Successful Treatment for Hepatoblastoma in Trisomy 18: A Case Report.

Children with trisomy 18 tend to develop hepatoblastoma. Since the introduction of appropriate management for organ malfunction, individuals with trisomy 18 have come to have a longer life expectancy. However, the predisposition to hepatoblastoma becomes a significant issue for the quality of a case. Here, we present a rare multifocal hepatoblastoma involving predominantly Couinaud segments 5 and 7 in a 10-month-old boy with trisomy 18. Though the first-line cisplatin monotherapy resulted in unsatisfactory tumor shrinkage, the second-line neoadjuvant chemotherapy administrating irinotecan and vincristine gave rise to significant tumor reduction in volume, leading to the completion of partial resection of the liver without the microscopic residual disease. The patient has been free from recurrence for 44 months. Because anatomical right hepatectomy can cause circulatory instability, including acute onset of pulmonary hypertension in trisomy 18 patients, physicians should balance treatment benefits and potential adverse effects. Our successful experience utilizing a combination of efficacious and less cardiotoxic neoadjuvant chemotherapy followed by the partial hepatectomy encourages physicians to treat a patient with trisomy 18 and tackle hepatoblastoma with a genetic background.

Ventilator-induced diaphragmatic dysfunction in extremely preterm infants: a pilot ultrasound study.

To investigate the development of diaphragmatic dysfunction in ventilated extremely preterm infants (EPI) using diaphragm ultrasound (DU). EPI of less than 28 weeks' gestational age who required mechanical ventilation within six hours of birth were included in this prospective, observational study. DU was performed once a day until four days of life. End-inspiratory and end-expiratory thicknesses of the diaphragm were measured, and the diaphragm thickening fraction was calculated. A total of 20 EPI were enrolled. After intubation, there was a progressive reduction in end-inspiratory thickness of the diaphragm from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 0.092), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0). There was also a significant reduction in the diaphragm thickening fraction from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 1.0), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0).    Conclusions: This study provides the first evidence of diaphragmatic dysfunction in ventilated EPI. We demonstrated a rapid progression of ventilator-induced diaphragmatic dysfunction, with a significant reduction in diaphragm thickness and thickening fraction within 24 h of ventilation. What is Known: • Over-assistance of the ventilator suppresses respiratory effort and induces diaphragm unloading, resulting in diaphragm atrophy or dysfunction. • Diaphragmatic dysfunction contributes to prolonged ventilator dependence and poor clinical outcomes. What is New: • Most extremely preterm infants develop diaphragmatic dysfunction after intubation within 24 hours. • Diaphragm thickness and contraction ability measured by ultrasound would be important indicators of worsening breathing or respiratory outcomes.

Gravity-induced loss of aeration and atelectasis development in the preterm lung: a serial sonographic assessment.

OBJECTIVE: To assess the impact of gravity and time on the changes in the distribution patterns of loss of aeration and atelectasis development in very preterm infants. STUDY DESIGN: Preterm infants less than 32 weeks gestation were included in this prospective, observational study. Infants were assessed via serial lung ultrasound (LUS) score in four lung zones, performed on days 7, 14, 21, and 28 after birth. RESULT: Eighty-eight patients were enrolled. There was a significant main effect of gravity (P < 0.001) and time (P = 0.01) on the LUS score between gravity-dependent lungs and non-dependent lungs. Moreover, there was a significant main effect of gravity (P = 0.003) on atelectasis development between the lungs. CONCLUSION: Gravity and time have an impact on the changes in the distribution patterns of gravity-induced lung injuries in preterm infants.

Podocyte sphingomyelin phosphodiesterase acid-like 3b decreases among children with idiopathic nephrotic syndrome.

AIM: Sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b), a regulator of the cytoskeleton, is expressed on podocytes. Recent reports present evidence that it is directly targeted by rituximab in the treatment of intractable nephrotic syndrome. However, the implications of SMPDL-3b for treatment of paediatric-onset idiopathic nephrotic syndrome (INS) remain unclear. This study aimed to investigate the level of expression of SMPDL-3b in urine, serum, and biopsy specimens and explore its implications in treatment of patients with INS. METHODS: Levels of urinary SMPDL-3b among 31 patients (20 in remission and 11 in relapse) with INS were analysed by dot blotting. For reference of precise quantitative analysis, we examined urinary excretion of SMPDL-3b from 10 patients with INS by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in both remitted and relapsed status. The levels of serum SMPDL-3b among 20 patients (13 in remission and 7 in relapse or onset) with INS were also measured using enzyme-linked immunosorbent assay. Further, the immunoreactivity of SMPDL-3b in the biopsy specimens obtained from patients with INS was compared with those from patients with proteinuric IgA nephropathy, lupus nephritis, and non-proteinuric controls. RESULTS: Urinary excretion of SMPDL-3b in patients with INS was significantly decreased in relapse cases compared with cases of remission and other types of proteinuric glomerular disease or controls by both dot blotting and LC-MS/MS method. On the other hand, serum SMPDL-3b level in INS was not different between cases of remission and relapse. Glomerular immunoreactivity of SMPDL-3b in patient with INS in remission was almost the same level to that of control. CONCLUSION: The expression of SMPDL-3b on podocytes is specifically decreased in paediatric-onset INS and its urinary excretion level reflects such conditions.

ISG56 is involved in CXCL10 expression induced by TLR3 signaling in BEAS-2B bronchial epithelial cells.

Purpose and aim of the study: Bronchial epithelial cells play an important role in immune response against viral infections. Toll-like receptor 3 (TLR3) is a pathogen recognition receptor that recognizes viral double-stranded RNA (dsRNA). Activation of TLR3 induces the expression of interferon (IFN)-ß, and newly synthesized IFN-ß exhibits anti-viral activity by upregulating the expression of IFN-stimulated genes (ISGs). ISG56 encodes a multifunctional protein with tetratricopeptide motifs and is involved in anti-viral reactions through various mechanisms. Expression of chemokines such as CXCL10, which induces leukocyte chemotaxis, is essential for defense against airway microbes. However, regulation of chemokine expression by ISG56 in bronchial epithelial cells has not been fully investigated. The aim of this study was to examine the expression of ISG56 and its role in CXCL10 production in BEAS-2B bronchial epithelial cells treated with dsRNA.Materials and methods: BEAS-2B bronchial epithelial cells were treated with polyinosinic-polycytidylic acid (poly IC), a synthetic TLR3 ligand. The mRNA and protein expression levels of ISG 56 were analyzed by quantitative reverse transcription polymerase chain reaction and western blotting. The effect of knocking down TLR3, IFN-ß, and ISG56 was examined using RNA interference. The protein expression of CXCL10 in culture medium was measured using an enzyme-linked immunosorbent assay.Results: Poly IC induced ISG56 expression in a concentration- and time- dependent manner. RNA interference showed that ISG56 induction was inhibited by knockdown of TLR3 or IFN-ß and that ISG 56 knockdown decreased CXCL10 expression.Conclusions: ISG56 was induced by poly IC through TLR3/IFN-ß axis, and ISG56 may positively regulated CXCL10 expression in BEAS-2B cells. ISG56 may modulate anti-viral innate immunity, at least in part, by regulating the expression of CXCL10 in bronchial epithelial cells.

Endothelial expression of fractalkine (CX3CL1) is induced by Toll-like receptor 3 signaling in cultured human glomerular endothelial cells.

Background: Endothelial expression of membrane-bound fractalkine/CX3CL1 (Fkn) reportedly acts as a strong mediator of inflammation. Toll-like receptor 3 (TLR3) axes are thought to play some roles in the development of chronic glomerulonephritis (CGN) including lupus nephritis (LN). However, detailed mechanism of TLR3-mediated Fkn expression in glomerular endothelial cells (GECs) remains to be elucidated.Methods: We examined the effect of polyinosinic-polycytidylic acid (poly IC) on Fkn expression in cultured human GECs. Fkn mRNA and protein levels were quantified by real-time PCR and enzyme-linked immunosorbent assay, respectively. To further elucidate the effects of poly IC on this signaling pathway, we used small-interfering RNA (siRNA) to knockdown expression of TLR3, nuclear factor (NF)-κB p65, interferon (IFN)-ß, and IFN regulatory factor 3 (IRF3). We then analyzed whether pretreatment of chloroquine or dexamethasone (DEX) inhibits poly IC-induced Fkn expression.Results: We found that poly IC-induced Fkn expression in GECs, and that this involved NF-κB, IFN-ß, and IRF3. Pretreating cells with chloroquine, but not DEX attenuated poly IC-induced Fkn expression in GECs.Conclusion: Since the activation of TLR3/NF-κB/IFN-ß/Fkn and TLR3/IRF3/Fkn axes is involved in inflammatory reactions in GECs, intervention of glomerular TLR3 signaling may be a suitable therapeutic strategy for treating CGN especially LN.

Cytosolic Sensors of Viral RNA Are Involved in the Production of Interleukin-6 via Toll-Like Receptor 3 Signaling in Human Glomerular Endothelial Cells.

BACKGROUND/AIMS: Dysregulation of interleukin-6 (IL-6) production in residual renal cells may play a pivotal role in the development of glomerulonephritis (GN). Given that Toll-like receptor 3 (TLR3) signaling has been implicated in the pathogenesis of some forms of GN, we examined activated TLR3-mediated IL-6 signaling in cultured normal human glomerular endothelial cells (GECs). METHODS: We treated GECs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of IL-6 and the cytosolic viral RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) using reverse transcription quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays. To further elucidate the effects of poly IC on this signaling pathway, we subjected the cells to small interfering RNA (siRNA) against TLR3, interferon (IFN)-ß, RIG-I, and MDA5. RESULTS: We found that poly IC induced the expression of RIG-I, MDA5 and IL-6 via TLR3/IFN-ß signaling in GECs. siRNA experiments revealed that both MDA5 and RIG-I were involved in the poly IC-induced expression of IL-6, with MDA5 being upstream of RIG-I. CONCLUSION: Interestingly, cytosolic sensors of viral RNA were found to be involved in IL-6 production via TLR3 signaling in GECs. Regional activation of TLR3/IFN-ß/ MDA5/RIG-I/IL-6 axis due to viral and "pseudoviral" infections is involved in innate immunity and inflammatory reactions in GECs. We believe this signaling pathway also plays a pivotal role in the development of some forms of GN.

Chloroquine attenuates TLR3-mediated plasminogen activator inhibitor-1 expression in cultured human glomerular endothelial cells.

BACKGROUND: Chloroquine, an antimalarial agent, has been reported to prevent the risk of thrombosis and decrease renal damage in patients with systemic lupus erythematosus (SLE); however, its detailed mechanisms remain unclear. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis and is involved in fibrin deposition in glomeruli. Since upregulation of glomerular Toll-like receptor 3 (TLR3) signaling reportedly plays a pivotal role in the pathogenesis of lupus nephritis (LN), we examined whether chloroquine affects TLR3-mediated expression of PAI-1 in cultured human glomerular endothelial cells (GECs). METHODS: We examined the effect of polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, on PAI-1 and tissue plasminogen activator (t-PA) expression in GECs. Then, we analyzed whether pretreatment of chloroquine or dexamethasone inhibits poly IC-induced expression of these proteins using reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Poly IC increased PAI-1 expression in a time- and concentration-dependent manner, but did not affect t-PA expression in GECs. RNA interference against TLR3 inhibited poly IC-induced PAI-1 expression. Interestingly, pretreating cells with chloroquine, and also hydroxychloroquine, but not dexamethasone, attenuated poly IC-induced PAI-1 expression in GECs. CONCLUSION: Considering that TLR3 signaling is implicated in LN pathogenesis, our results suggest that chloroquine exert postulated renoprotective effects by inhibiting PAI-1 expression.

Interferon-stimulated gene 60 (ISG60) constitutes a negative feedback loop in the downstream of TLR3 signaling in hCMEC/D3 cells.

Brain capillary endothelial cells are the component of blood brain barrier, and the first line of defense against viruses invading into brain. We demonstrate that treatment of hCMEC/D3 cells, a human brain capillary endothelial cell line, with a Toll-like receptor 3 (TLR3) agonist polyinosinic-polycytidylic acid (poly IC) induces the expression of interferon (IFN)-stimulated gene 60 (ISG60), and this reaction was mediated by IFN-ß. Knockdown of ISG60 increased the poly IC-induced expression of IFN-ß and an IFN-ß-inducible chemokine CXCL10. This indicates that ISG60 constitutes a negative feedback loop in the downstream of TLR3/IFN-ß. ISG60 in brain capillary endothelial cells may contribute to prevent excess immune reactions associated with viral infections.

Severe intrinsic acute kidney injury associated with therapeutic doses of acetaminophen.

Acetaminophen is a commonly used medication to manage fever and pain in children and the drug is generally considered to be safe when used at appropriate therapeutic dosages. Recently, we encountered the case of a 3-year-old Japanese girl who suffered from severe intrinsic acute kidney injury (AKI) after therapeutic doses of acetaminophen for a fever due to viral infection. Renal biopsy indicated severe acute tubular necrosis with a significant striped interstitial fibrosis and mild interstitial inflammation. Unfortunately, she developed chronic kidney disease thereafter. This is the youngest case of biopsy-proven severe intrinsic AKI associated with therapeutic doses of acetaminophen. Acetaminophen, even if administered at therapeutic dosages, may be dangerous in selected children, especially with possible pre-existing volume depletion.