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1.
Eur J Neurol ; 27(2): 235-243, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31408242

RESUMO

BACKGROUND AND PURPOSE: The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. METHODS: In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. RESULTS: There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. CONCLUSIONS: Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.


Assuntos
Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Proteína C/análise , Adulto , Estudos Transversais , Progressão da Doença , Receptor de Proteína C Endotelial/genética , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Proteína S/análise , Transdução de Sinais , Resultado do Tratamento
2.
Pharmacogenomics J ; 18(3): 422-430, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28719598

RESUMO

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.


Assuntos
Aripiprazol/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Risperidona/sangue , Esquizofrenia/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Aripiprazol/administração & dosagem , Criança , Pré-Escolar , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Humanos , Masculino , Proteínas de Neoplasias/genética , Olanzapina/administração & dosagem , Olanzapina/sangue , Pediatria/tendências , Polimorfismo Genético , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/sangue , Risperidona/administração & dosagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Adulto Jovem
3.
Eur J Neurol ; 25(9): 1169-1176, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29758118

RESUMO

BACKGROUND AND PURPOSE: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. METHODS: In all, 138 MS patients [85 with relapsing-remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. RESULTS: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. CONCLUSIONS: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.


Assuntos
Biomarcadores/sangue , Hemostasia , Esclerose Múltipla/sangue , Proteína ADAMTS13/sangue , Mapeamento Encefálico , Estudos de Casos e Controles , Hemorragia Cerebral/complicações , Hemorragia Cerebral/diagnóstico por imagem , Feminino , Glicoproteínas/sangue , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/diagnóstico por imagem , Inibidor 1 de Ativador de Plasminogênio/sangue
4.
Epidemiol Infect ; 145(13): 2848-2855, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28770694

RESUMO

Brain abscess is uncommon in paediatric population, but of clinical importance because of significant long-term morbidity and mortality. In this multicentre study, promoted by the Italian Society for Paediatric Infectious Diseases, we retrospectively collected patients aged 0-18 years, with a diagnosis of 'brain abscess'. Seventy-nine children were included; the median age was 8·75 years. As predisposing factor, 44 children had preceding infections. The Gram-positive cocci were mostly isolated (27 cases). Sixty (76%) children underwent a surgical intervention. Intravenous antibiotic therapy was administered in all patients, then switched to oral treatment. Clinical sequelae were recorded in 31 (39·2%) children. Twenty-one of them had a single sequela, of which, the most represented, was epilepsy in nine of them. This study focus the attention on the need to have standardized national guidelines or adequate recommendations on type and duration of antibiotic treatment.


Assuntos
Antibacterianos/uso terapêutico , Bactérias/isolamento & purificação , Abscesso Encefálico/epidemiologia , Adolescente , Antibacterianos/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Abscesso Encefálico/tratamento farmacológico , Abscesso Encefálico/microbiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Prevalência , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
5.
Biochim Biophys Acta ; 1854(10 Pt A): 1351-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26012870

RESUMO

Alterations in coagulation factor X (FX) activation, mediated by the extrinsic VIIa/tissue factor (FVIIa/TF) or the intrinsic factor IXa/factor VIIIa (FIXa/FVIIIa) complexes, can result in hemorrhagic/prothrombotic tendencies. However, the molecular determinants involved in substrate recognition by these enzymes are poorly defined. Here, we investigated the role of arginine 386 (chymotrypsin numbering c202), a surface-exposed residue on the FX catalytic domain. The naturally occurring FX386Cys mutant and FX386Ala variant were characterized. Despite the unpaired cysteine, recombinant (r)FX386Cys was efficiently secreted (88.6±21.3% of rFXwt) and possessed normal clearance in mice. rFX386Cys was also normally activated by FVIIa/TF and displayed intact amidolytic activity. In contrast, rFX386Cys activation by the FIXa/FVIIIa complex was 4.5-fold reduced, which was driven by a decrease in the kcat (1.6∗10(-4) s(-1) vs 5.8∗10(-4) s(-1), rFXwt). The virtually unaltered Km (70.6 nM vs 55.6nM, rFXwt) suggested no major alterations in the FX substrate exosite. Functional assays in plasma supplemented with rFX386Cys indicated a remarkable reduction in the thrombin generation rate and thus in coagulation efficiency. Consistently, the rFX386Ala variant displayed similar biochemical features suggesting that global changes at position 386 impact the intrinsic pathway activation. These data indicate that the FXArg386 is involved in FIXa/FVIIIa-mediated FX activation and help in elucidating the bleeding tendency associated with the FX386Cys in a rare FX deficiency case. Taking advantage of the unpaired cysteine, the rFX386Cys mutant may be efficiently targeted by thiol-specific ligands and represent a valuable tool to study FX structure-function relationships both in vitro and in vivo.


Assuntos
Coagulação Sanguínea/genética , Fator X/metabolismo , Fator Xa/metabolismo , Mutação , Animais , Testes de Coagulação Sanguínea , Domínio Catalítico , Fator IXa/genética , Fator IXa/metabolismo , Fator VIIIa/genética , Fator VIIIa/metabolismo , Fator X/química , Fator X/genética , Fator Xa/química , Fator Xa/genética , Células HEK293 , Humanos , Cinética , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Trombina/genética , Trombina/metabolismo
6.
Eur J Clin Microbiol Infect Dis ; 35(1): 1-18, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26476550

RESUMO

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease.


Assuntos
Testes Diagnósticos de Rotina/métodos , Tuberculose/diagnóstico , Criança , Humanos , Pediatria/métodos
7.
Phys Chem Chem Phys ; 17(47): 31707-14, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26559245

RESUMO

X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD) were used to probe the electronic structure and magnetic moment of Mn in Heusler compounds with different crystallographic structure. The results were compared with theoretical calculations of the magnetic and electronic properties, and it was found that in full and half Heusler alloys, Mn is metallic on both sublattices. The magnetic moment is large and localized when octahedrally coordinated by the main group element, consistent with previous theoretical work, and reduced when the main group coordination is tetrahedral. The magnetic and electronic properties of Mn in full and half Heusler compounds are strongly dependent on the structure and sublattice, a fact that can be exploited to design new materials.

8.
Eur Rev Med Pharmacol Sci ; 25(13): 4490-4498, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34286491

RESUMO

OBJECTIVE: To quantify the annual healthcare resource utilization, costs and mortality rate for a large cohort of Italian patients with compensated (CC) and decompensated cirrhosis (DC). PATIENTS AND METHODS: A population-based cohort study was conducted through the data-linkage of mortality for all-cause, hospitalizations and outpatient drugs and service databases of the Campania Region. All adults hospitalized with cirrhosis diagnosis (2007-2015) were grouped in CC and DC (prevalent patients) on January 1, 2016 and followed for 1-year. Incident patients with DC (2015) were also retrieved and followed from discharge date up to 1-year. Negative binomial regression was used to estimate Incidence Rate Ratios (IRRs) for predictors of all-cause hospitalizations. Costs were evaluated from the Italian National Health Service perspective and expressed in euro patient/year. RESULTS: A total of 21,433 prevalent cirrhotic patients (57.1% CC and 42.9% DC) and 1,371 incident patients with DC were identified. During a 1-year, 21.5% of prevalent patients with CC were admitted for acute events, 26.8% of those with DC and 55.4% of incident patients with DC. Ascites (IRR=1.71;95% CI: 1.37-2.14) and hepatic encephalopathy (IRR=1.35; 95% CI: 1.04-1.77) at index admission were strong predictors of hospitalizations in incident DC patients. The 1-year mortality rate was respectively 5.8% and 10.1% for prevalent patients with CC and DC and 35.6% for incident patients with DC. Direct costs amounted to 3,194€ patient/year for the prevalent CC group and 4,001€ patient/year for the DC group and 13,806 € patient/year for incident individuals with DC. CONCLUSIONS: The burden of cirrhosis dramatically differs between CC and DC patients, especially after the first decompensation episode. Ascites and hepatic encephalopathy at index admission were strong predictors of hospitalizations in incident DC patients.


Assuntos
Ascite/epidemiologia , Efeitos Psicossociais da Doença , Encefalopatia Hepática/epidemiologia , Hospitalização/economia , Cirrose Hepática/epidemiologia , Adolescente , Adulto , Idoso , Ascite/economia , Ascite/etiologia , Ascite/terapia , Estudos de Coortes , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Encefalopatia Hepática/economia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/terapia , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Itália/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/economia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
9.
Nat Commun ; 12(1): 5677, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34584083

RESUMO

Tsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types.

10.
Eur J Clin Invest ; 40(3): 281-4, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20415703

RESUMO

BACKGROUND: Analbuminaemia (OMIM #103600) is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. The trait is caused by a variety of mutations within the albumin gene. DESIGN: We report here the clinical and molecular characterization of a new case of congenital analbuminaemia in a 4-year-old Italian girl diagnosed on the basis of the low level of circulating albumin (= 10.0 g L(-1)). The albumin gene was screened by single-strand conformation polymorphism and heteroduplex analysis and the mutated region submitted to DNA sequencing. RESULTS: The proband was found to be homozygous, and both parents heterozygous, for a novel deletion in exon 8 (c.920delT). The subsequent frame-shift should have given rise to a putative polypeptide chain of 304 amino acid residues, which we could not identify in the proband's serum. CONCLUSIONS: A novel analbuminaemia causing mutation was identified and characterized at the clinical level in a child. The molecular diagnosis of the trait is based on the rapid localization of the mutation within the albumin gene by single-strand conformation polymorphism and heteroduplex analysis, followed by DNA sequencing of the mutated region.


Assuntos
Análise Mutacional de DNA , Albumina Sérica/deficiência , Albumina Sérica/genética , Criança , Éxons/genética , Feminino , Mutação da Fase de Leitura , Humanos , Itália , Polimorfismo Conformacional de Fita Simples
11.
Med Lav ; 101(3): 218-27, 2010.
Artigo em Italiano | MEDLINE | ID: mdl-20812663

RESUMO

BACKGROUND: Evaluation of occupational exposures can assist with practice modifications, redesign of equipment, and targeted educational efforts. OBJECTIVES: The aim of this analysis was to identify trends that will aid in the prediction and prevention of accidents. METHODS: Our data were collected from 1999 to 2008 during a surveillance programme of occupational exposure to blood or other potentially infectious materials in a middle Dental School by using a standard coded protocol. RESULTS: Altogether 51 exposures were reported. Of these, 45/51 (88%) were percutaneous and 6/51 (12%) were of the mucosa, involving a splash in the eye of dental care workers (DCW). Of these 22/51 (43%) occurred among dental students, 17/51 (33%) among DCWs attending master and doctorate courses, 11/51 (22%) among DCWs attending as tutors and visiting professors and 1/51 (2%) among staff. Regarding the circumstances of the exposures, 37/51 (73%) and 14/51 (27%) of the accidents occurred respectively during and after the use of a device; of latter, 1/14 (7%) was connected with instrument cleaning and with laboratory activity, 10/14 (71%) occurred when a DCW collided with a sharp object, and 2/14 (4%) happened during other activities. The instrument and the body part most likely to be involved were needles and fingers. The overall exposure rate was 5.15 +/- 0.72 standard error per 10,000 patient procedures. CONCLUSIONS: Our results may serve as a benchmark that other Dental Schools could adopt to assess accident frequency.


Assuntos
Sangue , Líquidos Corporais , Odontologia , Exposição Ocupacional/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ferimentos Penetrantes Produzidos por Agulha/epidemiologia , Vigilância da População , Fatores de Tempo , Adulto Jovem
12.
Eur J Histochem ; 53(1): 25-34, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19351610

RESUMO

Almost all ascidian larvae bear three mucus secreting and sensory organs, the adhesive papillae, at the anterior end of the trunk, which play an important role during the settlement phase. The morphology and the cellular composition of these organs varies greatly in the different species. The larvae of the Clavelina genus bear simple bulbous papillae, which are considered to have only a secretory function. We analysed the adhesive papillae of two species belonging to this genus, C. lepadiformis and C. phlegraea, by histological sections and by immunolocalisation of b-tubulin and serotonin, in order to better clarify the cellular composition of these organs. We demonstrated that they contain at least two types of neurons: central neurons, bearing microvilli, and peripheral ciliated neurons. Peripheral neurons of C. lepadiformis contain serotonin. We suggest that these two neurons play different roles during settlement: the central ones may be chemo- or mechanoreceptors that sense the substratum, and the peripheral ones may be involved in the mechanism that triggers metamorphosis.


Assuntos
Larva/fisiologia , Urocordados/ultraestrutura , Animais , Imuno-Histoquímica , Larva/ultraestrutura , Microscopia Confocal , Neurônios/química , Urocordados/fisiologia
13.
J Dairy Sci ; 92(7): 3074-80, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19528585

RESUMO

Housing conditions for dairy cows are thought to affect lameness, but almost no experimental work has addressed this link. The aim was to assess the effect of one feature of free-stall design, the position of the neck rail, testing the prediction that cows will be more likely to become lame if using pens with the neck rail positioned such that it prevents standing fully inside the stall. Cows (n = 32) were housed in 8 pens. Treatments were tested using a crossover design; treatments were allocated alternately to pens at the beginning of the experiment and switched halfway through the 10-wk experiment. Cows spent 27 +/- 3 min/d standing with all 4 feet in stalls with less restrictive neck rails. In contrast, cows averaged just 1 +/- 3 min/d when the neck rail was positioned restrictively. Cows spent less time standing with only the front 2 feet in the stall with less restrictive neck rails (33 vs. 49 +/- 6 min/d). Gait scores improved when cows were kept in the less restrictive stalls and worsened when cows were kept in pens with the restrictive neck rail (median score 2.5 vs. 3.5 after 5 wk on treatment). Of 13 new cases of lameness, 11 occurred in pens with the restrictive neck-rail position. Similarly, of the 16 new cases of sole lesions, 15 occurred during the period when cows were housed in pens with a restrictive neck rail. Stalls with the neck rail positioned less restrictively had higher contamination scores than stalls with the restrictive neck rails (3.7 vs. 0.4 +/- 0.2), and cows using those stalls had dirtier udders and longer teat-cleaning times (8.3 vs. 7.0 +/- 0.2 min for 12 cows). This study provides the first experimental evidence that aspects of stall design can reduce the risk of lameness and hoof disease. The results illustrated that changes in design that resulted in improvements in cow comfort and hoof health came at the expense of cow and stall cleanliness.


Assuntos
Doenças dos Bovinos/epidemiologia , Indústria de Laticínios/normas , Abrigo para Animais/normas , Higiene/normas , Coxeadura Animal/epidemiologia , Glândulas Mamárias Animais/fisiologia , Animais , Bovinos , Estudos Cross-Over , Feminino , Distribuição Aleatória , Fatores de Risco , Fatores de Tempo
14.
J Med Genet ; 44(12): 750-62, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17766364

RESUMO

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Translocação Genética , Anormalidades Múltiplas/genética , Aborto Habitual/genética , Adulto , Pré-Escolar , Quebra Cromossômica , Transtornos Cromossômicos/patologia , Coloração Cromossômica , Feminino , Doenças Fetais/genética , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hibridização de Ácido Nucleico , Oogênese , Fenótipo , Diagnóstico Pré-Natal , Espermatogênese
16.
Virologie (Montrouge) ; 12(2): 117-135, 2008 Apr 01.
Artigo em Francês | MEDLINE | ID: mdl-36131421

RESUMO

Geminiviruses are single-stranded DNA viruses that infect most plants worldwide. They replicate through a rolling circle mechanism which allows the production of a large amount of single-stranded viral DNA. This mechanism has been studied in detail for prokaryotic replicons but has also been described for eukaryotic replicons. The viral Rep protein is the key element in this process and combines three functions essential for replication: recognition of the viral origin of replication, cleavage of the origin and production of the primer necessary to replicate the viral DNA, and a replicative helicase activity. Furthermore by associating with several host proteins Rep interferes with the cell cycle control to produce a favourable environment for the replication of the virus. Recent advances have been reported concerning the demonstration of the helicase activity of Rep protein and the tertiary structure of its N-terminal domain; our review will focus on these two aspects in relation with the rolling circle replication mechanism.

17.
Acta Otorhinolaryngol Ital ; 38(3): 222-224, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29984798

RESUMO

SUMMARY: Chronic rhinosinusitis (CRS) is a debated topic in the international rhinologic literature because of its high prevalence, heterogeneity of clinical manifestations and unpredictability of disease course. Recently, the focus in CRS research has moved to identify biological subtypes that might explain its aetiology and clinical variability. However, these analyses are still expensive and limited to scientific purposes, so that they cannot be used on a large scale in daily practice. For this reason, we wondered if it was possible to define a risk stratification for CRS patients based only on first level investigations. The heterogeneity of the disease has given us a large amount of data compelling to find an additional storage system. Herein, we present the results of our work, the RhinoBank, as we believe that it is an easy-to-use tool for those professionals dealing with CRS and an effective system to exploit in clinical research.


Assuntos
Coleta de Dados/métodos , Bases de Dados Factuais , Rinite/diagnóstico , Sinusite/diagnóstico , Doença Crônica , Humanos , Rinite/complicações , Sinusite/complicações
18.
J Thromb Haemost ; 16(10): 2035-2043, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29993188

RESUMO

Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. SUMMARY: Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fator IX/genética , Fator IX/metabolismo , Hemofilia B/tratamento farmacológico , Mutação de Sentido Incorreto , Fenilbutiratos/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Hemofilia B/sangue , Hemofilia B/genética , Humanos , Transporte Proteico , Via Secretória
20.
Virologie (Montrouge) ; 11(1): 27-42, 2007 Feb 01.
Artigo em Francês | MEDLINE | ID: mdl-34753255

RESUMO

Nanoviridae family comprises genus Nanovirus (viruses infecting legume plants) and Babuvirus (viruses infecting banana plants). Nanovirus genomes consist of multiple circular single-stranded DNAs of about 1 kb each. They are encapsidated individually in small icosahedral particles. Each DNA molecule encodes only one protein. Nanoviruses replicate in the nucleus of infected plants by a rolling-circle replication mechanism initiated by viral Rep protein. Multiple DNAs encoding similar but clearly distinct Rep proteins have been described for each nanovirus. All Rep proteins of a given nanovirus are functional and each initiates replication of the DNA by which it is encoded (auto-replication). Only the Master Rep protein is able to initiate replication of other genome components (trans-replication). Induction of nanovirus disease by cloned genome components was established only for Faba bean necrotic yellows virus.

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