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Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.T he mammalian neocortex is highly organized into six neuronal layers. This laminar structure is responsible for the complex motor, sensory, and cognitive functions of the mammalian brain (1). Neuronal migration plays an important role in the establishment of this layered structure. Cortical neurons are generated within the ventricular zone (VZ) or subventricular zone (SVZ), and migrate along radial fibers toward the pial surface. Newly born excitatory neurons migrate radially into the cortical plate (CP) past the neurons born earlier, resulting in a birth date-dependent "inside-out" alignment of the neurons in the CP (2-4).Reelin is a glycoprotein that is secreted by the Cajal-Retzius cells in the marginal zone (MZ) of the cortex during neocortical development (5-7). This glycoprotein is essential for establishment of the aforementioned birth date-dependent layered structure of the neocortex, because the CP neurons show an almost inverted alignment in the neocortex of the Reelindeficient, reeler mice. In addition, neurons born at the same time tend to be distributed broadly and not to form clear layers in the reeler cortex (8, 9). Although extensive studies, including at the molecular level, have been conducted to determine the role of Reelin in neuronal migration i...

Atopic dermatitis is a pruritic, eczematous dermatitis, the symptoms of which chronically fluctuate with remissions and relapses. Although a high psychosomatic and economic burden caused by atopic dermatitis is expected, few studies have been conducted estimating the cost of illness, including the self‐medication costs and productivity loss due to atopic dermatitis. The aim of this study was to conduct a cross‐sectional, Web‐based survey of the direct medical costs, self‐medication costs and productivity loss for adult atopic dermatitis patients, and estimate the burden of Japanese adult atopic dermatitis patients by disease severity. In a physician survey, the medical resource consumption related to medical treatments was surveyed by disease severity. The direct medical costs were calculated by multiplying the medical resource consumption and medical fee corresponding to each treatment. Based on the results of a patient survey, the self‐medication costs and productivity loss were estimated by sex and disease severity. Atopic dermatitis‐related productivity loss was calculated based on absenteeism, presenteeism, overall work impairment for employed workers and activity impairment for housewives. The nationwide estimations were calculated based on the estimated number of atopic dermatitis patients, employed workers with atopic dermatitis, and housewives with atopic dermatitis in their 20s–50s in Japan. Based on the surveys, all costs per patient and the scores increased with disease severity. The cost of illness for adult atopic dermatitis patients in Japan was estimated to be approximately JPY 3 trillion/year. Considering the physical and mental burdens, the burden of illness for adult atopic dermatitis was demonstrated to be vast.

Pulmonary arterial hypertension (PAH) is a disease that imposes a significant burden on patients. Although multiple treatment options for PAH are available, head-to-head comparisons are difficult to conduct. Network meta-analysis (NMA) can be a useful alternative for direct comparison to estimate the relative effectiveness of multiple treatments. The objective of the present study was to conduct a systematic review and NMA to evaluate the relative effectiveness among oral PAH medications.Data collection was performed by searching the Cochrane Central Register of Controlled Trials (CENTRAL) and Ichushi-Web. Randomized controlled trials (RCTs) assessing at least 1 of the following 3 outcome measurements; 6-minute walk distance test (6MWD), WHO functional class (WHOFC), and mean pulmonary artery pressure (mPAP) were included (PROSPERO registration number: CRD42015016557). Outcomes were evaluated by estimating the differences in the mean change from baseline or by estimating the odds ratios. Analyses were performed using WinBUGS 1.4.3.Seven double-blind RCTs were eligible. NMA results showed similar improvements in 6MWD for all medications assessed. Bosentan and sildenafil caused a statistically significant improvement in WHOFC compared to other medications.The relative effectiveness of oral PAH medications could be compared using NMA, which suggested the superiority of bosentan and sildenafil in the improvement of WHOFC.

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