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Showing papers by "Catholic University of the Sacred Heart published in 2009"


Journal ArticleDOI
TL;DR: A key role for NMS in the clinical frame of PD is supported and the need to address them specifically in clinical trials using dedicated scales is addressed.
Abstract: We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales.

1,151 citations


Journal ArticleDOI
24 Apr 2009-Science
TL;DR: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage and provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
Abstract: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.

1,144 citations


Journal ArticleDOI
TL;DR: It is confirmed that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk, however, a substantial proportion of head and head cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head andneck cancer among women and among young-onset cases.
Abstract: Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter ( ψ ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk ( ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

858 citations


Journal ArticleDOI
Richard A. Gibbs1, Jeremy F. Taylor2, Curtis P. Van Tassell3, William Barendse4, William Barendse5, Kellye Eversole, Clare A. Gill6, Ronnie D. Green3, Debora L. Hamernik3, Steven M. Kappes3, Sigbjørn Lien7, Lakshmi K. Matukumalli8, Lakshmi K. Matukumalli3, John C. McEwan9, Lynne V. Nazareth1, Robert D. Schnabel2, George M. Weinstock1, David A. Wheeler1, Paolo Ajmone-Marsan10, Paul Boettcher11, Alexandre Rodrigues Caetano12, José Fernando Garcia13, José Fernando Garcia11, Olivier Hanotte14, Paola Mariani15, Loren C. Skow6, Tad S. Sonstegard3, John L. Williams16, John L. Williams15, Boubacar Diallo, Lemecha Hailemariam17, Mário Luiz Martinez12, C. A. Morris9, Luiz Otávio Campos da Silva12, Richard J. Spelman18, Woudyalew Mulatu14, Keyan Zhao19, Colette A. Abbey6, Morris Agaba14, Flábio R. Araújo12, Rowan J. Bunch4, Rowan J. Bunch5, James O. Burton16, C. Gorni15, Hanotte Olivier15, Blair E. Harrison5, Blair E. Harrison4, Bill Luff, Marco Antonio Machado12, Joel Mwakaya14, Graham Plastow20, Warren Sim5, Warren Sim4, Timothy P. L. Smith3, Merle B Thomas4, Merle B Thomas5, Alessio Valentini21, Paul D. Williams5, James E. Womack6, John Woolliams16, Yue Liu1, Xiang Qin1, Kim C. Worley1, Chuan Gao6, Huaiyang Jiang1, Stephen S. Moore20, Yanru Ren1, Xingzhi Song1, Carlos Bustamante19, Ryan D. Hernandez19, Donna M. Muzny1, Shobha Patil1, Anthony San Lucas1, Qing Fu1, Matthew Peter Kent7, Richard Vega1, Aruna Matukumalli3, Sean McWilliam5, Sean McWilliam4, Gert Sclep15, Katarzyna Bryc19, Jung-Woo Choi6, Hong Gao19, John J. Grefenstette8, Brenda M. Murdoch20, Alessandra Stella15, Rafael Villa-Angulo8, Mark G. Wright19, Jan Aerts16, Jan Aerts22, Oliver C. Jann16, Riccardo Negrini10, Michael E. Goddard23, Michael E. Goddard24, Ben J. Hayes24, Daniel G. Bradley25, Marcos V.B. da Silva12, Marcos V.B. da Silva3, Lilian P.L. Lau25, George E. Liu3, David J. Lynn26, David J. Lynn25, Francesca Panzitta15, Ken G. Dodds9 
24 Apr 2009-Science
TL;DR: Data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation.
Abstract: The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.

769 citations


Journal ArticleDOI
TL;DR: In this review article, for the first time, a personalized management of no-reflow is proposed on the basis of the assessment of the prevailing mechanisms of no -reflow operating in each patient.

719 citations


Journal ArticleDOI
TL;DR: A review of the state of the art in understanding the processes involved in the exchange of trace gases and aerosols between the earth's surface and the atmosphere can be found in this article.

627 citations



Journal ArticleDOI
TL;DR: R is a useful test, the classification may be useful in clinical/therapeutical decisions, and CTS classification appeared reliable with significant differences between groups.
Abstract: Objectives To evaluate the following points about carpal tunnel syndrome (CTS): 1) characterization of a wide population; 2) sensitivity of electrodiagnostic tests, and particularly the contribution of disto-proximal ratio test; 3) validity of a neurophysiological classification developed by us. Material and methods Prospective study in 500 hands with CTS symptoms. Neurophysiological "standard" tests were always performed: sensory nerve conduction velocity (SNCV) first- and third digit-wrist and distal motor latency (DML). In "standard negative" hands disto-proximal ratio technique (R) was performed. Neurophysiological classification: Extreme CTS (absence of median motor, sensory responses), Severe (absence of sensory response, abnormal DML), Moderate (abnormal SNCV, abnormal DML), Mild (abnormal SNCV, normal DML), Minimal (abnormal R or other segmental/comparative test, normal standard tests). Results Sensibility of standard tests: 77%. R increased the diagnostic yield by 20%. CTS classification appeared reliable with significant differences between groups. Conclusion R is a useful test, the classification may be useful in clinical/therapeutical decisions.

417 citations


Journal ArticleDOI
TL;DR: This review reports current knowledge regarding the roles that cadmium (Cd), mercury (Hg), arsenic (As), lead (PB), manganese (Mn), and zinc (Zn) play as endocrine-disrupting chemicals (EDCs).
Abstract: This review reports current knowledge regarding the roles that cadmium (Cd), mercury (Hg), arsenic (As), lead (PB), manganese (Mn), and zinc (Zn) play as endocrine-disrupting chemicals (EDCs). The influence of these metals on the endocrine system, possible mechanisms of action, and consequent health effects were correlated between experimental animals and humans. Analysis of the studies prompted us to identify some critical issues related to this area and showed the need for more rigorous and innovative studies. Consequently, it was recommended that future studies need to: (1) identify the mechanisms of action, because at the present time only a few have been elucidated-in this context, the possible presence of hormesis need to be determined, as currently this was reported only for exposure Cd and As; (2) study the possible additive, synergistic, or antagonistic effects on the endocrine system following exposure to a mixture of metals since there is a lack of these studies available, and in general or occupational environments, humans are simultaneously exposed to different classes of xenobiotics, including metals, but also to organic compounds that might also be EDCs; (3) assess the potential adverse effects on the endocrine system of low-level exposures to metals, as most of the information currently available on EDCs originates from studies in which exposure levels were particularly high; and (4) assess the effects on the endocrine and reproductive systems of other metals that are present in the general and occupational environment that have not yet been evaluated.

398 citations


Journal ArticleDOI
TL;DR: This study provides overwhelming confirmation of three associations previously reported in a genome-wide study and shows further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC).
Abstract: To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

388 citations


Journal ArticleDOI
TL;DR: A critical role is revealed in mediating the effects of the IGF-1 pathway and a feedback loop between miR-1 expression and theIGF-1 signal transduction cascade is demonstrated.
Abstract: Background— MicroRNAs (miRNAs/miRs) are small conserved RNA molecules of 22 nucleotides that negatively modulate gene expression primarily through base paring to the 3′ untranslated region of target messenger RNAs. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. In this study, we investigated the molecular mechanisms through which miR-1 intervenes in regulation of muscle cell growth and differentiation. Methods and Results— On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1; (2) miR-1 and IGF-1 protein levels are correlated inversely in models of cardiac hypertrophy and failure as well as in the C2C12 skeletal muscle cell model of differentiation; (3) the activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 express...

Journal ArticleDOI
TL;DR: It is shown that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family.
Abstract: N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2(S2G) in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2(S2G) in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.

Journal ArticleDOI
TL;DR: Specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes, in molecular features and in disease‐risk stratification are identified, and misregulated microRNAs expression profiles characterize human medullOBlastomas, and may provide potential targets for novel therapeutic strategies.
Abstract: Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk-adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c-Myc overexpressing tumors) and in disease-risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth-inhibitory function. This property has been addressed for miR-9 and miR-125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies.

Journal ArticleDOI
TL;DR: VEGF-A appears to be a novel mediator of IBD by promoting intestinal angiogenesis and inflammation, and agents that block VEGf-A signaling might reduce intestinal inflammation in patients with IBD.

Journal ArticleDOI
TL;DR: These adolescents use the Internet for many hours per week; most utilize dysfunctional coping strategies and show worse interpersonal relations than peers who do not show signs of PIU.
Abstract: International literature has identified a stable correlation between problems in the sphere of adolescents' personal relationships and potential Internet dependence. The objective of this research is to verify in an Italian context the relationship among problematic Internet use (PIU), the quality of interpersonal relationships, and the cognitive strategies habitually used by adolescents to face daily problems. The participants in the research were 98 adolescents ages 14 to 19 (M = 16.28 years). The following instruments were administered to the participants: the Internet Addiction Test (IAT), the Test of Interpersonal Relationships (TRI); and the Children's Coping Strategies Checklist (CCSC). Parents of the participants were administered the Child Behavior Checklist (CBCL). Of the participants, 36.7% showed signs of PIU. These adolescents use the Internet for many hours per week; most utilize dysfunctional coping strategies and show worse interpersonal relations than peers who do not show signs ...

Journal ArticleDOI
TL;DR: In this article, aqueous microwave-assisted extraction of total phenols from black tea powder was investigated in an ordinary household microwave oven, and the results varied depending on how the ratio was modified (that is at either constant tea mass or water volume), due to the characteristics of microwave heating.

Journal ArticleDOI
TL;DR: The present large pooled analysis of randomized trials suggests that thrombectomy (in particular manual thromBectomy) significantly improves the clinical outcome in patients with STEMI undergoing mechanical reperfusion and that its effect may be additional to that of IIb/IIIa-inhibitors.
Abstract: Aims Thrombectomy in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is associated to better myocardial reperfusion. However, no single trial was adequately powered to asses the impact of thrombectomy on long-term clinical outcome and to identify patients at higher benefit. Thus, we sought to assess these issues in a collaborative individual patient-data pooled analysis of randomized studies (study acronym: ATTEMPT, number of registration: NCT00766740). Methods and results Individual data of 2686 patients enrolled in 11 trials entered the pooled analysis. Primary endpoint of the study was all-cause mortality. Major adverse cardiac events (MACE) were considered as the occurrence of all-cause death and/or target lesion/vessel revascularization and/or myocardial infarction (MI). Subgroups analysis was planned according to type of thrombectomy device (manual or non-manual), diabetic status, IIb/IIIa-inhibitor therapy, ischaemic time, infarct-related artery, pre-PCI TIMI flow. Clinical follow-up was available in 2674 (99.6%) patients at a median of 365 days. Kaplan–Meier analysis showed that allocation to thrombectomy was associated with significantly lower all-cause mortality ( P = 0.049). Thrombectomy was also associated with significantly reduced MACE ( P = 0.011) and death + MI rate during the follow-up ( P = 0.015). Subgroups analysis showed that thrombectomy is associated to improved survival in patients treated with IIb/IIIa-inhibitors ( P = 0.045) and that the survival benefit is confined to patients treated in manual thrombectomy trials ( P = 0.011). Conclusion The present large pooled analysis of randomized trials suggests that thrombectomy (in particular manual thrombectomy) significantly improves the clinical outcome in patients with STEMI undergoing mechanical reperfusion and that its effect may be additional to that of IIb/IIIa-inhibitors.

Journal ArticleDOI
TL;DR: To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, subjects with a diagnosis of NS, LS, and CFCS were screened for the entire coding sequence of the gene.
Abstract: Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS–mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 0:1–8, 2009. © 2009 Wiley-Liss, Inc.


Journal ArticleDOI
TL;DR: This study shows for the first time that CgPDR1 mutations are not only responsible for in vitro/in vivo azole resistance but that they can also confer a selective advantage under host conditions.
Abstract: CgPdr1p is a Candida glabrata Zn(2)-Cys(6) transcription factor involved in the regulation of the ABC-transporter genes CgCDR1, CgCDR2, and CgSNQ2, which are mediators of azole resistance. Single-point mutations in CgPDR1 are known to increase the expression of at least CgCDR1 and CgCDR2 and thus to contribute to azole resistance of clinical isolates. In this study, we investigated the incidence of CgPDR1 mutations in a large collection of clinical isolates and tested their relevance, not only to azole resistance in vitro and in vivo, but also to virulence. The comparison of CgPDR1 alleles from azole-susceptible and azole-resistant matched isolates enabled the identification of 57 amino acid substitutions, each positioned in distinct CgPDR1 alleles. These substitutions, which could be grouped into three different “hot spots,” were gain of function (GOF) mutations since they conferred hyperactivity to CgPdr1p revealed by constitutive high expression of ABC-transporter genes. Interestingly, the major transporters involved in azole resistance (CgCDR1, CgCDR2, and CgSNQ2) were not always coordinately expressed in presence of specific CgPDR1 GOF mutations, thus suggesting that these are rather trans-acting elements (GOF in CgPDR1) than cis-acting elements (promoters) that lead to azole resistance by upregulating specific combinations of ABC-transporter genes. Moreover, C. glabrata isolates complemented with CgPDR1 hyperactive alleles were not only more virulent in mice than those with wild type alleles, but they also gained fitness in the same animal model. The presence of CgPDR1 hyperactive alleles also contributed to fluconazole treatment failure in the mouse model. In conclusion, this study shows for the first time that CgPDR1 mutations are not only responsible for in vitro/in vivo azole resistance but that they can also confer a selective advantage under host conditions.

Journal ArticleDOI
TL;DR: In this article, the authors calculate indices of central bank autonomy (CBA) for 163 central banks as of end-2003, and comparable indices for a subgroup of 68 central banks up to the end-1980s.
Abstract: This paper calculates indices of central bank autonomy (CBA) for 163 central banks as of end-2003, and comparable indices for a subgroup of 68 central banks as of the end of the 1980s. The results confirm strong improvements in both economic and political CBA over the past couple of decades, although more progress is needed to boost political autonomy of the central banks in emerging market and developing countries. Our analysis confirms that greater CBA has on average helped to maintain low inflation levels. The paper identifies four broad principles of CBA that have been shared by the majority of countries. Significant differences exist in the area of banking supervision where many central banks have retained a key role. Finally, we discuss the sequencing of reforms to separate the conduct of monetary and fiscal policies.

Journal ArticleDOI
TL;DR: Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades.
Abstract: Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtype

Journal ArticleDOI
TL;DR: NAFLD is highly prevalent among psoriasis patients, where it is closely associated with obesity (overall and abdominal), metabolic syndrome, and PsA, and more likely to cause severe liver fibrosis (compared with nonPs- NAFLD).

Journal ArticleDOI
16 Apr 2009-Oncogene
TL;DR: Cytogenetic and molecular analysis shows that the two types of CSCs within different regions of the same human GBM bear quite diverse tumorigenic potential and distinct genetic anomalies, and, yet, derive from common ancestor cells.
Abstract: Glioblastomas (GBMs) contain transformed, self-maintaining, multipotent, tumour-initiating cancer stem cells, whose identification has radically changed our perspective on the physiology of these tumours Currently, it is unknown whether multiple types of transformed precursors, which display alternative sets of the complement of properties of true cancer stem cells, can be found in a GBM If different subsets of such cancer stem-like cells (CSCs) do exist, they might represent distinct cell targets, with a differential therapeutic importance, also depending on their characteristics and lineage relationship Here, we report the presence of two types of CSCs within different regions of the same human GBM Cytogenetic and molecular analysis shows that the two types of CSCs bear quite diverse tumorigenic potential and distinct genetic anomalies, and, yet, derive from common ancestor cells This provides critical information to unravel the development of CSCs and the key molecular/genetic components underpinning tumorigenicity in human GBMs

Journal ArticleDOI
TL;DR: A close monitoring and a careful biopsy policy may help early recognition of RS in CLL patients using stereotyped BCR, particularly if combined with IGHV4-39.
Abstract: Purpose: Few biological prognosticators are useful for prediction of Richter syndrome (RS), representing the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. Stereotyped B-cell receptors (BCR) may have prognostic effect in CLL progression. We tested the prognostic effect of stereotyped BCR for predicting RS transformation. Experimental Design: The prevalence of stereotyped BCR was compared in RS ( n = 69) versus nontransformed CLL ( n = 714) by a case-control analysis. Subsequently, the effect of stereotyped BCR at CLL diagnosis on risk of RS transformation was actuarially assessed in a consecutive CLL series ( n = 753). Results: RS ( n = 69) displayed a higher prevalence of stereotyped BCR ( P P IGHV4-39/IGHD6-13/IGHJ5 carried the highest risk of RS transformation [hazard ratio (HR), 24.50; P P = 0.001) and IGHV4-39 usage (HR, 4.03; P = 0.004) as independent predictors of RS transformation. The combination of IGHV4-39 usage and stereotyped BCR in the same patient identified CLL with a very high risk of RS transformation (5-year risk, 68.7%). The risk carried by stereotyped BCR and IGHV4-39 usage was specific for RS transformation and had no effect on CLL progression without transformation. Conclusions: Analysis of BCR features may help identify CLL patients at risk of RS. A close monitoring and a careful biopsy policy may help early recognition of RS in CLL patients using stereotyped BCR, particularly if combined with IGHV4-39 .

Journal ArticleDOI
TL;DR: The authors compare single round vs runoff elections under plurality rule, allowing for partly endogenous party formation, and show that under runoff elections, the number of political candidates is larger, but the influence of extremist voters on equilibrium policy and hence policy volatility are smaller, because the bargaining power of the political extremes is reduced compared to single round elections.
Abstract: We compare single round vs runoff elections under plurality rule, allowing for partly endogenous party formation. Under runoff elections, the number of political candidates is larger, but the influence of extremist voters on equilibrium policy and hence policy volatility are smaller, because the bargaining power of the political extremes is reduced compared to single round elections. The predictions on the number of candidates and on policy volatility are confirmed by evidence from a regression discontinuity design in Italy, where cities above 15,000 inhabitants elect the mayor with a runoff system, while those below hold single round elections.

Journal ArticleDOI
TL;DR: There are gaps in research and clinical practice that lead to frequent medication errors in older adults, which must be solved by future studies and by regulatory measures in order to support errorless and appropriate use medications in these people.
Abstract: 1. Older people have substantial interindividual variability in health, disability, age-related changes, polymorbidity, and associated polypharmacy, making generalization of prescribing recommendations difficult. 2. Medication use in older adults is often inappropriate and erroneous, partly because of the complexities of prescribing and partly because of many patient, provider, and health system factors that substantially influence the therapeutic value of medications in aged people. 3. A high prevalence of medication errors in older adults results on the one hand from accumulation of factors that contribute to medication errors in all age groups, such as polypharmacy, polymorbidity, enrollment in several disease-management programmes, and fragmentation of care. On the other hand, specific geriatric aspects play a role in these medication errors; these include age-related pharmacological changes, lack of specific evidence on the efficacy and safety of medications, underuse of comprehensive geriatric assessment, less availability of drug formulations offering geriatric doses, and inadequate harmonization of geriatric recommendations across Europe. 4. The dearth of geriatric clinical pharmacology and clinical pharmacy services compounds the difficulties. 5. There are gaps in research and clinical practice that lead to frequent medication errors in older adults, which must be solved by future studies and by regulatory measures in order to support errorless and appropriate use medications in these people.


Journal ArticleDOI
TL;DR: A diagnosis of MI according to the new guidelines applies to 15% of patients undergoing PCI and these patients are at high risk of further adverse events both during the hospital stay and at 18 months.
Abstract: Aim: Elevation of Troponin after scheduled percutaneous coronary intervention (PCI) is a recognized consequence. We sought to evaluate the prognostic significance and impact of the newly published definition of PCI-related myocardial infarction (MI) according to which any troponin elevation >3 times the upper reference limit identify a peri-procedural MI. Methods: Search of BioMedCentral, CENTRAL, mRCT and PubMed (updated May 2008). Outcomes of interest were: MACE [the composite of all cause death, MI, repeat target vessel PCI (re-PCI) and coronary artery bypass grafting (CABG)]; single end points were also assessed. Results: Fifteen studies have been included totalling 7578 patients. Troponin elevation occurred in 28.7% of the procedures. The incidence of PCI-related MI according to the new definition was 14.5%. During the hospitalization, any level of raised troponin was associated with an increased risk of MACE [OR 11.29 (3.00–42.48), Number needed to harm (NNH) 5], death [OR 7.16 (1.95–26.27), NNH = 100], MI [OR 30.85 (6.05–157.38), NNH = 4] and re-PCI [OR 4.13 (1.23–13.88), NNH = 50]. Patients with PCI-related MI had an increased risk of death [OR 17.25 (2.71–109.96), NNH = 100] and re-PCI [OR 10.86 (3.2–36.94), NNH = 25]. At follow up of 18 months any troponin elevation was associated with an increased risk of MACE [OR 1.48 (1.12–1.96), NNH = 20], death [OR 2.19 (1.59–3.00), NNH = 50], MI [OR 3.29 (2.71–6.31), NNH = 33] and re-PCI [OR 1.47 (1.06–2.03), NNH = 25]. In patients with PCI-related MI the risk of MACE was further increased: OR 2.25 (1.26–4.00), NNH = 3. An increase of the troponin level below the cut-off was not associated with MACE. Conclusion: A diagnosis of MI according to the new guidelines applies to 15% of patients undergoing PCI and these patients are at high risk of further adverse events both during the hospital stay and at 18 months.

Journal ArticleDOI
TL;DR: Preliminary evidence indicates that moderate CR may promote muscle mitochondrial biogenesis in middle‐aged human subjects, and further research is warranted to investigate whether CR may represent a safe and efficient strategy to delay the onset and mitigate the progression of sarcopenia in older adults.
Abstract: Sarcopenia, the loss of muscle mass and function, is a common feature of aging and impacts on individual health and quality of life. Several cellular mechanisms have been involved in the pathogenesis of this syndrome, including mitochondrial dysfunction, altered apoptotic and autophagic signaling, and, more recently, trace metal dyshomeostasis. Calorie restriction (CR) without malnutrition has been shown to ameliorate the age-related loss of muscle mass in a variety a species. Mechanisms of protection span from preservation of mitochondrial functional and structural integrity to mitochondrial biogenesis, reduction of oxidative stress, and favorable modulation of apoptotic and autophagic signaling pathways. Importantly, preliminary evidence indicates that moderate CR may promote muscle mitochondrial biogenesis in middle-aged human subjects. Further research is warranted to investigate whether CR may represent a safe and efficient strategy to delay the onset and mitigate the progression of sarcopenia in older adults.