Study on oxidative stress and inflammatory/antioxidant substance levels in autism spectrum disorder.

BACKGROUND: The etiology of autism spectrum disorder (ASD) includes oxidative stress and brain inflammation. We investigated the relationship among oxidative stress markers, in vivo inflammatory substances, and antioxidants that can be easily measured in the clinic and compared them between children with ASD and those with typical development (TD). METHODS: Sixty-one children with TD and 199 with untreated ASD were investigated. They were Japanese children aged 2-15 years and were divided into those aged <7 and ≥7 years. Serum levels of reactive oxygen metabolites (ROMs), high-sensitivity C-reactive protein (hsCRP), prolactin (PRL), albumin (Alb), total bilirubin (T-Bil), and uric acid (UA) were measured. These measurements were compared between TD and ASD, and the relationship between oxidative stress and relevant laboratory parameters was analyzed. RESULTS: The hsCRP and PRL levels were significantly higher in patients with ASD than in those with TD. Among those aged <7 years, hsCRP and PRL were significantly higher in those with ASD than in those with TD. Among those aged ≥7 years, ROMs, hsCRP, and PRL were significantly higher in those with ASD than in those with TD. In ASD, ROMs were significantly correlated with hsCRP, Alb, T-Bil, and PRL. In contrast, no significant correlations were found in the TD group except for the relationship between ROMs and hsCRP in those aged <7 years. CONCLUSION: The results suggest that serum levels of in vivo inflammatory substances, stress-related substances, and antioxidants are altered in ASD under oxidative stress.

Three cases in which drug-induced hyponatremia was improved by replacing carbamazepine with lacosamide.

Carbamazepine often causes drug-induced hyponatremia. Hyponatremia due to carbamazepine may be improved by changing to the same mechanism of action, lacosamide.

Assessment of oxidative stress in autism spectrum disorder using reactive oxygen metabolites and biological antioxidant potential.

There are several studies on oxidative stress of Autism Spectrum Disorder (ASD), but in these cases there is no study to measure oxidative stress and antioxidant capacity at the same time or studies considering childhood development. Therefore, this study comprehensively assessed the level of oxidative stress in ASD children by simultaneously measuring reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP). The subjects were Japanese, 77 typical development (TD) children, 98 ASD children, samples were plasma. The subjects were divided into age groups: toddlers/preschool age (2-6 years) and school age (7-15 years), to compare the relationships among the d-ROMs levels and BAP/d-ROMs ratios. Furthermore, the correlations between the Parent-interview ASD Rating Scales (PARS) scores and the measured values were analyzed. The levels of d-ROMs were significantly higher in the ASD (7-15 years) than in TD (7-15 years). The PARS scores were significantly higher in the ASD and were significantly correlated with d-ROMs levels. These results suggested that d-ROMs and BAP/d-ROMs ratios could be objective, measured indicators that could be used in clinical practice to assess stress in ASD children.

Evaluation of the efficacy of drug treatment based on measurement of the oxidative stress, using reactive oxygen metabolites and biological antioxidant potential, in children with autism spectrum disorder and attention deficit hyperactivity disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, mainly characterized by impairment of social communication and restricted interests. ASD is frequently accompanied by attention deficit hyperactivity disorder (ADHD), which is characterized by carelessness, hyperactivity and impulsivity (ASD/ADHD). It has been suggested that ASD and ADHD are associated with oxidative stress, that is, that patients with ASD/ADHD are in a state of increased oxidative stress. There are currenr tly no objective or biological test criteria for evaluating the efficacy of drug therapy in these patients. The purpose of this study was to evaluate whether oxidative stress markers [serum reactive oxygen metabolites (d-ROMs) levels and biological antioxidant potential (BAP)] can be used as objective indicators for evaluating the efficacy of drug treatment in ASD/ADHD patients. METHODS: The subjects of this study subjects were 50 Japanese patients with ASD/ADHD aged 4 to 14 years old. Serum samples were obtained from the patients to measure the serum levels of d-ROMs and the serum BAP. The study subjects were divided into two age groups: preschool children (4 to 6 years old) and school-age children (7 to 14 years old), and the serum levels of d-ROMs, serum BAP, serum BAP/d-ROMs ratio (hereinafter, the prefix serum will be dropped), and scores on the Parent-interview ASD Rating Scales-Text Revision (PARS-TR) and ADHD Rating Scale (ADHD-RS) were determined before and after drug therapy and compared between the two groups. In addition, changes in the d-ROMs, BAP and BAP/d-ROMs ratio and changes in the scores on the PARS-TR and ADHD-RS after treatment were also analyzed. RESULTS: Significant decrease of the d-ROMs, BAP, and scores on the PARS-TR and ADHD-RS, with a significant increase of the BAP/d-ROMs ratio, was observed after treatment. In addition, a significant correlation was observed between the changes in the d-ROMs and changes in the scores on the PARS-TR and ADHD-RS after treatment in the school-age ASD/ADHD children. CONCLUSION: Our results suggest the possibility that the serum level of d-ROMs may be useful as an objective assessment marker to supplement the subjective assessment of the effects of drug treatment in school-age children with ASD/ADHD.

S-1 and CPT-11 Plus Ramucirumab (IRIS+Rmab) as Second-Line Chemotherapy for Patients with Oxaliplatin-Refractory Metastatic Colorectal Cancer (mCRC): A Multicenter Phase II Study in Japan (N-DOCC-F-C-1701).

This multicenter phase II N-DOCC-F-C-1701 trial is being planned in order to investigate the efficacy and safety of CPT-11+S-1 +Ramucirumab (IRIS+Rmab), which is anticipated to have a stronger anti-tumor effect than IRIS+Bmab in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (L-OHP) containing regimen, in consideration of the result of RAISE, FIRIS and some phase II trials of IRIS+Bevacicizumab (Bmab). The number of patients is set at 38 for the statistical analysis, assuming an expected median PFS of 5.0 months (threshold: 3.0 months). The primary endpoint of the study is the progression free survival (PFS), and the secondary endpoints are the overall response rate (ORR), overall survival (OS), adverse events (AE), quality of life (QOL) and review of nausea and vomiting. This trial is registered in the UMIN Clinical Trials Registry as UMIN000028170. We intend to start conducting the trial in September 1, 2017. If this trial meets the endpoint, IRIS+Rmab might be supported as a new optional standard regimen for mCRC.

Evaluation of oxidative stress and antioxidant capacity in healthy children.

BACKGROUND: Measurement of the levels of the derivatives of reactive oxygen metabolites (d-ROMs) and of the biological antioxidant potential (BAP) enables simultaneous assessment of oxidation degree and antioxidant capacity, using the same sample and testing equipment. At present, reference values of healthy adults are clarified, but the reference value of healthy children is unknown. This study was undertaken to clarify the age-related changes and the reference values of d-ROMs and BAP in healthy children. METHODS: The study population consisted of 77 children, ranging in age from 2 to 15 years, in normal mental and physical health as examined by a pediatrician, and seven healthy adult volunteers. Serum samples were obtained from the subjects for assay. Using these samples, d-ROMs and BAP values were measured, and the relationship with age was analyzed. RESULTS: The d-ROMs level decreased as the age increased, while the BAP showed no correlation with the age. The d-ROMs level was significantly higher in 2-6 years group than in 7-11 years group, 12-15 years group, or healthy adults group. The BAP/d-ROMs ratio, an index of antioxidant capacity, increased significantly with higher age. CONCLUSION: This study was carried out for the first time in healthy children in oxidative stress assessment using d-ROMs and BAP. In the infancy 2-6 years, the d-ROMs value was significantly higher and the BAP/d-ROMs ratio was significantly lower. From this, it was suggested that age should be considered when performing oxidative stress assessment using d-ROMs and BAP in children.

Impact of Oxidative Stress and Newer Antiepileptic Drugs on the Albumin and Cortisol Value in Severe Motor and Intellectual Disabilities With Epilepsy.

BACKGROUND: Epilepsy is a common complication in patients with severe motor and intellectual disabilities (SMID). There are no reports as yet of the effects of these medications in vivo other than their epileptic efficacy. The purpose of this study was to clarify the effects of the newer antiepileptic drugs (AEDs) on the blood biochemical parameters and oxidative stress in SMID with epilepsy by comparing the therapeutic effects between a group of patients receiving lamotrigine (LTG) and levetiracetam (LEV) in addition to the conventional AEDs (newer AED group) and a group receiving conventional AEDs alone (old AED group). METHODS: The study population consisted of 44 SMID patients with epilepsy, of which 23 were allocated to the newer AED group and 21 were allocated to the old AED group. In the newer AED group, measurements of the reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP) and serum albumin were carried out at the following two time points: 1 week before and 1 year after the start of administration of the newer AEDs. In the old AED group, measurements of the same variables were performed at two time points 1 year apart. RESULTS: A significant decrease of the d-ROM levels and a significant increase of the BAP were noted in the newer AED group. A significant elevation of the serum albumin was also evident. In the old AED group, a significant increase of the d-ROMs levels was noted at the second measurement. Cortisol levels which have been described to be related to the albumin, revealed a significant decrease of the serum cortisol in relation to elevation of serum albumin in the newer AED group. CONCLUSIONS: The present study results suggest that the addition of newer AEDs reduces the oxidative stress load and improves the antioxidant potential of the body. Furthermore, the present data also demonstrate that the newer AEDs have indirect impact on biological parameters.

A study of oxidative stress and the newer antiepileptic drugs in epilepsy associated with severe motor and intellectual disabilities.

BACKGROUND: Patients with severe motor and intellectual disabilities (SMID) are those who have both severe intellectual disabilities and severe physical disabilities. Intractable epilepsy is often associated with SMID. The purpose of this study was to elucidate the relationship between epilepsy associated with SMID and oxidative stress, and to clarify the safety and efficacy of the newer antiepileptic drugs (newer AEDs), lamotrigine and levetiracetam. METHODS: This study was conducted in 27 SMID patients with epilepsy who were treated with the newer AEDs. The patient characteristics and the safety and efficacy of the newer AEDs were investigated. The reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP) levels were measured as indicators of the degree of oxidative stress. The relationship between the investigation results (the patient characteristics, and the safety and efficacy of the newer AEDs) and the results of measurements of the d-ROMs/BAP were analyzed. RESULTS: All the patients who discontinued the newer AEDs had abnormal plasma d-ROM levels. In addition, all the patients who developed adverse events also had abnormal d-ROM levels. Furthermore, there was a trend toward a lower response rate in patients with higher plasma d-ROM levels. CONCLUSION: The results of this study suggested that d-ROM levels are useful for predicting the safety and efficacy of the newer AEDs (lamotrigine, levetiracetam) in SMID patients with intractable epilepsy. Therefore, d-ROMs could be important biomarkers for determining the safety and efficacy of drug therapy in SMID patients with epilepsy.

Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities.

BACKGROUND: The medical care of severe motor and intellectual disabilities (SMID) depends on the empirical medical care. Epileptic seizure specific to SMID is difficult to suppress using anti-epileptic drugs, and its tendency to persist for long periods poses an issue. The present study was undertaken to evaluate the relationship between epileptic seizure in cases with SMID and oxidative stress in the living body by examining endogenous antioxidants, the degree of oxidation (reactive oxygen metabolites (d-ROMs)), and the biological antioxidant potential (BAP) as indicators. METHODS: Target patients were 43 SMID epilepsy patients. Blood was sampled before breakfast and medication. As for the specimen, d-ROMs and BAP were measured using the free radical analyzer. RESULTS: The present study did not reveal any correlation between endogenous antioxidants (albumin) and the frequency of epileptic seizures. On the other hand, d-ROMs were correlated with the frequency of epileptic seizure. In particular, strong correlations between the frequency of epileptic seizures and the d-ROMs/BAP ratio as well as the BAP/d-ROMs ratio were noted. CONCLUSIONS: These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID.

Fabrication of a magnesium alloy with excellent ductility for biodegradable clips.

To develop a biodegradable clip, the equivalent plastic strain distribution during occlusion was evaluated by the finite element analysis (FEA) using the material data of pure Mg. Since the FEA suggested that a maximum plastic strain of 0.40 is required to allow the Mg clips, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed here by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Small gas cavity due to degradation was observed following implantation of the developed Mg-Zn-Ca clip by in vivo micro-CT. Histological analysis, minimal observed inflammation, and an only small decrease in the volume of the implanted Mg-Zn-Ca clip confirmed its excellent biocompatibility. FEA using the material data for ductile Mg-Zn-Ca also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg-Zn-Ca alloy. These results suggest that the developed Mg-Zn-Ca alloy is a suitable material for biodegradable clips. STATEMENT OF SIGNIFICANCE: Since conventional magnesium alloys have not exhibited significant ductility for applying the occlusion of vessels, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Finite element analysis using the material data for the ductile Mg-Zn-Ca alloy also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg-Zn-Ca alloy.

A FRMD7 variant in a Japanese family causes congenital nystagmus.

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.

[Successful treatment of epilepsy and circadian rhythm disturbance with levetiracetam in a patient with dentatorubral-pallidoluysian atrophy (DRPLA)].

We report a 21-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA) showing progressive myoclonus epilepsy (PME), who responded to levetiracetam (LEV) at an initial dose of 1,000 mg/day. The patient developed epilepsy at the age of 10 years, and also showed intellectual regression. Various antiepileptic drugs showed no effects on generalized tonic seizures, tonic-clonic seizures, and myoclonus. Addition of LEV (1,000 mg/day) led to the reduction of myoclonus and tonic-clonic seizures, and improved the EEG and sleep-wake rhythm. He had a better appetite and gain weight. It is suggested that LEV may improve quality of life in patients with DRPLA, in addition to reducing the frequency of epileptic seizures.

Cyclin I is involved in the regulation of cell cycle progression.

Cyclins control cell cycle progression by regulating the activity of cyclin-dependent kinases (Cdks). Cyclin I is a member of the cyclin family because of the presence of a cyclin box motif. It has been suggested that Cyclin I is involved in various biological processes, such as cell survival, angiogenesis, and cell differentiation. However, whether or not Cyclin I has a role in regulating the cell cycle similarly to other cyclins has yet to be clarified. Therefore, we investigated the role for Cyclin I in cell cycle progression. We showed that the protein level of Cyclin I oscillated during the cell cycle, and that Cyclin I was subjected to ubiquitination and degradation in cells. The interaction between Cyclin I and Cdk5 was detected in cells overexpressed with both proteins. Furthermore, depletion of Cyclin I by siRNAs prevented cell proliferation, suggesting the positive role of Cyclin I for the cell cycle progression. In addition, flow cytometric analysis revealed that cells depleted of Cyclin I were accumulated at G2/M phases. By using HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we further confirmed that knockdown of Cyclin I induced cell cycle arrest at S/G2/M phases. These results strongly suggest that Cyclin I has the role in the regulation of cell cycle progression.

Developmental changes in facial expression recognition in Japanese school-age children.

PURPOSE: Facial expressions hold abundant information and play a central part in communication. In daily life, we must construct amicable interpersonal relationships by communicating through verbal and nonverbal behaviors. While school-age is a period of rapid social growth, few studies exist that study developmental changes in facial expression recognition during this age. This study investigated developmental changes in facial expression recognition by examining observers' gaze on others' expressions. SUBJECTS: 87 school-age children from first to sixth grade (41 boys, 46 girls). METHOD: The Tobii T60 Eye-tracker(Tobii Technologies, Sweden) was used to gauge eye movement during a task of matching pre-instructed emotion words and facial expressions images (neutral, angry, happy, surprised, sad, disgusted) presented on a monitor fixed at a distance of 50 cm. RESULTS: In the task of matching the six facial expression images and emotion words, the mid- and higher-grade children answered more accurately than the lower-grade children in matching four expressions, excluding neutral and happy. For fixation time and fixation count, the lower-grade children scored lower than other grade children, gazing on all facial expressions significantly fewer times and for shorter periods. CONCLUSION: It is guessed that the stage from lower grades to middle grades is a turning point in facial recognition.

X-linked inhibitor of apoptosis protein mediates neddylation by itself but does not function as a NEDD8-E3 ligase for caspase-7.

X-linked inhibitor of apoptosis protein (XIAP) is a potent antagonist of caspases, and functions as a ubiquitin-E3 ligase by itself and for caspases. Recently, NEDD8, a ubiquitin-like modifier, has been suggested to be used for modification of caspase-7 mediated by XIAP. However, it is not clear whether caspase-7 is a bona fide target for NEDD8. Here we showed that no neddylation of caspase-7 but that of XIAP itself was observed under the conditions in which caspase-7 was modified with ubiquitin. These results reveal that XIAP does not function as a NEDD8-E3 ligase for caspase-7 in vivo.

Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study.

PURPOSE: To evaluate the GABA(A) receptor in the autistic brain, we performed (123)I-IMZ SPECT in patients with ASD. We compared (123)I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. SUBJECTS AND METHODS: The subjects consisted of 24 patients with ASD (mean age, 7.3±3.5 years), including 9 with autistic disorder (mean age, 7.0±3.7 years) and 15 with Asperger's disorder (mean age, 7.5±3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8±3.6 years) without intellectual delay as a control group. For an objective evaluation of the (123)I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. RESULTS: In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of (123)I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. CONCLUSION: The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of (123)I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).

Contribution of caspase(s) to the cell cycle regulation at mitotic phase.

Caspases have been suggested to contribute to not only apoptosis regulation but also non-apoptotic cellular phenomena. Recently, we have reported the involvement of caspase-7 to the cell cycle progression at mitotic phase by knockdown of caspase-7 using small interfering RNAs and short hairpin RNA. Here we showed that chemically synthesized broad-spectrum caspase inhibitors, which have been used to suppress apoptosis, prevented the cell proliferation in a dose-dependent manner, and that the subtype-specific peptide-based caspase inhibitor for caspase-3 and -7, but not for caspase-9, inhibited cell proliferation. It was also indicated that the BIR2 domain of X-linked inhibitor of apoptosis protein, functioning as an inhibitor for caspase-3 and -7, but not the BIR3 domain which plays as a caspase-9 inhibitor, induced cell cycle arrest. Furthermore, flow cytometry revealed that the cells treated with caspase inhibitors arrested at G(2)/M phase. By using HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, the prevention of the cell proliferation by caspase inhibitors induced cell cycle arrest at mitotic phase accompanying the accumulation of the substrates for APC/C, suggesting the impairment of the APC/C activity at the transition from M to G(1) phases. These results indicate that caspase(s) contribute to the cell cycle regulation at mitotic phase.

Simultaneous laparoscopic hand-assisted hepatectomy and splenectomy for liver cancer with hypersplenism: report of a case.

Hepatocellular carcinoma accompanied by portal hypertension and hypersplenism is difficult to treat medically and surgically due to pancytopenia and the development of collateral circulation. In this study, we were able to safely and simultaneously perform a laparoscopically-assisted splenectomy and partial hepatectomy. The characteristics of this procedure include: (1) the shared use of a medial wound made through laparoscopically-assisted surgery; (2) improved safety for manipulating areas that were difficult to observe with a camera in a case of splenomegaly; (3) a preventive ligation of the splenic artery; (4) improved hemostatic function using LigaSure Impact; and (5) hemorrhage control through manual manipulations and the Pringle maneuver during liver parenchymal transection. The surgery was safely performed using the above points.

Head circumference and body growth in autism spectrum disorders.

Research has shown that there is a relationship between increased head circumference and autism spectrum disorders (ASD). This study examined this relationship during the first year of life in subjects with ASD. We compared 280 children with ASD and 609 controls. In the ASD-male group, increases were observed in head circumference from 3 to 12months, in height from 3 to 9months, and in body weight from 3 to 6 and 12months. On the other hand, in the ASD-female group increases in head circumference, in body height, and in body weight were only observed at 3months. After adjusting for height, weight, and age, only the head circumference in the male ASD group was significantly increased from 6 to 9months after birth, reaching a peak at 6months after birth. No difference was found in the female ASD group. Although body overgrowth in the ASD group also started early after birth, the increase in head circumference was more marked than that in body growth. The values of physical measurements in the first year may be useful, minimally invasive parameters for the early detection of autism in combination with observing the timing of certain behaviors such as smiling, eye contact, crawling, pointing, and joint attention.

The characteristics of AD/HD symptoms, self-esteem, and aggression among serious juvenile offenders in Japan.

Eighty-three inmates of a correctional facility, who committed serious offences, participated in this study. They were all male and aged 14-17 years, with a mean age of 15.5 (SD=1.21) years. Eighty-six age- and sex-matched controls were enrolled. Some psychological questionnaires such as on self-esteem and aggression were conducted in both groups. The aims of the present study were as follows: first, to clarify the characteristics of the subjects, such as IQ, psychological traits, and AD/HD symptoms; second, to examine how the subjects' self-esteem and aggression changed and/or improved on admission and at the time of parole (during the correctional educational period). For the results of paired t-tests, the self-esteem of subjects changed little. Therefore, our findings suggest that the improvement of antisocial behavior and transition of self-esteem are not directly linked with each other. Most inmates of the correctional facility showed a borderline IQ, markedly low self-esteem, unstable aggression, and serious AD/HD symptoms. In addition, the low self-esteem of subjects was not consistently elevated during the correctional education period. Moreover, their aggression was strongly correlated with AD/HD symptoms, both on admission and at the time of parole.