RESUMO
Environmental and genetic factors seem to play a pathogenetic role in multiple sclerosis (MS). The genetic component is partly suggested by familial aggregation of cases; however, MS families with affected subjects over different generations have rarely been described. The aim of this study was to report clinical and genetic features of a multigenerational MS family and to perform a review of the literature on this topic. We describe a multigenerational Italian family with six individuals affected by MS, showing different clinical and neuroradiological findings. HLA-DRB1* typing revealed the presence of the DRB1*15:01 allele in all the MS cases and in 4/5 non-affected subjects. Reports on six multigenerational MS families have previously been published, giving similar results. The HLA-DRB1*15:01 allele was confirmed to be linked to MS disease in this family; moreover, its presence in non-affected subjects suggests the involvement of other susceptibility factors in the development and expression of the disease, in accordance with the complex disease model now attributed to MS.
Assuntos
Saúde da Família , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Esclerose Múltipla/genética , Adulto , Bases de Dados Bibliográficas/estatística & dados numéricos , Avaliação da Deficiência , Feminino , Testes Genéticos , Genótipo , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etnologia , Esclerose Múltipla/fisiopatologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: We report the ophthalmic findings of a patient with type Ia glycogen storage disease (GSD Ia), DiGeorge syndrome (DGS), cataract and optic nerve head drusen (ONHD). CASE PRESENTATION: A 26-year-old white woman, born at term by natural delivery presented with a post-natal diagnosis of GSD Ia. Genetic testing by array-comparative genomic hybridization (CGH) for DGS was required because of her low levels of serum calcium. The patient has been followed from birth, attending the day-hospital every six months at the San Paolo Hospital, Milan, outpatient clinic for metabolic diseases and previously at another eye center. During the last day-hospital visit, a complete eye examination showed ONHD and cataract in both eyes. Next Generation Sequencing (NGS) was subsequently done to check for any association between the eye problems and metabolic aspects. CONCLUSIONS: This is the first description of ocular changes in a patient with GSD Ia and DGS. Mutations explaining GSD Ia and DGS were found but no specific causative mutation for cataract and ONHD. The metabolic etiology of her lens changes is known, whereas the pathogenesis of ONHD is not clear. Although the presence of cataract and ONHD could be a coincidence; the case reported could suggest that hypocalcemia due to DGS could be the common biochemical pathway.
Assuntos
Catarata/etiologia , Síndrome de DiGeorge/complicações , Doença de Depósito de Glicogênio/complicações , Drusas do Disco Óptico/etiologia , Campos Visuais , Adulto , Catarata/diagnóstico , Hibridização Genômica Comparativa , Síndrome de DiGeorge/diagnóstico , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Drusas do Disco Óptico/diagnóstico , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Approximately 5%-10% of cases are familial (FALS) and the remaining are sporadic (SALS). To date FUS mutations are responsible for 4%-6% of familial cases as well as 0.7%-1.8% of sporadic cases. METHODS: The frequency of FUS mutations was investigated in an Italian cohort of 500 SALS and 40 FALS patients through direct sequencing of exons 5, 6, 13, 14 and 15. RESULTS: Eight FUS mutation carriers were identified in five SALS (1%) and three FALS (7.5%), five already known and three new mutations: a de novo mutation was identified in a sporadic subject as well as the co-presence of FUS/C9ORF72 mutations in a FALS subject. The molecular and clinical details of the three patients harbouring a novel mutation (G245V, G509D and R491C) are presented here. Moreover the co-presence of the R491C mutation and C9ORF72 pathological expansion was found according to the oligogenic disease model. CONCLUSIONS: In conclusion our results revealed a higher frequency of FUS mutation carriers (7.5%) in FALS compared to literature data together with a higher presence of female gender.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Proteína FUS de Ligação a RNA/genética , Adulto , Idoso , Estudos de Coortes , Éxons , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Fatores SexuaisRESUMO
We report the identification of a novel mutation in the fork-head box C1 (FOXC1) gene which occurred de novo in an Italian patient with unrecognized Axenfeld-Rieger syndrome. He was previously diagnosed as having late recognized primary congenital glaucoma at the age of 14 years and was subsequently subjected to multiple surgical interventions due to uncontrolled intraocular pressure and progressive visual field loss. After exclusion of mutations in CYP1B1 and MYOC, trio-whole-exome sequencing revealed de novo in frame deletion in the coding region of the FOXC1 gene (c.407_409delGTC, p.V137del) leading to a deletion of the evolutionary conserved amino acid Valine at position 137 of the protein. Molecular modeling predicted that Val137 deletion impairs FOXC1 DNA-binding capacity and transcriptional activation. Since loss-of-function mutations in FOXC1 are associated with Axenfeld-Rieger syndrome, the genetic findings in combination with re-evaluation of the patient's clinical data resulted in a corrected diagnosis of Axenfeld-Rieger syndrome with developmental glaucoma. We therefore suggest that in addition to CYP1B1 and MYOC, FOXC1 should be included in the genetic analysis of cases with unclear glaucomatous phenotypes to ensure proper diagnosis, adequate treatment and appropriate genetic counseling.
Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/diagnóstico , Fatores de Transcrição Forkhead/genética , Glaucoma/diagnóstico , Adulto , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Análise Mutacional de DNA , Diagnóstico Tardio , Exoma/genética , Anormalidades do Olho/genética , Oftalmopatias Hereditárias , Fatores de Transcrição Forkhead/química , Glaucoma/genética , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Estrutura Secundária de ProteínaRESUMO
Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, headaches, intracerebral hemorrhages, and focal neurological deficits; they can also be clinically silent and occur as a sporadic or an autosomal dominant condition. Three genes have been identified as causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3, mapping, respectively, on chromosomes 7q, 7p, and 3q. Here, we report an Italian family affected by CCM due to a MGC4607 gene mutation, on exon 4. All the affected subjects suffered from seizures, and some of them underwent surgery for removal of a cavernous angioma. Brain MRI showed multiple lesions consistent with CCMs in all patients. Spinal and cutaneous cavernous angiomas were present too. This report underlines the need for a careful interdisciplinarity among neurologists, neuroradiologists, neurosurgeons, geneticists, ophthalmologists, and dermatologists for a total evaluation of the different manifestations of familial CCM. This points out that only referral centers are organized to offer a multidisciplinary management of this disease.
Assuntos
Proteínas de Transporte/genética , Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Mutação , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/diagnóstico , Criança , Éxons , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Humanos , Masculino , Linhagem , Neoplasias Cutâneas/diagnósticoRESUMO
OBJECTIVES: It has been suggested that a low plasma high-density lipoprotein cholesterol (HDL-C) level contributes to the high cardiovascular disease risk of patients with chronic kidney disease (CKD), especially those undergoing haemodialysis (HD). The present study was conducted to gain further understanding of the mechanism(s) responsible for the low HDL-C levels in patients with CKD and to separate the impact of HD from that of the underlying CKD. METHODS: Plasma lipids and lipoproteins, HDL subclasses and various cholesterol esterification parameters were measured in a total of 248 patients with CKD, 198 of whom were undergoing HD treatment and 40 healthy subjects. RESULTS: Chronic kidney disease was found to be associated with highly significant reductions in plasma HDL-C, unesterified cholesterol, apolipoprotein (apo)A-I, apoA-II and LpA-I:A-II levels in both CKD cohorts (with and without HD treatment). The cholesterol esterification process was markedly impaired, as indicated by reductions in plasma lecithin:cholesterol acyltransferase (LCAT) concentration and activity and cholesterol esterification rate, and by an increase in the plasma preß-HDL content. HD treatment was associated with a further lowering of HDL levels and impaired plasma cholesterol esterification. The plasma HDL-C level was highly significantly correlated with LCAT concentration (R = 0.438, P < 0.001), LCAT activity (R = 0.243, P < 0.001) and cholesterol esterification rate (R = 0.149, P = 0.031). Highly significant correlations were also found between plasma LCAT concentration and levels of apoA-I (R = 0.432, P < 0.001), apoA-II (R = 0.275, P < 0.001), LpA-I (R = 0.326, P < 0.001) and LpA-I:A-II (R = 0.346, P < 0.001). CONCLUSION: Acquired LCAT deficiency is a major cause of low plasma HDL levels in patients with CKD, thus LCAT is an attractive target for therapeutic intervention to reverse dyslipidaemia, and possibly lower the cardiovascular disease risk in these patients.
Assuntos
Hipoalfalipoproteinemias/etiologia , Deficiência da Lecitina Colesterol Aciltransferase/complicações , Insuficiência Renal Crônica/complicações , Apolipoproteínas/metabolismo , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , Esterificação/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/sangue , Triglicerídeos/metabolismoRESUMO
BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; -1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF.
Assuntos
Esclerose Lateral Amiotrófica/genética , Predisposição Genética para Doença/genética , Mutação/genética , Gravidez/genética , Regiões Promotoras Genéticas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Análise de Variância , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Estudos Retrospectivos , Superóxido Dismutase/genética , Superóxido Dismutase-1RESUMO
Unruptured intracranial aneurysms represent a decisional challenge. Treatment risks have to be balanced against an unknown probability of rupture. A better understanding of the physiopathology is the basis for a better prediction of the natural history of an individual patient. Knowledge about the possible determining factors arises from a careful comparison between ruptured versus unruptured aneurysms and from the prospective observation and analysis of unbiased series with untreated, unruptured aneurysms. The key point is the correct identification of the determining variables for the fate of a specific aneurysm in a given individual. Thus, the increased knowledge of mechanisms of formation and eventual rupture of aneurysms should provide significant clues to the identification of rupture-prone aneurysms. Factors like structural vessel wall defects, local hemodynamic stress determined also by peculiar geometric configurations, and inflammation as trigger of a wall remodeling are crucial. In this sense the study of genetic modifiers of inflammatory responses together with the computational study of the vessel tree might contribute to identify aneurysms prone to rupture. The aim of this article is to underline the value of a unifying hypothesis that merges the role of geometry, with that of hemodynamics and of genetics as concerns vessel wall structure and inflammatory pathways.
Assuntos
Aneurisma Roto/etiologia , Aneurisma/etiologia , Aneurisma Intracraniano/etiologia , Aneurisma/genética , Aneurisma/patologia , Aneurisma Roto/genética , Aneurisma Roto/patologia , Meio Ambiente , Hemodinâmica , Humanos , Aneurisma Intracraniano/genética , Aneurisma Intracraniano/patologia , Fatores de RiscoRESUMO
The activity of heparanase is responsible for heparan sulfate cleavage, thus resulting in the release of heparan sulfate-bound growth factors. Since heparanase activity is upregulated in several tumor types and is implicated in the malignant behavior, the enzyme is regarded as a promising target for antitumor therapy. Based on previous evidence that the heparanase inhibitor SST0001, a non-anticoagulant N-acetylated glycol split heparin, is effective against an Ewing's sarcoma model, the present study was performed to extend the preclinical evaluation of SST0001 to a panel of pediatric sarcoma models, representative of various tumor histotypes (soft tissue and bone sarcomas) and to further elucidate its mode of action. SST0001 treatment downregulated several angiogenic factors in the conditioned media of sarcoma cells, inhibited the pro-invasive effect of heparin-binding factors (VEGF, bFGF, HGF, PDGF), and abrogated PDGF receptor tyrosine phosphorylation. Subcutaneous administration of SST0001 was very effective, resulting in a significant growth inhibition (range, 64-95%) of all tested tumor xenografts. The efficacy of SST0001 was enhanced in combination with antiangiogenic agents (bevacizumab, sunitinib) as documented by the high rate of complete response. The synergistic effect of SST0001 in combination with antiangiogenic agents is consistent with the heparanase mode of action and with the relevant role of heparin-binding proangiogenic/growth factors in the malignant behavior of sarcoma cells.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Heparina/análogos & derivados , Osteossarcoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Criança , Sinergismo Farmacológico , Feminino , Glucuronidase/antagonistas & inibidores , Glucuronidase/metabolismo , Heparina/farmacologia , Heparina/uso terapêutico , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/prevenção & controle , Osteossarcoma/irrigação sanguínea , Osteossarcoma/patologia , Pirróis/farmacologia , Pirróis/uso terapêutico , Rabdomiossarcoma/irrigação sanguínea , Rabdomiossarcoma/patologia , Sunitinibe , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry-like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow-up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms.
Assuntos
Encéfalo , Sistema Nervoso Central/patologia , Hemangioma Cavernoso do Sistema Nervoso Central , Proteínas Associadas aos Microtúbulos , Proteínas Proto-Oncogênicas , Encéfalo/metabolismo , Encéfalo/patologia , Sistema Nervoso Central/metabolismo , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Aconselhamento Genético , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/fisiopatologia , Hemangioma Cavernoso do Sistema Nervoso Central/terapia , Humanos , Proteína KRIT1 , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Convulsões/genética , Convulsões/patologiaRESUMO
Increased oxidative stress is known to play a role in the pathogenesis of atherosclerosis, and polymorphisms in genes encoding for enzymes involved in modulation of oxidant stress, such as paraoxonases (PONs), provide a potentially powerful approach to study the risk of disease susceptibility. Aim of our study is to investigate the possible association among PONs polymorphisms, clinical and metabolic factors, and atherothrombotic events in an Italian population. We evaluated in 105 subjects, with or without atherosclerotic risk factors, the presence of PON1 L55M, PON1 Q192R, and PON2 S311C genetic variants, as well as lipid profile, the concentration of aminothiols (blood reduced glutathione, plasma total glutathione, homocysteine, cysteine, cysteinyl glycine), and malondialdehyde as markers of lipid peroxidation. Clinical, biochemical, and genetic variables were correlated with a history of atherothrombosis. Previous atherothrombotic events were found in 42 patients (40 %): myocardial infarction in 24, stroke or transient ischemic attack in 18. By multiple logistic regression analysis, hypertension (OR = 5.538; 95 % CI 2.202-13.902, P < 0.001), HDL-cholesterol concentration (OR = 0.947; 95 % CI 0.910-0.985, P = 0.007), and the presence of C allele in PON2 gene (OR = 3.595; 95 % CI 1.247-10.361, P = 0.018) were independently associated with atherothrombotic events. Our study sheds light on the role of PON2 as a possible cofactor in determining the risk of events together with the well-known risk markers HDL-cholesterol and hypertension.
Assuntos
Arildialquilfosfatase/genética , Trombose/genética , Alelos , Cisteína/sangue , Feminino , Predisposição Genética para Doença , Genótipo , Glutationa/sangue , Homocisteína/sangue , Humanos , Hipertensão/genética , Ataque Isquêmico Transitório/genética , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Acidente Vascular Cerebral/genéticaRESUMO
The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM) with the identification of the CCM1, CCM2, and CCM3 genes. Recently, we have recruited a patient with an X/3 balanced translocation that exhibits CCM. By fluorescent in situ hybridization analysis, sequence analysis tools and database mining procedures, we refined the critical region to an interval of 200-kb and identified the interrupted ZPLD1 gene. We detected that the mRNA expression level of ZPLD1 gene is consistently decreased 2.5-fold versus control (P=0.0006) with allelic loss of gene expression suggesting that this protein may be part of the complex signaling pathway implicated in CCM formation.
Assuntos
Cromossomos Humanos Par 3 , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , Translocação Genética , Adulto , Linhagem Celular , Quebra Cromossômica , Bases de Dados de Proteínas , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/fisiologia , Imageamento por Ressonância Magnética , Fenótipo , Insuficiência Ovariana Primária/complicações , Insuficiência Ovariana Primária/genética , RNA Mensageiro/metabolismo , Inativação do Cromossomo X/genéticaRESUMO
PURPOSE: A growing evidence in the scientific literature suggests that oxidative damage plays a pathogenic role in primary open-angle glaucoma. Therefore, it is of interest to test whether drugs effective against glaucoma display antioxidant activity. We test the hypothesis that the classic beta-blocker therapy for glaucoma with timolol involves the activation of antioxidant protective mechanisms towards endothelial cells. METHODS: Oxidative stress was induced in cultured human endothelial cells by iron/ascorbate with or without timolol pretreatment. Analysed parameters included cell viability (neutral red uptake and tetrazolium salt tests), lipid peroxidation (thiobarbituric reactive substances), and occurrence of molecular oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine). RESULTS: Oxidative stress decreased 1.8-fold cell viability, increased 3.0-fold lipid peroxidation and 64-fold oxidative damage to DNA. In the presence of timolol, oxidative stress did not modify cell viability, whereas lipid peroxidation was increased 1.3-fold, and DNA oxidative damage 3.6-fold only. CONCLUSIONS: The obtained results indicate that timolol exerts a direct antioxidant activity protecting human endothelial cells from oxidative stress. These cells employ mechanisms similar to those observed in the vascular endothelium. It is hypothesized that this antioxidant activity is involved in the therapeutic effect of this drug against glaucoma.
Assuntos
Anti-Hipertensivos/farmacologia , Glaucoma de Ângulo Aberto/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Timolol/farmacologia , Animais , Câmara Anterior/efeitos dos fármacos , Câmara Anterior/metabolismo , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glaucoma de Ângulo Aberto/patologia , HumanosRESUMO
PURPOSE: To assess the role of genetic polymorphisms in venous thrombosis events (VTE) using Artificial Neural Networks (ANNs), a model for solving non-linear problems frequently associated with complex biological systems, due to interactions between biological, genetic and environmental factors. METHODS: A database was generated from a case-control study of venous thrombosis, using 238 patients and 211 controls. The database of 64 variables included age, gender and a panel of 62 genetic variants. Three different ANNs were compared, with logistic regression for the accuracy of predicting cases and controls. RESULTS: ANNs yielded a better performance than the logistic regression algorithm. Indeed, through ANNs models, the 62 variables related to genetic variants were first reduced to a set of 9, and then of 3 (MTHFR 677 C/T, FV arg506gln, ICAM1 gly214arg). CONCLUSIONS: The findings of this study illustrate the power of ANN in evaluating multifactorial data, and show that the different sensitivities of the models of elaboration are related to the characteristics of the data. This may contribute to a better understanding of the role played by genetic polymorphisms in VTE, and help to define, if possible, a test panel of genetic variants to estimate an individual's probability of developing the disease.
Assuntos
Genes/genética , Predisposição Genética para Doença , Redes Neurais de Computação , Polimorfismo Genético , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Simulação por Computador , Bases de Dados Factuais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Trombose Venosa/epidemiologiaRESUMO
Idiopathic recurrent acute pericarditis (IRAP) is suspected to be an autoimmune phenomenon. We studied 46 consecutive patients. We looked for: 1) the occurrence of new diagnoses of autoimmune diseases during our follow up; 2) HLA typing; and 3) the presence of the most frequent mutations linked to familial Mediterranean fever (FMF gene or MEFV). HLA typing was done in 21 patients at loci B, DRB1, DQA1 and DQB1. MEFV gene was looked in 23 patients using specific primers. During the follow-up we made a new diagnosis of primary Sjögren's syndrome in four patients (8.7%) and of rheumatoid arthritis in one patient (2.2%). HLA B14, DRB1*01 and DQB1*0202 were significantly more prevalent, but we did not find a typical HLA typing. MEFV gene was searched: exon 10 was checked by sequence and the E148Q mutation by restriction site analysis. No mutations were found. In conclusion, the prevalence of definite immunorheumatological diseases and the absence of the mutations linked to FMF reinforce the notion that idiopathic acute recurrent pericarditis is an autoimmune condition.
Assuntos
Febre Familiar do Mediterrâneo/genética , Mutação , Pericardite/genética , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/genética , Evolução Biológica , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Humanos , Itália , Masculino , Pericardite/etiologia , Pericardite/imunologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologiaRESUMO
Testicular cancer can impair spermatogenesis. In addition, chemotherapy or radiotherapy used for its treatment further damage testicular function mainly affecting highly proliferating germ cells. The multifaceted etiology of male infertility includes, among others, alterations of male reproductive tract differentiation such as monolateral or bilateral congenital absence of vas deferens and perturbations in adrenal steroid synthesis on a genetic basis such as 21beta-hydroxylase deficiency. Herein, we report the case of a male patient with primary infertility, probably related to a combination of genetic and acquired factors with different expressions over time.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Carcinoma in Situ/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Oligospermia/complicações , Neoplasias Testiculares/diagnóstico , 17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/complicações , Adulto , Carcinoma in Situ/complicações , Carcinoma in Situ/radioterapia , Sulfato de Desidroepiandrosterona/sangue , Dexametasona , Hormônio Foliculoestimulante/sangue , Glucocorticoides , Humanos , Masculino , Mutação , Obesidade/complicações , Esteroide 21-Hidroxilase/genética , Neoplasias Testiculares/complicações , Neoplasias Testiculares/radioterapia , Testosterona/sangue , Ducto Deferente/patologiaRESUMO
Relatively little is known about the biocompatibility of the soldered or laser-welded joints of dental appliances. We investigated the reaction of human gingival fibroblasts cultured in vitro in direct contact with samples of soldered and laser-welded joints from orthodontic lingual arches. Contrast phase light microscopy was used to evaluate cell adhesion, morphology and proliferation after 6 and 24h and after 7 and 16 days. Scanning electron microscopy (SEM) was performed at 16 days. Our in vitro findings provide evidence that laser-welded orthodontic appliances have superior fibroblast biocompatibility.
Assuntos
Soldagem em Odontologia/efeitos adversos , Fibroblastos/patologia , Fibroblastos/fisiologia , Reação a Corpo Estranho/patologia , Gengiva/patologia , Gengiva/fisiopatologia , Braquetes Ortodônticos/efeitos adversos , Adulto , Adesão Celular , Divisão Celular , Tamanho Celular , Sobrevivência Celular , Células Cultivadas , Análise de Falha de Equipamento , Reação a Corpo Estranho/etiologia , Humanos , Masculino , Teste de Materiais/métodosRESUMO
ST1926 is a novel related adamantyl retinoid endowed with potent antiproliferative and apoptogenic activity. The drug induced an early G1/S cell cycle arrest which was associated with a typical DNA damage response including modulation of genes involved in cell cycle regulation and DNA repair. The evidence of the drug ability to induce a significant extent of DNA strand breaks after short-term exposure is consistent with the cellular response. ST1926 is active by oral administration both on hematological and on solid tumors. The more marked antitumor effect showed by ST1926 in immuno-competent mice rather than in tumor xenografts suggests a contribution of indirect host-mediated antitumor effects in addition to a direct antiproliferative activity against tumor cells.
Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Antineoplásicos/farmacologia , Cinamatos/farmacologia , Adamantano/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Cinamatos/uso terapêutico , Modelos Animais de Doenças , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Sensibilidade e Especificidade , Resultado do Tratamento , Células Tumorais CultivadasRESUMO
Chrysanthones are secondary metabolites, isolated from Ascochyta chrysanthemi, with a methyl-benzoisoquinoline or methyl-benzoisochromene system. Three compounds were tested for their cytotoxicity properties on endothelial cells (EC) and two different tumor cell lines and for their ability to inhibit EC migration. Structure-function relationship considerations suggested that the methylisoquinolinic moiety is important for the cytotoxic activity, whereas the methylisochromene moiety confers an endothelial selectivity to the structures. In general, compared to the activity of known antiproliferative and antiangiogenic compounds, chrysanthones showed weaker activities. However, they present a basis for the synthesis of new derivatives.