The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus (prh) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II–IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in prh mutants’ corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the prh mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus.

Live visualisation of electrolytes during mouse embryonic development using electrolyte indicators

Studies have shown that some electrolytes, including Na+ and K+, play important roles in embryonic development. However, these studies evaluated these electrolytes by using inhibitors or knockout mice, with no mention on the changes in the intracellular electrolyte concentrations during embryogenesis. In this study, we used the electrolyte indicators CoroNa Green AM and ION Potassium Green-2 AM to directly visualise intracellular concentrations of Na+ and K+, respectively, at each embryonic developmental stage in mouse embryos. We directly observed intracellular electrolyte concentrations at the morula, blastocyst, and hatching stages. Our results revealed dynamic changes in intracellular electrolyte concentrations; we found that the intracellular Na+ concentration decreased, while K+ concentration increased during blastocoel formation. The degree of change in intensity in response to ouabain, an inhibitor of Na+/K+ ATPase, was considered to correspond to the degree of Na+/K+ ATPase activity at each developmental stage. Additionally, after the blastocyst stage, trophectoderm cells in direct contact with the blastocoel showed higher K+ concentrations than in direct contact with inner cell mass, indicating that Na+/K+ ATPase activity differs depending on the location in the trophectoderm. This is the first study to use CoroNa Green AM and ION Potassium Green-2 AM in mouse embryos and visualise electrolytes during embryonic development. The changes in electrolyte concentration observed in this study were consistent with the activity of Na+/K+ ATPase reported previously, and it was possible to image more detailed electrolyte behaviour in embryo cells. This method can be used to improve the understanding of cell physiology and is useful for future embryonic development studies

Acute development of collateral circulation and therapeutic prospects in ischemic stroke

In acute ischemic stroke, collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia, and in increasing the successful recanalization rate without hemorrhagic transformation. We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome, and it disappears promptly once the effective recanalization is achieved. Contrary to the belief that collateral vessels develop over time in chronic stenotic condition, there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress, which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries. We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1, which is a known shear-stress mechanosensing protein

Upregulation of lipoprotein receptors on brain endothelial cells and neurons in the early phase of ischemic stroke in mice

Current understanding on the mechanisms of acute stroke highlights the importance of targeting brain endothelial cells (ECs), which regulate blood–brain barrier (BBB) disruption, neuronal cell death, and immune cell infiltration. Because the transcellular pathway through ECs is activated immediately after stroke onset, understanding transporter expression should facilitate development of an efficient drug delivery system to ischemic ECs. Here, we examined BBB leakage profiles and expression of three lipoprotein receptors, lowdensity lipoprotein receptor (LDLR), scavenger receptor class B member 1 (SRB1), and LDLR-related protein 1 (LRP1), in a mouse model of permanent middle cerebral artery occlusion (MCAO). Evans blue staining showed a biphasic BBB disruption with one peak at 6 h and the other at 3 days after MCAO. The tight junction protein occludin in the ischemic cortex significantly decreased at 3 days, but not 6 h, after MCAO. LDLR, SRB1, and LRP1 mRNA levels were significantly up-regulated early after MCAO. LDLR and SRB1 proteins were colocalized predominantly in brain ECs, whereas LRP1 was localized in neurons in the ischemic cortex. The early overexpression of lipoprotein receptors after stroke suggests that lipoprotein-associated lipids could be suitable ligands for drug delivery into ECs and neurons in the acute ischemic brain

A case of sialadenitis observed as an irAE of atezolizumab: A case report

Various symptoms emerge as immune-related adverse events of immune checkpoint inhibitor (ICI).A 73-year-old woman, a non-smoker, receiving chemotherapy including atezolizumab for lung adenocarcinoma, presented with fever, bilateral parotid swelling and sicca syndrome after four courses of chemotherapy. Because the lesions were not localized, the diagnosis was ICI-related sialadenitis rather than infectious. Prednisolone improved salivary gland swelling quickly. Six months after the last administration of ICI, there was no obvious progression of lung cancer.To our knowledge, this is the first case of sialadenitis caused by atezolizumab. ICI-related sialadenitis may be a good prognostic marker for lung cancer

Prognostic factors in interstitial lung disease associated with primary Sjögren's syndrome: a retrospective analysis of 33 pathologically-proven cases.

INTRODUCTION: Interstitial lung disease associated with primary Sjögren's syndrome (pSS-ILD) shows several patterns such as nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). Although UIP is a well-recognized prognostic determinant in idiopathic interstitial pneumonias, whether this is also the case in pSS-ILD is unclear. The objectives of this study were to evaluate the prognostic effect of UIP, and to identify the prognostic factors in pSS-ILD. METHODS: A retrospective review of medical records identified 33 consecutive patients with pathologically-proven pSS-ILD. Each patient was classified into each ILD pattern by multidisciplinary analysis. Baseline clinical-radiologic-pathologic characteristics and survival rates were compared between the ILD patterns. Finally, the prognostic factors in pSS-ILD were assessed by univariate and subsequent multivariate analyses using Cox's proportional hazards regression model. RESULTS: pSS-ILD patients were diagnosed with NSIP (n = 22) or UIP (n = 11). The median follow-up period was 110 months, and five-year survival rate was 87.3% in the total patient population. The prognosis of the UIP patients was not significantly different from that of the NSIP patients (NSIP to UIP, hazard ratio [HR]: 0.77, 95% confidence interval [CI]: 0.18-3.36, P = 0.73). Multivariate analysis identified PaCO2 (HR: 1.68 per 1 Torr increase, 95% CI: 1.24-2.28, P < 0.01), extent of reticular abnormality on high-resolution CT (HR: 4.17 per 1-grade increment, 95% CI: 1.18-14.73, P = 0.03), and severity of fibroblastic foci (HR: 9.26 per 1-grade increment, 95% CI: 1.74-49.35, P < 0.01) as prognostic factors in pSS-ILD. CONCLUSIONS: UIP in pSS-ILD was not related to poorer prognosis than NSIP. Assessment of detailed clinical-radiologic-pathologic findings is more important than distinguishing UIP to evaluate prognosis in this disease

Live visualisation of electrolytes during mouse embryonic development using electrolyte indicators.

Studies have shown that some electrolytes, including Na+ and K+, play important roles in embryonic development. However, these studies evaluated these electrolytes by using inhibitors or knockout mice, with no mention on the changes in the intracellular electrolyte concentrations during embryogenesis. In this study, we used the electrolyte indicators CoroNa Green AM and ION Potassium Green-2 AM to directly visualise intracellular concentrations of Na+ and K+, respectively, at each embryonic developmental stage in mouse embryos. We directly observed intracellular electrolyte concentrations at the morula, blastocyst, and hatching stages. Our results revealed dynamic changes in intracellular electrolyte concentrations; we found that the intracellular Na+ concentration decreased, while K+ concentration increased during blastocoel formation. The degree of change in intensity in response to ouabain, an inhibitor of Na+/K+ ATPase, was considered to correspond to the degree of Na+/K+ ATPase activity at each developmental stage. Additionally, after the blastocyst stage, trophectoderm cells in direct contact with the blastocoel showed higher K+ concentrations than in direct contact with inner cell mass, indicating that Na+/K+ ATPase activity differs depending on the location in the trophectoderm. This is the first study to use CoroNa Green AM and ION Potassium Green-2 AM in mouse embryos and visualise electrolytes during embryonic development. The changes in electrolyte concentration observed in this study were consistent with the activity of Na+/K+ ATPase reported previously, and it was possible to image more detailed electrolyte behaviour in embryo cells. This method can be used to improve the understanding of cell physiology and is useful for future embryonic development studies

Clinical Features of Idiopathic Interstitial Pneumonia with Systemic Sclerosis-Related Autoantibody in Comparison with Interstitial Pneumonia with Systemic Sclerosis.

Patients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD.This study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies.We retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody.Patients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD.Data from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD

Kaplan–Meier survival curves for patients with interstitial lung disease associated with primary Sjögren’s syndrome.

<p>(a) Survival curve for the total patient population. Five-year survival rate was 87.3%. (b) Comparison of survival curves between the NSIP (n = 22) and UIP (n = 11) patients. Open circles or open squares show censored cases in NSIP group or UIP group, respectively. The prognosis between the two groups was not significantly different (<i>P</i> = 0.93 in log–rank test). UIP: usual interstitial pneumonia; NSIP: nonspecific interstitial pneumonia.</p