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Cetica V.,Azienda Ospedaliero | Sieni E.,Azienda Ospedaliero | Pende D.,Istituto di Ricovero e Cura rattere Scientifico | Danesino C.,University of Pavia | And 10 more authors.
Journal of Allergy and Clinical Immunology | Year: 2016

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. Objective This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. Methods From our registry, we have analyzed a total of 500 unselected patients with HLH. Results Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having "sporadic" HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. Conclusion We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL. © 2015 The Authors.

Kasem A.J.,08 E. 96th St No. 17C | Bulloch B.,08 E. 96th St No. 17C | Henry M.,Pediatric Hematology and Oncology | Shah K.,08 E. 96th St No. 17C | Dalton H.,Pediatric Critical Care
Pediatric Emergency Care | Year: 2012

OBJECTIVE: To evaluate the clinical use of procalcitonin (PCT) as a rapid marker for the identification of bacteremia in the emergency department (ED) population of children with fever and a central venous catheter (CVC). METHODS: Children were identified on presentation to the ED with a chief complaint of fever and who had a CVC. Fever was defined as 38°C or higher orally. Patients were excluded from the study if they had received antibiotics within the previous 24 hours of presenting to the ED, if they had a peripherally inserted central catheter line or by parental refusal. On presentation to the ED, all patients had a complete blood cell count with differential, blood culture from the central line, and PCT levels drawn. All had empiric antibiotics initiated. Blood culture results were recorded, and in the case of positive cultures, time to positive culture was noted. RESULTS: Sixty-two patients (aged 5 months-18 y) were enrolled, and 14 (23%) had a positive culture. Mean PCT value in bacteremic patients was 18.47 ± 31.6 ng/mL and 0.65 ± 1.2 ng/mL in nonbacteremic patients (P < 0.001). Median PCT for negative blood culture was 0.23 ng/mL (interquartile range, 0.11-0.61) and 1.15 ng/mL for a positive blood culture (interquartile range, 0.45-29.16). The receiver operating characteristic analysis identified a level of PCT of 0.3 ng/mL as the best cutoff point that produced a sensitivity of 93% and a specificity of 63% (area under the curve, 0.82). CONCLUSIONS: The PCT levels are useful in identifying children with fever and a CVC who are bacteremic in the ED. Copyright © 2012 by Lippincott Williams & Wilkins.

Fiuza-Luces C.,Hospital Universitario 12 Of Octubre Research Institute I12 | Simpson R.J.,University of Houston | Ramirez M.,Pediatric Hematology and Oncology | Lucia A.,European University at Madrid | Berger N.A.,Case Western Reserve University
Bone Marrow Transplantation | Year: 2016

Allogeneic hematopoietic stem cell transplant, to reconstitute the hematopoietic and immune status of patients undergoing myeloablative therapy for hematologic disorders, has been of great benefit in minimizing or eradicating disease and extending survival. Patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) are subject to many comorbidities among which the most significant, affecting quality of life (QoL) and survival, are acute GvHD (aGvHD) and chronic GvHD (cGvHD), resulting from donor lymphocytes reacting to and damaging host tissues. Physical activity and exercise have clearly been shown, in both children and adults, to enhance fitness, improve symptomatology and QoL, reduce disease progression and extend survival for many diseases including malignancies. In some cases, vigorous exercise has been shown to be equal to or more effective than pharmacologic therapy. This review addresses how cGvHD affects patients' physical function and physical domain of QoL, and the potential benefits of exercise interventions along with recommendations for relevant research and evaluation targeted at incorporating this strategy as soon as possible after allo-HSCT and ideally, as soon as possible upon diagnosis of the condition leading to allo-HSCT. © 2016 Macmillan Publishers Limited. All rights reserved.

Becton L.J.,Medical University of South Carolina | Kalpatthi R.V.,Pediatric Hematology and Oncology | Rackoff E.,Medical University of South Carolina | Disco D.,Medical University of South Carolina | And 3 more authors.
Pediatric Nephrology | Year: 2010

Sickle cell disease (SCD) is associated with a large spectrum of renal abnormalities, one of which, microalbuminuria/proteinuria (MA/P), is a known predictor of end-stage renal disease. We studied 90 children with SCD (57% male; mean age 11.4±5.2 years) to determine the prevalence and examine clinical correlates of MA/P. The average of two spot urine microalbumin-to- creatinine samples obtained 6 months apart was recorded. Medical records were reviewed for demographic and biochemical data. Medication use, resting office blood pressures (BP), vaso-occlusive pain crises (VOC), and monthly transfusions were recorded. Fourteen children (15.5%) had MA/P. Hemoglobin (Hb) levels were significantly lower in the children with MA than in those without MA/P (8.8±1.1 vs. 9.8±1.4 g/dL, respectively) and were significantly correlated with MA (rho=0.24, p=0.03). Children with MA were more likely to have abnormal BP (p=0.058), with 5/14 being hypertensive or pre-hypertensive. In a multivariate logistic regression model of MA, both Hb and BP classification remained in the final model. MA is a simple screening biomarker of early kidney injury in children with SCD. Larger studies to evaluate predictive factors of MA and the relationship to BP are needed. © 2010 IPNA.

Taylor K.R.,Institute of Cancer Research | Mackay A.,Institute of Cancer Research | Truffaux N.,University Paris - Sud | Butterfield Y.S.,BC Cancer Agency | And 19 more authors.
Nature Genetics | Year: 2014

Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-Î 2 signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease. © 2014 Nature America, Inc. All rights reserved.

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