Long-Term Control of Macular Edema With Adalimumab After Cataract Surgery in a Japanese Child With Juvenile Idiopathic Arthritis: Case Report and Review of 26 Japanese Patients

Juvenile idiopathic arthritis-associated uveitis is rare in the Japanese population. In this article, we report a child whose macular edema was controlled for years after cataract surgery with adalimumab, and reviewed 26 Japanese patients in the literature. In this case report, a 4-year-old boy developed band keratopathy, posterior iris synechiae, and complicated cataract in both eyes. Oral prednisolone prescribed at another hospital was discontinued due to high intraocular pressure in both eyes as a steroid responder. At the age of 5 years, he started oral methotrexate 8 mg weekly for recurrent bilateral iridocyclitis and then underwent lensectomy with core vitrectomy in both eyes. Planned intraocular lens implantation was cancelled at surgery because the anterior vitreous had severe inflammatory opacity with diffuse retinal edema in both eyes. Due to persistent macular edema in both eyes 5 months postoperatively, at the age of 6 years, he began to use adalimumab injection 20 mg every 2 weeks. The macular structure depicted by optical coherence tomography became normal in 2 months. At final visit at the age of 11 years, he had the best-corrected visual acuity of 0.8 in the right eye and 0.4 in the left eye, with adalimumab 40 mg every 2 weeks and methotrexate 8 mg weekly. In conclusion, macular edema persistent despite oral methotrexate after cataract surgery could be controlled for long term by adalimumab in a child with juvenile idiopathic arthritis. In the Japanese literature, only 26 additional cases with juvenile idiopathic arthritis-associated uveitis have been reported so far

Bilateral Optic Disc Swelling as a Plausible Common Ocular Sign of Autoinflammatory Diseases: Report of Three Patients with Blau Syndrome or Cryopyrin-Associated Periodic Syndrome

The aim of this study is to describe bilateral optic disc swelling in three consecutive patients with Blau syndrome or cryopyrin-associated periodic syndrome at a single institution. Case 1 was a 30-year-old woman receiving 25 mg etanercept twice weekly who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 5 months old and genetically diagnosed with Blau syndrome with CARD15/NOD2 mutation (N670K) at 13 years old. At 10 years old, she began to have uveitis with optic disc swelling in both eyes, resulting in macular degeneration and optic disc atrophy at 17 years old only when etanercept was introduced. Case 2 was a 21-year-old man receiving adalimumab every 2 weeks who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 1.5 years old and genetically diagnosed as Blau syndrome with CARD15/NOD2 mutation (C495Y) at 5 years old. At 8 years old, around the time of adalimumab introduction, he began to show bilateral optic disc swelling which continued until the age of 16 years when the dose of adalimumab was increased. Case 3 was a 20-year-old woman receiving canakinumab every 8 weeks for systemic symptoms such as fever, headache, vomiting, and abdominal pain and later for sensorineural hearing disturbance on both sides. She had been diagnosed genetically with cryopyrin-associated periodic syndrome with NLRP3 mutation (Y859C) at 7 years old. At 5 years old, she was found to have bilateral optic disc swelling, which continued until the age of 10 years when she began receiving canakinumab (IL-1β inhibitor). Bilateral optic disc swelling might be tentatively designated as a plausible common ocular feature, if it occurred, in autoinflammatory diseases to pay more attention to ophthalmic complications in rare diseases

Correlation between national surveillance and search engine query data on respiratory syncytial virus infections in Japan

Background The respiratory syncytial virus (RSV) disease burden is significant, especially in infants and children with an underlying disease. Prophylaxis with palivizumab is recommended for these high-risk groups. Early recognition of a RSV epidemic is important for timely administration of palivizumab. We herein aimed to assess the correlation between national surveillance and Google Trends data pertaining to RSV infections in Japan. Methods The present, retrospective survey was performed between January 1, 2018 and November 14, 2021 and evaluated the correlation between national surveillance data and Google Trends data. Joinpoint regression was used to identify the points at which changes in trends occurred. Results A strong correlation was observed every study year (2018 [r = 0.87, p < 0.01], 2019 [r = 0.83, p < 0.01], 2020 [r = 0.83, p < 0.01], and 2021 [r = 0.96, p < 0.01]). The change-points in the Google Trends data indicating the start of the RSV epidemic were observed earlier than by sentinel surveillance in 2018 and 2021 and simultaneously with sentinel surveillance in 2019. No epidemic surge was observed in either the Google Trends or the surveillance data from 2020. Conclusions Our data suggested that Google Trends has the potential to enable the early identification of RSV epidemics. In countries without a national surveillance system, Google Trends may serve as an alternative early warning system

Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of beta-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS

Inhibitory Effects of Edaravone, a Free Radical Scavenger, on Cytokine-induced Hyperpermeability of Human Pulmonary Microvascular Endothelial Cells:A Comparison with Dexamethasone and Nitric Oxide Synthase Inhibitor

Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the trans-human PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α＋IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS

Idiopathic Chondrolysis of the Hip Treated by Immunosuppressive Therapy and Arthroscopic Intervention

Idiopathic chondrolysis of the hip (ICH), a very rare disorder of unknown etiology, occurs mainly in female adolescents. Characterized by pain, limp, stiffness and radiological narrowing joint space from the rapid destruction of the articular cartilage, ICH sometimes results in ankyloses. We present the case of a 10-year-old girl diagnosed with ICH based on arthroscopic inspection and synovium biopsy. The femoral deformity appeared gradually, like a cam-type femoroacetabular impingement. She was treated with intensive rehabilitation and immunosuppressive drug. We later performed an arthroscopic bumpectomy for residual symptoms. She achieved a favorable outcome as a 15-year-old at the latest follow-up

Successful use of dupilumab for egg-induced eosinophilic gastroenteritis with duodenal ulcer: a pediatric case report and review of literature

Background Non-esophageal eosinophilic gastrointestinal disorder (non-EoE-EGID) is a rare disease in which eosinophils infiltrate parts of the gastrointestinal tract other than the esophagus; however, the number of patients with non-EoE-EGID has been increasing in recent years. Owing to its chronic course with repeated relapses, it can lead to developmental delays due to malnutrition, especially in pediatric patients. No established treatment exists for non-EoE-EGID, necessitating long-term systemic corticosteroid administration. Although the efficacy of dupilumab, an anti-IL-4/13 receptor monoclonal antibody, for eosinophilic esophagitis, has been reported, only few reports have demonstrated its efficacy in non-EoE EGIDs. Case presentation A 13-year-old boy developed non-EoE-EGID with duodenal ulcers, with chicken eggs as the trigger. He was successfully treated with an egg-free diet, proton pump inhibitors, and leukotriene receptor antagonists. However, at age 15, he developed worsening upper abdominal pain and difficulty eating. Blood analysis revealed eosinophilia; elevated erythrocyte sedimentation rate; and elevated levels of C-reactive protein, total immunoglobulin E, and thymic and activation-regulated chemokines. Upper gastrointestinal endoscopy revealed a duodenal ulcer with marked mucosal eosinophilic infiltration. Gastrointestinal symptoms persisted even after starting systemic steroids, making it difficult to reduce the steroid dose. Subcutaneous injection of dupilumab was initiated because of comorbid atopic dermatitis exacerbation. After 3 months, the gastrointestinal symptoms disappeared, and after 5 months, the duodenal ulcer disappeared and the eosinophil count decreased in the mucosa. Six months later, systemic steroids were discontinued, and the duodenal ulcer remained recurrence-free. The egg challenge test result was negative; therefore, the egg-free diet was discontinued. Blood eosinophil count and serum IL-5, IL-13, and eotaxin-3 levels decreased after dupilumab treatment. The serum levels of IL-5 and eotaxin-3 remained within normal ranges, although the blood eosinophil counts increased again after discontinuation of oral prednisolone. Conclusions Suppression of IL-4R/IL-13R-mediated signaling by dupilumab may improve abdominal symptoms and endoscopic and histologic findings in patients with non-EoE-EGID, leading to the discontinuation of systemic steroid administration and tolerance of causative foods

Serum Procalcitonin Levels in Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion

Procalcitonin (PCT) is used as a biomarker in severe infections. Here, we retrospectively investigated levels of serum PCT, C-reactive protein (CRP), and inflammatory cytokines (IL-6, TNF-alpha, and IFN-gamma) in the second phase of patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). Nine AESD pediatric patients (4 men, 5 women; AESD group) admitted to Okayama University Hospital from 2010 to 2016 were compared with 10 control patients with febrile seizures (FS) (3 men, 7 women; FS group). Mean PCT concentrations (ng/mL) in the AESD and FS groups were significantly different, at 9.8 +/- 6.7 and 0.8 +/- 0.9, respectively (p = 0 0006). CRP (mg/dL) were 0.79 +/- 0.89 and 1.4 +/- 1.0 (p = 0 94), respectively; IL-6 (pg/mL) were 449.7 +/- 705.0 and 118.3 +/- 145.4 (p = 0 20), respectively; TNF-alpha (pg/mL) were 18.6 +/- 12.5 and 16.6 +/- 6.0 (p = 0 67), respectively; and IFN-gamma (pg/mL) were 79.6 +/- 158.5 and 41.9 +/- 63.7 (p = 0 56), respectively. Ratios of PCT to CRP were 27.5 +/- 34.2 and 3.2 +/- 6.8 (p < 0 0001), respectively. The sensitivity and specificity in the diagnosis of AESD using a cutoff of PCT/CRP ratio of 1.0 were 79% and 100%, respectively. These results suggest that PCT and the PCT/CRP ratio are useful in auxiliary diagnosis of the second stage of AESD, and in AESD, PCT is likely to increase through a different mechanism

Epidemiology of Pediatric Acute Encephalitis/Encephalopathy in Japan

We studied the etiology of pediatric acute encephalitis/encephalopathy (pAEE) using epidemiological data obtained from a nationwide survey in Japan. Two-step questionnaires were sent to the pediatric departments of hospitals throughout the country in 2007, querying the number of the cases during 2005-2006 as the first step, and asking for the details of clinical information as the second step. In all, 636 children with pAEE (age ≤ 15 years) were enrolled. For the known etiology of pAEE (63.5% of the total cases), 26 microbes and 2 clinical entities were listed, but the etiology of 36.5% remained unknown. Influenza virus (26.7%), exanthem subitum (12.3%), and rotavirus (4.1%) were the most common, and the incidence of pAEE peaked at the age of 1 year. This trend was common among all etiologies. Among the neurological symptoms observed at the onset of pAEE, seizures were observed more often in patients aged ≤ 3 years, although abnormal speech and behavior were also common in older children. Undesirable outcomes (death and neurological sequelae) occurred at high rates in patients with any known etiology other than mycoplasma. In conclusion, these findings provide comprehensive insight into pAEE in Japan

Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: relation to maternal and neonatal characteristics

This study examined the clinical and biological importance of thioredoxin-1, a redox-active defensive protein that controls multiple biological functions, in pregnant women. We measured serum concentrations of thioredoxin-1, total hydroperoxides, and redox potential in 60 pregnant women at the early third trimester: gestational age of 27-29 weeks. The thioredoxin-1 concentration (mean +/- SD) was 90 +/- 42 ng/ml. Total hydroperoxides was 471 +/- 105 U.CARR (1 U.CARR = 0.08 mg/dl H2O2). Redox potential was 2142 +/- 273 mu mol/l. The total hydroperoxides: redox potential ratio (oxidative stress index) was 0.23 +/- 0.08. Thioredoxin-1, total hydroperoxides, and oxidative stress index were higher and redox potential was lower than in blood of healthy adults. Total hydroperoxides and redox potential were mutually correlated significantly and negatively. Thioredoxin-1 correlated significantly and negatively and redox potential correlated significantly and positively with body weight and body mass index. Thioredoxin-1 and redox potential correlated significantly and positively with uric acid and albumin, respectively. Thioredoxin-1 and oxidative stress index correlated significantly and negatively and redox potential significantly and positively with neonatal birth weight. These results suggest that high concentrations of thioredoxin-1 are linked to high oxidative stress status in pregnant women and that neonatal birth weight is affected by the maternal oxidative condition during later pregnancy