Pediatric management challenges of hyperglycemic hyperosmolar state: case series of Korean adolescents with type 2 diabetes

The hyperglycemic hyperosmolar state (HHS) is considered the most fatal complication of type 2 diabetes mellitus (DM). The number of case reports describing pediatric HHS has increased recently in parallel with obesity and the prevalence of type 2 DM in pediatric patients. In this study, we investigated the patient characteristics and outcomes of HHS in 9 adolescents with obesity and type 2 DM. Almost all patients exhibited mixed clinical features of HHS and diabetic ketoacidosis (DKA), including characteristics such as hyperosmolality and ketoacidosis. These features made definitive diagnosis difficult; 5 out of 9 patients were initially diagnosed with DKA and were treated accordingly. Patients who were initially diagnosed with HHS received a more vigorous and appropriate fluid replacement than other patients did. No patients died, although 3 exhibited complications, such as arrhythmia, acute kidney injury requiring renal replacement therapy, rhabdomyolysis, and acute pancreatitis. Hyperosmolality with consequent severe dehydration is considered a significant factor contributing to the outcomes of patients with HHS. Therefore, early recognition of hyperosmolality is crucial for an appropriate diagnosis and adequate fluid rehydration to restore perfusion in the early period of treatment to improve patient outcomes for this rare but serious emerging condition in pediatric patients.

SARS-CoV-2 Infection of Microglia Elicits Pro-inflammatory Activation and Apoptotic Cell Death

Accumulating evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes various neurological symptoms in coronavirus disease 2019 (COVID-19) patients. The most dominant immune cells in the brain are microglia. Yet, the relationship between neurological manifestations, neuroinflammation, and host immune response of microglia to SARS-CoV-2 has not been well characterized. Here, we report that SARS-CoV-2 can directly infect human microglia, eliciting M1-like pro-inflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA-seq analysis also revealed that ER stress and immune responses were induced in the early and apoptotic processes in the late phase of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced pro-inflammatory cytokines such as interleukin (IL)-1{beta}, IL-6, and tumour necrosis factor (TNF-), but not the anti-inflammatory cytokine IL-10. After this pro-inflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of pro-inflammatory microglial IL-6 and TNF- and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in COVID-19 patients. IMPORTANCERecent studies reported neurological manifestations and complications in COVID-19 patients, which are associated with neuroinflammation. As microglia are the dominant immune cells in brains, it needs to be elucidate the relationship between neuroinflammation and host immune response of microglia to SARS-CoV-2. Here, we suggest that SARS-CoV-2 can directly infect human microglia with cytopathic effect (CPE) using human microglial clone 3 (HMC3). The infected microglia were promoted to pro-inflammatory activation following apoptotic cell death. This pro-inflammatory activation was accompanied by the high production of pro-inflammatory cytokines, and led to neurotoxic-M1 phenotype polarization. In vivo, murine microglia were infected and produced pro-inflammatory cytokines and provoked a chronic loss using K18-hACE2 mice. Thus, our data present that SARS-CoV-2-infected microglia are potential mediators of neurological problems in COVID-19 patients. In addition, HMC3 cells are susceptible to SARS-CoV-2 and exhibit the CPE, which can be further used to investigate cellular and molecular mechanisms of neuroinflammation reported in COVID-19 patients.

Psoriasis-like skin disorder in transgenic mice expressing a RIG-I Singleton-Merten syndrome variant.

Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2-/- transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.

The Efficacy of Bisphosphonates for Prevention of Osteoporotic Fracture: An Update Meta-analysis

BACKGROUND: The efficacy of bisphosphonates for osteoporotic fracture has been consistently reported in recent randomized controlled trials (RCTs) enrolling hundreds of patients. The objective of this study was to update knowledge on the efficacy of available bisphosphonates in the prevention of vertebral and non-vertebral fractures. METHODS: An approach “using systematic reviews” on PubMed and Cochrane Library was taken. Twenty-four RCTs investigating the effects of bisphosphonates for the prevention of osteoporotic fracture were included in final analysis. A pairwise meta-analysis was conducted with a random effects model. Subgroup analysis was performed according to the type of bisphosphonate. RESULTS: The use of bisphosphonate decrease the risk of overall osteoporotic fracture (odds ratio [OR] 0.62; P<0.001), vertebral fracture (OR 0.55; P<0.001) and non-vertebral fracture (OR 0.73; P<0.001). Subgroup analysis indicated that zoledronic acid showed the lowest risk reduction (OR 0.61; P<0.001) for overall osteoporotic fractures but no significance was observed for etidronate (OR 0.34; P=0.127). CONCLUSIONS: This update meta-analysis re-confirmed that bisphosphonate use can effectively reduce the risk of osteoporotic fracture. However, there is a lack of evidence regarding etidronate for the prevention of osteoporotic fracture.

Refining prognostic stratification of human papillomavirus-related oropharyngeal squamous cell carcinoma: different prognosis between T1 and T2

PURPOSE: To validate the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and investigate whether a modified classification better reflects the prognosis. MATERIALS AND METHODS: Medical records of patients diagnosed with non-metastatic HPV-related OPSCC between 2010 and 2016 at a single institution were retrospectively reviewed. HPV status was determined by immunohistochemical analysis of p16 and/or HPV DNA polymerase chain reaction (PCR). We reclassified TNM stage T0-1 and N0-1 as group A, T2-3 or N2 as B, and T4 or N3 as C. Survival analysis according to 8th AJCC/UICC TNM staging and the modified classification was performed. RESULTS: Of 383 OPSCC patients, 211 were positive for HPV DNA PCR or p16. After exclusion, 184 patients were included in this analysis. Median age was 56 years (range, 31 to 81 years). Most primary tumors were in the palatine tonsil (148 tumors, 80%). The eighth AJCC/UICC TNM classification could not differentiate between stage I and II (p = 0.470) or II and III (p = 0.209). Applying modified grouping, the 3-year overall survival rate of group A was significantly higher than that of group B and C (98% vs. 91%, p = 0.039 and 98% vs. 78%, p < 0.001, respectively). Differentiation between group B and C was marginally significant (p = 0.053). CONCLUSION: The 8th AJCC/UICC TNM staging system did not clearly distinguish the prognosis of stage II from that of other stages. Including the T2N0-1 group in stage II may improve prognostic stratification.

Role of fractionated radiotherapy in patients with hemangioma of the cavernous sinus

PURPOSE: We performed this retrospective study to investigate the outcomes of patients with hemangioma of the cavernous sinus after fractionated radiotherapy. MATERIALS AND METHODS: We analyzed 10 patients with hemangioma of the cavernous sinus who were treated with conventional radiotherapy between January 2000 and December 2016. The median patient age was 54 years (range, 31–65 years), and 8 patients (80.0%) were female. The mean hemangioma volume was 34.1 cm3 (range, 6.8–83.2 cm3), and fractionated radiation was administered to a total dose of 50–54 Gy with a daily dose of 2 Gy. RESULTS: The median follow-up period was 6.8 years (range, 2.2–8.8 years). At last follow-up, the volume of the tumor had decreased in all patients. The average tumor volume reduction rate from the initial volume was 72.9% (range, 18.9–95.3%). All 10 of the cranial neuropathies observed before radiation therapy had improved, with complete symptomatic remission in 9 cases (90%) and partial remission in 1 case (10%). No new acute neurologic impairments were reported after radiotherapy. One probable compressive optic neuropathy was observed at 1 year after radiotherapy. CONCLUSION: Fractionated radiotherapy achieves both symptomatic and radiologic improvements. It is a well-tolerated treatment modality for hemangiomas of the cavernous sinus.

Refining prognostic stratification of human papillomavirus-related oropharyngeal squamous cell carcinoma: different prognosis between T1 and T2

PURPOSE: To validate the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and investigate whether a modified classification better reflects the prognosis. MATERIALS AND METHODS: Medical records of patients diagnosed with non-metastatic HPV-related OPSCC between 2010 and 2016 at a single institution were retrospectively reviewed. HPV status was determined by immunohistochemical analysis of p16 and/or HPV DNA polymerase chain reaction (PCR). We reclassified TNM stage T0-1 and N0-1 as group A, T2-3 or N2 as B, and T4 or N3 as C. Survival analysis according to 8th AJCC/UICC TNM staging and the modified classification was performed. RESULTS: Of 383 OPSCC patients, 211 were positive for HPV DNA PCR or p16. After exclusion, 184 patients were included in this analysis. Median age was 56 years (range, 31 to 81 years). Most primary tumors were in the palatine tonsil (148 tumors, 80%). The eighth AJCC/UICC TNM classification could not differentiate between stage I and II (p = 0.470) or II and III (p = 0.209). Applying modified grouping, the 3-year overall survival rate of group A was significantly higher than that of group B and C (98% vs. 91%, p = 0.039 and 98% vs. 78%, p < 0.001, respectively). Differentiation between group B and C was marginally significant (p = 0.053). CONCLUSION: The 8th AJCC/UICC TNM staging system did not clearly distinguish the prognosis of stage II from that of other stages. Including the T2N0-1 group in stage II may improve prognostic stratification.

Role of fractionated radiotherapy in patients with hemangioma of the cavernous sinus

PURPOSE: We performed this retrospective study to investigate the outcomes of patients with hemangioma of the cavernous sinus after fractionated radiotherapy. MATERIALS AND METHODS: We analyzed 10 patients with hemangioma of the cavernous sinus who were treated with conventional radiotherapy between January 2000 and December 2016. The median patient age was 54 years (range, 31–65 years), and 8 patients (80.0%) were female. The mean hemangioma volume was 34.1 cm3 (range, 6.8–83.2 cm3), and fractionated radiation was administered to a total dose of 50–54 Gy with a daily dose of 2 Gy. RESULTS: The median follow-up period was 6.8 years (range, 2.2–8.8 years). At last follow-up, the volume of the tumor had decreased in all patients. The average tumor volume reduction rate from the initial volume was 72.9% (range, 18.9–95.3%). All 10 of the cranial neuropathies observed before radiation therapy had improved, with complete symptomatic remission in 9 cases (90%) and partial remission in 1 case (10%). No new acute neurologic impairments were reported after radiotherapy. One probable compressive optic neuropathy was observed at 1 year after radiotherapy. CONCLUSION: Fractionated radiotherapy achieves both symptomatic and radiologic improvements. It is a well-tolerated treatment modality for hemangiomas of the cavernous sinus.

The Guideline of Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder: Developed by ADHD Translational Research Center

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric conditions. In 2007, the Korean Academy of child and Adolescent Psychiatry developed Korean ADHD practice parameter. Advances in the scientific evidence of ADHD caused practice parameter to be modified and updated. The present guidelines developed by ADHD translational research center summarize current literature for the treatment of ADHD in children and adults. This parameter includes the clinical evaluation for ADHD, comorbid conditions associated with ADHD, clinical feature and course, research on the etiology of the disorder, and psychopharmacological and non-pharmacological treatments for ADHD.

Clinical Characteristics According to the Presence of Restricted, Repetitive Behaviors and Interests in Children with High Functioning Autism Spectrum Disorder

OBJECTIVES: The objective of this study was to investigate the relationship between restricted, repetitive behaviors and interests (RRBI) and autistic symptoms in Korean high functioning autism spectrum disorder (ASD) children and to examine the structure of RRBI. METHODS: Participants included 147 high functioning ASD subjects and 181 unaffected siblings. ASD subjects were divided into two groups based on the presence of RRBI. The domain scores of the Korean version of Autism Diagnostic Interview-Revised (K-ADI-R), Korean version of Asperger Syndrome Diagnostic Scale and total scores of Korean translated version of Social Responsiveness Scale, Korean version of Social Communication Scale were used for comparison of ASD symptoms between the groups. Eleven items from the RRBI domain of the K-ADI-R were used in principal axis factor analysis (PAF). RESULTS: A statistically lower nonverbal IQ score was observed for ASD with RRBI than for ASD without RRBIs, and more social deficit, communication deficit, and behavioral and emotional problems were observed for ASD with RRBI compared to ASD without RRBI. Using PAF, two distinct factors were identified. 'Resistance to trivial changes in environment', 'Difficulty with minor changes in personal routine & environment', and 'Compulsion/ritual' were included as one factor. CONCLUSION: Analysis of the data suggests that the presence of RRBI in high functioning ASD is associated with a more severe presentation of autistic disorder. In addition, there appears to be heterogeneity within RRBI in autism except insistence on sameness.

Current Source Analysis of Interictal Spikes in Two Patients With Gelastic Epilepsy-Hypothalamic Hamartoma Syndrome

BACKGROUND: Interictal spikes in gelastic epilepsy-hypothalamic hamartoma syndrome are mainly in the fronto-temporal area. Current source analysis of the interictal spikes has not been done enough. We tried the current source analysis in 2 patients with gelastic epilepsy-hypothalamic hamartoma syndrome using both of the discrete and distributed models. METHODS: Twenty 1 sec epochs including the negative peak of the spikes, were selected from one or two electroencephalographic recordings respectively in each patient. These 20 epochs were averaged into a single spike. The current dipole sources of the averaged spike were analyzed and located on a spherical head model. The current source density of the negative peak point of the averaged spike was located on the Talairach human brain map. RESULTS: The current dipole sources were in the right subcallosal gyrus, or the right or left anterior cingulate gyri. The current source density was distributed in the bilateral medial frontal area including the anterior cingulate gyri. CONCLUSIONS: The interictal spikes of patients with gelastic epilepsy-hypothalamic hamartoma syndrome may be generated by the current sources located in the bilateral medial frontal area.