Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Non-invasive intravital observation of lingual surface features using sliding oral mucoscopy techniques in clinically healthy subjects.

To investigate intravital morphological features of the broader area of the lingual mucosa in clinically healthy subjects, and to attempt to evaluate subclinical conditions, we evaluated detailed intravital morphological features of the lingual mucosa using our newly developed oral contact mucoscopy techniques. Clinically healthy subjects (female: 19-22 years, average age: 20.27 years, and n = 28) were enrolled. A position indicator stain was placed on the lingual mucosal surface, and sliding images were captured and then reconstructed. In addition, the lingual mucosa was divided into six areas, and morphometry of the fungiform and filiform papillae was performed. The results were statistically analyzed. There were two morphological features among clinically healthy subjects involving the filiform papillae: the length of the papillae and the degree of biofilm (tongue coat) deposition. We defined a modified tongue coat index (mTCI) with scores ranging from 0 (tongue coating not visible) to 0.5, 1, 1.5, and 2 (thick tongue coating) for six sections of the tongue dorsum. No subjects received a score of 2. Significant differences were found in the mTCI between the six sections of the tongue dorsum, especially between the posterior areas and the lingual apex. The fungiform papillae of some subjects exhibited elongated morphological changes. Our findings suggest that magnified lingual dorsum examination of a broader area is especially important in accurate screening for subclinical or transient conditions of potential lingual mucosal diseases. For this purpose, our new oral mucoscopy and non-invasive intravital observational techniques were especially effective.

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Clinical characteristics of pediatric febrile urinary tract infection in Japan.

BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.

Phenotypical variety of insulin resistance in a family with a novel mutation of the insulin receptor gene.

A novel mutation of insulin receptor gene (INSR gene) was identified in a three generation family with phenotypical variety. Proband was a 12-year-old Japanese girl with type A insulin resistance. She showed diabetes mellitus with severe acanthosis nigricans and hyperinsulinemia without obesity. Using direct sequencing, a heterozygous nonsense mutation causing premature termination at amino acid 331 in the alpha subunit of INSR gene (R331X) was identified. Her father, 40 years old, was not obese but showed impaired glucose tolerance. Her paternal grandmother, 66 years old, has been suffered from diabetes mellitus for 15 years. Interestingly, they had the same mutation. One case of leprechaunism bearing homozygous mutation at codon 331 was identified. These findings led to the hypothesis that R331X may contribute to the variation of DM in the general population in Japan. An extensive search was done in 272 participants in a group medical examination that included 92 healthy cases of normoglycemia and 180 cases already diagnosed type 2 DM or detected hyperglycemia. The search, however, failed to detect any R331X mutation in this local population. In addition, the proband showed low level C-peptide/insulin molar ratio, indicating that this ratio is considered to be a useful index for identifying patients with genetic insulin resistance. In conclusion, a nonsense mutation causing premature termination after amino acid 331 in the alpha subunit of the insulin receptor was identified in Japanese diabetes patients. Further investigations are called for to address the molecular mechanism.

Johanson-blizzard syndrome: loss of glucagon secretion response to insulin-induced hypoglycemia.

Johanson-Blizzard syndrome is a rare autosomal recessive disorder characterized by aplasia of the alae nasi, aplasia cutis, dental anomalies, postnatal growth retardation and pancreatic exocrine aplasia. Some endocrinological dysfunctions--growth hormone (GH) deficiency, hypothyroidism, and diabetes mellitus--are known to complicate this syndrome. We report here a Japanese infant with Johanson-Blizzard syndrome presenting with failure to thrive. Endocrinological examination by insulin-induced hypoglycemia showed not only the presence of GH deficiency, but also the loss of the glucagon secretion response to hypoglycemia. This complication suggests abnormal input of autonomic nerves to the islets of pancreas in Johanson-Blizzard syndrome.

A case report of pediatric fulminant hepatitis treated with plasma diafiltration.

Plasma diafiltration (PDF) is blood purification therapy in which simple plasma exchange is performed with a membrane plasma separator while dialysate flows outside the hollow fibers. A 14-year-old boy with fulminant hepatitis underwent two sessions of PDF and one session of hemodiafiltration. We infused filtered replacement fluid for artificial kidneys at a dialysate flow rate of 600 mL/h and a replacement flow rate of 450 mL/h. We infused fresh frozen plasma (1200 mL) and 25% albumin solution (50 mL) intravenously over 8 h. Each PDF session lasted 8 h. The patient's total bilirubin, interleukin-18, and cystatin C levels decreased with treatment, and he recovered from hepatic failure. PDF may be an extremely useful blood purification therapy for pediatric fulminant hepatitis in terms of both medical economics and cytokine removal.

Pulse methylprednisolone therapy in type 3 adenovirus pneumonia with hypercytokinemia.

Adenovirus pneumonia is uncommon but its severe infection has a mortality as high as 10%, and survivors may have residual airway damages, manifested by bronchiectasis, bronchiolitis obliterans, or pulmonary fibrosis. We report a case of adenovirus pneumonia demonstrating fatal respiratory distress. Adenovirus was isolated from pharyngeal specimens using cell culture and typed as serotype 3 by a combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. The patient characteristically showed hypercytokinemia, characterized by increased levels of lactate dehydrogenase, ferritin, and several cytokines including interferon-gamma and interleukin-6. We treated the patient with pulse methylprednisolne therapy (25 mg/kg/day, for 3 days), resulting in the rapid amelioration of respiratory distress. This is the first report describing the treatment of pulse methylprednisolone therapy in fatal adenovirus pneumonia. During the clinical course, serum Krebs von den Lungen-6 (KL-6), which is a marker for the activity of diffuse interstitial lung disease, was elevated, suggesting that serum KL-6 could be available as a marker of pulmonary prognosis in viral pneumonia.

Split notochord syndrome: ileal duplication causing intermittent episodes of vomiting.

Split notochord syndrome is a group of developmental abnormalities caused by abnormal splitting or deviation of the notochord, clinically resulting in the duplicated bowel associated with vertebral anomalies. In this syndrome, initial presentations due to duplicated bowel, vomiting, abdominal pain, and failure to thrive, usually occur before 1 year of age. We here report a 12-year-old boy with intermittent vomiting, previously diagnosed with cyclic vomiting syndrome. On abdominal x-ray examination, a defect in the closure of posterior vertebral arches was observed in the 5th lumbar vertebral body, indicating the complication of spina bifida occulta. This finding suggested the diagnosis of split notochord syndrome. A magnetic resonance imaging study revealed a cystic mass lesion in the pelvic cavity. (99m)Tc-pertechnetate scintigraphy, which is frequently used to detect ectopic gastric mucosa for the diagnosis of Meckel's diverticulum, showed a positive spot corresponding to the cystic mass lesion. Surgical resection of the cystic mass lesion demonstrated ileal duplication with ectopic gastric mucosa. Surgical findings suggest that symptoms of the patient were due to ulceration, inflammation, or bleeding caused by acid-peptic juice secreted from ectopic gastric mucosa. Duplication of the alimentary tract should be considered as a possible cause in patients with symptoms suggesting cyclic vomiting syndrome.

Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese.

Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure. One Japanese patient with renal hypouricemia demonstrated compound heterozygous mutations of the URAT1 gene (Q297X and IVS2+1G>A). It was suggested that these two mutations are recurrent mutations of the URAT1 gene in a Japanese population. In addition, we expect the prevalence of renal hypouricemia, 0.23%, from the analysis of serum urate levels in 1,730 Japanese children.

Multicentric osteosarcoma with long-term survival.

We present a 14-year-old girl with multicentric osteosarcoma who has survived for over 9 years to date. The patient first noticed right knee pain in 1992. Radiographs showed a destructive and sclerotic lesion of the right distal femur. Similar small sclerotic lesions were seen in the proximal metaphysis of the right femur, proximal site of the right humerus, and mid-posterior of the left humerus. A diagnosis of multicentric osteosarcoma was made on a biopsy of the right distal femur. The sclerotic lesions of the bilateral humeri disappeared after systemic chemotherapy (T-20), and thus wide excisions of the right distal femur and proximal femur were performed in 1993. New lesions appeared in the left iliac bone and the first lumbar vertebra on bone scintigraphy 24 months after the first surgery. Chemotherapy and wide excisions of the left iliac bone and the first lumbar vertebra were performed. The patient was well at the latest follow-up in April 2003, with no evidence of local recurrence or distant metastasis, but recently renal dysfunction appeared.

Merit of the cuff-shaving procedure in children with chronic infection.

Catheter replacement and cuff-shaving are per-formed as a surgical treatment against tunnel infection(TI) in patients on chronic peritoneal dialysis. The efficacy of catheter replacement is well established, but that of cuff-shaving is not. For the purpose of evaluating the efficacy of cuff-shaving, we compared the time interval between each procedure and subsequent TI. In order to perform this comparison, we reviewed data from 32 cuff-shaving procedures and 29 catheter replacement procedures at Tokyo Metropolitan Kiyose Children's Hospital in the period from 1 March 1991 to 1 May 2001, retrospectively. There was no significant difference in the time interval between each procedure and subsequent TI(P=0.284). The incidence of recurrence was no more than 12.5% for the cuff-shaving procedures. The incidence of peritonitis due to post-surgery TI with the cuff-shaving procedures was 9.3% and 6.8% with the replacement procedure (P=0.725). There was no significant variation in time interval to post-cuff-shaving TI according to the reason for the cuff-shaving procedure. In conclusion,cuff-shaving may be worth considering for TI in adequately selected patients.

Renovascular hypertension due to antithrombin deficiency in childhood.

Inherited antithrombin deficiency generally causes a predisposition toward vascular thrombus above the age of 15 years. A 1-year-old boy developed renal hypertension caused by renal artery obstruction due to thrombus formation. This thrombus formation was attributed to antithrombin deficiency caused by a novel SERPINCI gene mutation (AT III Akita, M352R). This suggests that antithrombin deficiency can cause renal artery obstruction, inducing renal hypertension through vascular thrombosis even in children.

Involvement of endothelial cell adhesion molecules in the development of anti-Thy-1 nephritis.

To study an involvement of glomerular endothelial cells in the development of anti-Thy-1 nephritis, we examined the expression of endothelial cell adhesion molecules during the course of this model. Ribonuclease protection assay elucidated that expression of mRNA for intercellular adhesion molecule-1 (ICAM-1) was markedly enhanced in the glomeruli with a peak at 2 h (6.5-fold, p < 0.05) after the anti-Thy-1 antibody injection when mesangial cell lysis was recognized and IL-1beta mRNA expression was induced in the glomeruli. The glomerular ICAM-1 was predominantly localized in the endothelial cells and was intensely immunostained at day 1 in the glomerular endothelial cells. In contrast, platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial-cadherin mRNA expression increased gradually with a peak at day 6 (2.6-fold (p < 0.05) and 4.2-fold (p < 0.05), respectively) in the glomeruli with mesangial proliferative lesion. PECAM-1 was also immunolocalized in the glomerular endothelial cells and the immunoreactivity was greatly enhanced at day 6. Glomerular expression of vascular cell adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 (E-selectin) was unchanged at a low level during the course of anti-Thy-1 nephritis. Blocking of ICAM-1 by administration of anti-ICAM-1 antibody showed significant decrease in the number of polymorphonuclear leukocytes accumulating in the glomeruli by 45.7% (9.4 +/- 0.2 vs. 5.1 +/- 0.1 per glomerular cross section, p < 0.01) at 2 h. These results suggest a significant involvement of glomerular endothelial cells in the development and repair of anti-Thy-1 nephritis via direct or indirect intercellular interactions between mesangial cells and glomerular endothelial cells.