RESUMO
The off-label use of drugs is very common in cancer treatment for many reasons. This practice is challenging for pharmacists who practice in oncology, for bureaucratic and medico-legal reasons and for reasons concerning ethics. Several Italian legislative Acts and Laws allow pharmacists to have a voice in the management of off-label use of drugs in oncology and offer instruments to allow reasoning from an ethical perspective. The main aim of this paper was to identify the role of pharmacists within the ethical context in the off-label use of drugs in oncology, taking into account the legislative framework and clinical oncology setting. We consider the existing norms to develop an ethical perspective, through the values underlying the Laws and Acts. From a hermeneutical perspective, we focus on the actual oncology setting to identify the ethical space. The off-label use of drugs in Italy is currently regulated by Law 648/96, Law 94/98 and Decree Law on the therapeutic use of drugs under clinical investigation. From the oncology pharmacist's perspective, the application of the Laws mentioned is often problematic. The disease itself brings forth many ethical issues. In particular, human experience is extremely important in oncology and cannot be separated from other considerations. When faced with the common choice of oncologists to use drugs off-label the late stages of the disease or after many chemotherapy attempts, pharmacists have to take responsibility for the sick person. This usually involves collaboration with the physician, within a process oriented by the 'circumstances of compromise in ethics'. The pharmacist practising in oncology should promote real collaboration especially with the physician for the benefit of the sick person. The pharmacist has to maintain his/her professional integrity, and orient it towards accurate evaluation of the so-called 'circumstances of compromise in ethics'.
Assuntos
Antineoplásicos/uso terapêutico , Ética Farmacêutica , Neoplasias/tratamento farmacológico , Papel Profissional , Rotulagem de Medicamentos , Humanos , Itália , Legislação de Medicamentos , Oncologia , FarmáciaRESUMO
BACKGROUND: The aim of this study was to examine the prognostic value of admission N-terminal-pro-brain natriuretic peptide (NT-proBNP) measurements for the outcome of adverse events, and to compare it with that of cardiac troponin T in the assessment of risk in patients with acute coronary syndrome (ACS) during the hospital stay and at six months following hospital discharge. METHODS: The study population consisted of 200 Asian Indian patients admitted with a diagnosis of ACS to the Coronary Care Unit at RK Khan Hospital, Durban, South Africa. A reference group comprising 100 healthy Indian individuals drawn from the same community and who did not suffer from cardiovascular disease was also analysed. RESULTS: The majority of patients presented with ST segment elevation myocardial infarction (STEMI) (71%), whereas 14.5% had non-ST segment elevation MI (NSTEMI), and the remaining 14.5% had unstable angina. Patients had multiple risk factors for coronary heart disease (CHD) including hypertension (59%), hypercholesterolaemia (59%), smoking (57%), diabetes mellitus (51%), obesity (46%), and a strong family history of CHD (55%). NT-proBNP levels were significantly increased in patients with STEMI (p = 0.005) and NSTEMI (p = 0.002) who developed adverse events during their hospital stay, compared with those who did not. At the six-month followup, although NT-proBNP levels were higher in patients with STEMI and NSTEMI who developed adverse events, these differences were not statistically significant. No differences in troponin T levels were detected in patients with STEMI and NSTEMI who developed adverse events, compared to those who did not, either during the hospital stay, or at six months after release. At hospital admission, 24% of patients with unstable angina who had elevated NT-proBNP levels and normal troponin T concentrations developed adverse events, compared to 38% at six months. NT-proBNP levels in the reference group were comparable with those reported in other populations. CONCLUSION: This study demonstrated that elevation in admission NT-proBNP levels is an important determinant of acute and intermediate cardiac risk in patients with ACS. NT-proBNP concentrations were superior to those of troponin T as prognostic markers in both STEMI and NSTEMI. In a low-risk group of patients with unstable angina and negative troponin T concentrations, elevated NT-proBNP levels constituted a risk for the development of adverse cardiovascular events. Therefore, NT-proBNP should be included in the risk assessment of ACS to provide guidance for further therapeutic strategies.
Assuntos
Doença das Coronárias/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Biomarcadores/sangue , Estudos Transversais , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The relationship between polymorphisms in the genes for plasminogen activator inhibitor type 1(PAI-1) and platelet glycoprotein IIIa (PGIIIa), clinical and environmental features, and the risk of premature coronary heart disease (CHD) in Asian Indian subjects living in South Africa, has been investigated. METHODS: The prevalence of the PAI-1 promoter 4G/5G and the PGIIIa PI A1A2 polymorphisms was examined in 195 unrelated Asian Indian patients ( Assuntos
Integrina beta3/genética
, Infarto do Miocárdio/genética
, Inibidor 1 de Ativador de Plasminogênio/genética
, Polimorfismo Genético
, Adolescente
, Adulto
, Humanos
, Índia/etnologia
, Pessoa de Meia-Idade
, Fatores de Risco
, Índice de Gravidade de Doença
, Fumar
, África do Sul
RESUMO
BACKGROUND: The relationship between pro-coagulant gene polymorphisms, clinical features and the risk of premature coronary heart disease (CHD) in Indian Asian subjects resident in South Africa has been investigated. METHODS: The prevalence of the beta-fibrinogen -455G/A and -148C/T, and the factor VII 10 bp 5' promoter insertion/deletion and R353Q polymorphisms were examined in 195 unrelated Indian Asian patients (< or = 45 years) who presented with myocardial infarction (MI). Results were compared with those from 107 unaffected siblings (18-45 years) and 300 healthy age- and race-matched control subjects. RESULTS: Overall, none of the polymorphisms examined here showed any association with MI. However, when stratified according to obesity, patients with a BMI > 30 kg/m2 had a significantly higher frequency of the beta-fibrinogen variant alleles, compared with non-obese patients (19% vs 9%; p = 0.025) and controls (19% vs 9%; p = 0.003). Furthermore, the highest frequency of variant alleles occurred in obese smokers (24%), compared with 4% in non-obese non-smokers (p = 0.003) and 9% in control subjects (p < 0.001). The factor VII R353Q and promoter insertion variants, on the other hand, were associated with higher HDL and lower LDL levels (p = 0.034 and 0.04, respectively). CONCLUSION: In young Indian Asians who are both obese and smoke, the beta-fibrinogen genetic polymorphisms -455G-->A and -148C-->T, which are in linkage disequilibrium, are significant risk factors for the development of MI. Factor VII genetic variants, namely the 10 bp promoter insertion/deletion and R353Q polymorphisms, may possibly play a protective role through their association with elevated HDL and low LDL levels, respectively.
Assuntos
Coagulação Sanguínea/genética , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/genética , Polimorfismo Genético , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Fator VII/genética , Fator VII/metabolismo , Fibrinogênio/genética , Fibrinogênio/metabolismo , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Índia/etnologia , Lipoproteínas HDL/sangue , Lipoproteínas HDL/genética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/genética , Pessoa de Meia-Idade , Obesidade/etnologia , Obesidade/genética , Fatores de Risco , Fumar/etnologia , Fumar/genética , África do Sul/epidemiologia , África do Sul/etnologia , Função Ventricular Esquerda/genéticaRESUMO
Significant differences in the prevalence of coronary heart disease (CHD) exist with respect to gender, age and ethnicity. The disease has been reported to be higher in Indian populations that have emigrated from the Indian subcontinent. The aim of this study was to examine differences in major cardiovascular risk factors and clinical outcome in South African Asian Indians of different age groups and gender, who presented with acute coronary syndromes (ACS). The study cohort consisted of 2 290 consecutive patients, admitted between 1996 and 2002, who were divided into three age subgroups: young ( = 45 years; 20%), middle age (> 45 to = 65 years; 59%), and old age (> 65 years; 21%). All three age groups were predominantly male, but this was more evident in the younger (88%) and middle age groups (71%), and became less striking as the proportion of females increased with age. Smoking was more common in young men compared with young women (p < 0.01). Diabetes mellitus (21%) and hypertension (18%) were seen less frequently in young patients but this was confined to men only. Total cholesterol was elevated in 65 to 70% of all patients while high-density lipoprotein (HDL) levels were significantly lower in men compared with women for all age subsets. Hospital mortality was extremely low in young (1%) and middle-aged patients (2%), but was expectedly higher in older patients (8%; p < 0.0001). A family history of CHD was the most common familial vascular disease seen. Young patients were more often subjected to diagnostic and therapeutic interventions. They had more aggressive disease, with 48% of those subjected to angiographic studies having triple vessel disease (TVD), and 14% undergoing coronary artery bypass grafting (CABG). Triple vessel disease was also detected most commonly in middle-aged (64%) and old patients (75%). In conclusion, significant differences in risk factor status were found in South African Indians between genders and for different age groups. Also, young Indians in this study differed markedly from other young population groups with CHD, in that they frequently had premature atherosclerosis with diffuse and aggressive disease.
Assuntos
Angina Instável/etnologia , Infarto do Miocárdio/etnologia , Fatores Etários , Idoso , Angina Instável/terapia , Angioplastia Coronária com Balão , Ponte de Artéria Coronária , Feminino , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Fatores de Risco , África do Sul/epidemiologia , Síndrome , Terapia TrombolíticaRESUMO
The lipoprotein(a) [Lp(a)] and apolipoprotein E (apoE) polymorphisms have been shown to be important genetic determinants of cardiovascular risk. Their effect on coronary heart disease (CHD) is less clear, particularly in Asian Indians who are at high risk for this disease. The aim of this study was to examine the association of the Lp(a) promoter pentanucleotide repeat polymorphism and the apoE codon 112 and 158 genotypes in 195 young South African Indian patients (< or = 45 years) with myocardial infarction (MI). Results were compared with 300 healthy age-matched control subjects drawn from the same community and 107 unaffected siblings (18-45 years). In addition, fasting lipograms were performed on all patients and a detailed history of conventional risk factors and family background was obtained. Of the six different Lp(a) alleles detected, the 8-repeat sequence was most frequently seen. However, no difference in frequencies existed between patient and control groups. The most frequently occurring apoE genotype in the three study groups was E3/E3 (patients 71%; siblings 70%; controls 70%). A significant difference in the E3/E4 genotype was seen between patients and controls (23% vs 14%; p = 0.018) and between siblings and controls (24% vs 14%; p = 0.027). These patients were also more likely to have significantly higher low-density lipoprotein (LDL) and lower high-density lipoprotein (HDL) levels (p = 0.005 and 0.045, respectively). No association was observed between any of the Lp(a) or apoE genotypes and conventional risk factors such as smoking, diabetes, hypertension, obesity or a family history of CHD. In conclusion, the apoE3/E4 genotype is strongly associated with the incidence of myocardial infarction in young South African Indians. This genotype also adversely affects LDL and HDL cholesterol levels, both of which contribute to premature atherosclerosis. In contrast, the Lp(a) pentanucleotide repeat polymorphism does not appear to have any aetiological role in MI in this population.
Assuntos
Apolipoproteínas E/genética , Lipoproteína(a)/genética , Infarto do Miocárdio/sangue , Apolipoproteína E3 , Apolipoproteína E4 , Apolipoproteínas E/sangue , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Genótipo , Humanos , Incidência , Índia/etnologia , Lipoproteína(a)/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Polimorfismo Genético , Fatores de Risco , África do Sul/epidemiologiaRESUMO
Various risk factors have been implicated in the causation of cervical cancer including human papillomavirus (HPV), the early genes (E6 and E7 ) of which encode the main transforming proteins. Studies have suggested that steroid hormones may enhance the expression of these genes leading to loss of p53 gene-mediated cell apoptosis. A total of 120 cervical tissue samples were obtained from patients with proven cervical cancer. Patients who used depo-medroxyprogesterone acetate steroid contraception were recruited as part of the steroid arm. Only HPV DNA type 16 samples were used for the study. Controls included three cell lines (CaSki, SiHa, & C33A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal housekeeping gene. Of 120 patients, there were 111 patients with HPV type 16 identified. Of this number, RNA was present in 63 samples. There were 30 women (30/63) who used steroid contraception. In relation to patients who used contraception, HPV 16 E6 gene expression was present in 79% (n = 23) and 88% (n = 30) of steroid users compared to nonusers, respectively. In total there were 25 patients (40%) with expression of the HPV 16 E6*I gene and 30 patients with expression of the E6*II gene. There were 57% of steroid users (n = 17) who had expression of the E6*I/E6*II gene, compared to 52% (n = 17) of nonusers (P = 0.800). From a molecular level, this study does not confirm the role of injectable progesterones in cervical carcinogenesis.
Assuntos
Anticoncepcionais Femininos/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Proteínas Oncogênicas Virais/biossíntese , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Proteínas Repressoras , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Idoso , Apoptose , Estudos de Casos e Controles , Transformação Celular Neoplásica , Anticoncepcionais Femininos/uso terapêutico , DNA Viral/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Acetato de Medroxiprogesterona/uso terapêutico , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Neoplasias do Colo do Útero/etiologiaRESUMO
Mutations in the BRCA and p53 tumor suppressor genes are implicated in the oncogenesis of ovarian tumors although their exact roles remain unclear. Despite recognized ethnic differences in the frequency of ovarian cancer and in genetic polymorphisms between populations, studies carried out so far have focused almost entirely on Caucasian subjects. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we examined blood and/or primary epithelial ovarian tumor tissue from 75 black South African women for the presence of the three most commonly occurring BRCA 1 and 2 mutations (185delAG, 5382insC and 6174delT). The p53 codon 72 allele status was also examined and results were compared to a reference cohort comprising 340 ethnically matched subjects. None of the BRCA 1 or 2 mutations were detected in the patient group. The codon 72 Arg allele frequency in lymphocytic DNA was not significantly different compared with the control group. In contrast, in ovarian tumor DNA, the Arg allele was found significantly more frequently than in the controls; this was observed in terms of both Arg allele frequency (45% vs. 31%; P = 0.017) and Arg homozygosity (20% vs. 9%; P = 0.039). Tumors with the more aggressive serous papillary cystadenomatous histology had a markedly higher Arg frequency (45%) than the mucinous cystadenomas (25%). The higher frequency of the Arg allele detected in this study in black South Africans with ovarian tumors suggests a possible role in malignant transformation and may constitute a risk factor for ovarian and other epithelial cancers through mechanisms yet to be elucidated.
Assuntos
População Negra/genética , Carcinoma/genética , Genes BRCA1 , Genes BRCA2 , Genes p53 , Mutação , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma/etnologia , Carcinoma/patologia , DNA de Neoplasias , Feminino , Genes Supressores de Tumor , Marcadores Genéticos/genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Prognóstico , Estudos de Amostragem , Sensibilidade e EspecificidadeRESUMO
Although coronary heart disease (CHD) is extremely common in South African Indians, there is little published data on the possible causes leading to myocardial infarction (MI) in young Indians. The aim of this study was to identify common environmental risk factors and to examine the relationship between two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677 C right arrow-hooked T and 1298 A right arrow-hooked C in young South African Indians with MI. Demographic and risk factor data were obtained from245 patients = 45 years with MI who were admitted to the RK Khan Hospital, Durban. Venous blood from 195 of the 245 patients with MI, as well as from the sublings of the MI patients (n = 107), and 300 healthy age-matched Indian control subjects, were collectd from genetic analysis. Cigarette smoking was the most important risk factor, occurring in three-quarters of patients, followed by dyslipidaemia in half of the subjects. Diabetes (19%) and hypertension (22%) were found not to be major risk factors for MI. A strong familial link was observed not only for a history of CHD (54%), but also for diabetes (42%) and hypertension (41%). No difference was found in the thermolabile variant of the MTFHR gene (677 C right arrow-hooked T) or the second variant 1298 A right arrow-hooked C between controls and patients with MI or their siblings. The two polymorphisms did not appear to work in synergy, neither was there any relationship to common risk factors for CHD. In conclusion, smoking, dyslipidaemia and obesity were the most common phenotypic risk factors for MI. Neither the 667 C right arrow-hooked T nor the 1298 A right arrow-hooked C MTFHR variants appeared to be risk factors for premature CHD in this group.
Assuntos
Predisposição Genética para Doença , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/genética , Polimorfismo Genético , Adulto , Fatores Etários , Sequência de Bases , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Humanos , Hiperlipidemias/complicações , Incidência , Índia/etnologia , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/sangue , Pessoa de Meia-Idade , Dados de Sequência Molecular , Obesidade/complicações , Reação em Cadeia da Polimerase , Probabilidade , Fatores de Risco , Estudos de Amostragem , África do Sul/epidemiologia , Estatísticas não ParamétricasRESUMO
The usefulness of the arginine (Arg) residue at codon 72 of the p53 tumor suppressor gene as a marker for the risk of cervical cancer remains unclear. Studies to date have focused mainly on Caucasian subjects despite marked ethnic variations in both the p53 polymorphism and the frequency of cervical carcinoma. Furthermore, not all studies have taken into account the type of human papillomavirus (HPV) infection present. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we determined the p53 codon 72 status in 281 black South African women with cervical cancer and 340 ethnically matched healthy control subjects. In addition, HPV DNA was confirmed in 190 cervical tumors and the viral type determined. Results showed that overall more cancer patients than control subjects had an Arg allele at codon 72 with respect to both genotype and allelotype (P < 0.05). A significantly higher (P < 0.001) Arg allele frequency (55%) was also observed in patients whose tumors contained low or intermediate risk HPV DNA compared with control subjects (31%); the Arg homozygosity rate was 34% and 9% in patients and controls, respectively (P < 0.001). In contrast, patients harboring HPV 16/18 infections showed no differences in p53 status compared with controls. It would appear that, in the absence of HPV 16/18 infections, the Arg allele at codon 72 of the p53 tumor suppressor gene may constitute a risk factor for carcinogenesis of the cervix.
Assuntos
Genes p53/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções Tumorais por Vírus/genética , Neoplasias do Colo do Útero/virologia , População Negra/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virologia , Estudos de Casos e Controles , Códon , Primers do DNA , DNA Viral/genética , Feminino , Humanos , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fatores de Risco , África do Sul , Neoplasias do Colo do Útero/genéticaRESUMO
Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.
Assuntos
Efeito Fundador , Doenças Metabólicas/genética , Sitosteroides/metabolismo , Arteriosclerose/genética , Colesterol na Dieta/metabolismo , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 2 , Dieta , Genótipo , Haplótipos , Homozigoto , Humanos , Absorção Intestinal/genética , Desequilíbrio de Ligação , Repetições de Microssatélites/genética , Modelos Genéticos , Linhagem , FilogeniaRESUMO
The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol na Dieta/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Lipoproteínas/genética , Lipoproteínas/metabolismo , Sitosteroides/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Absorção , Sequência de Aminoácidos , Animais , Sequência de Bases , Colesterol na Dieta/administração & dosagem , Clonagem Molecular , Análise Mutacional de DNA , Europa (Continente)/etnologia , Éxons/genética , Feminino , Humanos , Japão , Lipoproteínas/química , Masculino , Camundongos , Dados de Sequência Molecular , Mutação/genética , América do Norte , Linhagem , Filogenia , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Alinhamento de Sequência , Sitosteroides/administração & dosagemRESUMO
The p53 codon 72 genotype was examined in blood samples taken from 121 Zulu-speaking black South African women with histologically proven squamous carcinoma of the cervix. Freshly biopsied tumour tissue was also available for human papillomavirus subtyping from 100 of these women. A control group consisted of 251 healthy race-matched women attending a contraceptive service facility. The results show that there were no statistically significant differences in the frequency of the homozygous arginine genotype between patients with cancer of cervix, irrespective of human papillomavirus status, and healthy controls. This finding suggests that the arginine allele does not predispose towards viral tumour genesis in this population, and supports the findings of research done in other ethnic groups.
Assuntos
Carcinoma de Células Escamosas/genética , Genes p53/genética , Polimorfismo Genético/genética , Neoplasias do Colo do Útero/genética , Alelos , Arginina/sangue , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Papillomaviridae/isolamento & purificação , Prolina/sangue , Fatores de Risco , África do Sul/etnologia , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/virologiaRESUMO
Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevaIonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.
Assuntos
Hidroximetilglutaril-CoA Redutases/fisiologia , Erros Inatos do Metabolismo Lipídico/enzimologia , Fitosteróis/sangue , Adolescente , Adulto , Arteriosclerose/complicações , Arteriosclerose/enzimologia , Arteriosclerose/genética , Criança , Resina de Colestiramina , Feminino , Ligação Genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Linhagem , Polimorfismo Genético , Xantomatose/complicações , Xantomatose/enzimologia , Xantomatose/genéticaRESUMO
OBJECTIVE: To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia. SUBJECTS: A three-generation kindred with clinically and biochemically diagnosed medullary thyroid cancer. METHOD: Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses. RESULTS: A heterozygote T-->C (Cys-->Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a pre-emptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members. CONCLUSION: Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers.
Assuntos
Carcinoma Medular/diagnóstico , Análise Mutacional de DNA , Testes Genéticos , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Adulto , Calcitonina/sangue , Carcinoma Medular/genética , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Hiperparatireoidismo/diagnóstico , Hiperparatireoidismo/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Linhagem , Pentagastrina , Proto-Oncogene Mas , Análise de Sequência de DNARESUMO
The aim of this study was to determine the possible usefulness of prolactin as a tumour marker in cancer of the cervix. Serum prolactin levels were measured using an enzyme linked immunosorbent assay in 105 women divided into malignant, pre-malignant and control groups. Elevated levels of prolactin were found in 42.9% of patients with malignant disease, 22.9% of controls and 14.2% of individuals with premalignant disease. The differences were not statistically significant. Although prolactin levels were found to be elevated in some patients with malignant disease of the cervix, further studies are needed to establish whether this is of clinical significance.
RESUMO
This paper deals with the connection which has been held on 8th July 1997 in collaboration with the JPL of the NASA, Pasadena, California, between the Eighth International Conference on the Advanced Robotics (ICAR '97) in course at Monterey, California and the Telerobotics Laboratory of Politecnico di Milano connected in a multipoint teleconference through the MCU of Rome with the Aula Magna of the same Politecnico and the Palace Business of the Giureconsulti of the Chamber of Commerce of Milan. The demonstration has allowed to telecontrol a scara robot of the Sankyo and an ABB robot, which have affected simulations of operations of biopsy to the prostate, to the liver and to the breast, a mechanical hand and a model of a car, disposed in a space destined to reproduce the Martian ground, from Monterey to Milan by means of the INTERNET+ISDN connection from. In fact the event has taken place four days after the landing on Mars happily successful of the spatial probe Pathfinder from which it has gone out the "Sojourner" robot, telecontrolled from the JPL of the NASA, which has begun to take photos of the Martian ground and also some of these images have been transmitted in the course of the connection.
Assuntos
Redes de Comunicação de Computadores , Robótica , Telepatologia , Algoritmos , Biópsia/métodos , California , Humanos , ItáliaRESUMO
AIM: To ascertain the extent of retinoblastoma protein (pRB) expression in comparison to p53 protein and human papilloma viruses (HPV) 16/18 status in cervical carcinomas. METHODS: Fifty cases of invasive cervical carcinoma were HPV typed for genotypes 16 and 18 using consensus primers by polymerase chain reaction (PCR). Immunohistochemistry for pRB and p53 was done on formalin fixed tissue using microwave antigen retrieval and commercially available antibodies. RESULTS: Forty five cases were squamous carcinomas, three were adenocarcinomas, and two were adenosquamous carcinomas. Thirty one cases were HPV 16 positive and one was HPV 18. Sixteen cases showed +4 pRB expression and a further 11 were +3 positive. Seven cases were negative. Only five cases (10%) showed +4 p53 immunostaining, while seven were negative and 15 were +1. Of the 16 pRB +4 positive cases, one was negative for p53 and a further seven were +1 positive. This inverse pattern of staining between pRB and p53 had a p value of < 0.001. No correlation was observed between HPV 16/18 status and p53 and/or pRB staining. CONCLUSIONS: pRB is expressed in the majority of cases of cervical cancer (86%), with more than 75% (+4) of the tumour cell population being positive in 16 cases (32%). There appears to be a general inverse pattern of staining between pRB (high) and p53 (low) in cervical cancer. The expression of both pRB and p53 proteins is independent of the HPV 16/18 status of the tumour.
Assuntos
Papillomaviridae/classificação , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Adenocarcinoma/metabolismo , Adenocarcinoma/virologia , Northern Blotting , Carcinoma Adenoescamoso/metabolismo , Carcinoma Adenoescamoso/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Infecções Tumorais por Vírus/complicaçõesRESUMO
We examined 232 breast carcinomas for c-erbB-2 amplification by Southern analysis using two different cDNA probes. Using these same probes, 95 of these tumors were also examined for mRNA expression by Northern analysis. Amplification was detected in 20 and 17% of the tumors with the probes pHER 2 and pCER 204, respectively, but only 10% showed amplification with both probes. A significantly higher incidence (p < 0.01) of mRNA overexpression was detected with the pHER 2 probe (34%) compared with the pCER 204 probe (16%), with only 11% of tumors demonstrating overexpression with both probes. A total of 10 tumors (11%) exhibited amplification as well as overexpression with pHER 2, whereas significantly fewer (3%) manifested both abnormalities with the larger pCER 204 probe (p < 0.05). Amplification of c-erbB-2, as detected with the pHER 2 probe but not with the pCER 204 probe, was significantly associated with the absence of both estrogen and progesterone receptors (p < 0.05 and p < 0.01, respectively). No relationship was found with other clinical prognostic indicators, such as nodal involvement and metastases. As determined by either probe, overexpression was not associated with prognostic indicators. There was no significant difference in the c-erbB-2 status of tumors from different racial groups.