Drug-induced crystalluria attributable to tosufloxacin in children.

BACKGROUND: Drug-induced crystalluria is reportedly caused by a large number of drugs. Tosufloxacin (TFLX), a second-generation fluoroquinolone antibiotic, is reported to cause kidney injury and crystalluria. We retrospectively analyzed patients with crystalluria caused by TFLX to clarify the clinical course of TFLX-induced crystalluria in children. METHODS: This study was designed as a retrospective case series using the database of the National Center for Global Medicine covering the period from January 1, 2020 to March 31, 2021. We enrolled pediatric patients aged 15 years or younger with crystalluria attributable to TFLX treated in our pediatric department and collected clinical data. RESULTS: Thirteen patients were diagnosed with crystalluria attributable to TFLX. The median age of the patients at diagnosis was 4.0 years (range, 0.8-15 years; interquartile range = 1.2-8.8 years), and five patients (38%) were male. Six patients (46%) had gastrointestinal symptoms such as vomiting and abdominal pain, and 12 patients (92%) had decreased oral intake. The median time to diagnosis after TFLX administration was 4 days (range, 2-7 days; interquartile range = 3-6 days). All patients received TFLX at the appropriate dose. Two patients (17%) were diagnosed with acute kidney injury, and both had gastrointestinal symptoms such as vomiting and abdominal pain. CONCLUSIONS: Crystalluria induced by TFLX occurred despite administration of the appropriate dose of TFLX. Physicians should recognize crystalluria and renal injury attributable to TFLX. It may be possible to prevent renal injury by discontinuing drug therapy.

Case Report: Ciclosporin A for Refractory Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a new syndrome involving the development of severe dysfunction in multiple organs after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Because the pathophysiology of MIS-C remains unclear, a treatment strategy has not yet been established. We experienced a 12-year-old boy who developed MIS-C at 56 days after SARS-CoV-2 infection and for whom ciclosporin A (CsA) was effective as a third-line treatment. He had a high fever on day 1, and developed a rash on the trunk, swelling in the cervical region, and palmar erythema on day 2. On days 3, he developed conjunctivitis and lip redness, and fulfilled the criteria for classical Kawasaki disease (KD). Although intravenous immunoglobulin infusion (IVIG) was started on day 4, fever persisted and respiratory distress and severe abdominal pain developed. On day 5, because he fulfilled the criteria for MIS-C, methylprednisolone pulse was started for 3 days as a second-line treatment. However, he did not exhibit defervescence and the symptoms continued. Therefore, we selected CsA as a third-line treatment. CsA was so effective that he became defervescent and his symptoms disappeared. In order to clarify the relationship with treatment and the change of clinical conditions, we examined the kinetics of 71 serum cytokines to determine their relationships with his clinical course during the three successive treatments. We found that CsA suppressed macrophage-activating cytokines such as, IL-12(p40), and IL-18 with improvement of his clinical symptoms. CsA may be a useful option for additional treatment of patients with MIS-C refractory to IVIG + methylprednisolone pulse.

Case Report: Changes in Cytokine Kinetics During the Course of Disease in a Japanese Patient With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that is reportedly linked to coronavirus disease 2019. Affected patients present with gastrointestinal symptoms and cardiovascular dysfunction, in addition to Kawasaki disease-like features, suggesting the potential for overlapping disease mechanisms. Kawasaki disease has been reported among individuals of East Asian ethnicities, whereas there is minimal clinical literature regarding the occurrence of MIS-C among individuals of Asian ethnicities. A few reports thus far have described changes in cytokine kinetics during the course of disease in patients with MIS-C. We followed the temporal cytokine kinetics in a 9-year-old Japanese girl who exhibited a classical trajectory of MIS-C. The patient exhibited right cervical swelling and pain, abdominal pain, vomiting, and lip reddening, which developed 31 days after she was diagnosed with severe acute respiratory syndrome coronavirus-2 infection. The patient was diagnosed with Kawasaki disease on her fifth day of illness; because she fulfilled the criteria for MIS-C, she was also diagnosed with this disease on her fifth day of illness. Her fever rapidly resolved upon administration of intravenous immunoglobulin, aspirin, and prednisolone. On the patient's sixth day of illness, she developed acute myocarditis, which was treated with two diuretics and one vasodilator; the myocarditis ameliorated within a few days. Analyses of temporal kinetics for 71 serum cytokines revealed several patterns of cytokine changes that were consistent with the patient's clinical course of disease. Importantly, there was a clear distinction between cytokines that did and did not decrease rapidly following post-treatment fever resolution. These findings may be useful for the assessment of disease status and selection of therapy in patients with similar symptoms; they may also provide insights for basic and clinical research regarding MIS-C.

Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Related Microglial Activation in Neonatal Hypoxic-Ischemic Encephalopathy: Morphologic Consideration.

Neonatal hypoxic-ischemic encephalopathy (nHIE) is a major neonatal brain injury. Despite therapeutic hypothermia, mortality and sequelae remain severe. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with the pathophysiology of nHIE. In this study, morphologic change and microglial activation under the nHIE condition and LOX-1 treatment were investigated. The microglial activity and proliferation were assessed with a novel morphologic method, immunostaining, and quantitative PCR in the rat brains of both nHIE model and anti-LOX-1 treatment. Circumference ratio, the long diameter ratio, the cell area ratio, and the roundness of microglia were calculated. The correlation of the morphologic metrics and microglial activation in nHIE model and anti-LOX-1 treated brains was evaluated. LOX-1 was expressed in activated ameboid and round microglia in the nHIE model rat brain. In the evaluation of microglial activation, the novel morphologic metrics correlated with all scales of the nHIE-damaged and treated brains. While the circumference and long diameter ratios had a positive correlation, the cell area ratio and roundness had a negative correlation. Anti-LOX-1 treatment attenuated morphologic microglial activation and proliferation, and suppressed the subsequent production of inflammatory mediators by microglia. In human nHIE, round microglia and endothelial cells expressed LOX-1. The results indicate that LOX-1 regulates microglial activation in nHIE and anti-LOX-1 treatment attenuates brain injury by suppressing microglial activation.

Clinical trial of the CP stent for pulmonary artery stenosis: the first investigator-initiated clinical trial for pediatric interventional cardiology in Japan.

Stenting is an important treatment option for pulmonary artery stenosis (PS) associated with congenital heart disease (CHD). However, no stent has been approved for this indication in Japan, despite negotiation between academia and the regulatory bodies for longer than 20 years. To evaluate efficacy and safety of the CP stent, we performed the first investigator-initiated clinical trial for pediatric interventional cardiology in Japan. This trial was designed as a single-arm, prospective, clinical trial. Patients who had postoperative PS associated with CHD were included. Stenting was attempted in 24 cases and succeeded in 22 cases. The median age of the patients was 11 years (3-36 years) and weight was 38 kg (12-69 kg), while follow-up for 12 months was completed. In all 22 cases, stenting was successful, with a 50% increase in the minimum lumen diameter (MLD) in 86.4% of patients (90% confidence interval, 68.4-96.2%). The mean percent change in MLD was 119.3 ± 52.5%. In two-ventricle repair, the mean percent change in systolic right ventricular/aortic pressure was - 8.5 ± 16.1%, while that of pressure gradient was - 55.9 ± 41.7%. In single-ventricle repair, the percent change in the mean pressure gradient was - 100.0 ± 0%, while that of SaO2 was 1.4 ± 1.7%. No serious adverse events or significant restenosis was reported. The CP stent is highly effective and safe for PS associated with CHD. This study has significant importance in not only scientific but also social considerations.

Outcome of implantable cardioverter defibrillator therapy for congenital heart disease.

BACKGROUND: The use of implantable cardioverter defibrillator (ICD) therapy for congenital heart disease (CHD) has been increasing, but few studies have reported on the efficacy of ICD therapy in Japanese CHD patients. METHOD: Twelve CHD patients (median age, 35 years) with first ICD implantation were examined. Median follow-up duration was 2.9 years. Demographic information, implant electrical parameters, appropriate and inappropriate discharge data and complications were recorded for all implants from 2003 to 2010. RESULTS: Implant indication was primary prevention in two patients and secondary prevention in 10. Overall four patients received one or more discharges; three patients (25%) with secondary prevention received nine appropriate discharges. Inappropriate discharge attributed to sinus tachycardia occurred in two patients (16.7%). Only one patient experienced the late complication of skin erosion at the generator implantation site. CONCLUSIONS: Patients with CHD experienced significant rates of appropriate discharges and lower complications. But given that the indications of ICD implantation were mostly for secondary prevention, the ratio of appropriate shocks might be lower than in previous studies. In the primary prevention patients, the benefit of ICD was not clear because no appropriate discharges were seen during follow up. Although ICD implantation for CHD is beneficial for preventing sudden cardiac death, careful decision making and a large, long-term prospective study is required for the determination of the efficacy of ICD therapy in Japanese patients with CHD.