A 5‐HT2A/2C receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane,mitigates developmental neurotoxicity of ethanol to serotonergic neurons

Prenatal ethanol exposure causes the reduction of serotonergic (5‐HTergic) neurons in the midbrain raphe nuclei. In the present study, we examined whether an activation of signaling via 5‐HT_2A and 5‐HT_2C receptors during the fetal period is able to prevent the reduction of 5‐HTergic neurons induced by prenatal ethanol exposure. Pregnant Sprague–Dawley rats were given a liquid diet containing 2.5 to 5.0% (w/v) ethanol on gestational days (GDs) 10 to 20 (Et). As a pair‐fed control, other pregnant rats were fed the same liquid diet except that the ethanol was replaced by isocaloric sucrose (Pf). Each Et and Pf group was subdivided into two groups; one of the groups was treated with 1 mg/kg (i.p.) of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), an agonist for 5‐HT_2A/2C receptors, during GDs 13 to 19 (Et‐DOI or Pf‐DOI), and another was injected with saline vehicle only (Et‐Sal or Pf‐Sal). Their fetuses were removed by cesarean section on GD 19 or 20, and fetal brains were collected. An immunohistological examination of 5‐HTergic neurons in the fetuses on embryonic day 20 using an antibody against tryptophan hydroxylase revealed that the number of 5‐HTergic neurons in the midbrain raphe nuclei was significantly reduced in the Et‐Sal fetuses compared to that of the Pf‐Sal and Pf‐DOI fetuses, whereas there were no significant differences between Et‐DOI and each Pf control. Thus, we concluded that the reduction of 5‐HTergic neurons that resulted in prenatal ethanol exposure could be alleviated by the enhancement of signaling via 5‐HT_2A/2C receptors during the fetal period.     

Current human T‐cell lymphotropic virus type 1 mother‐to‐child transmission prevention status in Kagoshima

The aim of this study was to assess the current human T‐cell lymphotropic virus type 1 (HTLV‐I) mother‐to‐child transmission (MTCT) prevention system in Kagoshima Prefecture. We investigated the rate of carrier pregnant women from obstetrics facilities in Kagoshima by mail in 2012 and compared our results with previous study results. We interviewed carrier pregnant women about their choices for infant nutrition, and we interviewed midwives about the follow‐up system. In 2012, 8719 screening tests were performed, covering 58.1% of all pregnant women in Kagoshima; the rate of carrier pregnant women was 1.3%. Of 59 carriers, 39 chose short‐term breast‐feeding. The HTLV‐I carrier rate among pregnant women in Kagoshima has declined. The current HTLV‐I MTCT prevention system in Kagoshima is effective, but not sufficient. To bring the nutrition methods to completion, various types of support are needed. Further studies will elucidate many unsolved problems concerning MTCT.     

Branchio‐oto‐renal syndrome: Comprehensive review based on nationwide surveillance in Japan

Branchio‐oto‐renal (BOR) syndrome is an autosomal dominant disorder characterized by branchiogenic malformation, hearing loss and renal anomalies. The prevalence of BOR syndrome is 1/40 000 in Western countries, and nationwide surveillance in 2009–2010 identified approximately 250 BOR patients in Japan. Three causative genes for BOR syndrome have been reported thus far: EYA1, SIX1, and SIX5, but the causative genes for approximately half of all BOR patients remain unknown. This review article discusses the epidemiology, clinical symptoms, genetic background and management of BOR syndrome.     

Elastase, α1‐proteinase inhibitor,and interleukin‐8 in pre‐dialyzed and hemodialyzed patients with chronic kidney disease

Background: Neutrophil elastase in complex with α₁‐proteinase inhibitor (NE‐α₁PI) and interleukin (IL)‐8 may serve as indicators of neutrophil activation and inflammatory stage. The aim of the study was to evaluate NE‐α₁PI, α₁‐PI, and IL‐8 levels in the blood of patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) or conservatively treated (CT). The influence of a single HD session on the investigated parameters was also assessed. Methods: Blood samples were obtained from two groups of hemodialyzed patients (children/young adults [group HD1, n= 8] and adults [group HD2, n= 13]), as well as 13 CT patients and a group of healthy subjects. The proteins were measured using enzyme‐linked immunosorbent assay or radial immunodiffusion. Results: There were no significant differences in NE‐α₁PI, α₁‐PI, and IL‐8 concentrations between the HD1 and HD2 patients. The levels of NE‐α₁PI were considerably higher than normal in both groups of HD patients (before and after the HD session) and in the CT patients. Higher titers of NE‐α₁PI (P < 0.05) and α₁‐PI (P < 0.01) were obtained in the adults during the course of HD. Increased NE‐α₁PI was positively correlated with α₁‐PI. The serum concentration of IL‐8 was significantly higher in the HD2 patients before and after dialysis than in the controls. Conclusions: The data indicate that in CKD patients, neutrophils are highly activated both in the pre‐dialyzed period and on regular HD. Contact with the dialysis membrane during HD causes a significant increase in blood NE‐α₁PI and α₁‐PI in adults, but not in children/young adults. NE‐α₁PI seems to be a much better indicator of an inflammatory state in CKD patients than free α₁‐PI or IL‐8.     

Optimal birth weight percentile cut‐offs in defining small‐ or large‐for‐gestational‐age

Aims: It remains questionable what birth weight for gestational age percentile cut‐offs should be used in defining clinically important poor or excessive foetal growth. We aimed to evaluate the optimal birth weight percentile cut‐offs for defining small‐ or large‐for‐gestational‐age (SGA or LGA). Methods: In a birth cohort‐based analysis of 17 979 120 non‐malformation singleton live births, U.S. 1995–2001, we assessed the optimal birth weight percentile cut‐offs for defining SGA and LGA. The 25th–75th percentile group served as the reference. Primary outcomes are the risk ratios (RR) of neonatal death and low 5‐min Apgar score (<4) comparing SGA or LGA versus the reference group. More than 2‐fold risk elevations were considered clinically significant. Results: The 15th birth weight cut‐off already identified SGA infants at more than 2‐fold risk of neonatal death at pre‐term, term or post‐term, except for extremely pre‐term births <28 weeks (continuous risk reductions over increasing birth weight percentiles). LGA was associated with a reduced risk of low 5‐min Apgar score at pre‐term, but an elevated risk at term and post‐term. The 97th cut‐off identified LGA infants at 2‐fold risk of low 5‐min Apgar at term. Conclusion: The commonly used 10th and 90th birth weight percentile cut‐offs for defining SGA and LGA respectively seem largely arbitrary. The 15th and 97th percentiles may be the optimal cut‐offs to define SGA and LGA respectively.     

Challenges in genetic counseling because of intra‐familial phenotypic variation of oral‐facial‐digital syndrome type 1

Oral‐facial‐digital syndrome type 1 (OFD1; MIM 311200) is characterized by multiple anomalies of the oral cavity, face and digits. We report a family with OFD1, where two female siblings and their mother shared the same mutation of the responsible gene (OFD1) c.1193_1196delAATC. Phenotypic variability was observed among them; the mother showed minimal features of OFD1, whereas her two daughters showed partial features and the full spectrum of OFD1, respectively. Thus, OFD1 was suspected only after a health check‐up during pregnancy of the second patient showing fetal brain anomaly and maternal polycystic kidney. For these reasons, there was a delay in the recognition of OFD1 in this family. Patients with OFD1 show phenotypic variability, which poses challenges for genetic counseling.     

Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Deletions on chromosome 6q are rarely reported in the literature, and genotype‐phenotype correlations are poorly understood. We report a child with a deletion of the 6q21‐q22 chromosomal region, providing some intriguing results about the correlation between this region and acro‐cardio‐facial syndrome, congenital heart disease, split hand and foot malformation, and epilepsy.     

Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen‐activator inhibitor‐1

We describe three cases of sinusoidal obstruction syndrome/venoocclusive disease (SOS) in pediatric patients with acute lymphoblastic leukemia (ALL). All three episodes occurred during or just after the induction or reinduction phase of treatment based on prednisone/dexamethasone, vincristine, daunorubicin, and pegylated‐l ‐asparaginase. SOS episodes were categorized as mild/moderate and resolved in 7, 10, and 16 days using supportive measures or defibrotide therapy. In all three episodes, the clinical diagnosis of SOS was associated with a significant increase in plasminogen‐activator inhibitor‐1 (PAI‐1) that reduced with patient clinical improvement. PAI‐1 warrants study as a diagnostic marker for SOS in ALL.     

Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1‐CREB1 fusion to the interleukin‐6 receptor antibody tocilizumab

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has been associated with EWSR1‐CREB1 gene fusion. Outcome in patients with unresectable distant metastases is generally fatal. Interleukin‐6 (IL‐6) secretion has been described in tumors with EWSR1‐CREB1 fusion, and may promote tumor growth due to autocrine stimulation. Tocilizumab is an IL‐6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL‐6 secretion. We describe a child with metastatic AFH with EWSR1‐CREB1 fusion and elevated IL‐6 whose disease progressed during treatment with traditional chemotherapeutic agents, but improved after targeted therapy with tocilizumab.