partial correlation coefficients between the BQSS Summary Scores and representative scores of other executive function tests, using age as the control variable. Among the scores of the various examinations, the Perseverative Errors of Nelson of the Wisconsin Card Sorting Test, the raw scores of the Mazes (WISC-III), the Digit Span (WISC-III), and the Block Design (WISC-III) were correlated significantly with two to four BQSS Summary Scores (P<0.05 or P<0.01). In contrast, the scores of the Trail Making Test, the Stroop Test, and the Commission Error of Continuous Performance Test-II did not show a significant correlation with any of the BQSS Summary Scores. The ROCF evaluated with the BQSS reflects not only visuoperceptual ability and visuoconstructional ability, but also executive function, especially planning and organization. However, a new BQSS Summary Score should be devised since no existing BQSS index specifically reflects executive functions with an outstandingly strong correlation.

[Clinical application of the modified wisconsin card sorting test to children with attention deficit/hyperactivity disorder].

The cases with attention deficit/hyperactivity disorder (AD/HD) are known to have difficulties in performing various neuropsychological tests related to the executive function. Among them, the Wisconsin Card Sorting Test (WCST) is already applied to many children with AD/HD. There are, however, differences in the measurement of WCST, and also in the background conditions of the patients, such as the status of medication and the level of Intelligence Quotient (IQ), and presumably as a result, the outcome of WCST shows a diversity. The Keio version WCST (KWCST) is a modified WCST by reducing the number of cards and presenting subjects in two steps separated by a short pause, during which a brief instruction is given. This study was undertaken to compare the performances of children with AD/HD to normal controls using KWCST according to full-scale IQ (FIQ) and also the subtypes of AD/HD. Subjects in this study were 21 unmedicated children with AD/HD, ranging from 5 to 15 years of age, and 21 normal controls who were matched on sex and age. Children with AD/HD whose FIQ was above 80 showed significant low scores in such indices as categories achieved (CA), total errors (TE) , and nonperseverative errors of Nelson (NPEN) in the second step. As to the analysis according to the subtypes, the predominantly inattentive type showed significant low scores in CA, TE and NPEN of the second step, while the combined and predominantly hyperactive-impulsive types showed no significant differences compared with the normal controls. These results suggest that patients with AD/HD have difficulties in effectively utilizing their experiences in the first step as well as instructions which are given before the second step, and also indicate the importance of the second step from a view of the clinical applications.

[Effect of development and aging on the modified Wisconsin Card Sorting Test in normal subjects].

The Wisconsin card sorting test (WCST) is applied to various types of neurological disorders. Since WCST requires the examinee's sustained efforts, it is not readily applicable to children with developmental disorders. In order to overcome this weakness, Keio version WCST (KWCST) was developed by reducing the number of cards from 128 to 48 and presenting them in two steps separated by a short pause. During which a brief instruction was given. This study was performed to clarify the changes with age in indices of KWCST and to obtain the normative value. Three hundred thirty five normal subjects, ranging from 5 to 82 years of age were examined. A simple regression analysis showed a significant age-related changes. Subjects between the middle thirties and the middle forties showed the best score in such indices as the categories achieved, perseverative errors of Nelson, difficulties of maintaining set, numbers of response cards until the first category achieved, and total errors. Most of the scores were improved in the second step across the all age groups, which might have resulted from learning during the first step and the instruction provided before the second step. KWCST can be performed briefly, and is suitable for cases with attention deficit/hyperactivity disorder and pervasive developmental disorder.