Strippoli R.,Bambino Gesu Children Hospital |
Benedicto I.,Hospital Universitario Of La Princesa |
Benedicto I.,CIBER ISCIII |
Perez-Lozano M.L.,Hospital Universitario Of La Princesa |
And 2 more authors.
Journal of Cell Science | Year: 2010
Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells is a pathological process that occurs during peritoneal dialysis. EMT leads to peritoneal fibrosis, ultrafiltration failure and eventually to the discontinuation of therapy. Signaling pathways involved in mesothelial EMT are thus of great interest, but are mostly unknown. We used primary mesothelial cells from human omentum to analyze the role of the p38 MAPK signaling pathway in the induction of EMT. The use of specific inhibitors, a dominant-negative p38 mutant and lentiviral silencing of p38α demonstrated that p38 promotes E-cadherin expression both in untreated cells and in cells co-stimulated with the EMT-inducing stimuli transforming growth factor (TGF)-β1 and interleukin (IL)-1β. p38 inhibition also led to disorganization and downregulation of cytokeratin filaments and zonula occludens (ZO)-1, whereas expression of vimentin was increased. Analysis of transcription factors that repress E-cadherin expression showed that p38 blockade inhibited expression of Snail1 while increasing expression of Twist. Nuclear translocation and transcriptional activity of p65 NF-κB, an important inducer of EMT, was increased by p38 inhibition. Moreover, p38 inhibition increased the phosphorylation of TGF-β-activated kinase 1 (TAK1), NF-κB and IκBα. The effect of p38 inhibition on E-cadherin expression was rescued by modulating the TAK1-NF-κB pathway. Our results demonstrate that p38 maintains E-cadherin expression by suppressing TAK1-NF-κB signaling, thus impeding the induction of EMT in human primary mesothelial cells. This represents a novel role of p38 as a brake or 'gatekeeper' of EMT induction by maintaining E-cadherin levels.
Rucci N.,University of L'Aquila |
Capulli M.,University of L'Aquila |
Piperni S.G.,University of L'Aquila |
Cappariello A.,Bambino Gesu Children Hospital |
And 4 more authors.
Journal of Bone and Mineral Research | Year: 2015
Mechanical loading represents a crucial factor in the regulation of skeletal homeostasis. Its reduction causes loss of bone mass, eventually leading to osteoporosis. In a previous global transcriptome analysis performed in mouse calvarial osteoblasts subjected to simulated microgravity, the most upregulated gene compared to unit gravity condition was Lcn2, encoding the adipokine Lipocalin 2 (LCN2), whose function in bone metabolism is poorly known. To investigate the mechanoresponding properties of LCN2, we evaluated LCN2 levels in sera of healthy volunteers subjected to bed rest, and found a significant time-dependent increase of this adipokine compared to time 0. We then evaluated the in vivo LCN2 regulation in mice subjected to experimentally-induced mechanical unloading by (1) tail suspension, (2) muscle paralysis by botulin toxin A (Botox), or (3) genetically-induced muscular dystrophy (MDX mice), and observed that Lcn2 expression was upregulated in the long bones of all of them, whereas physical exercise counteracted this increase. Mechanistically, in primary osteoblasts transfected with LCN2-expression-vector (OBs-Lcn2) we observed that Runx2 and its downstream genes, Osterix and Alp, were transcriptionally downregulated, and alkaline phosphatase (ALP) activity was less prominent versus empty-vector transduced osteoblasts (OBs-empty). OBs-Lcn2 also exhibited an increase of the Rankl/Opg ratio and IL-6 mRNA, suggesting that LCN2 could link poor differentiation of osteoblasts to enhanced osteoclast stimulation. In fact, incubation of purified mouse bone marrow mononuclear cells with conditioned media from OBs-Lcn2 cultures, or their coculture with OBs-Lcn2, improved osteoclastogenesis compared to OBs-empty, whereas treatment with recombinant LCN2 had no effect. In conclusion, our data indicate that LCN2 is a novel osteoblast mechanoresponding gene and that its regulation could be central to the pathological response of the bone tissue to low mechanical forces. © 2014 American Society for Bone and Mineral Research.
Rooryck C.,University College London |
Diaz-Font A.,University College London |
Osborn D.P.S.,University College London |
Chabchoub E.,University Hospitals of Leuven |
And 19 more authors.
Nature Genetics | Year: 2011
3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome. © 2011 Nature America, Inc. All rights reserved.
Coello A.F.,Hospital Universitario Of Bellvitge |
Duvaux S.,Montpellier University |
De Benedictis A.,Bambino Gesu Children Hospital |
De Benedictis A.,University of Insubria |
And 3 more authors.
Journal of Neurosurgery | Year: 2013
Neural foundations underlying visual agnosia are poorly understood. The authors present the case of a patient who underwent awake surgery for a right basal temporooccipital low-grade glioma in which direct electrostimulation was used both at the cortical and subcortical level. Brain mapping over the inferior longitudinal fascicle generated contralateral visual hemiagnosia. These original findings are in agreement with recent tractography data that have confirmed the existence of an occipitotemporal pathway connecting occipital visual input to higher-level processing in temporal lobe structures. This is the first report of a true transient visual hemiagnosia elicited through electrostimulation, supporting the crucial role of inferior longitudinal fascicle in visual recognition. ©AANS, 2013.
Buonuomo P.S.,Bambino Gesu Children Hospital |
Bartuli A.,Bambino Gesu Children Hospital |
Rabacchi C.,University of Modena and Reggio Emilia |
Bertolini S.,University of Genoa |
Calandra S.,University of Modena and Reggio Emilia
Journal of Clinical Lipidology | Year: 2015
Background Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. Results A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. Conclusions GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene. © 2015 National Lipid Association.
Buonsenso D.,Catholic University of the Sacred Heart |
Lancella L.,Bambino Gesu Children Hospital |
Delogu G.,Catholic University of the Sacred Heart |
Krzysztofiak A.,Bambino Gesu Children Hospital |
And 4 more authors.
Pediatric Infectious Disease Journal | Year: 2012
BACKGROUND: Tuberculosis (TB) is among the top 10 causes of child death worldwide. Nevertheless, childhood disease has been neglected by tuberculosis control programs. METHODS: This was a retrospective study of patients < 16 years of age diagnosed with active TB in 2 tertiary hospitals in Rome (Italy), between 1990 and 2009. RESULTS: Two hundred fourteen cases of active tuberculosis were identified (132 definite, 82 probable). Pulmonary involvement was the most common form (75.5%), followed by lymphadenopathy (15.4%) and central nervous system TB (11%). Fever (51.86%) and cough (40%) were the most common presenting symptoms. A total of 23.4% of children were asymptomatic on admission. Sensitivities of the tuberculin skin test and the quantiferon test were 93.4% and 97%, respectively. Both tests performed in 52 children agreed in 49 cases (94%). Sensitivities for culture, Ziehl-Neelsen staining and polymerase chain reaction were 58%, 25% and 66.3%, respectively. The adult source case was identified in 28% of cases. History of contact with a patient with active TB was associated with pulmonary TB (P = 0.0014), whereas negative history of contact was associated with lymph node (P = 0.0064) and central nervous system TB (P = 0.05). CONCLUSIONS: Our study emphasizes the difficulty in managing children with suspected TB, because the absence of constitutional symptoms cannot exclude TB, and bacteriologic confirmation is the exception. Immunologic diagnosis can be a valuable tool to identify TB-infected children because the quantiferon test showed high sensitivity in all age groups. This is of primary importance because early identification of children with latent tuberculous infection and appropriate chemoprophylaxis represent, to date, the most important tool to reduce the burden of TB. Copyright © 2012 by Lippincott Williams &Wilkins.
Giorgio V.,Bambino Gesu Children Hospital |
Prono F.,Bambino Gesu Children Hospital |
Graziano F.,Bambino Gesu Children Hospital |
Nobili V.,Bambino Gesu Children Hospital
BMC Pediatrics | Year: 2013
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives. © 2013 Giorgio et al.; licensee BioMed Central Ltd.
Velardi P.,University of Rome La Sapienza |
Stilo G.,University of Rome La Sapienza |
Tozzi A.E.,Bambino Gesu Children Hospital |
Gesualdo F.,Bambino Gesu Children Hospital
Artificial Intelligence in Medicine | Year: 2014
Background: Digital traces left on the Internet by web users, if properly aggregated and analyzed, can represent a huge information dataset able to inform syndromic surveillance systems in real time with data collected directly from individuals. Since people use everyday language rather than medical jargon (e.g. runny nose vs. respiratory distress), knowledge of patients' terminology is essential for the mining of health related conversations on social networks. Objectives: In this paper we present a methodology for early detection and analysis of epidemics based on mining Twitter messages. In order to reliably trace messages of patients that actually complain of a disease, first, we learn a model of naïve medical language, second, we adopt a symptom-driven, rather than disease-driven, keyword analysis. This approach represents a major innovation compared to previous published work in the field. Method: We first developed an algorithm to automatically learn a variety of expressions that people use to describe their health conditions, thus improving our ability to detect health-related "concepts" expressed in non-medical terms and, in the end, producing a larger body of evidence. We then implemented a Twitter monitoring instrument to finely analyze the presence and combinations of symptoms in tweets. Results: We first evaluate the algorithm's performance on an available dataset of diverse medical condition synonyms, then, we assess its utility in a case study of five common syndromes for surveillance purposes. We show that, by exploiting physicians' knowledge on symptoms positively or negatively related to a given disease, as well as the correspondence between patients' "naïve" terminology and medical jargon, not only can we analyze large volumes of Twitter messages related to that disease, but we can also mine micro-blogs with complex queries, performing fine-grained tweets classification (e.g. those reporting influenza-like illness (ILI) symptoms vs. common cold or allergy). Conclusions: Our approach yields a very high level of correlation with flu trends derived from traditional surveillance systems. Compared with Google Flu, another popular tool based on query search volumes, our method is more flexible and less sensitive to changes in web search behaviors. © 2014 Elsevier B.V.
DE Ioris M.A.,Bambino Gesu Children Hospital
Anticancer research | Year: 2012
Although high-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma (NBL), the most effective conditioning regimen still remains to be identified. Forty-one high-risk NBL entered into local protocol based on induction chemotherapy, surgery and HDC with either etoposide/thiotepa/cyclophophamide (ETC) or i.v. busulfan and L-PAM (Bu/L-PAM). Thirty-seven patients underwent HDC; 29 with ETC and 8 with Bu/L-PAM. No toxic deaths were recorded. The 5-year progression-free survival (PFS) of patients given ETC was 21% (95% confidence interval CI (9-36%), while PFS for patients given Bu/L-PAM was 88% (95% CI=39-98%) (p<0.05). In multivariate analysis, treatment with the ETC regimen predicted progression/recurrence with a hazard ratio (HR) of 16.8 (p<0.05), as well as MYCN amplification which had an HR of 4.4 (p<0.05). Although the number of studied cases is limited, our data suggest that in high-risk NBL the combination of Bu/L-PAM is superior to the ETC regimen.
Elena B.,Bambino Gesu Children Hospital
Vaccine | Year: 2011
Although varicella is commonly regarded as a mild childhood disease, complications may occur and frequently require hospitalization. The aim of this study was to establish the type and frequency of varicella complications among hospitalized paediatric patients over a 4.5-year period. This analysis included the medical charts of 306 patients admitted to the Infectious Disease Unit, Children Hospital Bambino Gesù, Roma, Italy from 2006 to 2010 for varicella disease. The most common complications were haematological disorders (41.5%) followed by neurological ones (23.5%). Varicella vaccination in childhood immunization program must be increased. Copyright © 2010 Elsevier Ltd. All rights reserved.