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Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, −0.57; 95% CI, −1.27 to 0.13; P = 0.023) and confirmatory trials (−0.41; −0.62 to −0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = −0.78; 95% CI, −1.21 to −0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = −0.46; 95% CI, −0.90 to −0.01) and 6 weeks (P = 0.10, Cohen’s d = −0.35; 95% CI, −0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = −1.24; 95% CI, −1.71 to −0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

Atypical eye gaze is an established clinical sign in the diagnosis of autism spectrum disorder (ASD). We propose a computerized diagnostic algorithm for ASD, applicable to children and adolescents aged between 5 and 17 years using Gazefinder, a system where a set of devices to capture eye gaze patterns and stimulus movie clips are equipped in a personal computer with a monitor. We enrolled 222 individuals aged 5–17 years at seven research facilities in Japan. Among them, we extracted 39 individuals with ASD without any comorbid neurodevelopmental abnormalities (ASD group), 102 typically developing individuals (TD group), and an independent sample of 24 individuals (the second control group). All participants underwent psychoneurological and diagnostic assessments, including the Autism Diagnostic Observation Schedule, second edition, and an examination with Gazefinder (2 min). To enhance the predictive validity, a best-fit diagnostic algorithm of computationally selected attributes originally extracted from Gazefinder was proposed. The inputs were classified automatically into either ASD or TD groups, based on the attribute values. We cross-validated the algorithm using the leave-one-out method in the ASD and TD groups and tested the predictability in the second control group. The best-fit algorithm showed an area under curve (AUC) of 0.84, and the sensitivity, specificity, and accuracy were 74, 80, and 78%, respectively. The AUC for the cross-validation was 0.74 and that for validation in the second control group was 0.91. We confirmed that the diagnostic performance of the best-fit algorithm is comparable to the diagnostic assessment tools for ASD.

This case–control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O2·−) and alkoxyl radical (RO·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ·OH, O2·−, and RO· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

Background Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. Methods We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18 years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0–5, 6–11, and 12–18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. Results In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10 years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. Limitations It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects’ age. Conclusions There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10 years.

Abnormalities of lipid metabolism contribute to ASD pathogenesis has been argued, but the mechanisms are not fully understood. We characterized the lipids metabolism in ASD children by lipidomics, and identified the dramatic alterations of 71 metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function. Identified fatty acids (FAs) indicated the correlations with clinical social interaction score of ASD diagnosis as well as lipoproteins-triglyceride concentrations in ASD. We also found the specific reduction of very-low-density lipoprotein (VLDL) in ASD, which showing correlations with a decrease of APOB concentrations in ASD. We further found a significant increase in APOJ known as a sensor for oxidative stress, demonstrating enhancing oxidative stress in ASD is due to VLDL-specific dyslipidemia. These results demonstrate the increases in FAs are due to VLDL-specific degradation, providing novel insights to uncover the mechanisms such as oxidative stress generations via mitochondrial dysfunction underlying ASD pathology. Funding Statement: This work was supported by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.M.; the Grant-in-Aid for Scientific Research on Innovative Areas (#21200014) from MEXT to H.M.; SENSHIN Medical Research Foundation to H.M. and N.U.; Hamamatsu Foundation for Science and Technology Promotion to H.M.; the Grant-in-Aid for Early-Career Scientists (18K14814) from the Japan Society for the Promotion of Science (JSPS) to N.U.; Takeda Science Foundation to H.M. and N.U.; The Osaka Medical Research Foundation for Intractable Diseases to N.U.; Research Grant for Public Health Science to N.U.; Eli Lilly Japan Research Grant to N.U.; the Grant for Life Cycle Medicine from Faculty of Medical Sciences, University of Fukui to N.U. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures were approved by the Ethics Committee of the University of Fukui and the Hamamatsu University School of Medicine, and were conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. All participants were given a complete description of the study and provided written informed consent from their parent and/or legal guardian before enrolled.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18–48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P

Background Previous research studies have assessed the relationship between attention to social information and peripheral (e.g., plasma and salivary) oxytocin (OT) levels in typically developing (TD) children and children with autism spectrum disorder (ASD). A relationship between them was observed in TD children, but not in children with ASD. However, this relationship remains unexamined in other age groups. To clarify whether this lack of association is maintained throughout development in individuals with ASD, we aimed to assess the relationship between salivary OT levels and attention to social information in adolescents and adults with and without ASD. Methods We recruited male adolescents and adults with ASD (n = 17) and TD participants (n = 24). Using the all-in-one eye-tracking system Gazefinder, we measured the percentage fixation time allocated to social information. We also measured the salivary OT levels and Autism Spectrum Quotient (AQ) of participants. Subsequently, we confirmed group differences and conducted a correlation analysis to investigate the relationships between these three measures. Results Salivary OT levels did not show any significant difference between the ASD and TD groups and were negatively correlated with the AQ in the whole-group analysis, but not in within-group analysis. Individuals with ASD had significantly lower percentage fixation times than did TD individuals for eye regions in human faces with/without mouth motion, for upright biological motion, and for people regions in the people and geometry movies. The percentage of fixation for geometric shapes in the people and geometry movies was significantly higher in the ASD than in the TD group. In the TD group, salivary OT levels were positively correlated with percentage fixation times for upright biological motion and people and negatively correlated with inverted biological motion and geometry. However, no significant correlations were found in the ASD group. Conclusions Our exploratory results suggest that salivary OT levels in adolescents and adults with ASD are less indicative of attention to social stimuli than they are in TD adolescents and adults. It is suggested that their association is slightly weaker in adolescents and adults with ASD and that this attenuated relationship appears to be maintained throughout development.

Atlantoaxial instability (AAI)/subluxation commonly occurs in small breed dogs. Ventral stabilization techniques using screws and/or pins and a plate or, more commonly, polymethylmethacrylate are considered to provide the most favorable outcome. However, the implantation of screws of sufficient sizes for long-term stability becomes challenging in toy breed dogs (e.g.

Spatial working memory (SWM) dysfunction is a feature of attention deficit hyperactivity disorder (ADHD). Previous studies suggested that behavioral performance in self-generated SWM improves through development in children with and without ADHD. Nevertheless, developmental changes in the neural underpinnings of self-generated SWM are unknown.Using near-infrared spectroscopy, hemodynamic activity in the prefrontal cortex (PFC) was measured in 30 children with ADHD (9.5 ± 1.6 years-old) and 35 TD children (9.0 ± 1.6 years-old) while they performed a self-generated SWM task. We then investigated correlations between age and behavioral performance, and between age and hemodynamic activity in the PFC for each group.Both groups showed a negative correlation with age and number of errors [ADHD: r(28)=-0.37, p=0.040; TD: r(33)=-0.59, p0.001], indicating that self-generated SWM improves through development. The TD group showed a positive correlation between age and oxygenated hemoglobin in the frontal pole [10ch: r(33)=0.41, p=0.013; 11ch; r(33)=0.44, p=0.008] and bilateral lateral PFC [4ch: r(33)=0.34, p=0.049; 13ch; r(33)=0.54, p=0.001], while no significant correlation was found in the ADHD group. Furthermore, regression slopes for the frontal pole significantly differed between the TD and ADHD groups [10ch: t(61)=2.35, p=0.021; 11ch: t(61)=2.05, p=0.044].Children with ADHD showed abnormalities in functional maturation of the frontal pole, which plays a role in manipulating and maintaining information associated with self-generated behavior.

Background Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. Methods An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. Findings Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. Interpretation Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. Funding This study was supported mainly by MEXT, Japan.

The introduction of laparoscopic surgery has also been beneficial for patients with gynecological malignancies. In this respect, surgeons should receive related training in the context of human resource development. Hands-on training was introduced using Thiel-embalmed human cadavers (THCs) in 2014. To determine the usefulness of THCs, they were evaluated in terms of tissue color, consistency and operative tactility, among others, compared with in vivo laparoscopic training for gynecological malignancies. Hands-on training sessions using THCs were held for a total of 11 times at Ehime University Graduate School of Medicine between March 2014 and October 2017. Training on THCs included advanced laparoscopic procedures for radical hysterectomy type III. At the end of each training session, data were collected using a standardized, anonymous questionnaire termed the Likert scale. THCs ensured flexibility and plasticity of tissues and organs; therefore, the working space was similar to that in the living body under pneumoperitoneum. After analyzing the quality and consistency of tissue and organ color compared with in vivo conditions, most of the participants agreed or strongly agreed regarding the uterus, adnexa and ureter, but not regarding the large blood vessels. The highest scores were observed in the authenticity of the anatomical condition of each organ. Most participants strongly agreed that training using THCs would help improve their laparoscopic skills with a high level of satisfaction. Furthermore, most participants reported that they would recommend this training to other obstetrician-gynecologists. Laparoscopic training for gynecological malignancies using THCs was comparable to the in vivo conditions in terms of surgical view and operative tactility. Therefore, THCs may be an excellent training tool for improving laparoscopic surgical skills for gynecological malignancies.

Introduction: Ovarian borderline clear cell tumor is a very rare tumor accounting for less than 1% of borderline ovarian tumors. Currently, only 30 cases of borderline clear cell tumors have been reported. This borderline ovarian clear cell tumor often arises from endometriosis. But there are no definitive guidelines for the management of endometriosis with malignant transformation due to a lack of understanding of the mechanistic details that mediate the transformation of endometriosis into ovarian cancer. Case: A 52-year-old woman (G2 P2) who periodically underwent ultraso-nography over the course of 12 years in order to follow the endometrioma present in her left ovary. The diameter of the lesion was 46 mm and it remained largely unchanged. However, a solid region within the ovarian cyst was detected. After the surgery, the final pathological diagnosis was cystic clear cell tumor of borderline malignancy. Conclusion: It reported that risk factors of malignant transformation are older age, postmenopausal status, and larger tumor diameters were associated with a higher prevalence of cancer development. But it is recommended that patients with endometriosis, regardless of patient age or tumor size, undergo careful monitoring to detect changes in growth or the formation of solid regions for as long as the lesion is present.

Objective: In this study, we evaluated the management of cervical intraepithelial neoplasia (CIN) in pregnant women and evaluated the postpartum prognosis. Methods: Twenty-four pregnant women, who were diagnosed with CIN at Ehime University Hospital between January 2008 and October 2012, were recruited. The mode of delivery and pathophysiological examination results in the postpartum period were evaluated. Results: Four patients were antenatally diagnosed with either CIN1 or CIN2. Of these patients, CIN regressed or remained stable during pregnancy, and there was no disease progression in the postpartum period. Nine patients were diagnosed with severe dysplasia (CIN3) and eleven patients had carcinoma in situ (CIS). Of these patients, 5/9 (55%) and 4/11 (36%), respectively, had disease regression postnatally. No CIN lesion progressed to invasive carcinoma after delivery. Conclusions: We determined that many cases diagnosed antenatally with CIN regressed during the postpartum period, regardless of the grade of CIN. We recommend a conservative management strategy with careful ante- and postpartum examinations for pregnant women with CIN.

A 9-year-old male mixed breed cat showed chronic progressive neurological symptoms, which are represented by ataxia and seizures. At necropsy, spinal roots and spinal ganglions at the level of sixth cervical nerve to second thoracic nerve were bilaterally swollen and replaced by white mass lesions. Right brachial plexus and cranial nerves (III, V and VII) were also swollen. A mass lesion was found in the right frontal lobe of the cerebrum. Histologically, neoplastic lymphocytes extensively involved the peripheral nerves, and they infiltrated into the cerebral and spinal parenchyma according to the peripheral nerve tract. Immunohistochemically, most neoplastic lymphocytes were positive for CD20. The clinical and histological features in this case resemble those of neurolymphomatosis in humans.

Objective This study was conducted to validate the Advanced Test of Attention (ATA) of the visual attention version of Japanese children with attention deficit/hyperactivity disorder (ADHD) and to evaluate the efficacy of methylphenidate (OROS-MPH) and atomoxetine medications. Methods To assess pharmacotherapy efficacy, the visual version of ATA was administered to 42 children with ADHD. Results were assessed using discriminant analysis, ANOVA for indices of ATA before and after medication treatment, and correlation analysis between the improvement of indices of ATA and clinical symptoms during medication treatment. Results Discriminant analysis showed that 69.0% of ADHD children were assigned correctly. The T score of commission errors increased as the trial progressed on the medication-off condition. T scores of commission errors and standard deviation of response times on medication-on condition were low compared to the medication-off condition. A few significant correlations were found between the improvements of indices of ATA and ADHD-Rating Scale (RS) during treatment. Conclusion The performance of the visual version of ATA on medication-off condition reflected the features of ADHD. Furthermore, the medication treatment effects were confirmed sufficiently. In addition, results suggest that indices of ATA reflected aspects of ADHD symptoms that are difficult to elucidate for ADHD-RS. For assessing symptoms and effects of medical treatment in children with ADHD, ATA might be a useful assessment tool.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalized weakness. It is caused by gene deletions or other mutations in the survival motor neuron 1 gene on chromosome 5q13. There are three types of SMA. Of these types, SMA type 1 (SMA1) is distinguished by the disease onset before 6 months of age and death within the first two years of life. We report a case study of a pregnant SMA1 gene carrier for whom a prenatal diagnosis was performed. The woman delivered a healthy baby, and she was free of anxiety due to the prenatal diagnosis. The case was a 34-year-old woman with a history of giving birth to children with SMA1(3 gravida 2 para). The first baby was diagnosed with SMA1 and died 9 months later. During her second pregnancy, the fetus was prenatally diagnosed with SMA1, and the parents chose to have an artificial abortion. In her third pregnancy, the fetus was prenatally diagnosed as a gene carrier of SMA1 and was delivered. During her fourth pregnancy, a prenatal diagnosis was performed using amniocentesis after genetic counseling, and the fetus was diagnosed as a gene carrier of SMA1. A 3.310 g female baby was delivered with Apgar scores of 9 at 1 minute and 9 at 5 minutes. When a prenatal diagnosis of SMA is performed, various guidelines should be followed, and the patient should be provided with genetic counseling.

Owing to progress in perinatal medicine, the survival of preterm newborns has markedly increased. However, the incidence of cerebral palsy has risen in association with increased preterm birth. Cerebral palsy is largely caused by cerebral hypoxic ischemia (HI), for which there are no effective medical treatments. We evaluated the effects of stromal cell-derived factor-1α (SDF-1α) on neonatal brain damage in rats. Left common carotid (LCC) arteries of seven-day-old Wistar rat pups were ligated, and animals were exposed to hypoxic gas to cause cerebral HI. Behavioral tests revealed that the memory and spatial perception abilities were disturbed in HI animals, and that SDF-1α treatment improved these cognitive functions. Motor coordination was also impaired after HI but was unimproved by SDF-1α treatment. SDF-1α reduced intracranial inflammation and induced cerebral remyelination, as indicated by the immunohistochemistry results. These data suggest that SDF-1α specifically influences spatial perception abilities in neonatal HI encephalopathy.

Multiple techniques have been used for the conservative treatment of high-grade cervical intraepithelial neoplasia (HG-CIN) in women of fertile age. Conization has been associated with stenosis of the cervix and a decrease in cervical mucus secretion, in addition to the increase in the risk of cervical canal shortening and problems during the perinatal period, including premature birth and premature rupture of membranes. Although the laser transpiration technique does not cause shortening of the cervical canal, it is associated with the recurrent risk of deep residual disease. The present study aimed to investigate the therapeutic safety and efficacy of the therapy performed using the transaction magnetic field induction heating device, AMTC400, in fertile patients with HG-CIN (excluding carcinoma in situ). Four premenopausal patients with CIN3 and high-risk human papilloma virus (HPV)-positive were treated using an AMTC400. Chronological colposcopic findings, high-risk HPV, final histological findings with conization and follow-up data were evaluated. All the treatments were successfully performed on the in-patients without anesthesia. Intra- and postoperative complications included minor pain and bleeding in all cases. Two of the cases (50%) were high-risk HPV-negative following the treatments. All cases exhibited a change in the observed color (to white), and subsequent epithelization following treatment. Although cytological analysis at 5 weeks following the treatment confirmed the cases were negative for intraepithelial lesions and malignancies, a definitive histology with conization 6 weeks following the treatment confirmed CIN1 and koilocytosis in all cases. The assessment of treatment effectiveness was determined as a moderate improvement in all cases. In conclusion, thermotherapy applied using AMTC400 represented a safe and effective treatment for HG-CIN in women of fertile age. However, additional improvements associated with the site of puncture needles are required. Further studies are required to confirm the long-term efficacy and reproductive outcomes.

The CD40 ligand (CD40L) is expressed by T cells and has a critical role in immune system regulation. Interventions targeting CD40L interactions following embryo implantation represent an approach to preventing preeclampsia (PE). To better understand the role of CD40L in PE, we developed a PE mouse model in which we examined how CD40L-induced immune activation affects embryo implantation. Blastocysts were incubated with CD40L-expressing adenovirus and then were transferred into the uterine horns of pseudopregnant ICR mice. Histology, biochemistry and flow cytometry experiments were performed to examine the characteristics of the mouse model. In early pregnancy, decidualization and spiral artery remodeling were reduced in CD40L-transfected mice (CD40L mice) compared with control mice. Hematoxylin-eosin (HE) staining revealed hemorrhaging and excess fibrin deposition at the labyrinth layer-junctional zone interface of the placenta, and PAS staining demonstrated prominent focal and segmental sclerosis with collapsed glomerular capillaries in the kidneys of the CD40L mice. Flow cytometry data showed that interferon-γ production derived from CD4(+) T cells was elevated in the splenic cells of CD40L mice. Blood pressure (measured by the tail-cuff method) and urine albumin concentrations were significantly increased in CD40L mice compared with control mice. Furthermore, the plasma concentrations of soluble Flt-1 and soluble endoglin were increased in CD40L mice, as occurs in human patients with PE. Thus, CD40L-induced T-helper cell type 1 differentiation during embryo implantation may have a critical role in the pathogenesis of a PE-like presentation in a novel mouse model of PE.

Anomalous junction of pancreaticobiliary duct (AJPBD) patients has an increased risk of gallbladder and bile duct carcinomas. However, the relevance of carcinoma with AJPBD is not fully clarified. We performed analysis of loss of heterozygosity (LOH) at p53 locus and immunohistochemistry of p53 and K-ras gene mutation in five cases of gallbladder carcinoma associated with AJPBD. LOH of p53 locus and overexpression of p53 were detected in two out of five (40%) and five out of five (100%), respectively, in the present study. K-ras gene mutation at codon 12 and 13 was not detected (0%, 0/5). These results suggest that aberrations of p53 are involved in carcinogenesis of gallbladder carcinoma associated with AJPBD. Next, in order to find the genetic events besides K-ras mutation and overexpression of mutant p53 in this disease, LOH analysis was performed using 72 microsatellite markers. High frequency of allelic loss (> 50%) was found on 2p (81.8%), 4p (50%), 4q (50%), 8q (60%), 9q (50%), 10p (50%), 14p (60%), 14q (50%), 16p (60%), 19p (50%), 21p (50%) and Xp (66.6%). The highest deletion regions on chromosome 2p24 (3/3, 100%), 14q22 (3/4, 75%) and 21q22 (3/4, 75%) were found. The present study suggests that gallbladder carcinoma associated with AJPBD has high frequent allelic loss and has two new regions which may harbor putative tumor suppressor genes.

Microsatellite instability (MI) has been detected in certain sporadic cancers as well as in hereditary non-polyposis colorectal cancer (HNPCC). In order to determine the precise clinicopathological characteristics of MI in endometrial cancer, we examined 90 sporadic endometrial cancers (83 endometrioid adenocarcinomas, 3 adenosquamous carcinomas, 3 papillary serous carcinomas, and 1 clear cell carcinoma) and eight lesions of endometrial hyperplasia for replication error (RER) using polymerase chain reaction amplification of CA repeated microsatellite sequences at 15 loci. RER was observed in 23 (28%) of the 83 endometrioid adenocarcinomas at at least one locus and in 19 (23%) at two or more loci (RER+ phenotype) in the seven most commonly observed loci, but not in carcinomas of other histological types or in endometrial hyperplasia. Lymphocyte infiltration around carcinoma cells, which is one of the histological features seen in tumors from HNPCC, was severer in RER+ phenotype tumors (79%, 11/14) than in the RER- tumors (25%, 11/44) (marked/moderate infiltration versus slight, P < 0.001, chi 2 test), when 58 tumors with muscular invasion were examined. The RER+ phenotype was associated with a higher parity and gravidity (P < 0.05, Wilcoxon test). However, RER+ phenotype was not associated with tumor stage, histological grade, muscular invasion, lymph node metastasis or patient survival. In conclusion, MI occurs in a subset of endometrial cancers, which often show marked infiltration of lymphocytes around the tumor.

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

The present study aimed to evaluate the efficacy and toxicities of nadaplatin-based concurrent chemoradiotherapy (CCRT) in patients with stage IIA to IVA cervical carcinoma. Patients with an International Federation of Gynecology and Obstetrics (FIGO) stage IIA to IVA cervical carcinoma were treated with nadaplatin-based CCRT, using high-dose rate intracavitary brachytherapy (HDR-ICBT) or radiotherapy (RT) alone, in patients with FIGO stage IIA to IVA cervical carcinoma. CCRT with nedaplatin (80 mg/m2) was administered on Days 1 and 29. The records of 17 women treated either with nadaplatin-based CCRT using HSR-ICBT (n=8) or RT alone (n=9), for stage IIA to IVA cervical carcinoma were retrospectively reviewed. The activity and toxicity were compared in the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. The 5-year overall survival rates in the CCRT and RT groups were 68.6 and 77.8%, respectively. The median OS of the CCRT and RT groups was 38.5 and 27.3 months, respectively. There was no significant difference in either PFS (P=0.618) or OS (P= 0.231). The most common grade 3–4 or higher toxicities in the CCRT groups were leuko-/neutropenia (37.5%). The frequency of acute grade 3–4 toxicity was higher in the CCRT compared to the RT group. However, no statistically significant difference was observed. Nedaplatin-based CCRT was safely performed. Although the prognosis of patients with FIGO stage IIA to IVA cervical carcinoma was not significantly improved, fewer distant relapses were observed in this treatment. Consequently, nedaplatin-based CCRT may be considered as a potential alternative to cisplatin-based CCRT in this patient population.

The cloaca is a single canal from which the urinary, genital, and intestinal tracts arise around gestational weeks 5-6. Persistent cloaca can result from cystic mass formation within the pelvis, which is commonly association with multiple developmental defects. VATER association, which is a spectrum of anomalies, manifested by vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, and renal dysplasia, arises from abnormalities in mesodermal differentiation. Recently, both conditions have been proposed to represent a continuous spectrum of anomalies, but the pathophysiology concerning the continuity of the development and the clinical condition are still unclear. Since renal failure becomes a serious problem after birth, timely infant delivery is essential to avoid loss of renal function. We report a patient, in whom the overlap between these two conditions was identified, and renal function was lost from one kidney. A polycystic mass was found in the fetal abdomen at 26 weeks of gestation. By ultrasonography, we detected a polycystic left kidney, a single umbilical artery, a ventricular septal defect, an esophageal atresia, ascites, an anal atresia, and a cystic mass with debris behind the bladder. The left kidney was non-functioning and the right kidney showed signs of hydronephrosis at 30 weeks of gestation. We measured the size and the blood flow of renal artery sequentially, and could deliver the fetus before the function was lost from the right kidney. Our observations will help inform future patients where prompt intervention can help improve renal function and infant health.

Wunderlich syndrome is a rare Mullerian anomaly consisting of uterine didelphy, cervical cyst, and ipsilateral renal agenesis [1]. It is likely that the malformations occur from embryonic arrest at 8 weeks of gestation, at which point the adjacent Mullerian and metanephric ducts are simultaneously affected. This anomaly inhibits the outflow of menstruation and causes menstrual blood to pool in the uterus; however, it is often asymptomatic anddifficult to diagnose [2]. A healthy 15-year-old female who had experienced normal pubertal events underwent menarche. Three months after menarche, she complained of lower abdominal pain, especially after menstruation. She was of moderate stature, with normal external genitalia, and a regular menstrual cycle. She was diagnosed by magnetic resonance imaging (MRI) as having a double uterus with a right cervical cyst (Fig. 1). Intravenous pyelography demonstrated right renal agenesis with normal function and contour of the left renal collecting system (Fig. 1). The left cervix was intact and the right cystic wall was resected using an ultrasonic cutting and coagulating surgical device (Harmonic scalpel; Johnson & Johnson, New Brunswick, NJ, USA). She was diagnosed with Wunderlich syndrome since the resected tissue demonstrated cervical glands. The postoperative course was uneventful. A healthy 18-year-old female complained of intermittent purulent vaginal discharge since menarche. She underwent menarche at the age of 12 years and experienced normal pubertal events. She had a history of regular menses with increasing lower abdominal pain lasting 2–4 days during each menstrual cycle. She was ofmoderate stature with normal external genitalia. Abdominal ultrasonography demonstrated a small pelvic cystic mass; MRI demonstrated uterus didelphys with a left cervical cyst containing homogeneous fluid compatible with old blood. Intravenous pyelography demonstrated left renal agenesis. The left cystic wall was resectedusinganultrasonic cutting andcoagulating surgical device, andWunderlich syndromewas diagnosed. The postoperative period was uneventful. Hematocervix of Wunderlich syndrome is diagnosed when the ipsilateral hemiuterus and vagina are not connected. Differential diagnosis includes Herlyn–Werner syndrome, which consists of a renal agenesis and an ipsilateral blind hemivagina [3]. Gartner's cysts of Herlyn–Werner syndrome can be pathologically differentiated from cervical cysts of Wunderlich syndrome. A Gartner's cyst is a cystic remnant of the mesonephric ducts in the vaginal wall, while a cervical cyst demonstrates cervical glands. Common clinical presentations of both Herlyn–Werner syndrome and Wunderlich syndrome are pelvic pain and/or dysmenorrhea shortly after menarche, in association with a vaginal/pelvic mass. When the cyst and vagina are connected, symptoms of abnormal vaginal discharge and bleeding are common. Abdominal and pelvic MRI studies are necessary to confirm and characterize thedetails of uterinemalformation and renal anomaly. Treatment is to resect as much of the obstructing vaginal septum as possible. Errors in surgical management can occur when the diagnosis is incorrect, and laparotomy is performed to explore and resect the intra-abdominal mass. Although fertility is not compromised, spontaneous abortion rate is high. However, patients who carry pregnancy to term often have no obstetric difficulties. Prompt and accurate diagnosis, and subsequent excision of the obstructing vaginal septum, is required in patients with ⁎ Corresponding author. Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791 0295, Japan. Tel.: +81 89 960 5379; fax: +81 89 960 5381. E-mail address: takeyu@m.ehime-u.ac.jp (Y. Matsubara).

Protein expression levels of E-cadherin and beta-catenin were examined in 39 primary and 10 metastatic ovarian carcinoma to elucidate the role of these molecules in the extension of ovarian carcinoma by immunohistochemistry. Twenty-two of 39 (56%) ovarian carcinomas were preserved type and 17 of 39 (44%) were reduced type of E-cadherin. In contrast, 36 of 39 (92%) ovarian carcinomas were preserved type and 3 of 39 (8%) were reduced type of beta-catenin. E-cadherin expression in well-differentiated carcinoma was higher than that in moderately/poorly-differentiated carcinoma (p

Recently case reports about latex allergy were increased. We have experienced severe latex allergy in a pregnant women after vaginal examination with a latex glove. A 33-year-old woman, 38 weeks pregenant, was hospitalized for management of fetal IUGR. She underwent a vaginal examination with a latex glove and soon developed severe anaphylactic reactions. Although two hours later her condition had remarkably improved, regular uterine contractions appeared, and fetal cardiotocogram showed late decelerations. So emergency cesarean section was performed under the situation without using any latex products. She delivered a male infant weighing 2,227 g (–2.21 SD) at 38 weeks gestation. His Apgar score was 5 points at 1 min and 8 points at 5 min. The latex-specific IgE of this patient was high and IgE for banana, avocado and kiwi were also positive. These foods showed cross-reactions with latex, but she had no history of allergic reactions against these foods. She had a history of atopic reactions and of atopic dermatitis while working as a nurse at the ICU. It is thought that this patient was in the high-risk group.

Highlights • We herein report a case of a 44-year-old Japanese woman diagnosed with stage IB1 atypical carcinoid of the uterine cervix. • After radical hysterectomy, she developed recurrence with aggressive clinical behavior, resistance to CPT-11 + cisplatin and paclitaxel + CBDCA chemotherapy.

Background The prevalence of autism spectrum disorders (ASDs) is higher in men than in women. The extreme male brain theory proposes that excessive prenatal testosterone activity could be a risk factor for ASDs. However, it is unclear whether prenatal sex hormone activity is a risk factor for women. The ratio of the length of the second to fourth digits (2D:4D) is considered to be a biomarker of the prenatal ratio of testosterone to estrogen. Therefore, this study compared the 2D:4D ratios of women with and without ASDs to determine if prenatal sex hormone activity could be a risk factor for ASDs in women. Methods The study included 35 Japanese men with ASDs, 17 Japanese women with ASDs, 59 typically developed (TD) Japanese men, and 57 TD Japanese women. We measured digit lengths and compared the 2D:4D ratios among the four groups. We also examined the relationship between the 2D:4D ratio and the autism-spectrum quotient score of each group. Results In our cohort, men with ASDs tended to have lower right-hand 2D:4D ratios relative to TD men. In contrast, the right 2D:4D ratios in women with ASDs were higher compared to those of TD women. No significant correlations were found between the 2D:4D ratios and the autism-spectrum quotient scores in any group. The higher right 2D:4D ratios in women could not be explained by age or full-scale intelligent quotients. This group difference was not found for the left 2D:4D or right–left 2D:4D ratios. Conclusions We found a reverse direction of abnormality in the right 2D:4D ratio for men and women with ASDs. It has been posited that high prenatal testosterone levels lead to a lower 2D:4D ratio. However, a recent animal study showed that testosterone injection to dam leads to a higher right 2D:4D ratio especially for female offspring, which might be mediated by abnormal adipose accumulation in the fingertip. Therefore, the present findings suggest that high prenatal testosterone could be a risk factor both for Japanese men and women with ASDs, elucidating one potential etiology of ASDs in women.

Background Gaze abnormality is a diagnostic criterion for autism spectrum disorder (ASD). However, few easy-to-use clinical tools exist to evaluate the unique eye-gaze patterns of ASD. Recently, we developed Gazefinder, an all-in-one eye-tracking system for early detection of ASD in toddlers. Because abnormal gaze patterns have been documented in various ASD age groups, we predicted that Gazefinder might also detect gaze abnormality in adolescents and adults. In this study, we tested whether Gazefinder could identify unique gaze patterns in adolescents and adults with ASD. Methods We measured the percentage of eye fixation time allocated to particular objects depicted in movies (i.e., eyes and mouth in human face movies, upright and inverted biological motion in movies that presented these stimuli simultaneously, and people and geometry in movies that presented these stimuli simultaneously) by male adolescents and adults with ASD (N = 26) and age-matched males with typical development (TD; N = 35). We compared these percentages between the two groups (ASD and TD) and with scores on the social responsiveness scale (SRS). Further, we conducted discriminant analyses to determine if fixation times allocated to particular objects could be used to discriminate between individuals with and without ASD. Results Compared with the TD group, the ASD group showed significantly less fixation time at locations of salient social information (i.e., eyes in the movie of human faces without lip movement and people in the movie of people and geometry), while there were no significant groupwise differences in the responses to movies of human faces with lip movement or biological motion. In a within-group correlation analysis, a few of the fixation-time items correlated with SRS, although most of them did not. No items significantly correlated with SRS in both ASD and TD groups. The percentage fixation times to eyes and people, which exhibited large effect sizes for the group difference, could differentiate ASD and TD with a sensitivity of 81.0 % and a specificity of 80.0 %. Conclusions These findings suggest that Gazefinder is potentially a valuable and easy-to-use tool for objectively measuring unique gaze patterns and discriminating between ASD and TD in male adolescents and adults. Electronic supplementary material The online version of this article (doi:10.1186/s13229-016-0083-y) contains supplementary material, which is available to authorized users.