Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ped.14720.

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: Effects of liposomal particles on immune function have not been adequately investigated. Earlier reports indicate that intravenous injection of rats with pegylated liposomes comprising chemically defined specific lipids produces myeloid derived suppressor-cell (MDSC)-like cells in the spleen. OBJECTIVES: After liposome injection, we sought a cell surface marker expressed specifically on splenic macrophages. Then we assessed the immunosuppressive activity of macrophages positive for the marker. Furthermore, we investigated whether immunosuppression induction is an immunopharmacological action specific to this pegylated liposome, or not. MATERIALS AND METHODS: After using a microarray system to screen genes enhanced by this liposome, we evaluated cell surface expression of gene products using flow cytometry. Liposomes of several kinds, each comprising one type of phospholipid, were prepared and evaluated for their ability to induce T-cell suppression. RESULTS: Microarray analysis indicated enhanced B7-H3 expression. Flow cytometry revealed that the B7-H3 molecule was expressed on splenic macrophages after liposome injection. B7-H3+ macrophages were positive for iNOS. Removing B7-H3+ cells restored T-cell proliferation. Similarly to this liposome, various liposomes with different long chain fatty acids induced T-cell suppression when accumulated in the spleen. CONCLUSIONS: Immunosuppressive cells induced by this pegylated liposome closely resemble MDSCs, especially B7-H3+ MDSCs. Immunosuppression induction is not a phenomenon specific to this liposome. Accumulation of long chain fatty acid in macrophages by internalization of liposomal nanoparticles might be related to macrophage acquisition of immunosuppressive activity in vivo.

DOI： 10.1080/08923973.2020.1837866

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Language：English   Publishing type：Research paper (scientific journal)  

Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.

DOI： 10.1016/j.ejmg.2020.104039

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Language：English  

We present the case of an 8-month-old boy with the repeated recurrence of vesicles from the time of birth and who subsequently manifested psychomotor developmental delay. We retrospectively diagnosed the patient with congenital herpes simplex virus (HSV) infection. Computed tomography showed multiple calcifications in the periventricular white matter and thalami. The bilateral deep white matter showed an abnormally high signal intensity on T2-weighted magnetic resonance imaging. The patient required consecutive, suppressive therapy with valacyclovir to prevent the repeated recurrence of vesicles. This case presented a milder phenotype of congenital HSV infection in comparison to previous reports, and highlights the importance of the careful examination for this disease when neonates present with skin lesions.

DOI： 10.1016/j.braindev.2020.01.003

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.braindev.2020.01.003

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BACKGROUND: The appropriate antimicrobial treatment period for febrile urinary tract infection (UTI) can be changed, depending on whether the patient has acute focal bacterial nephritis (AFBN). The aim of this study was to clarify the characteristics of AFBN compared with those of acute pyelonephritis (APN) and establish a strategy to detect AFBN. METHODS: A total of 77 patients diagnosed with febrile UTI were enrolled. They were divided into APN (n = 64) and AFBN groups (n = 13). The clinical data and other laboratory biomarkers were retrospectively analyzed. RESULTS: The time required for fever resolution after antimicrobial treatment was significantly longer in the AFBN group than in the APN group (2.77 days vs 1.11 days, respectively, P < 0.001). Also, the time to disappearance of pyuria after antimicrobial treatment was longer in the AFBN group than in the APN group (6.22 days vs 2.32 days, respectively, P = 0.001). Fever lasting >1.75 days after antimicrobial treatment had a sensitivity of 92% and specificity of 79% for the detection of AFBN, while pyuria disappearance after 4 days had a sensitivity of 88% and specificity of 85%. When patients fulfilled both cut-offs, the sensitivity and specificity were 89% and 97%. CONCLUSION: Acute focal bacterial nephritis was associated with fever of significantly longer duration after antimicrobial treatment, and it took a longer time for pyuria to disappear. Children with febrile UTI should be evaluated for AFBN if the fever persists ≥48 h after the initiation of antimicrobial treatment and if pyuria lasts for 4 days.

DOI： 10.1111/ped.13910

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ped.13910

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jpc.14442.

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DOI： 10.1111/jpc.14442

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The A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding-defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate-induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β-dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE2 was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658-E4667), but the IL-1β-dependent production of COX2 and PGE2 in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate-induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE2 production in IMFs by a Tpl2 kinase-independent pathway.

DOI： 10.4049/jimmunol.1700614

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Juvenile-onset systemic sclerosis (jSSc) is a rare condition, having unique characteristic features compared to adult-onset SSc. Although cardiac involvement (CI) is known as a leading cause of mortality overall in SSc, the importance of CI in jSSc has not been emphasized. Here we present a 13-year-old female with jSSc overlapped with dermatomyositis (DM) complicated CI. She developed skin thickness and induration, Raynaud's phenomenon, digital pitting scars in fingertips, and skeletal myositis. Oral prednisolone and pulse methotrexate treatment led to the improvement of skin findings; however two weeks after the initiation she suddenly presented with muscle pain and dyspnea within a few days. Cardiac investigations then showed pericardiac effusion and diastolic dysfunction due to significant biventricular hypertrophy causing heart failure. As pericardiac effusion and exacerbation of skeletal myositis were evident, steroid pulse therapy was initiated. Unexpectedly, not only the myositis but also the CI including diastolic dysfunction was improved. She thereafter followed a favorable clinical course without reactivation of the CI or cardiac fibrosis. As a conclusion, close attention to CI must be paid in jSSc patients, especially when skeletal muscle involvement is evident and immunosuppressive therapy may be effective for CI in jSSc in cases where it occurs abruptly.

DOI： 10.1155/2017/1479012

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DOI： 10.1186/2193-1801-3-171

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To evaluate the parameters associated with significant gastrointestinal (GI) involvement in Henoch-Schönlein Purpura (HSP), and construct a scoring system for the identification of patients at high risk of gross blood in stools. STUDY DESIGN: Data for HSP patients hospitalized at each of seven institutes were retrospectively analyzed. Patients were divided into four groups according to the consequent severity of GI involvement. Identification of laboratory parameters at the time of admission were then used to differentiate the groups, and a scoring system to predict gross intestinal bleeding was constructed. Prognostic efficiency, correlation with the subsequent duration of abdominal pain, and association with manifestations excluding abdominal pain were also analyzed. RESULTS: An analysis of variance (ANOVA) test showed significant intergroup differences in white blood cell (WBC) count, neutrophil count, serum albumin, potassium, plasma D-dimer and coagulation factor XIII activity. A scoring system consisting of these parameters showed a good prognostic value for gross intestinal bleeding in a receiver operating characteristic (ROC) analysis, and a cut-off value of 4 points showed a sensitivity of 90.0% and specificity of 80.6%. The score was also correlated with the duration of abdominal pain after admission. A significantly higher score (s) was observed in patients presenting with nephritis, although the predictive value was poor. CONCLUSION: A scoring system consisting of generally available parameters was of use in predicting severe GI involvement in HSP patients. Although further study is needed, initial therapy in accordance with disease activity may be taken into consideration using this scoring system.

DOI： 10.1186/2193-1801-3-171

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DOI： 10.1136/archdischild-2012-302230

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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BACKGROUND: Disseminated neonatal herpes simplex virus (HSV) infection causes a typical systemic inflammatory response syndrome and has a high mortality rate. However, the validity of anti-inflammatory intervention against this condition remains unknown. OBJECTIVES: We sought to demonstrate the sequential changes in the pathophysiology of disseminated neonatal HSV infections. STUDY DESIGN: The HSV serum copy number as well as high-mobility group box 1 (HMGB1) and cytochrome c concentrations, which predict the severity and mortality rate of sepsis, were sequentially evaluated in a patient with disseminated neonatal HSV infection caused by HSV-2. RESULTS: As the patient presented with evidence of hyper-inflammation and severe illness, we empirically undertook anti-inflammatory intervention that included the administration of prednisolone, high-dose immunoglobulin, and blood exchange therapy in addition to high-dose acyclovir (ACV) therapy. The patient survived without significant neurological sequela. We found that (1) the serum concentrations of both HMGB1 and cytochrome c were extremely high, (2) temporal increases in these biomarkers were observed after admission, and (3) interestingly, the increase in HMGB1 level preceded that of cytochrome c. These results suggested that the pathophysiology of this condition changed sequentially in a dramatic manner, and the timing of our anti-inflammatory intervention was prior to the transition of pathological status from hyper-inflammation to massive apoptosis. CONCLUSIONS: Anti-inflammatory intervention may only be effective if it is undertaken during the early phase of disseminated neonatal HSV infections.

DOI： 10.1016/j.jcv.2011.12.017

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DOI： 10.1016/j.jcv.2011.12.017

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BACKGROUND: Intrauterine transmission of cytomegalovirus (CMV) can occur even in CMV-seropositive mothers. Previous studies demonstrated re-infection with a newly acquired CMV strain during pregnancy had a major role in such transmission. Although reactivation of latently infected CMV is another plausible cause, no direct evidence has been documented. OBJECTIVES: We sought to identify the route(s) and maternal risk factor of CMV infection that occurred in consecutive pregnancies and resulted in symptomatic congenital infections. STUDY DESIGN: A newborn identified with congenital CMV infection in our newborn screening program developed hearing loss and subsequent nystagmus. The mother had a history of an elective abortion due to a severe fetal CMV infection 32 months prior to delivery of this newborn. We analyzed maternal serological changes and compared CMV genomic sequences in specimens obtained from the aborted fetus and the present case. We also analyzed immunological functions of the mother. RESULTS: Our major findings were as follows: (1) the aborted fetus and the present case were infected with the same strain. (2) The congenital infection that resulted in the abortion was due to a primary infection. (3) CMV DNA was undetectable in the mother's blood from 3 months after the abortion. These results strongly suggested that maternal viral reactivation caused the congenital infection in the present case. However, we could not find impairment of immunological functions in the mother. CONCLUSIONS: Viral reactivation in an apparently immunocompetent mother can cause symptomatic congenital CMV infection.

DOI： 10.1016/j.jcv.2010.06.021

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DOI： 10.1097/MPA.0b013e3181c65c2e

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MPA.0b013e3181c65c2e

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To clarify the impact of congenital cytomegalovirus (CMV) infection on developmental disabilities, 20 children with disabilities of unknown cause were analyzed. Five children were CMV positive and had no clinical manifestations at birth. Intracranial calcification was observed in 4 cases. Thus, congenital CMV infection is a significant cause of developmental disabilities.

DOI： 10.1086/598506

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