RESUMEN
BACKGROUND: Co-inheritance of heterozygous factor V deficiency with FV Leiden enhances the activated protein C resistance (APCR) associated with this mutation, resulting in pseudo-homozygous APCR. The role of FV deficiency in modulating thrombotic risk in this rare condition is poorly understood. METHODS AND RESULTS: We have identified in thrombophilic patients with FV deficiency a novel FV gene mutation (c. 4996G>A), predicting the Glu1608Lys substitution in the A3 domain. The heterozygous mutation was detected in three unrelated patients, two carriers of the FV Leiden mutation, and one of the FVHR2 haplotype. The Glu1608Lys change was also present in two subjects with mild FV deficiency, and absent in 200 controls. The FV1608Lys carriers showed reduced mean FV activity (42% +/- 12%) and antigen (53% +/- 18%) levels and, in Western blot analysis, reduced amounts of intact platelet FV. The restriction fragment length polymorphism (RFLP) study identified two haplotypes underlying the mutation, which suggests that it is recurrent. In heterozygous subjects the amount of FV1608Lys mRNA in white blood cells was similar to that produced by the counterpart alleles (FVWt or FVHR2). Recombinant FV1608Lys (rFV1608Lys), detected by Western blot in the conditioned medium, was indistinguishable from rFVWt and FV antigen and activity were found to be respectively 44% +/- 20% and 13% +/- 4% of rFVWt. CONCLUSIONS: Our data indicate that FVGlu1608Lys predicts a CRM (plasma)/CRMred (cell culture) FV deficiency, and may contribute to thrombophilia in carriers of FV Leiden and FVHR2 haplotype via a pseudo-homozygosity mechanism. Our findings help to define the molecular bases of FV deficiency and thrombophilia.
Asunto(s)
Deficiencia del Factor V/genética , Factor V/genética , Mutación Missense , Trombofilia/genética , Estudios de Casos y Controles , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Haplotipos , Heterocigoto , Humanos , Incidencia , Leucocitos/química , Masculino , Mutación Puntual , ARN Mensajero/análisis , Receptores de Superficie Celular/genéticaRESUMEN
To investigate simultaneously a defect affecting the protein C/protein S (PC/PS) anticoagulant pathway is possible thanks to a methodological approach (ProC(R) Global; Dade Behring) based on the activation of endogenous plasma PC by a snake venom extract. Factor V (FV) Leiden, the most frequent cause of hereditary thrombosis, is well detected by the test with sensitivity of 100% irrespective of the presence/absence of thrombosis in the subjects investigated. The test is also suited to detect PC or PS defect, but in this case the in vitro impairment of the PC/PS pathway is less pronounced particularly for PS defects (sensitivity for PC and PS defect, 85-100 and 30-90%, respectively). In this study, we hypothesized that the lower sensitivity described for PS defect, compared with those of PC and FV Leiden defects, could also be related to the clinical condition of the subject investigated (symptomatic/asymptomatic) rather than solely to the PS plasma activity/level. Therefore, we analyzed 126 subjects with single congenital defects in the PC/PS pathway: 46 subjects with PS deficiency (26 thrombotic cases and 20 asymptomatic relatives), 40 subjects with PC deficiency (25 thrombotic cases and 15 asymptomatic relatives), and 40 heterozygous FV Leiden subjects (25 thrombotic cases and 15 asymptomatic relatives). By a cut-off of normalized Agkistrodon contortix snake venom ratio of 0.84, the sensitivity in the whole group of cases (sensitivity a) was 76.1, 95.0 and 100%, respectively, for PS, PC and FV Leiden defects. The test failed to detect 11 (23.9%) among the 46 PS-deficient subjects, and all these cases except two belonged to the asymptomatic subgroup (9/20; 45%). Excluding the 20 asymptomatic relatives, the new sensitivity (sensitivity b) for the PS defect was 92.3%. The comparison of the sensitivity in the symptomatic PS cases and in the asymptomatic ones was significantly different (P = 0.010). Among the 40 PC-deficient subjects, only two (5.0%) were not detected by the test and they belonged indifferently to the two subgroups. Finally, none of the 40 FV Leiden heterozygotes were misdiagnosed by the test. These results suggest that in symptomatic PS-deficient cases the test could reflect a post-thrombotic effect and/or reveal potential unidentified prothrombotic influences assessing a prothrombotic risk condition.
Asunto(s)
Proteína C/análisis , Deficiencia de Proteína S/sangre , Juego de Reactivos para Diagnóstico/normas , Trombofilia/diagnóstico , Estudios de Casos y Controles , Errores Diagnósticos , Factor V/análisis , Femenino , Humanos , Masculino , Proteína C/genética , Proteína C/metabolismo , Proteína S/análisis , Factores de Riesgo , Sensibilidad y Especificidad , Trombofilia/sangre , Trombosis/sangreRESUMEN
AIMS AND BACKGROUND: The present report combines descriptive statistics (partly never published) on four neighboring areas of north-eastern (NE) Italy [Friuli-Venezia Giulia (1970-89) and Veneto (1970-87) regions and the provinces of Trento (1970-89) and Bolzano (1971-90)], and all Italy (1970-89). The aim was to highlight potential differences in mortality trends and promote a more systematic sharing of data and methodologies. METHODS: Death certificates stratified by cause, sex, age and residence were obtained from official publications of the Italian Central Institute of Statistics. Absolute numbers of deaths from different causes, age-standardized rates (on the basis of the European standard population) and percentage of change over the examined period for both sexes were computed for each geographic area. RESULTS: Unfavorable trends were seen for neoplasms of the upper aerodigestive tract, lung, breast, colorectum, bladder, kidney and pancreas and cutaneous malignant melanoma. Increases in most of these neoplasms were more marked in the 4 NE areas than in Italy, especially with respect to cancers of the upper aerodigestive tract in both sexes and cancer of the lung and ovary in women. In Bolzano, rates of neoplasms associated with tobacco and alcohol consumption were lower and less steeply increasing than in the other NE areas, most notably Trento, therefore, contributing to produce the lowest overall cancer mortality rates of NE areas. Cancers of the stomach, uterus, and testis and Hodgkin's disease presented consistent downward trends in all examined areas. CONCLUSIONS: The analysis of mortality trends across areas is consistent with elevated and still increasing cancer rates in the 4 NE areas considered, especially for tobacco and alcohol-related neoplasms and skin melanoma. Preventive strategies, based on epidemiologic knowledge, especially against tobacco and heavy alcohol consumption, and intense intermittent sun exposure, seem to be priorities and may benefit from systematic sharing of information, expertise and intervention tools in NE Italy. At least part of the lack of cancer deaths in Bolzano must be attributable to the deaths of Bolzano residents abroad (especially in Austria) and/or to differences in coding practices. This should be elucidated in future studies.
Asunto(s)
Neoplasias/mortalidad , Distribución por Edad , Causas de Muerte , Femenino , Humanos , Italia/epidemiología , Masculino , Mortalidad/tendencias , Distribución por SexoRESUMEN
Based on a review of the literature on human herpesvirus-8 (HHV8) and Kaposi's sarcoma (KS) and on the distribution of KS in Italy (Veneto region particularly), we hypothesize that the bite of bloodsucking arthropods is a cofactor in the seroconversion to HHV8 positivity and probably in the pathogenesis of KS. The bloodsucking arthropod releases with saliva powerful antihaemostatics and immunomodulators which may favour the replication and the establishment of the pathogen. Transmission would depend on the close contact of the child with a seropositive mother (or relatives) whose infective saliva is used to relieve itching and scratching at the arthropod bite's sites. During any deregulation of the immune system (e.g. ageing), local immune responses to new insect bites may induce virus activation which could prelude KS insurgence. The pathogen is not directly transmitted by the arthropod which merely prepares the cutaneous microenvironment for the virus. We have therefore introduced a new category of medically important arthropods, "promoter arthropods", besides those already defined as biological or mechanical vectors. Promoter arthropods are species able to induce in the host long-lasting, immediate or delayed-type hypersensitivity responses as well as local immunosuppression due to substances injected with their saliva. The striking variability of ORF-K1 gene of HHV8 could be due to the adaptation of the virus to the specific microenvironments resulting from the immune response to the salivary antigens characteristic of the bloodsucking arthropod species prevalent in each geographical area. It is worth noting that other viruses (especially Hepatitis B Virus) may exploit the same non-sexual transmission route.
Asunto(s)
Infecciones por Herpesviridae/transmisión , Herpesvirus Humano 8/fisiología , Mordeduras y Picaduras de Insectos/complicaciones , Insectos Vectores/virología , Psychodidae/virología , Sarcoma de Kaposi/etiología , Neoplasias Cutáneas/etiología , Animales , Burkina Faso/etnología , Estudios de Casos y Controles , Niño , Preescolar , Análisis por Conglomerados , Susceptibilidad a Enfermedades , Transmisión de Enfermedad Infecciosa , Europa (Continente) , Conducta Alimentaria , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Humanos , Terapia de Inmunosupresión , Mordeduras y Picaduras de Insectos/virología , Italia , Modelos Biológicos , Estudios Multicéntricos como Asunto , Prurito/etiología , Psychodidae/fisiología , Factores de Riesgo , Saliva/virología , Proteínas y Péptidos Salivales/inmunología , Sarcoma de Kaposi/epidemiología , Piel/lesiones , Neoplasias Cutáneas/epidemiología , Activación Viral , Replicación ViralRESUMEN
BACKGROUND: In the Venetian Tumour Registry a substantial quota of cases (55%) is accepted using an algorithm that automatically evaluates diagnostic evidence: this study aims at assessing the reliability of the information produced in this way. METHODS: A reabstraction study was conducted, which put a stratified sample of 1539 automatically accepted cases through a double-blind manual revision. RESULTS: A significantly higher proportion of prevalent cases were found among breast, prostate and larynx cancer cases without microscopic confirmation, while there is a clear strong inverse relationship between the number of concordant diagnostic sources and the proportions of discordant diagnoses: cases based only on a single cytology record are particularly unreliable. A small number of multiple cancers are not detected because of one of the rules applied. CONCLUSION: The overall proportion of incorrect decisions is not high and similar to those reported by other registries, but errors are correlated to the diagnostic evidence pattern. As a further check, we decided to revise clinical cases for the three sites mentioned manually, in order to reduce the numbers proportion of both prevalent cases, and all cytology-based diagnoses, so as to reduce the number of 'false positives'. Coverage of hospital discharge source has been extended in order to decrease the proportion of cases based only on pathology records.
Asunto(s)
Automatización , Neoplasias/epidemiología , Control de Calidad , Sistema de Registros , Algoritmos , Método Doble Ciego , Femenino , Humanos , Italia/epidemiología , Masculino , Neoplasias/clasificaciónRESUMEN
Two G-to-A mutations at positions 1691 of the factor V (FV) gene and 20210 of the prothrombin (FII) gene have been associated with an increased risk of venous thromboembolism. We report a thrombosis-prone family in which one subject--the propositus who exhibited combined heterozygous FV G1691A and FII G20210A mutations--showed spontaneous and early clinical onset (at 23 years), recurrences of deep-vein thrombosis and pulmonary embolism. His asymptomatic father carried the FII G20210A substitution and his mother, characterized by an isolated thrombotic episode on occasion of surgery (at 48 years), carried the FV G1691A substitution. In the maternal lineage, one of the propositus' uncles had thrombosis on occasion of a bone fracture (at 65 years) despite the absence of known prothrombotic defects. A sister of the propositus carried the FII G20210A and the brother the FV G1691A mutation. They have been asymptomatic until now. The propositus' two children, 20 and 16 years old, both carry the FV G1691A substitution and have been asymptomatic until now. The plasma levels of FII were higher in carriers of the FII G20210A allele if compared with noncarriers, and the activated protein C resistance phenotype, associated with the FV Leiden mutation, showed a complete correlation with the FV G1691A mutation. Despite the very limited number of thrombotic cases involved in this survey, which does not allow statistically sound conclusions, the data obtained from this family suggest that the synergy of inherited factors and transient risk conditions could play a key role in the occurrence of thrombotic accidents.
Asunto(s)
Factor V/genética , Mutación Puntual , Protrombina/genética , Trombosis de la Vena/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Recurrencia , Trombofilia/sangre , Trombofilia/diagnóstico , Trombofilia/genéticaRESUMEN
The role of a common polymorphism in the factor XIII A-subunit gene (FXIII Val34Leu) has been recently investigated as a protective genetic factor against arterial and venous thrombosis. In addition, the less frequent Leu34 allele has been described as a risk factor for intracerebral hemorrhage. We evaluated the prevalence of this polymorphism by PCR in three case-control studies of patients diagnosed as having primary intracerebral hemorrhage (PCH, n = 130), coronary heart diseases (CHD, n = 240; myocardial infarction/no myocardial infarction, 120/120), and cerebrovascular diseases (CVD, n = 240; cerebral infarction/transient ischaemic attack, 120/120). The matched control groups consisted of patients admitted to the hospital without history of vascular disease. In addition, 200 healthy subjects were investigated. The frequency of the mutated allele (Leu34) was higher in patients with PCH than in controls (33.8% vs. 23.1%, P = 0.009) and lower in CHD and CVD patients compared to controls (18.1% vs. 25.2%, P = 0.010 and 17.3% vs. 24.2%, P = 0.011, respectively). Moreover, among the patients with CHD, the Leu34 allele was underrepresented in cases with myocardial infarction than without (12.9% vs. 23.3%, P = 0.004) and than in controls (12.9% vs. 25.2%, P < 0.001). Similar findings were obtained in patients with CVD comparing the cases with cerebral infarction versus cases with transient ischaemic attack (12.5% vs. 22.1%, P = 0.008) and versus controls (12.5% vs. 24.2%, P < 0.001). Finally, considering altogether the groups of ischaemic patients (CHD and CVD, n = 480), it was noted a trend towards a higher mean age of the clinical onset in homozygotes for the Leu allele than in the wild types (P = 0.078). This study indicates that in our population possession of the FXIII Val34Leu mutation predisposes to the occurrence of primary intracerebral hemorrhage and protects against cerebral and myocardial infarction. A wider modulatory role in the progression and onset of atherothrombotic diseases could be ascribed to FXIII Val34Leu.
Asunto(s)
Sustitución de Aminoácidos , Arteriosclerosis/genética , Hemorragia Cerebral/genética , Factor XIII/genética , Genes , Mutación Missense , Polimorfismo Genético , Trombosis/genética , Edad de Inicio , Alelos , Arteriosclerosis/epidemiología , Estudios de Casos y Controles , Hemorragia Cerebral/epidemiología , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/genética , Comorbilidad , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Diabetes Mellitus/epidemiología , Progresión de la Enfermedad , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hiperlipidemias/epidemiología , Hipertensión/epidemiología , Ataque Isquémico Transitorio/epidemiología , Ataque Isquémico Transitorio/genética , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Reacción en Cadena de la Polimerasa , Subunidades de Proteína , Factores de Riesgo , Fumar/epidemiología , Trombosis/epidemiologíaRESUMEN
Between 1992 and 1997, we conducted a case-control study of oesophageal cancer in 3 areas of northern Italy. Cases were 275 men, ages 39-77 years (median age 60), with a first incident squamous-cell carcinoma of the oesophagus. Controls were 593 men, ages 36-77 years (median age 60) admitted for acute illnesses, unrelated to tobacco and alcohol, to major hospitals of the areas under surveillance. Number of daily cigarettes was strongly associated with risk [odds ratio (OR) for > or =25 cigarettes/day = 7.0)]. Long-duration smoking showed particularly elevated ORs (OR = 6.4 for > or =35 years), and excess risk declined after smoking cessation (OR = 1.5 after > or = 10 years). Oesophageal cancer risk steeply rose with increasing level of alcohol consumption. ORs were 6.2 for 35-55 drinks and 24.5 for 84 drinks or more per week. No trend in risk emerged for duration of alcohol drinking or age at start of drinking. The risk in the highest joint level of alcohol drinking and current smoking was increased 130 folds (i.e., compatible with a multiplicative model). Excess risk in drinkers chiefly derived from wine. In conclusion, alcohol drinking and cigarette smoking were both important, but the roles of dose and duration of exposure differed. The association with alcohol was stronger than the one with smoking by exposure intensity, but apparently unaffected by duration or other temporal variables.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma de Células Escamosas/etiología , Neoplasias Esofágicas/etiología , Fumar/efectos adversos , Adulto , Anciano , Carcinoma de Células Escamosas/epidemiología , Estudios de Casos y Controles , Neoplasias Esofágicas/epidemiología , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
A cancer registration network based on computerised coded diagnoses has been tested in the Veneto region, north-east Italy, with the goal of estimating cancer incidence during 1987-89. The results of the pilot study based on a population of 1,449,513 (33.1% of the total population of the region) indicate that the computer-assisted system successfully ascertained 61.3% of the cases. The quality indices appear to be close to those from other cancer registries in Europe. The increasing availability of computerised coded information from hospitals, pathology departments and death certificates can provide an important contribution to cancer registration, thus reducing the amount of manual work and consequently allowing cancer registration on larger populations at reduced costs.
Asunto(s)
Neoplasias/epidemiología , Sistema de Registros , Programas Informáticos , Certificado de Defunción , Europa (Continente) , Hospitales/estadística & datos numéricos , Humanos , Incidencia , Italia/epidemiología , Neoplasias/mortalidad , Neoplasias/patología , Neoplasias/radioterapia , Reproducibilidad de los ResultadosRESUMEN
The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression.