Presence of periorbital and conjunctival petechial hemorrhages in accidental pediatric drowning

Abstract The pathological findings of drowning are variable and non-specific. Petechial hemorrhages involving the periorbital region and the conjunctiva have been described in many causes of death, but are thought to be exceedingly uncommon in cases of drowning. However, such studies have not specifically addressed the pediatric population. The current study retrospectively examined 79 cases of accidental pediatric drowning for the presence of periorbital/conjunctival hemorrhages and analyzed factors that may have affected their presence. Ten victims had periorbital/ conjunctival petechial hemorrhages (13%), with five having periorbital petechiae, three having conjunctival petechiae, and two having both periorbital and conjunctival petechiae. The age and gender of the victim, site of drowning, resuscitation history and the presence of other pathological findings were not significantly associated with the presence of periorbital/conjunctival petechiae. However, as the interval between the drowning episode and autopsy increased, the incidence of periorbital/conjunctival petechiae decreased (28% for <24 h; 7% for >24 h). The presence of periorbital/conjunctival hemorrhages in a significant proportion of pediatric drowning victims confirms that the pathologist must add this finding to the spectrum of changes seen in pediatric drowning. Crow

Burkholderia multivorans septicemia in a pediatric liver transplant patient

“Cepacia syndrome”, caused by Burkholderia cepacia complex and often associated with cystic fibrosis, carries a high mortality rate. It is rare for Burkholderia multivorans, a species within the B. cepacia complex, to cause cepacia syndrome even among patients with cystic fibrosis. This is the first reported fatal case of cepacia syndrome caused by B. multivorans occurring in a pediatric liver transplant recipient who does not have cystic fibrosis. We describe the unique characteristics of this pathogen among the non–cystic fibrosis population and the importance of early recognition and treatment

Modulation by decitabine of gene expression and growth of osteosarcoma U2OS cells in vitro and in xenografts: Identification of apoptotic genes as targets for demethylation

<p>Abstract</p> <p>Background</p> <p>Methylation-mediated silencing of genes is one epigenetic mechanism implicated in cancer. Studies regarding the role of modulation of gene expression utilizing inhibitors of DNA methylation, such as decitabine, in osteosarcoma (OS) have been limited. A biological understanding of the overall effects of decitabine in OS is important because this particular agent is currently undergoing clinical trials. The objective of this study was to measure the response of the OS cell line, U2OS, to decitabine treatment both <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>Microarray expression profiling was used to distinguish decitabine-dependent changes in gene expression in U2OS cells, and to identify responsive loci with demethylated CpG promoter regions. U2OS xenografts were established under the sub-renal capsule of immune-deficient mice to study the effect of decitabine <it>in vivo </it>on tumor growth and differentiation. Reduced nuclear methylation levels could be detected in xenografts derived from treated mice by immunohistochemistry utilizing a 5-methylcytidine antibody. Decitabine treatment reduced tumor xenograft size significantly (p < 0.05). Histological analysis of treated U2OS xenograft sections revealed a lower mitotic activity (p < 0.0001), increased bone matrix production (p < 0.0001), and a higher number of apoptotic cells (p = 0.0329). Microarray expression profiling of U2OS cultured cells showed that decitabine treatment caused a significant induction (p < 0.0025) in the expression of 88 genes. Thirteen had a ≥2-fold change, 11 of which had CpG-island-associated promoters. Interestingly, 6 of these 11 were pro-apoptotic genes and decitabine resulted in a significant induction of cell death in U2OS cells <it>in vitro </it>(p < 0.05). The 6 pro-apoptotic genes (<it>GADD45A</it>, <it>HSPA9B</it>, <it>PAWR</it>, <it>PDCD5</it>, <it>NFKBIA</it>, and <it>TNFAIP3</it>) were also induced to ≥2-fold <it>in vivo</it>. Quantitative methylation pyrosequencing confirmed that the tested pro-apoptotic genes had CpG-island DNA demethylationas a result of U2OS decitabine treatment both <it>in vitro </it>and in xenografts</p> <p>Conclusion</p> <p>These data provide new insights regarding the use of epigenetic modifiers in OS, and have important implications for therapeutic trials involving demethylation drugs. Collectively, these data have provided biological evidence that one mode of action of decitabine may be the induction of apoptosis utilizing promoter-CpG demethylation of specific effectors in cell death pathways in OS.</p

Severe Primary Hyperparathyroidism Caused by Parathyroid Carcinoma in a 13‐Year‐Old Child; Novel Findings From HRpQCT

Primary hyperparathyroidism is a condition that occurs infrequently in children. Parathyroid carcinoma, as the underlying cause of hyperparathyroidism in this age group, is extraordinarily rare, with only a few cases reported in the literature. We present a 13-year-old boy with musculoskeletal pain who was found to have brown tumors from primary hyperparathyroidism caused by parafibromin-immunodeficient parathyroid carcinoma. Our patient had no clinical, biochemical, or radiographic evidence of pituitary adenomas, pancreatic tumors, thyroid tumors, pheochromocytoma, jaw tumors, renal abnormalities, or testicular lesions. Germline testing for AP2S1, CASR, CDC73/HRPT2, CDKN1B, GNA11, MEN1, PTH1R, RET, and the GCM2 gene showed no pathological variants, and a microarray of CDC73/HRPT2 did not reveal deletion or duplication. He was managed with i.v. fluids, calcitonin, pamidronate, and denosumab prior to surgery to stabilize hypercalcemia. After removal of a single parathyroid tumor, he developed severe hungry bone syndrome and required 3 weeks of continuous i.v. calcium infusion, in addition to oral calcium and activated vitamin D. Histopathological examination identified an angioinvasive parathyroid carcinoma with global loss of parafibromin (protein encoded by CDC73/HRPT2).HRpQCT and DXA studies were obtained prior to surgery and 18-months postsurgery. HRpQCT showed a resolution of osteolytic lesions combined with structural improvement of cortical porosity and an increase in both cortical thickness and density compared with levels prior to treatment. These findings highlight the added value of HRpQCT in primary hyperparathyroidism. In addition to our case, we have provided a review of the published cases of parathyroid cancer in children

Burkholderia multivorans septicemia in a pediatric liver transplant patient

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148247/1/ajt15065_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148247/2/ajt15065.pd

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: A randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes

Introduction: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. Methods and analysis: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. Ethics and dissemination: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. Trial registration number: NCT01566110

OPPOSING FUNCTIONS FOR A PROTEIN KINASE: A JNK1 DEPENDENT SWITCH DETERMINES THE ONCOGENIC OR TUMOR SUPPRESSIVE ACTIVITY OF ILK INRHABDOMYOSARCOMA

Background:The integrin-linked kinase (ILK) is a protein kinase involved in the regulation of pathogenic cancer cell behaviours, such as proliferation, survival and invasion. ILK appears to be pro-oncogenic in vitro and in vivo models of tumorigenesis. Rhabdomyosarcoma (RMS) is a primitive mesenchyme-derived tumor and is subclassified into primarily embryonal (ERMS) and alveolar (ARMS) variants. Patients who present with metastatic RMS tumors have a less than 20% chance of cure, suggesting a need to define novel targets for chemotherapeutic intervention. Methods: We used cell culture, murine xenografts and primary human tumors to examine ILK expression and functionality. RNAi and adenoviruses were used to knock down or over expressproteins, and SP600125 was used to inhibit JNK kinase activity. ERMS cells stablye xpressing PAX3-FOXO1A we regenerated using pcDNA3.1 with the full length PAX3-FOXO1A cDNA insert. Results: RNAi-mediated ablation of ILK induced stimulation of ERMS and inhibition of ARMS cell growth in vitro and in vivo. Overexpression of ILK, but not the ILK-R211A mutant reversed these effects. High-throughput screening of multiple tumor cell lines and mesenchymal progenitor cells demonstrated similar ILK anti-growth effects. Consistent with these results, clinical correlations made between ILK immunohistochemical staining intensity and patterns on an ERMS tumor tissue microarray revealed downregulation of ILK in stage III/IV primary tumors. Mechanistically, ILK silencing induced selective phosphorylation of the c-jun amino terminal kinase (JNK) and its target c-Jun in ERMS cells with attenuated phosphorylation in ARMS cells. ERMS cells express higher levels of JNK1 isoforms than ARMS cells. Introduction of the ARMS-associated PAX3-FOXO1A fusion gene into ERMS cells restored the oncogenic function of ILK and downregulated of JNK1. Coupling ILK siRNA with inhibition of the JNK-c-Jun signaling pathway in ERMS cells resulted in growth reductions and apoptotic induction. In contrast, coupling ILK knockdown with overexpression of JNK1 in ARMS cells resulted in growth and c-jun phosphorylation. Conclusion: In summary, these data suggest a model whereby the effect of ILK as an oncogene or tumor suppressor is determined by JNK1. Finally, this data suggests that ILK kinase inhibition may be warranted in ARMS tumors, and may be contraindicated in ERMS