Tiny Hydatidiform Mole Presenting As Pregnancy of Unknown Location.

Pregnancy of unknown location (PUL) is a condition in which a pregnancy test, such as elevation of serum or urine ß-human chorionic gonadotrophin (hCG) level, is rendered positive; however, intrauterine or extrauterine pregnancy cannot be confirmed by transvaginal sonography (TVS). Diagnostic dilation and curettage (D&C) or laparoscopy may be performed to search for the pregnancy location. We experienced a case of PUL in which D&C was performed and histological examination revealed a tiny complete hydatidiform mole within the uterine contents. A retrospective review of the clinical course of this case, such as the evaluation of serum ß-hCG levels and TVS findings, suggested that this medical entity could be explained by a tiny hydatidiform mole. In PUL, during D&C, when abnormal villi are detected, even if the lesion is tiny, a suspicion of a hydatidiform mole should be considered by the pathologists, and immunostaining and/or chromosome testing/molecular genotyping should be subsequently performed. Whether a tiny hydatidiform mole poses a risk of persistent gestational trophoblastic disease requires further study based on the accumulation of cases. D&C for PUL patients may be a useful procedure to determine such diagnoses and pick up cases.

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

A Recurrent Mucinous Neoplasm Originating From an Ovarian Mucinous Cystadenoma After an Adnexectomy As the First Procedure: A Case Report.

Ovarian mucinous cystadenomas are benign, but they can rarely recur if incompletely excised. We are the very first to report a case of recurrent mucinous neoplasm originating from an ovarian mucinous cystadenoma after adnexectomy as the first procedure. A 58-year-old woman was referred to our hospital with a two-year history of abdominal fullness. Magnetic resonance imaging (MRI) demonstrated a pelvi-abdominal cyst measuring 37 cm, without solid components within the cyst. A laparotomy revealed a huge cystic tumor originating from the right ovary. A right adnexectomy was performed without intraoperative cyst rupture or spillage. Histologically, the cyst was diagnosed as a mucinous cystadenoma. A month after the operation, ultrasonography revealed a cystic lesion measuring 1.8 cm adjacent to the right side of the uterine body. During the follow-up every three months, the cyst enlarged gradually, and an MRI performed 42 months after the operation revealed a cystic mass measuring 5.5 cm, including an internal protrusion. The second laparotomy revealed a cystic mass arising from the right surface of the uterine body, and a total hysterectomy and left adnexectomy were performed. Histologically, this uterine tumor was diagnosed as a mucinous borderline tumor that recurred from the ovarian mucinous cystadenoma. On histological examination of the resected uterus, the silken threads used at the first operation were observed in proximity to the tumor lesion. We speculated that the reason for the recurrence of our case may be the uterine-side remanence of the mucinous tumor cells from the first operation. Because the utero-ovarian ligament became short due to the large ovarian cyst, adnexectomy as a first procedure may be insufficient. A close follow-up of these patients is required for early detection of the recurrence, and attention is necessary for patients having malignant transformation due to an adenoma-borderline-malignant sequence of ovarian mucinous tumors.

The Role of the Ventromedial Prefrontal Cortex in Preferential Decisions for Own- and Other-Age Faces.

Own-age bias is a well-known bias reflecting the effects of age, and its role has been demonstrated, particularly, in face recognition. However, it remains unclear whether an own-age bias exists in facial impression formation. In the present study, we used three datasets from two published and one unpublished functional magnetic resonance imaging (fMRI) study that employed the same pleasantness rating task with fMRI scanning and preferential choice task after the fMRI to investigate whether healthy young and older participants showed own-age effects in face preference. Specifically, we employed a drift-diffusion model to elaborate the existence of own-age bias in the processes of preferential choice. The behavioral results showed higher rating scores and higher drift rate for young faces than for older faces, regardless of the ages of participants. We identified a young-age effect, but not an own-age effect. Neuroimaging results from aggregation analysis of the three datasets suggest a possibility that the ventromedial prefrontal cortex (vmPFC) was associated with evidence accumulation of own-age faces; however, no clear evidence was provided. Importantly, we found no age-related decline in the responsiveness of the vmPFC to subjective pleasantness of faces, and both young and older participants showed a contribution of the vmPFC to the parametric representation of the subjective value of face and functional coupling between the vmPFC and ventral visual area, which reflects face preference. These results suggest that the preferential choice of face is less susceptible to the own-age bias across the lifespan of individuals.

Using the in vitro drug sensitivity test to identify candidate treatments for transient abnormal myelopoiesis.

Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.

Subtle Cardiovascular Abnormalities in Prader-Willi Syndrome Might Begin in Young Adulthood.

Objective Patients with Prader-Willi syndrome (PWS) are known to have a high mortality rate. However, little is known about the exact reason for this, particularly in adults, because so few reports have been published. The present study examined cardiovascular abnormalities to determine the cause of death in adults with PWS. Methods From September 2017 to April 2019, a total of 18 adults with PWS, and, no history of cardiovascular diseases, were enrolled. We investigated the levels of the cardiovascular biomarkers: high-sensitivity C-reactive protein (hs-CRP) and troponin T (TnT). To estimate the cardiac function, we measured the left ventricular ejection fraction (LVEF), global longitudinal systolic strain (GLS) of the left ventricle, ratio of peak early mitral filling velocity (E) to early diastolic mitral annular velocity (E/e' ratio), mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) using standard and tissue Doppler echocardiography. Results The mean patient age was 28±9 years old. There were 11 men, and the mean body mass index was 45.1 kg/m2. Dyslipidemia (82%), diabetes mellitus (82%) and hypertension (83%) were commonly found as comorbidities. Most patients had elevated levels of hs-CRP (mean 1.007±0.538 mg/dL). The LVEF (mean 61%±5%) showed normal values, while the GLS (mean 15.0%±3.0%) was decreased. The TAPSE was mildly reduced (mean 16±3 mm). Conclusion These results suggest that subtle cardiovascular abnormalities have already begun in young adults with PWS. We need to manage obesity and the resultant obesity-related disorders in order to prevent heart failure and coronary atherosclerosis in PWS patients.

Incorporation of Halogenated Amino Acids into Antibody Fragments at Multiple Specific Sites Enhances Antigen Binding.

Expansion of the amino-acid repertoire with synthetic derivatives introduces novel structures and functionalities into proteins. In this study, we improved the antigen binding of antibodies by incorporating halogenated tyrosines at multiple selective sites. Tyrosines in the Fab fragment of an anti-EGF-receptor antibody 059-152 were systematically replaced with 3-bromo- and 3-chlorotyrosines, and simultaneous replacements at four specific sites were found to cause a tenfold increase in the affinity toward the antigen. Structure modeling suggested that this effect was due to enhanced shape complementarity between the antigen and antibody molecules. On the other hand, we showed that chlorination in the constant domain, far from the binding interface, of Rituximab Fab also increased the affinity significantly (up to 17-fold). Our results showed that antigen binding is tunable with the halogenation in and out of the binding motifs.

Pilot study of the combination of sorafenib and fractionated irinotecan in pediatric relapse/refractory hepatic cancer (FINEX pilot study).

BACKGROUND: Preclinical observations suggested a synergistic effect of sorafenib (SFN) and irinotecan (CPT-11) in hepatoblastoma (HB). Thus, we conducted a feasibility study of fractionated CPT-11 combined with SFN to develop a new therapy against relapsed/refractory pediatric hepatic cancer (HC). PROCEDURE: The study was originally designed as a phase I, standard 3+3 dose-finding study to evaluate dose-limiting toxicities (DLTs) for the regimen and the optimal CPT-11 dose in combination with SFN against relapsed/refractory pediatric HC, including HB and hepatocellular carcinoma (HCC). The enrolled patients received SFN at 200 mg/m2 every 12 hours or 400 mg/m2 every 24 hours daily combined with CPT-11 at 20 mg/m2 /day on days 1 to 5 as an initial level 1 dose. RESULTS: Six patients with HB (n = 4) or HCC (n = 2) were enrolled and treated with CPT-11 dose level 1. The median age at enrollment was 8.7 (6.2-16.3) years. All patients received platinum-containing chemotherapy, and five or two patients received CPT-11 or SFN before enrollment, respectively. Regimen toxicities were evaluable in all patients. One of six patients experienced a grade 4 transaminase levels increase, which was defined as a DLT per protocol. Grade 3/4 neutropenia and a grade 3 transaminase level increase occurred in three patients and one patient, respectively. All patients reported grade 1/2 toxicities such as anemia, skin toxicity, gastrointestinal symptoms, and hypoalbuminemia. CONCLUSIONS: Although the study was terminated before determining the maximum-tolerated CPT-11 dose, SFN and CPT-11 at the level 1 dose were concluded to be tolerable in pediatric patients with HC.

Factors influencing platelet normalization of transient abnormal myelopoiesis.

BACKGROUND: Abnormal blood cell counts are characteristic of patients with Down syndrome and transient abnormal myelopoiesis (TAM). Although some patients with TAM experience prolonged anemia or thrombocytopenia, hematological factors predicting blood cell count recovery have not been reported yet. The aim of this study was to investigate the factors influencing platelet normalization in TAM. METHODS: A retrospective review of the medical records of 21 patients with TAM admitted to the neonatal intensive care unit at Kanagawa Children's Medical Center between January 2007 and October 2014 was undertaken. RESULTS: In the 16 of 21 patients (76%) experiencing transient thrombocytopenia, a large number of blasts at diagnosis was found to be significantly associated with late platelet recovery (R = 0.669, P < 0.05), and higher platelet counts at diagnosis were significantly associated with later recovery (R = 0.719, P < 0.01). Indeed, a strong positive correlation between blast and platelet counts at diagnosis was found (R = 0.730, P < 0.01). CONCLUSIONS: Our data suggest that high platelet counts at TAM diagnosis might reflect abnormal thrombocyte production from blasts. Thus, physicians should be aware of the possibility of prolonged thrombocytopenia in patients with TAM who exhibit a high platelet and/or blast count at diagnosis.

Hypofractionated radiotherapy in children with diffuse intrinsic pontine glioma.

BACKGROUND: Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor, with radiation therapy (RT) the only intervention that transiently delays tumor progression. Hypofractionated RT and re-irradiation at first progression have gained popularity in improving the quality of life of such patients. METHODS: We performed a retrospective review of children with DIPG treated at Kanagawa Children's Medical Center from 2000 to 2018. RESULTS: A total of 24 cases were reviewed. Median age at diagnosis was 6.3 years (1.6-14.0). Twenty patients received RT only once. Thirteen patients received conventionally fractionated RT, and seven patients received hypofractionated RT as up-front RT. Severe toxicities were not observed in patients who received hypofractionated RT. Median OS and time to progression were similar between conventionally fractionated and hypofractionated RT groups.(9.7 [95% confidence interval(CI): 7.1-11.2] versus 11.0[95% CI: 5.2-13.6] months, P = 0.60; 4.2[95% CI: 1.8-8.3] versus 7.1 [95% CI:4.5-8.7] months, P = 0.38). Four patients received re-irradiation at first progression and all patients showed transient neurological improvement and survival more than a year after diagnosis. A 4-year-old boy was re-irradiated 5-and-a-half months after the first re-irradiation; following transient neurological improvement. He survived a further 5 months. CONCLUSION: Hypofractionated RT for children with newly diagnosed DIPG is well tolerated and feasible from the viewpoint of reducing a patient's burden of treatment. Re-irradiation at first progression is suggested to be beneficial.

Exploring disease-specific methylated CpGs in human male genital abnormalities by using methylated-site display-amplified fragment length polymorphism (MSD-AFLP).

The incidence of male reproductive system disorders, especially hypospadias, has been increasing in developed countries since the latter half of the 20th century. Endocrine-disrupting chemicals from the environment are considered to be involved in hypospadias onset through epigenetic alterations. This pilot study aimed to explore disease-specific methylated CpGs in human patient samples using the methylated-site display-amplified fragment length polymorphism (MSD-AFLP) technique developed by our research group [1]. We compared clinical samples from hypospadias and phimosis patients. Foreskin and blood samples were collected from one- to two-year-old patients with hypospadias (N = 3) and phimosis (N = 3) during surgical treatment. MSD-AFLP analysis showed significantly decreased CpG-methylation levels of genes such as MYH11 and increased CpG-methylation levels of genes such as PLA2G15 in hypospadias patients. Hierarchical clustering analysis showed that genes with significantly altered CpG levels were more markedly altered in DNA from blood than from foreskin. Because of the small number of samples, further investigation is necessary to elucidate the association between variations in CpG levels in foreskin and blood DNA and male genital abnormalities. However, our MSD-AFLP method appears to be a useful tool for exploring disease-specific methylated-CpGs in human epidemiological studies.

The Use of Pitch Accent in Word-Object Association by Monolingual Japanese Infants.

This study investigated the lexical use of Japanese pitch accent in Japanese-learning infants. A word-object association task revealed that 18-month-old infants succeeded in learning the associations between two nonsense objects paired with two nonsense words minimally distinguished by pitch pattern (Experiment 1). In contrast, 14-month-old infants failed (Experiment 2). Eighteen-month-old infants succeeded even for sounds that contained only the prosodic information (Experiment 3). However, a subsequent experiment revealed that 14-month-old infants succeeded in an easier single word-object task using pitch contrast (Experiment 4). These findings indicate that pitch pattern information is robustly available to 18-month-old Japanese monolingual infants in a minimal pair word-learning situation, but only partially accessible in the same context for 14-month-old infants.

Synthetic Tyrosine tRNA Molecules with Noncanonical Secondary Structures.

The L-shape form of tRNA is maintained by tertiary interactions occurring in the core. Base changes in this domain can cause structural defects and impair tRNA activity. Here, we report on a method to safely engineer structural variations in this domain utilizing the noncanonical scaffold of tRNAPyl. First, we constructed a naïve hybrid between archaeal tRNAPyl and tRNATyr, which consisted of the acceptor and T stems of tRNATyr and the other parts of tRNAPyl. This hybrid tRNA efficiently translated the UAG codon to 3-iodotyrosine in Escherichia coli cells, when paired with a variant of the archaeal tyrosyl-tRNA synthetase. The amber suppression efficiency was slightly lower than that of the "bench-mark" archaeal tRNATyr suppressor assuming the canonical structure. After a series of modifications to this hybrid tRNA, we obtained two artificial types of tRNATyr: ZtRNA had an augmented D (auD) helix in a noncanonical form and the D and T loops bound by the standard tertiary base pairs, and YtRNA had a canonical auD helix and non-standard interloop interactions. It was then suggested that the ZtRNA scaffold could also support the glycylation and glutaminylation of tRNA. The synthetic diversity of tRNA would help create new tRNA⁻aminoacyl-tRNA synthetase pairs for reprogramming the genetic code.

Statistical approach to identify food categories that determine daily intake levels of total and inorganic arsenic, lead and aluminium of Japanese diet.

Food categories that significantly contribute to daily intake of total arsenic (TAs), inorganic arsenic (iAs), lead (Pb) and aluminium (Al) were statistically sought for the 949 duplicate diet samples collected from 319 households in Japan. Daily intakes of TAs, iAs, Pb and Al were calculated based on measured element concentration in duplicate diet samples and weight of the samples. Amounts of consumption of 12 food categories of each duplicate diet sample were self-reported (beverage), interviewed (fat and oil, spices, and sugar) and actually weighted (other 9 categories) at the time of diet sampling. Multiple regression analyses were conducted by using daily element intake as dependent variable and amounts of daily consumption of the 12 food categories as independent variables. The most significant predictors were amount of daily consumption of 'Fish & Shellfish' for daily TAs intake and 'Rice & Rice products' for iAs intake. Other food categories contributed to daily intakes of the four elements with smaller coefficient. Some of the significant predictors identified in this study were consistent with the findings of the previous market basket surveys while others were not. The 12 food category consumption data moderately explained daily intake of TAs (Coefficient of determination adjusted for degree of freedom (adjusted R2) = 0.447) and iAs (0.307) while they only poorly explained daily intakes of Pb (0.229) and Al (0.117). The present results suggest that a Total Diet Study based on food consumption survey data and element contents of food from data base/literature will result in large errors in the estimation of daily element intake.

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

Does the prenatal bisphenol A exposure alter DNA methylation levels in the mouse hippocampus?: An analysis using a high-sensitivity methylome technique.

BACKGROUND: There is still considerable debate about the effects of exposure to bisphenol A (BPA) an endocrine disrupter at low doses. Recently, many studies using animal models have shown that prenatal BPA exposure induces behavioral and neuronal disorders due to epigenetic changes in the brain. However, striking evidence of epigenomic changes has to be shown. METHODS: To investigate whether low-dose BPA exposure in the fetal stage can alter CpG methylation levels in the central nervous system, the hippocampus of the inbred C57BL/6 J mouse as the target tissue was collected to detect alterations in CpG methylation levels using a highly sensitive method of genome-wide DNA methylation analysis, methylated site display-amplified fragment length polymorphism (MSD-AFLP). RESULTS: BPA showed the sex-hormone like effects on male reproductive organs. Although we examined the methylation levels of 43,840 CpG sites in the control and BPA (200 µg/kg/day)-treated group (6 mice per group), we found no statistically significant changes in methylation levels in any CpG sites. CONCLUSIONS: At least under the experimental condition in this study, it is considered that the effect of low-dose BPA exposure during the fetal stage on hippocampal DNA methylation levels is extremely small.

Long-Term Favorable Course of Aspergillus Endo-, Myo-, and Pericarditis.

Here, we report on a healthy 30-year-old man with no significant medical history, who tested negative for human immunodeficiency virus antigenemia but developed Aspergillus pancarditis. A case of this kind is extremely rare, and to the best of our knowledge, this is the first report of a patient with Aspergillus pancarditis, which generally leads to a very poor outcome, who had a long-term favorable clinical course. A biopsy from the right atrium of hypertrophied atrial septum was essential for obtaining the definitive diagnosis. Long-term administration of an effective antifungal oral agent might account for the patient's favorable outcome.

Bortezomib alters sour taste sensitivity in mice.

Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased. The increased sour taste sensitivity induced by bortezomib returned to the control level on cessation of its administration. These results suggest that an increase in protein expression of PKD2L1 enhances the sour taste sensitivity in bortezomib-administered mice, and this alteration is reversed on cessation of its administration.

Extensive Survey of Antibody Invariant Positions for Efficient Chemical Conjugation Using Expanded Genetic Codes.

The site-specific chemical conjugation of proteins, following synthesis with an expanded genetic code, promises to advance antibody-based technologies, including antibody drug conjugation and the creation of bispecific Fab dimers. The incorporation of non-natural amino acids into antibodies not only guarantees site specificity but also allows the use of bio-orthogonal chemistry. However, the efficiency of amino acid incorporation fluctuates significantly among different sites, thereby hampering the identification of useful conjugation sites. In this study, we applied the codon reassignment technology to achieve the robust and efficient synthesis of chemically functionalized antibodies containing Nε-(o-azidobenzyloxycarbonyl)-l-lysine (o-Az-Z-Lys) at defined positions. This lysine derivative has a bio-orthogonally reactive group at the end of a long side chain, enabling identification of multiple new positions in Fab-constant domains, allowing chemical conjugation with high efficiency. An X-ray crystallographic study of a Fab variant with o-Az-Z-Lys revealed high-level exposure of the azido group to solvent, with six of the identified positions subsequently used to engineer "Variabodies", a novel antibody format allowing various connections between two Fab molecules. Our findings indicated that some of the created Variabodies exhibited agonistic activity in cultured cells as opposed to the antagonistic nature of antibodies. These results showed that our approach greatly enhanced the availability of antibodies for chemical conjugation and might aid in the development of new therapeutic antibodies.