Repeated maternal separation causes transient reduction in BDNF expression in the medial prefrontal cortex during early brain development, affecting inhibitory neuron development.

It is widely accepted that maternal separation (MS) induces stress in children and disrupts neural circuit formation during early brain development. Even though such disruption occurs transiently early in life, its influence persists after maturation, and could lead to various neurodevelopmental disorders. Our recent study revealed that repeated MS reduces the number of inhibitory neurons and synapses in the medial prefrontal cortex (mPFC) and causes mPFC-related social deficits after maturation. However, how MS impedes mPFC development during early brain development remains poorly understood. Here, we focused on brain-derived neurotrophic factor (BDNF) involved in the development of inhibitory neurons, and examined time-dependent BDNF expression in the mPFC during the pre-weaning period in male rats exposed to MS. Our results show that MS attenuates BDNF expression only around the end of the first postnatal week. Likewise, mRNA expression of activity-regulated cytoskeleton-associated protein (Arc), an immediate-early gene whose expression is partly regulated by BDNF, also decreased in the MS group along with the reduction in BDNF expression. On the contrary, mRNA expression of tropomyosin-related kinase B (TrkB), which is a BDNF receptor, was scarcely altered, while its protein expression decreased in the MS group only during the weaning period. In addition, MS reduced mRNA levels of glutamic acid decarboxylase (GAD) 65, a GABA synthesizing enzyme, only during the weaning period. Our results suggest that repeated MS temporarily attenuates BDNF signaling in the mPFC during early brain development. BDNF plays a crucial role in the development of inhibitory neurons; therefore, transient attenuation of BDNF signaling may cause delays in GABAergic neuron development in the mPFC.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings.

Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70-90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited.Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment.Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model.Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000-3000 and 4000-5000 mg/dl, respectively.Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

The effects of early life stress on the excitatory/inhibitory balance of the medial prefrontal cortex.

Aversive environmental conditions during early life are known to cause long-lasting social deficits, similar to those observed in patients with neurodevelopmental disorders. However, the mechanism of how early life stress can cause social deficits is not well understood. To clarify how being in an aversive environment during development affects sociability, we conducted various analyses focusing on the excitatory and inhibitory (E/I) balance in the medial prefrontal cortex (mPFC) and how it is related to social deficits, with young adult male rats that had been exposed to maternal separation (MS). In our MS procedure, part of the pups were separated from each dam for 3 h, twice a day, during postnatal days 2-20, and then were used for each analysis at 9 weeks old. We identified that MS mainly reduced pre- and post-synaptic protein expression of inhibitory neurons in the mPFC, and that decreased the number of GAD67-positive interneurons and inhibitory synapses in the mPFC. Furthermore, MS impaired social behavior related to social recognition, which is closely linked to the mPFC, in the three-chamber sociability and social novelty test (3-CST). With relation to this social deficit, immunohistological analysis revealed that c-fos-positive cells in the mPFC of rats exposed to MS decreased during the 3-CST. Considering that inhibitory neurons in the mPFC play a role in synchronizing neural activation for information processing, our findings demonstrate that MS-induced E/I imbalance associated with cell activity in the mPFC leads to deficits in social recognition.

Fetal facial expressions in small-for-gestational-age and growth-restricted fetuses.

OBJECTIVE: To evaluate the frequencies of fetal facial expressions among appropriate-for-gestational-age (AGA), small-for-gestational-age (SGA), and growth-restricted (FGR) fetuses. METHODS: Four-dimensional (4D) ultrasound was used to examine the facial expressions of 50 AGA, 25 SGA, and six FGR fetuses between 28 and 35 weeks of gestation. The frequencies of seven facial expressions during 15-minute recordings were assessed. Comparison of facial expressions among the three groups was performed. RESULTS: Mouthing was the commonest facial expression at 28-35 weeks, and the frequency of mouthing was significantly higher than those of the other six facial expressions in AGA fetuses. Mouthing was the most frequent facial expression, but there was no significant difference in the frequency among mouthing, smiling and blinking in SGA fetuses. Moreover, mouthing displayed a significantly higher frequency than the other facial expressions, except for yawning, smiling, and blinking in FGR fetuses. However, there was no significant difference in the frequency of each facial expression among the three groups. CONCLUSIONS: Our results suggest that the frequencies of fetal facial expressions are not decreased in either SGA or FGR pregnancies. The absence of a decrease in the frequency of each fetal expression in FGR fetuses may be due to increased brain blood flow because of the brain-sparing effect. Moreover, accelerated maturation and development of the brain function, especially the central dopamine system, might be suspected in SGA and FGR fetuses.

HDlive Flow silhouette mode for the diagnosis of uterine enhanced myometrial vascularity/arteriovenous malformations.

We present our initial experience of using the HDlive Flow silhouette mode to construct images of two cases of uterine enhanced myometrial vascularity/arteriovenous malformations (EMV/AVMs). In the first case, the HDlive Flow silhouette mode clearly depicted a fused vascular tumor with irregular contour in the posterior myometrium. In the second case, a large hypervascular mass occupying the entire fundal lesion of the uterus was clearly identified using the HDlive Flow silhouette mode. Moreover, spatial relationships among the hypervascular mass, intrauterine blood collection, and dilated, spiral-shaped right uterine artery enabled the clear localization of the mass. The HDlive Flow silhouette mode provides a novel, unique sonographic image of uterine EMV/AVMs, and might facilitate their diagnosis and localization in the myometrium.

Flexible magnifying endoscopy with narrow band imaging for the diagnosis of uterine cervical tumors: A cooperative study among gastrointestinal endoscopists and gynecologists to explore a novel microvascular classification system.

Narrow band imaging with magnifying endoscopy (NBI-ME), which is useful for the assessment of micro-vessels, has excellent diagnostic potential for early gastrointestinal epithelial neoplasia. Conventional diagnostic tools for uterine cervical epithelial tumors are still unsatisfactory. An accurate diagnostic tool for uterine cervical epithelial tumors is required to preserve the reproductive ability of young women with uterine cervical tumors. Flexible NBI-ME was performed in patients with cervical squamous cell lesions that required further examinations based on their Pap smear results (cytology ≥ low-grade squamous intraepithelial lesion) at Kagawa University Hospital between April 2014 and April 2015. NBI-ME results concordant with the punch biopsy sites were compared with the histological results. A retrospective review of the NBI-ME images identified abnormal NBI-ME results regarding micro-vascular patterns. All images were categorized as having abnormal features. NBI-ME revealed the following vascular pattern differences of different stage tumors: Dot-like vessels without irregular arrangements and high density in cervical intraepithelial neoplasia (CIN) CIN1-CIN2; dot-like vessels with irregular arrangements and high density in CIN3-carcinoma in situ; crawling vessels in minimum invasive cancer; and willow branch vessels and new tumor vessels in invasive cancer. NBI-ME may be an effective diagnostic tool for uterine cervical epithelial tumors, which may lead to the establishment of a novel classification system.

Case of maternal and fetal deaths due to severe congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) during pregnancy.

Upshaw-Schulman syndrome (USS) involves a congenital deficiency of von Willebrand factor-cleaving metalloprotease (ADAMTS13) activity due to gene mutations. Female patients develop overt thrombotic thrombocytopenic purpura (TTP) caused by a decline of ADAMTS13 activity in pregnancy. A 23-year-old nulliparous Japanese woman died due to severe, rapid progression of TTP with intrauterine fetal death at 20 weeks of gestation after its onset, even though she underwent intensive treatment which included plasma exchange. She had a history of idiopathic thrombocytopenic purpura at the age of 3 years. The patient's ADAMTS13 activity was of very low level. It should be borne in mind that there is the possibility of rapidly progressive fulminant USS during pregnancy.

Three- and four-dimensional HDlive rendering image of fetal acrania/exencephaly in early pregnancy.

We present two cases of fetal acrania/exencephaly reconstructed employing the three- (3D) and four-dimensional (4D) HDlive rendering mode in early gestation. Two fetuses with acrania/exencephaly were studied with the 3D/4D HDlive rendering mode at 13 and 15 weeks, respectively. In Case 1, at 13 weeks' gestation, deformed and degenerated brain tissues were clearly shown using the 3D/4D HDlive rendering mode. In Case 2, at 15 weeks and 6 days of gestation, two amniotic bands and acrania/exencephaly were depicted with the 3D/4D HDlive rendering mode. Fragile brain hemispheres with amniotic bands were rocking with fetal movements. The 3D/4D HDlive rendering mode provides physicians, couples, and their families with important and additional information, and has the potential to supplement two-dimensional and conventional 3D ultrasound in diagnosing fetal acrania/exencephaly.

Three- and four-dimensional HDlive rendering images of normal and abnormal fetuses: pictorial essay.

BACKGROUND: Our objective is to present our experience of normal embryonic development and fetal anatomy and fetal anomalies reconstructed employing the three-dimensional (3D) and four-dimensional (4D) HDlive rendering mode. METHODS: A total of 18 normal embryos and fetuses and 21 abnormal fetuses (one case each of thoracic meningocele, thickened nuchal translucency, multicystic dysplastic kidney, gastroschisis, omphalocele, and ovarian cyst, five of hydrops fetalis, three of skeletal abnormality, three of chromosome abnormality, two of cystic hygroma, and two of amniotic band syndrome) at 7-36 weeks' gestation were studied using the 3D/4D HDlive rendering mode. RESULTS: In normal fetuses, marked embryonic development with advancing gestation was clearly shown in the first trimester of pregnancy, and various realistic facial expressions were noted in the second and third trimesters. In abnormal fetuses, anatomically realistic features such as gross specimens were obtained. In particular, 3D/4D HDlive provides new, realistic sensations for the diagnosis of amniotic band syndrome, skeletal abnormalities, and facial abnormalities. CONCLUSION: 3D/4D HDlive rendering images seem to be more readily discernible than those obtained by conventional 3D/4D sonography. 3D/4D HDlive may be an important modality in future embryonic research, fetal neurobehavioral assessment, and the evaluation of fetal anomalies.

Three-dimensional volume-rendered imaging of normal and abnormal fetal fluid-filled structures using inversion mode.

A total of six normal and eight abnormal fetuses at 16-38 weeks of gestation were studied using transabdominal three-dimensional sonography with an inversion mode. In normal fetuses, the stomach, gallbladder and bladder could be depicted. In particular, peristalsis of the stomach was noted. In the case of holoprosencephaly, fused hemispheres were evident. In the case of hydrocephalus, the enlargement of ventricular cavities was noted. In the case of bilateral pleural effusion, the spatial relationship and size of the effusions were depicted. In the case of meconium peritonitis, the spatial relationship between the dilated intestines and ascites was depicted. In two cases of hydronephrosis, the dilated renal pelvis and calyces were clearly shown. In the case of multicystic dysplastic kidney, the number and size of cysts were clearly identified. In the case of left ovarian cyst, the anatomical relationships among the ovarian cyst, kidney, stomach and bladder could be easily understood.