A Narrative Review on Diabetic Ketoacidosis in Children.

BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening complication in children with diabetes mellitus. There are considerable differences in the management approaches for DKA between different countries. One of the main areas of differences between guidelines is the administration of fluid, with most guidelines adopting a restrictive approach. This is based on the concern over cerebral oedema, a lethal sequela allegedly to be caused by excessive fluid administration. However, in recent years, new clinical studies suggest that there is no causal relationship between intravenous fluid therapy and DKA-related cerebral injury. The British Society of Paediatric Endocrinology updated its guideline in 2020 to adopt a more permissive approach to fluid administration, which has sparked controversy among some paediatricians. OBJECTIVES: The purpose of this article is to provide a narrative review on the management of DKA. METHODS: A PubMed search was performed with clinical queries using the key term "diabetic ketoacidosis". The search strategy included randomized controlled trials, clinical trials, meta-analyses, observational studies, guidelines, and reviews. The search was restricted to English literature and the age range of 18 years and younger. Moreover, we reviewed and compared major guidelines. CONCLUSION: The management of DKA involves early recognition, accurate diagnosis, meticulous fluid and insulin treatment with close monitoring of blood glucose, ketones, electrolytes, renal function, and neurological status. There is still limited clinical evidence to support either a restrictive or permissive approach in the fluid management of paediatric DKA patients. Clinicians should exercise caution when applying different guidelines in their clinical practice, considering the specific circumstances of individual paediatric patients.

A case series of appendicitis and pseudo-appendicitis in a paediatric intensive care unit.

INTRODUCTION: Appendicitis is a common childhood condition that can be diagnostically challenging. Severe cases may necessitate support in the critical or intensive care unit. These "critical appendicitis diagnoses" have rarely been described. CASE DESCRIPTION: We retrospective reviewed the PICU database of the Hong Kong Children's Hospital and identified cases of suspected and confirmed appendicitis. Clinical features, radiologic findings and final diagnosis of each case were summarized and reported in this case series. We review six anonymized cases of appendicitis managed in a paediatric intensive care unit (PICU) to illustrate the different age spectrum and clinical manifestations of the condition. Rupture of the inflamed appendix, peritonitis and pancreatitis were some of the complications encountered. Crohn disease was found in one case as an underlying diagnosis. Also, one girl clinically diagnosed with appendicitis was found to be a case of ruptured hepatoblastoma with no appendicitis (i.e., pseudoappendicitis). CONCLUSION: Prompt diagnosis, surgical removal of the inflamed appendix, and use of appropriate antimicrobials when indicated are essential in reducing mortality and morbidity associated with severe appendicitis. Significant premorbid conditions such as acute myeloid leukemia, mitochondrial encephalopathy lactic acidosis syndrome (MELAS), inflammatory bowel disease and complications may be present in patients needing intensive care as is illustrated in the present cases. Pseudoappendicitis is an important differential diagnosis. Imaging is crucial and useful in establishing and confirming the diagnosis of appendicitis and pseudo-appendicitis in these PICU cases.

Neural activation and connectivity during cued eye blinks in Chronic Tic Disorders.

OBJECTIVE: The pathophysiology of Chronic Tic Disorders (CTDs), including Tourette Syndrome, remains poorly understood. The goal of this study was to compare neural activity and connectivity during a voluntary movement (VM) paradigm that involved cued eye blinks among children with and without CTDs. Using the precise temporal resolution of electroencephalography (EEG), we used the timing and location of cortical source resolved spectral power activation and connectivity to map component processes such as visual attention, cue detection, blink regulation and response monitoring. We hypothesized that neural activation and connectivity during the cued eye blink paradigm would be significantly different in regions typically associated with effortful control of eye blinks, such as frontal, premotor, parietal, and occipital cortices between children with and without CTD. METHOD: Participants were 40 children (23 with CTD, 17 age-matched Healthy Control [HC]), between the ages of 8-12 (mean age = 9.5) years old. All participants underwent phenotypic assessment including diagnostic interviews, behavior rating scales and 128-channel EEG recording. Upon presentation of a cue every 3 s, children were instructed to make an exaggerated blink. RESULTS: Behaviorally, the groups did not differ in blink number, latency, or ERP amplitude. Within source resolved clusters located in left dorsolateral prefrontal cortex, posterior cingulate, and supplemental motor area, children with CTD exhibited higher gamma band spectral power relative to controls. In addition, significant diagnostic group differences in theta, alpha, and beta band power in inferior parietal cortex emerged. Spectral power differences were significantly associated with clinical characteristics such as tic severity and premonitory urge strength. After calculating dipole density for 76 anatomical regions, the CTD and HC groups had 70% overlap of top regions with the highest dipole density, suggesting that similar cortical networks were used across groups to carry out the VM. The CTD group exhibited significant information flow increase and dysregulation relative to the HC group, particularly from occipital to frontal regions. CONCLUSION: Children with CTD exhibit abnormally high levels of neural activation and dysregulated connectivity among networks used for regulation and effortful control of voluntary eye blinks.

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Pitfall of 18F-FDG PET/CT in Characterization of Relapsed Multisystem Lymphomatoid Granulomatosis.

We present serial 18F-FDG PET/CT findings in a case of grade 3 pulmonary lymphomatoid granulomatosis positive for the Epstein-Barr virus. The patient experienced a transient complete response to R-CHOP chemotherapy and subsequent multisystem recurrence, predominately involving the subcutaneous region of the torso on 18F-FDG PET/CT. Biopsy of the most hypermetabolic subcutaneous lesion demonstrated grade 1 cutaneous lymphomatoid granulomatosis negative for the Epstein-Barr virus. This report highlights the role of 18F-FDG PET/CT in characterizing and monitoring disease progression and regression, as well as the limitations of 18F-FDG PET/CT in accurate grading of multisystem recurrence, given the diversity of clinical and histopathologic features of lymphomatoid granulomatosis.

A novel human glucocorticoid receptor SNP results in increased transactivation potential.

Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.

A parietal biomarker for ADHD liability: as predicted by the distributed effects perspective model of ADHD.

BACKGROUND: We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent distributed effects model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH-biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD. METHOD: The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities [i.e., ADHD risk factors (RFs)]. RESULTS: Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry (RPA) was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of RPA were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs. CONCLUSION: Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability.

Hyperactive Human Glucocorticoid Receptor Isoforms and their Implications for the Stress Response.

Glucocorticoids are indispensable therapeutic agents in diseases of inflammation, but their effectiveness in treating advanced septic shock has been inconsistent. Our understanding of the mechanisms causing this variability to steroid therapy remains limited. Previous studies in our laboratory have implicated human glucocorticoid receptor (hGR) polymorphisms as one of the likely reasons for this variability. We examined the effect of two single-nucleotide polymorphisms (SNPs) on the transactivation potential of the hGR in the absence and presence of exogenous steroids. An isoform containing a novel naturally occurring human SNP, T1463C, was found to have a hyperactive response with treatment of all three steroids examined while maintaining low activity in the absence of steroids, relative to reference hGR. In comparison, another hGR isoform with the A2297G SNP, previously identified in our laboratory, demonstrated hyperactive transactivational response in the absence of steroids; however, it had a significant increase in activity after treatment with only one of the glucocorticoids (hydrocortisone) tested. These results offer a possible explanation for the clinical variability seen among individuals in response to stress or shock.

Visual Network Asymmetry and Default Mode Network Function in ADHD: An fMRI Study.

BACKGROUND: A growing body of research has identified abnormal visual information processing in attention-deficit hyperactivity disorder (ADHD). In particular, slow processing speed and increased reliance on visuo-perceptual strategies have become evident. OBJECTIVE: The current study used recently developed fMRI methods to replicate and further examine abnormal rightward biased visual information processing in ADHD and to further characterize the nature of this effect; we tested its association with several large-scale distributed network systems. METHOD: We examined fMRI BOLD response during letter and location judgment tasks, and directly assessed visual network asymmetry and its association with large-scale networks using both a voxelwise and an averaged signal approach. RESULTS: Initial within-group analyses revealed a pattern of left-lateralized visual cortical activity in controls but right-lateralized visual cortical activity in ADHD children. Direct analyses of visual network asymmetry confirmed atypical rightward bias in ADHD children compared to controls. This ADHD characteristic was atypically associated with reduced activation across several extra-visual networks, including the default mode network (DMN). We also found atypical associations between DMN activation and ADHD subjects' inattentive symptoms and task performance. CONCLUSION: The current study demonstrated rightward VNA in ADHD during a simple letter discrimination task. This result adds an important novel consideration to the growing literature identifying abnormal visual processing in ADHD. We postulate that this characteristic reflects greater perceptual engagement of task-extraneous content, and that it may be a basic feature of less efficient top-down task-directed control over visual processing. We additionally argue that abnormal DMN function may contribute to this characteristic.

Abnormal Parietal Brain Function in ADHD: Replication and Extension of Previous EEG Beta Asymmetry Findings.

BACKGROUND: Abundant work indicates ADHD abnormal posterior brain structure and function, including abnormal structural and functional asymmetries and reduced corpus callosum size. However, this literature has attracted considerably less research interest than fronto-striatal findings. OBJECTIVE: To help address this imbalance, the current study replicates and extends our previous work showing abnormal parietal brain function in ADHD adults during the Conner's Continuous Performance Test (CPT). METHOD: Our previous study found that ADHD adults had increased rightward EEG beta (16-21 Hz) asymmetry in inferior parietal brain regions during the CPT (p = 0.00001), and that this metric exhibited a lack of normal correlation (i.e., observed in controls) with beta asymmetry at temporal-parietal regions. We re-tested these effects in a new ADHD sample and with both new and old samples combined. We additionally examined: (a) EEG asymmetry in multiple frequency bands, (b) unilateral effects for all asymmetry findings, and (c) the association between EEG asymmetry and a battery of cognitive tests. RESULTS: We replicated our original findings by demonstrating abnormal rightward inferior parietal beta asymmetry in adults with ADHD during the CPT, and again this metric exhibited abnormal reduced correlation to temporal-parietal beta asymmetry. Novel analyses also demonstrated a broader pattern of rightward beta and theta asymmetry across inferior, superior, and temporal-parietal brain regions, and showed that rightward parietal asymmetry in ADHD was atypically associated with multiple cognitive tests. CONCLUSION: Abnormal increased rightward parietal EEG beta asymmetry is an important feature of ADHD. We speculate that this phenotype may occur with any form of impaired capacity for top-down task-directed control over sensory encoding functions, and that it may reflect associated increase of attentional shifting and compensatory sustained/selective attention.

Single nucleotide polymorphisms and type of steroid impact the functional response of the human glucocorticoid receptor.

BACKGROUND: Clinical trials evaluating the use of steroids in septic shock have shown variable outcomes. Our previous studies have implicated human glucocorticoid receptor (hGR) polymorphisms as a possible cause of altered steroid response. To further evaluate this variability, we hypothesized that hGR polymorphisms along with type of steroid influence the functional response. METHODS: Total RNA was isolated from healthy human blood samples and surveyed for the hGR gene. The National Center for Biotechnology Information hGRα sequence was used as a reference, and two unique single nucleotide polymorphisms (SNPs) (A214G and T962C) were selected for evaluation. Functional response was measured using a luciferase reporting assay after transfecting hGR isoforms into tsA201 cells and stimulation with graded concentrations of hydrocortisone (HYD), methylprednisolone (MPS), and dexamethasone (DEX). RESULTS: Each isoform had a unique dose-response curve with the optimal activity depending on concentration and type of steroid. The presence of either SNP A214G or T962C resulted in a decreased response when compared with hGRα when stimulated with HYD (P < 0.01). The same decreased response occurred for the SNPs with DEX stimulation, but at a much lower concentration range than HYD (P < 0.01). However, in the presence of MPS, SNP A214G resulted in greater activity when compared with hGRα (P < 0.01), whereas the presence of T962C resulted in activity equivalent to hGRα. CONCLUSIONS: SNPs, type of steroid, and concentration range impact the functional response of the hGR. A greater understanding of hGR polymorphisms and steroid response may further elucidate mechanisms explaining the variable response seen with patient treatment.

Enhanced steroid response of a human glucocorticoid receptor splice variant.

Glucocorticoids remain a recommended therapy in advanced septic shock despite the often unpredictable response, and our understanding of the mechanisms regulating the steroid and stress response remains limited. Since the initial sequencing of the human glucocorticoid receptor α and ß gene (hGRα and hGRß), only three additional splice variants have been identified--all of which have been postulated to contribute to steroid resistance. During a survey of 97 healthy humans' blood, we identified two novel hGR splice isoforms (hGR-S1 and hGR-S1(-349A) retaining intron H between exons 8 and 9. Human GR-S1(-349A) contained a base deletion causing an early termination and a truncated protein of 118 amino acids, whereas hGR-S1 had an early termination occurring within intron H and resulted in a 745-amino acid protein. Both isoforms had decreased transactivation potentials compared with hGRα when tested in the absence of exogenous steroids. However, after treating with exogenous steroids, dose-response studies showed hGR-S1(-349A) had a substantial augmentation in activity at higher concentrations of hydrocortisone and methylprednisolone when compared with hGRα, whereas hGR-S1 did not. Removal of the 3' untranslated region (3'UTR) of the hGR-S1(-349A) mRNA sequence resulted in a loss of the augmented response. The isoform hGR-S1(-349A) augments the response to steroids, and this significant response appears to be critically regulated by the 3'UTR. The identification and evaluation of these unique hGR isoforms helps further the understanding of the complex genetic regulation of the stress and steroid response.

Surfactant therapy for acute respiratory distress in severe pediatric burn injury: a case series.

After severe burn injury, pediatric patients often succumb to complications of respiratory failure. Surfactant has been used to improve pulmonary gas exchange for severe respiratory distress in other pediatric populations but has not been studied in pediatric burn-injured patients. Here, the authors report a case series of seven severely burned pediatric patients who received surfactant for acute respiratory distress and severe hypoxemia. Seven cases were reviewed of pediatric patients who received surfactant for severe acute respiratory distress. Data analyzed included age, TBSA burned, height, weight, mechanism of injury, total intensive care unit days, hospital days, and ventilator days. Modes of ventilation, peak inspiratory pressure, oxygen requirement, arterial blood gas analysis, blood pressure, and heart rate were analyzed before and the day following surfactant therapy. Four patients had reduced oxygen requirements following surfactant administration (FiO(2): 0.66 ± 0.23-0.48 ± 0.025). Three patients showed no reduction in oxygen requirements (FiO(2): 0.95 ± 0.09-0.90 ± 0.0). The remaining four patients who had reduced oxygen requirements received surfactant earlier following their injury (4.8 ± 0.9 days postinjury vs 17.7 ± 8 days postinjury) and had less derangement in oxygenation before surfactant dosing (PaO(2):FiO(2) ratio: 105.2 ± 26.4 vs 64.5 ± 5.2). Surfactant therapy may offer a therapeutic option during acute respiratory distress for severely burned pediatric patients. Surfactant may be useful early in the course of severe hypoxemia and acute respiratory distress but may not be effective as a salvage modality.

Novel hyperactive glucocorticoid receptor isoform identified within a human population.

Glucocorticoids serve as important therapeutic agents in diseases of inflammation, but clinical use, especially in advanced septic shock, remains controversial because of the unpredictable response. Prior studies correlate human glucocorticoid receptor (hGR) isoforms with a decreased response to steroid therapy. Further analysis of additional hGR isoforms may improve the understanding of the steroid response. Ninety-seven human volunteers' blood samples were surveyed for hGR isoforms. An isoform matching National Center for Biotechnology Informatics (NCBI) hGRα (hGR NCBI) served as a reference. Two isoforms were of particular interest-one isoform had three nonsynonymous single-nucleotide polymorphisms (SNPs) (hGR NS-1), and the second had a single-nucleotide deletion (hGR DL-1) resulting in a truncated protein. Transactivation potentials were measured using a luciferase reporter assay. Human glucocorticoid receptor NS-1 had activity more than twice of hGR NCBI, whereas hGR DL-1 demonstrated less than 10% of the activity of hGR NCBI. Cotransfection of two isoforms revealed that the presence of hGR NS-1 increased transactivation potential, whereas hGR DL-1 decreased activity. Synthetic constructs isolating individual and paired SNPs of hGR NS-1 were created to identify the SNP responsible for hyperactivity. Transactivation studies revealed a SNP within the ligand-binding domain exerted the greatest influence over hyperactivity. In evaluating the response to hydrocortisone, hGR NCBI and hGR NS-1 displayed an increased dose-dependent response, but hGR NS-1 had a response more than twice hGR NCBI. Characterization of the novel hyperactive hGR NS-1 provides insight into a possible mechanism underlying the unpredictable response to steroid treatment.

Correlation of magnetic resonance imaging with histopathology in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an asymptomatic cardiac disease characterized by fatty infiltration of the right ventricular myocardium and often results in sudden cardiac death. ARVD/C diagnosis includes the assessment of fatty infiltration, which can be achieved noninvasively with cardiovascular magnetic resonance (CMR). The standard CMR protocol places the signal-generating coil directly on the anterior chest wall and produces a nonspecific high intensity signal that obscures the high signal from fatty infiltration. The aim of this study was to determine whether increasing the coil-to-chest distance would improve identification of fatty infiltration. Thoraces from seven embalmed cadavers were imaged on a conventional 1.5 Tesla CMR scanner using the control protocol and an experimental protocol, with a 6 cm coil-to-chest distance. A representative axial MR image and corresponding gross section of the heart were analyzed in each case. Fatty infiltration was graded in a blinded fashion on the MR images with independent histopathologic assessment. In five of the seven cases, the experimental protocol provided a correlation between CMR and histopathology that was as good as or better than the control protocol. The experimental protocol was also better in preventing false positive diagnosis in cases of minimal infiltration. Thus, the experimental protocol showed a stronger correlation with histopathology than did the control protocol. Increasing the distance between the anterior surface coil and chest wall may improve classification of presence or absence of fatty infiltration in the right ventricular myocardium, potentially improving the noninvasive detection of ARVD/C with CMR.