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OBJECTIVE: The Young Epilepsy Section-Italian chapter (YES-I) is the Italian section of the International League Against Epilepsy (ILAE)-YES. It was founded in 2019 with the aim of increasing the involvement of young epileptologists within scientific associations and facilitating their educational training. The Education and Career Task Force designed a survey on the impact of gender inequality on the educational and professional growth of young epileptologists. METHODS: The survey was proposed via QR code during the 43rd National Congress of the Italian League Against Epilepsy (Padua, 8-10 June 2022), and subsequently distributed via email until 7th September 2022. RESULTS: Of the respondents, 73.6% were female. Of note, 51% of the entire sample answered that they found "no impact" of gender on educational activities (64.3% male against 46.1% female). Only 10% of women stated they have seen very much gender-related inequality in their education or career. However, the majority of our cohort (66%) thought that gender had a negative impact on progression within a scientific society, as well as in female leadership roles in clinical practice (67.9%). Furthermore female medical staff received little work recognition (56.6%). Lastly, 83% of responders did not have children, and only 37.7% declared their colleagues to be empathic in relation to absences for family emergencies. CONCLUSIONS: Lack of awareness of the gender inequality issue might explain inconsistencies in the findings of our survey. Despite the remarkable progress of women rights over the last century, our survey suggests that disparities in academic and decision-making roles exist also in the epileptology field.
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Epilepsia , Equidade de Gênero , Criança , Humanos , Masculino , Feminino , Epilepsia/epidemiologia , Inquéritos e Questionários , Itália/epidemiologiaRESUMO
BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Órgãos Governamentais , Humanos , Itália , Neoplasias/tratamento farmacológicoRESUMO
RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified. Among the most important ones, one can mention prokaryotic ribosomal RNA which is the target of several marketed antibiotics, viral RNAs or oncogenic microRNAs that are tightly involved in the development and progression of various cancers. Oligonucleotides are efficient and specific RNA targeting agents but suffer from poor pharmacodynamic and pharmacokinetic properties. For this reason, a number of synthetic small-molecule ligands have been identified and studied upon screening of chemical libraries or focused design of RNA binders. In this review, we report the most relevant examples of synthetic compounds bearing sufficient selectivity to envisage clinical studies and future therapeutic applications with a particular attention for the main strategies that can be undertaken toward the improvement of selectivity and biological activity.
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BACKGROUND: Neurofibromatosis type 1 is a genetic disorder associated with cognitive deficits, learning disabilities and behavioral problems. These domains appear to have a still controversial debated association with local areas of T2-hyperintensities on MRI images, called unidentified bright objects (UBOs). METHODS: A cohort of 36 children (aged 7-11 years) included consecutively, underwent neuropsychological and behavioral assessment to determine their cognitive and neuropsychological profile, and the frequency of specific learning disabilities. MRI examination was used to determine the impact of UBOs' presence, number, and location on the cognitive, neuropsychological and behavioral profile, and also the presence of optic glioma. RESULTS: The mean full intelligence quotient was 104.6; only one child had mild intellectual disability. Forty one percent of children had a diagnosis of specific learning disabilities and reading was mainly involved. Twenty per cent had attention problems. All children had normal scores in visuo-motor and visuo-perceptual tests. UBOs were present in 94.0% of the MRI examinations. Two children had optic glioma. Children with UBOs in a specific location and children with UBOs elsewhere were statistically compared, no one of the location seemed to have an impact on general cognition measured with full intelligence quotient. The thalamus was associated with problems in calculation and striatum with behavioral problems. An inverse relationship between the number of UBOs and the full intelligence quotient was present, but without a statistical significance. CONCLUSIONS: In this study, the specific location of UBOs did not seem to influence the general cognitive profile and also the relationship between their number and the full intelligence quotient was not significant; these results are still controversial in literature. Finally, the presence of UBOs in the thalamus and striatum may represent a neuroradiological pattern that influences performances in calculation and behavior respectively in children with Neurofibromatosis type 1.
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Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Neurofibromatose 1/patologia , Neurofibromatose 1/psicologia , Adolescente , Criança , Transtornos Cognitivos/epidemiologia , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: NLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members. METHODS: Fifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB-responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1ß (IL-1ß), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed. RESULTS: In the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1ß. However, the kinetics of PAMP-induced IL-1ß secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated. CONCLUSION: Even with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1ß are associated with this mild autoinflammatory phenotype.
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Temperatura Baixa/efeitos adversos , Síndromes Periódicas Associadas à Criopirina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/metabolismo , Saúde da Família , Feminino , Células HEK293 , Humanos , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/imunologia , Linhagem , Fenótipo , População Branca/genéticaRESUMO
Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder. Although most CCHS associated PHOX2B mutations occur de novo, about 10% of the cases are inherited from apparently asymptomatic parents, thus confirming variable expressivity and incomplete penetrance of PHOX2B mutations. Three asymptomatic parents of children affected with CCHS, and found to carry the same PHOX2B expansion mutations as their siblings, were studied by overnight polysomnography and somatic mosaicism analysis. In one case, significant sleep breathing control anomalies were detected, while the other two resulted in normal. In tissue-specific allele studies, mosaicism with a comparatively low mutant allele proportion was showed in the two unaffected adult carriers. Accurate polysomnography and assessment of the degree of somatic mosaicism should be conducted in asymptomatic carriers of PHOX2B mutations, as they may unmask subclinical but significant anomalies.
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Proteínas de Homeodomínio/genética , Hipoventilação/genética , Mutação , Fatores de Transcrição/genética , Adulto , Alanina/genética , Criança , Pré-Escolar , Saúde da Família , Feminino , Estudos de Associação Genética , Humanos , Hipoventilação/congênito , Hipoventilação/fisiopatologia , Masculino , Pais , Peptídeos/genética , Polissonografia , Síndrome , Expansão das Repetições de TrinucleotídeosRESUMO
SPRY2 is an inducible inhibitor of signalling mediated by tyrosine kinases receptors, whose targeting causes intestinal hyperganglionosis in mice. In this light, we have undertaken a mutational analysis of the SPRY2 gene in patients affected with intestinal neuronal dysplasia (IND), without detecting nucleotide changes in any of the 26 DNA samples analysed, with the exception of two already known polymorphic variants. A role of the SPRY2 gene in IND pathogenesis can be thus excluded.
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Variação Genética/genética , Enteropatias/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Análise Mutacional de DNA , Frequência do Gene/genética , Humanos , Enteropatias/patologia , Enteropatias/fisiopatologia , Proteínas de Membrana , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genéticaAssuntos
Fator VIII/genética , Testes Genéticos/métodos , Hemofilia A/genética , Éxons , Feminino , Deleção de Genes , Humanos , Masculino , Gravidez , Estudos RetrospectivosRESUMO
Podocin (NPHS2) expression in podocytes is associated with variable degrees of proteinuria and progression to renal failure in different glomerular diseases that suggests different expression profiles in NPHS2 promoter. Three functional polymorphisms in NPHS2 promoter (-51T, -116T, and -535 insCTTTTTT(3)) were found determining strong downregulation (-73, -59, and -82%, respectively) of the reporter gene expression when transfected in podocytes. Electrophoretic mobility shift assay experiments showed that all wild-type variants (-51G, -116C, and -535 insCTTTTTT(2)) formed specific DNA-protein complexes with podocyte nuclear extracts that were abolished by the presence of the rare forms (-51T, -116T, and -535 insCTTTTTT(3)). In the case of -51G, upstream stimulatory factor-1 (USF1) was identified as the specific trans element in accord to binding inhibition experiments and USF1 RNAi silencing. Haplotype analysis of 204 normal controls and 545 patients with renal diseases (308 immunoglobulin (Ig)A nephropathy and 237 focal segmental glomerulosclerosis) evidenced that -116/-51 and -535/P2OL formed two blocks in strong linkage disequilibrium in both normal and pathological cohorts. The high NPHS2 promoter profile -116C/-51G haplotype was more frequent in patients with IgA nephropathy (P-value=0.005) and was associated with a better clinical outcome in terms of proteinuria and creatinine levels. Overall our study describes functional variants of NPHS2 promoter and characterizes trans-acting elements that modulate podocin expression in the kidney. High producer NPHS2 promoter haplotypes seem protective in patients with chronic glomerular diseases.
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Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Nefropatias/genética , Proteínas de Membrana/genética , Regiões Promotoras Genéticas , Proteinúria/genética , Adolescente , Adulto , Idoso , Animais , Linhagem Celular , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Creatinina/sangue , Interpretação Estatística de Dados , Progressão da Doença , Feminino , Seguimentos , Frequência do Gene , Variação Genética , Glomerulonefrite por IGA/genética , Glomerulosclerose Segmentar e Focal/genética , Haplótipos , Humanos , Lactente , Luciferases/genética , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/genética , Podócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Fatores de TempoAssuntos
Proteínas de Homeodomínio/genética , Hipoventilação/genética , Mutação , Peptídeos/genética , Transtornos Intrínsecos do Sono/genética , Fatores de Transcrição/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , Análise Mutacional de DNA , Expansão das Repetições de DNA , Sequência Rica em GC , Heterozigoto , Humanos , Hipoventilação/congênito , Hipoventilação/diagnóstico , Recém-Nascido , Dados de Sequência Molecular , Fenótipo , Reação em Cadeia da Polimerase , Transtornos Intrínsecos do Sono/congênito , Transtornos Intrínsecos do Sono/diagnóstico , SíndromeRESUMO
Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.
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Proteínas de Transporte/genética , Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Glaucoma/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Tirosina Fosfatases/genética , Adolescente , Idade de Início , Sequência de Aminoácidos , Doença de Charcot-Marie-Tooth/complicações , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Consanguinidade , Análise Mutacional de DNA , Doenças Desmielinizantes/complicações , Feminino , Genes Recessivos , Glaucoma/complicações , Humanos , Masculino , Dados de Sequência Molecular , Marrocos , Mutação , Monoéster Fosfórico Hidrolases/genética , Mapeamento Físico do Cromossomo , Proteínas Tirosina Fosfatases não Receptoras , Homologia de Sequência de Aminoácidos , Síndrome , TunísiaRESUMO
Lysyl oxidase is an extracellular enzyme that controls the maturation of collagen and elastin. Lysyl oxidase and collagen III often show similar expression patterns in fibrotic tissues. Therefore, we investigated the influence of lysyl oxidase overexpression on the promoter activity of human COL3A1 gene. Our results showed that when COS-7 cells overexpressed the mature form of lysyl oxidase, the activity of the human COL3A1 promoter was increased up to an average of 12 times when tested by luciferase reporter assay. The effect was specific, because other promoters were not affected. Moreover, lysyl oxidase effect was abolished by beta-aminopropionitrile, a specific inhibitor of its catalytic activity. Electrophoretic mobility shift assay showed a binding activity in the region from -101 to -77 that was significantly increased by lysyl oxidase overexpression. The binding was specifically competed by the cold probe, and the mutagenesis of this region abolished both the binding activity in gel retardation and lysyl oxidase stimulation of COL3A1 promoter in transfection experiments. We identified the binding activity as Ku antigen in its two components: Ku80 and Ku70. This study suggests a new coordinated mechanism by which lysyl oxidase might control the development of fibrosis.
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Antígenos Nucleares , Colágeno/genética , DNA Helicases , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/genética , Proteína-Lisina 6-Oxidase/metabolismo , Ativação Transcricional , Aminopropionitrilo/farmacologia , Animais , Sequência de Bases , Células COS , Sondas de DNA/genética , Sondas de DNA/metabolismo , Proteínas de Ligação a DNA/análise , Fibroblastos , Fibrose/enzimologia , Fibrose/metabolismo , Genes Reporter , Humanos , Autoantígeno Ku , Dados de Sequência Molecular , Mutação , Proteínas Nucleares/análise , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Proteína-Lisina 6-Oxidase/genética , Especificidade por Substrato , TransfecçãoRESUMO
BACKGROUND: Previous work from our laboratory demonstrated upregulation of type III collagen by cyclosporin A (CsA) in a cellular model of renal fibroblasts 'in vitro', suggesting that a mechanism of gene transcriptional activation might be responsible for collagen accumulation in renal fibrosis resulting from chronic CsA treatment. METHODS: We analysed in the same cellular model: (i) COL3A1 mRNA expression by RT-PCR; (ii) COL3A1 promoter activity by transfection of renal fibroblasts with constructs containing promoter fragments of different length fused to a reporter gene; (iii) expression of transcription factors by western blot analysis; (iv) DNA-protein binding by gel retardation assays with nuclear extracts from CsA-treated and untreated cells; and (v) site-directed mutagenesis of COL3A1 promoter to verify the role of a short DNA segment as CsA responsive element. RESULTS: CsA induced a 3-5-fold increase in COL3A1 mRNA that was paralleled by a stimulation of the COL3A1 promoter. Degradation of COL3A1 mRNA was comparable in CsA-treated and -untreated cells. The target region was first limited to a 178 bp fragment from -117 to +61 (pFV1). By gel retardation, utilizing several oligonucleotides that covered the whole length of pFV1, we detected a factor able to bind the promoter DNA (oligo 31) in nuclear extracts after 3 h treatment with CsA. The binding was absent in untreated cells and it was not detected when a 10-base mutation was introduced in oligonucleotide 31. Finally, the same substitution mutation at the site of binding of this factor abolished the stimulatory effect of CsA on COL3A1 promoter. Some transcription factors, whose potential binding sites are included in the above promoter fragment, were induced by CsA treatment either soon (3 h) or late (24-72 h) after treatment and were detected by western blot analysis. CONCLUSIONS: CsA induces the synthesis of type III collagen by stimulating a pathway leading to activation of COL3A1 promoter and upregulation of COL3A1 mRNA. A short promoter fragment, proximal to the transcription start site, is the target of CsA stimulation.
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Colágeno/genética , Ciclosporina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Chlorocebus aethiops , DNA/metabolismo , Fibroblastos , Humanos , Rim , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of a sequential chemo-radiotherapeutic treatment on the basis of an earlier report by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients with histologically diagnosed malignant gliomas entered the study. Fifteen patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin (40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks. Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on the preoperative volume. RESULTS: Thirteen patients had measurable disease and were evaluable for response. After chemotherapy we obtained 3 CRs (complete remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13). The median duration of response was 10 months. The median survival of the entire patients population was 9 months with 33% survival rates at 1 year. Hematological toxicity grade 4 in one patient and grade 3 in two patients were the major complications due to chemotherapy. CONCLUSIONS: Our sequential chemo-radiotherapeutic regimen appears to have significant activity in adults with newly diagnosed high-grade gliomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Irradiação Craniana , Glioblastoma/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Astrocitoma/tratamento farmacológico , Astrocitoma/radioterapia , Astrocitoma/cirurgia , Astrocitoma/terapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Irradiação Craniana/efeitos adversos , Esquema de Medicação , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Glioblastoma/cirurgia , Doenças Hematológicas/induzido quimicamente , Humanos , Nefropatias/induzido quimicamente , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Oligodendroglioma/tratamento farmacológico , Oligodendroglioma/radioterapia , Oligodendroglioma/cirurgia , Projetos Piloto , Indução de Remissão , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Vômito/etiologiaRESUMO
BACKGROUND: Newer diagnostic modalities such as serum markers and acute rest myocardial perfusion imaging (MPI) have been evaluated diagnostically in patients with chest pain in the emergency department (ED), but never concurrently. We compared these two modalities in distinguishing patients in the ED with symptomatic myocardial ischemia from those with non-cardiac causes. METHODS: Serum markers and acute technetium-99m sestamibi/tetrofosmin rest MPI were obtained in 75 patients admitted to the ED with chest pain and nondiagnostic electrocardiograms. Venous samples were drawn at admission and 8 to 24 hours later for total creatine kinase, CK-MB fraction, troponin T, troponin I, and myoglobin. Three nuclear cardiologists performed blinded image interpretation. Coronary artery disease (CAD) was confirmed either by diagnostic testing or by the occurrence of myocardial infarction (MI). RESULTS: Acute rest MPI results were abnormal in all 9 patients with MI. An additional 26 patients had objective evidence of CAD confirmed by diagnostic testing. The sensitivity of acute rest MPI for objective evidence of CAD was 73%. Serum troponin T and troponin I were highly specific for acute MI but had low sensitivity at presentation. Individual serum markers had very low sensitivity for symptomatic myocardial ischemia alone. In the multivariate regression model, only acute rest MPI and diabetes were independently predictive of CAD. CONCLUSION: At the time of presentation and 8 to 24 hours later, acute rest MPI has a better sensitivity and similar specificity for patients with objective evidence of CAD when compared with serum markers.
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Biomarcadores/sangue , Dor no Peito/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Dor no Peito/sangue , Doença das Coronárias/diagnóstico por imagem , Creatina Quinase/sangue , Complicações do Diabetes , Eletrocardiografia , Feminino , Humanos , Isoenzimas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Isquemia Miocárdica/sangue , Mioglobina/sangue , Compostos Organofosforados , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Análise de Regressão , Descanso , Sensibilidade e Especificidade , Método Simples-Cego , Tecnécio Tc 99m Sestamibi , Troponina I/sangue , Troponina T/sangueRESUMO
OBJECTIVES: To evaluate the prevalence and the dynamics of HIV-1 subtypes in Romanian adults and children, and to investigate the origins of the nosocomial epidemic. DESIGN: A total of 1000 serum and plasma samples, from adults (n = 579) and children (n = 421) who were diagnosed as being HIV-1-infected during 1990-1997 in 39 of the 41 Romanian districts, were serotyped. Viral DNA was isolated from blood samples of 84 patients and the viruses were genotyped. METHODS: Serotyping was performed with a peptide subtype-specific enzyme immunoassay (SSEIA), based on in vitro competition for antibody binding between the representative V3 peptides of the different clades (A-F). Proviral HIV-1 DNA was genotyped by heteroduplex mobility assay or by sequence analysis of the C2-V3 env region. RESULTS: SSEIA showed that 93% of the samples from horizontally infected children were serotype F, 1% were serotype B, and the remaining 6% were uninterpretable. In vertically infected children, 74% of strains were serotype F, 10% were serotype A, 3% were serotype B, and 3% were serotype E. Serotype F was also the dominant subtype in adults (68%), but serotypes A, B, C, D and E were also detected. SSEIA gave indeterminate results in 7% of cases. A strong correlation (90%) between serotyping and genotyping for subtype F was found. Analysis of the relative incidence of the different serotypes over a 7-year period (1990-1997) showed a stable distribution. CONCLUSIONS: Subtype F largely dominates the epidemiology of HIV-1 infection in both children and adults in Romania, although other major subtypes are present. The predominance of subtype F in Romania may be a future potential source of HIV-1 variability in Europe.
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Infecções por HIV/virologia , HIV-1/genética , Adulto , Sequência de Aminoácidos , Criança , Variação Genética , Genótipo , Infecções por HIV/epidemiologia , HIV-1/classificação , Humanos , Incidência , Dados de Sequência Molecular , Romênia/epidemiologia , SorotipagemRESUMO
Single medial olivocochlear (MOC) neurons were recorded from the cochlea of the anesthetized guinea pig. We used tones and noise presented monaurally and binaurally and measured responses for sounds up to 105 dB sound pressure level (SPL). For monaural sound, MOC neuron firing rates were usually higher for noise bursts than tone bursts, a situation not observed for afferent fibers of the auditory nerve that were sampled in the same preparations. MOC neurons also differed from afferent fibers in having less saturation of response. Some MOC neurons had responses that continued to increase even at high sound levels. Differences between MOC and afferent responses suggest that there is convergence in the pathway to olivocochlear neurons, possibly a combination of inputs that are at the characteristic frequency (CF) with others that are off the CF. Opposite-ear noise almost always facilitated the responses of MOC neurons to sounds in the main ear, the ear that best drives the unit. This binaural facilitation depends on several characteristics that pertain to the main ear: it is higher in neurons having a contralateral main ear (contra units), it is higher at main-ear sound levels that are moderate (approximately 65 dB SPL), and it is higher in neurons with low discharge rates to main-ear stimuli. Facilitation also depends on parameters of the opposite-ear sound: facilitation increases with noise level in the opposite ear until saturating, is greater for continuous noise than noise bursts, and is usually greater for noise than for tones. Using optimal opposite-ear facilitators and high-level stimuli, the firing rates of olivocochlear neurons range up to 140 spikes/s, whereas for moderate-level monaural stimuli the rates are <80 spikes/s. At high sound levels, firing rates of olivocochlear neurons increase with CF, an increase that may compensate for the known lower effectiveness of olivocochlear synapses on outer hair cells responding to high frequencies. Overall, our results demonstrate a high MOC response for binaural noise and suggest a prominent role for the MOC system in environments containing binaural noise of high level.
Assuntos
Cóclea/citologia , Cóclea/fisiologia , Neurônios/fisiologia , Ruído , Núcleo Olivar/citologia , Núcleo Olivar/fisiologia , Estimulação Acústica , Animais , Feminino , Lateralidade Funcional/fisiologia , Cobaias , MasculinoRESUMO
We sequenced and phylogenetically analyzed the reverse transcriptase (RT) regions of the pol genes of 14 human immunodeficiency virus type 1 (HIV-1) isolates from Romanian patients, which were classified as subtype F on the basis of env gene structure. The RT sequences showed that the strains clustered phylogenetically and were equidistant from other HIV-1 subtypes as shown by the neighbor-joining and maximum-likelihood methods, allowing us to define HIV-1 subtype F according to the pol classification. The subtype F RT sequences differed from reported group M RT sequences by 10.94% (for nucleotides) and 7.6% (for amino acids). Phenotypic analysis of subtype F susceptibility to three classes of antiretroviral compounds showed an increase in the 50% inhibitory concentration of the tetrahydroimidazo[4,5,1-jk] [1,4]-benzodiazepin-2-(1H)-one and -thione (TIBO) derivate R82913 for one strain which was naturally resistant to this compound. This first report of subtype F pol sequences confirms the perfect correlation between the phylogenetic positions determined by env and pol analyses and suggests that virus variability might influence the efficacy of antiretroviral treatments. This finding warrants a global evaluation of the phenotypic and genotypic susceptibility of HIV-1 subtypes to antiretroviral drugs.