Caironi P.,University of Milan |
Tognoni G.,Consorzio Mario Negri Sud |
Masson S.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri |
Fumagalli R.,University of Milan Bicocca |
And 11 more authors.
New England Journal of Medicine | Year: 2014
BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P = 0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P = 0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P = 0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P = 0.29). No significant differences in other secondary outcomes were observed between the two groups. CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.) Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Chang Q.,Sloan Kettering Cancer Center |
Bournazou E.,Sloan Kettering Cancer Center |
Sansone P.,Sloan Kettering Cancer Center |
Berishaj M.,Sloan Kettering Cancer Center |
And 21 more authors.
Neoplasia (United States) | Year: 2013
We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis. © 2013 Neoplasia Press, Inc. All rights reserved.
PubMed | UO di Pediatria, University of Modena and Reggio Emilia, Clinica Pediatrica, UOC di Malattie Metaboliche ed Endocrinologia Pediatrica A.O.U. Policlinico di Bari and 10 more.
Type: Journal Article | Journal: PloS one | Year: 2015
Being overweight or obese is one of the most common reasons that children and adolescents are teased at school. We carried out a study in order to investigate: i) the relation between weight status and school bullying and ii) the relation between weight status categories and types of victimization and bullying in an outpatient sample of Italian children and adolescents with different degrees of overweight from minimal overweight up to severe obesity.Nine-hundred-forty-seven outpatient children and adolescents (age range 6.0-14.0 years) were recruited in 14 hospitals distributed over the country of Italy. The participants were classified as normal-weight (N = 129), overweight (N = 126), moderately obese (N = 568), and severely obese (N = 124). The nature and extent of verbal, physical and relational bullying and victimization were assessed with an adapted version of the revised Olweus bully-victim questionnaire. Each participant was coded as bully, victim, bully-victim, or not involved.Normal-weight and overweight participants were less involved in bullying than obese participants; severely obese males were more involved in the double role of bully and victim. Severely obese children and adolescents suffered not only from verbal victimization but also from physical victimization and exclusion from group activities. Weight status categories were not directly related to bullying behaviour; however severely obese males perpetrated more bullying behaviour compared to severely obese females.Obesity and bullying among children and adolescents are of ongoing concern worldwide and may be closely related. Common strategies of intervention are needed to cope with these two social health challenges.
Inaba S.,Columbia University |
Mintz G.S.,Columbia University |
Farhat N.Z.,Elyria Memorial Hospital Regional Medical Center |
Fajadet J.,Clinique Pasteur |
And 9 more authors.
JACC: Cardiovascular Imaging | Year: 2014
Objectives This study investigated coronary artery remodeling patterns associated with clinical outcomes. Background In the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree: An Imaging Study in Patients With Unstable Atherosclerotic Lesions) study, reported predictors of nonculprit lesion (NCL) major adverse cardiac events (MACE) were an intravascular ultrasound (IVUS) minimal lumen area (MLA) ≤4 mm2, a plaque burden ≥70%, and a IVUS-virtual histology (VH) thin-cap fibroatheroma (TCFA), but not lesion site remodeling. Methods Overall, 697 consecutive patients with an acute coronary syndrome were enrolled and underwent 3-vessel gray-scale and IVUS-VH; 3,223 NCLs were identified by IVUS. The remodeling index (RI) was calculated as the external elastic membrane area at the MLA site divided by the average of the proximal and distal reference external elastic membrane areas. First, one third of the patients were randomly selected to determine RI cutoffs related to NCL MACE (development cohort). Receiver-operating characteristic analysis showed that there were 2 separate cut points that predicted NCL MACE: RI = 0.8789 and RI = 1.0046 (area under the curve = 0.663). These cut points were used to define negative remodeling as an RI <0.88, intermediate remodeling as an RI of 0.88 to 1.00, and positive remodeling as an RI >1.00. Second, we used the remaining two-thirds of patients to validate these cut points with respect to lesion morphology and clinical outcomes (validation cohort). Results Kaplan-Meier curve analysis in the validation cohort showed that NCL MACE occurred more frequent (and equally) in negative and positive remodeling lesions compared with intermediate remodeling lesions. In this cohort, negative remodeling lesions had the smallest MLA, positive remodeling lesions had the largest plaque burden, and VH TCFA, especially VH TCFA with multiple necrotic cores, was most common in negatively remodeling lesions. Conclusions The present study showed the novel concept that positive and negative lesion site remodeling was associated with unanticipated NCL MACE in the PROSPECT study. (PROSPECT: An Imaging Study in Patients With Unstable Atherosclerotic Lesions [PROSPECT]; NCT00180466).
Ioana M.,Radboud University Nijmegen |
Ioana M.,University of Medicine and Pharmacy of Craiova |
Ioana M.,Carol Davila University of Medicine and Pharmacy |
Ferwerda B.,Radboud University Nijmegen |
And 11 more authors.
Innate Immunity | Year: 2012
Infectious diseases exert a constant evolutionary pressure on the innate immunity genes. TLR4, an important member of the TLR family, specifically recognizes conserved structures of various infectious pathogens. Two functional TLR4 polymorphisms, Asp299Gly and Thr399Ile, modulate innate host defense against infections, and their prevalence between various populations has been proposed to be influenced by local infectious pressures. If this assumption is true, strong local infectious pressures would lead to a homogeneous pattern of these ancient TLR4 polymorphisms in geographically-close populations, while a weak selection or genetic drift may result in a diverse pattern. We evaluated TLR4 polymorphisms in 15 ethnic groups in Iran, to assess whether infections exerted selective pressures on different haplotypes containing these variants. The Iranian subpopulations displayed a heterogeneous pattern of TLR4 polymorphisms, comprising various percentages of Asp299Gly and Thr399Ile, alone or in combination. The Iranian sample, as a whole, showed an intermediate mixed pattern when compared with commonly-found patterns in Africa, Europe, Eastern Asia and the Americas. These findings suggest a weak, or absent, selection pressure on TLR4 polymorphisms in the Middle-East that does not support the assumption of an important role of these polymorphisms in the host defense against local pathogens. © The Author(s) 2011.
Gasparre G.,University of Bologna |
Kurelac I.,University of Bologna |
Capristo M.,University of Bologna |
Iommarini L.,University of Bologna |
And 12 more authors.
Cancer Research | Year: 2011
The oncogenic versus suppressor roles of mitochondrial genes have long been debated. Peculiar features of mitochondrial genetics such as hetero/homoplasmy and mutation threshold are seldom taken into account in this debate. Mitochondrial DNA (mtDNA) mutations generally have been claimed to be protumorigenic, but they are also hallmarks of mostly benign oncocytic tumors wherein they help reduce adaptation to hypoxia by destabilizing hypoxia-inducible factor-1α (HIF1α). To determine the influence of a disassembling mtDNA mutation and its hetero/homoplasmy on tumorigenic and metastatic potential, we injected mice with tumor cells harboring different loads of the gene MTND1 m.3571insC. Cell cultures obtained from tumor xenografts were then analyzed to correlate energetic competence, apoptosis, α-ketoglutarate (α-KG)/succinate (SA) ratio, and HIF1α stabilization with the mutation load. A threshold level for the antitumorigenic effect of MTND1 m.3571insC mutation was defined, above which tumor growth and invasiveness were reduced significantly. Notably, HIF1α destabilization and downregulation of HIF1α-dependent genes occurred in cells and tumors lacking complex I (CI), where there was an associated imbalance of α-KG/SA despite the presence of an actual hypoxic environment. These results strongly implicate mtDNA mutations as a cause of oncocytic transformation. Thus, the antitumorigenic and antimetastatic effects of high loads of MTND1 m.3571insC, following CI disassembly, define a novel threshold-regulated class of cancer genes. We suggest these genes be termed oncojanus genes to recognize their ability to contribute either oncogenic or suppressive functions in mitochondrial settings during tumorigenesis. ©2011 AACR.
Fusco D.,Policlinico Universitario sola Malpighi |
Vargiolu M.,Policlinico Universitario sola Malpighi |
Vidone M.,Policlinico Universitario sola Malpighi |
Mariani E.,Policlinico Universitario sola Malpighi |
And 7 more authors.
Human Molecular Genetics | Year: 2010
The tyrosine kinase receptor RET51 is expressed in distinct families of neurons where it promotes different functions. FKBP52 is an immunophilin with neuroprotective effects on different kinds of neurons. In this paper, we demonstrate that RET51 activation by both glial cell line-derived neurotrophic factor (GDNF) and NGF triggers the formation of RET51/FKBP52 complex. The substitution of the tyrosine 905 of RET51, a key residue phosphorylated by both GDNF and NGF, disrupts the RET51/FKBP52 complex. NGF and GDNF have a functional role in dopaminergic (DA) neurons where RET51 and FKBP52 are expressed with a yet undefined function. To clarify if RET51/FKBP52 complex should exert its function in DA neurons, we used an indirect approach by screening the genes encoding for RET51 and FKBP52 in a group of 30 Parkinson's disease patients. The degeneration of DA neurons is the main feature of PD, which is associated to a complex multifactorial aetiology combining environmental, age-related and genetic factors. We found a compound heterozygous carrying two mutations in RET and FKBP52 that are sufficient to disrupt the RET51/FKBP52 complex, indicating its potential role in PD. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Kurelac I.,Dip. di Science Mediche e Chirurgiche |
MacKay A.,The Breakthrough Breast Cancer Research Center |
Lambros M.B.K.,The Breakthrough Breast Cancer Research Center |
Cesare E.D.,Dip. di Science Mediche e Chirurgiche |
And 10 more authors.
Human Molecular Genetics | Year: 2013
Mitochondrial DNA (mtDNA) mutations leading to the disruption of respiratory complex I (CI) have been shown to exhibit anti-tumorigenic effects, at variance with those impairing only the function but not the assembly of the complex, which appear to contribute positively to cancer development. Owing to the challenges in the analysis of the multi-copy mitochondrial genome, it is yet to be determined whether tumour-associated mtDNA lesions occur as somatic modifying factorsor as germ-line predisposing elements. Here we investigated the whole mitochondrial genome sequence of 20 pituitary adenomas with oncocytic phenotype and identified pathogenic and/or novel mtDNA mutations in 60% of the cases. Using highly sensitive techniques, namely fluorescent PCR and allele-specific locked nucleic acid quantitative PCR, we identified the most likely somatic nature of these mutations in our sample set, since none of the mutations was detected in the corresponding blood tissue of the patients analysed. Furthermore, we have subjected a series of 48 pituitary adenomas to a high-resolution array comparative genomic hybridization analysis, which revealed that CI disruptive mutations, and the oncocytic phenotype, significantly correlate with low number of chromosomal aberrations in the nuclear genome. We conclude that CI disruptive mutations in pituitary adenomas are somatic modifiers of tumorigenesis most likely contributing not only to the development of oncocytic change, but also to a less aggressive tumour phenotype, as indicated by a stable karyotype. © The Author 2012. Published by Oxford University Press. All rights reserved.
Mathias M.,University of Colorado at Denver |
Ernst B.J.,University of Colorado at Denver |
Pichi F.,Policlinico Universitario sola Malpighi |
Torrazza C.,Policlinico Universitario sola Malpighi |
And 2 more authors.
Retina | Year: 2012
PURPOSE: The purpose of this study was to evaluate the characteristics and thermal properties of a chandelier endoillumination probe under conditions that may induce thermal damage. METHODS: Experimental evaluation of a surgical ophthalmic instrument under ex vivo conditions. RESULTS: A 27-gauge dual-tip chandelier endoillumination probe was exposed to air, saline, porcine uveal tissue, and human blood using a Xenon light source at 100% intensity. No alteration of probe tip morphology was observed in air or saline at 10-minute exposure. After exposure to uveal tissue and blood, thermal melting of the probe tip was noted at 10 minutes. Beam focus and intensity were observed to diminish in the probe tips that underwent thermal melting. A thermal imaging device was used to demonstrate increased thermal intensity from the probe tip that had been covered with uveal tissue compared with a control tip in air. CONCLUSION: Thermal melting of a chandelier fiber probe has been reported only once previously in the literature after exposure to porcine Tenon capsular tissue. We report two separate conditions that may induce thermal damage to a fiber optic probe including encapsulation of uveal tissue at the probe tip and exposure to blood. Vitreoretinal surgeons should be aware of this potential complication. © The Ophthalmic Communications Society, Inc.
Porcelli A.M.,University of Bologna |
Ghelli A.,University of Bologna |
Ceccarelli C.,Policlinico Universitario sola Malpighi |
Lang M.,University of Bologna |
And 16 more authors.
Human Molecular Genetics | Year: 2010
We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1a and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of α-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1α stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1a stabilization. © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.