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1.
Clin Genet ; 87(2): 141-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24597975

RESUMO

The BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3'-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colestase Intra-Hepática/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/mortalidade , Adrenoleucodistrofia/patologia , Adulto , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/mortalidade , Encefalopatias Metabólicas Congênitas/patologia , Criança , Pré-Escolar , Colestase Intra-Hepática/mortalidade , Colestase Intra-Hepática/patologia , Creatina/deficiência , Creatina/genética , Deleção de Genes , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/mortalidade , Deficiência Intelectual/patologia , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/mortalidade , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência
2.
Mol Genet Metab ; 107(3): 433-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23031365

RESUMO

BACKGROUND: GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis resulting in severe neurological complications in untreated patients. Currently available treatment is only successful to stop disease progression, but is not sufficient to reverse neurological complications occurring prior to diagnosis. Normal neurodevelopmental outcome in a patient, treated in the newborn period, highlights the importance of early diagnosis. METHODS: Targeted mutation analysis (c.59G>C and c.327G>A) in the GAMT gene by the QIAxcel system and GAA measurement by a novel two-tier method were performed in 3000 anonymized newborn blood dot spot cards. RESULTS: None of the targeted mutations were detected in any newborn. Two novel heterozygous variants (c.283_285dupGTC; p.Val95dup and c.278_283delinsCTCGATGCAC; p.Asp93AlafsX35) were identified by coincidence. Carrier frequency for these insertion/deletion types of GAMT mutations was 1/1475 in this small cohort of newborns. GAA levels were at or above the 99th percentile (3.12 µmol/l) in 4 newborns. Second-tier testing showed normal results for 4 newborns revealing 0.1% false positive rate. No GAMT mutations were identified in 4 of the newborns with elevated GAA levels in the first tier testing. CONCLUSION: This is the first two-tier study to investigate carrier frequency of GAMT deficiency in the small cohort of newborn population to establish evidence base for the first steps toward newborn screening for this treatable neurometabolic disorder.


Assuntos
Guanidinoacetato N-Metiltransferase/genética , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos dos Movimentos/congênito , Adulto , Alelos , Sequência de Bases , Creatina/sangue , Análise Mutacional de DNA , Diagnóstico Precoce , Feminino , Frequência do Gene , Guanidinoacetato N-Metiltransferase/sangue , Guanidinoacetato N-Metiltransferase/deficiência , Heterozigoto , Humanos , Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/sangue , Masculino , Dados de Sequência Molecular , Transtornos dos Movimentos/sangue , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Mutagênese Insercional , Triagem Neonatal , Deleção de Sequência
3.
Clin Genet ; 79(3): 264-72, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20528887

RESUMO

The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.


Assuntos
Heterozigoto , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Inativação do Cromossomo X/genética , Adulto , Idoso , Células Cultivadas , Creatina/metabolismo , Feminino , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Pessoa de Meia-Idade , Mutação , Países Baixos , Testes Neuropsicológicos
4.
Psychooncology ; 18(10): 1080-7, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19189274

RESUMO

OBJECTIVES: The Distress Thermometer (DT) is a promising instrument to get insight into distress experienced by cancer patients. At our Family Cancer Clinic the DT, including an adapted problem list, was completed by 100 women at increased risk of developing hereditary breast cancer (mean age 45.2 years; SD: 10.5). Additionally, the women filled in either the Hospital Anxiety and Depression Scale as psychological component (n=48) or the somatic subscale of the Symptom Checklist-90 as somatic component (n=50) to identify associations with the DT-score. Further, the women filled in an evaluation form. RESULTS: The median score on the DT was 2 (range: 0-9). With regression analysis adjusted for age, the contribution of mood and somatic complaints, respectively, was investigated. The standardized regression coefficient for anxiety was 0.32 (ns), for depression 0.14 (ns) and for the somatic subscale 0.49 (p<0.001). The explained variance for anxiety and depression was 16%, and for somatic complaints 24%. The differences between the coefficients were not significant. Evaluation forms were returned by 73 women. In 50% of the cases, the physician had discussed the DT/problem list, which was appreciated by the majority of these women (80%). Sixty-two percent of the women would recommend the use of the DT for other patients. CONCLUSION: The use of the DT/problem list seems promising for the current population, and was appreciated by the majority of the women. As mood and somatic complaints did not differ significantly in explaining the experienced distress, other candidate factors need to be examined.


Assuntos
Neoplasias da Mama/psicologia , Testes Psicológicos , Estresse Psicológico/psicologia , Adulto , Ansiedade/etiologia , Ansiedade/psicologia , Neoplasias da Mama/genética , Depressão/etiologia , Depressão/psicologia , Feminino , Humanos , Fatores de Risco , Estresse Psicológico/etiologia
5.
J Viral Hepat ; 15(6): 399-408, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18248334

RESUMO

We employed recently developed statistical methods to explore the epidemic behaviour of hepatitis C subtype 1a and subtype 3a among injecting drug users (IDUs) in Flanders, Belgium, using new gene sequence data sampled among two geographically distinct populations of IDUs. First the extent of hepatitis C transmission across regions/countries was studied through calculation of association indices. It was shown that viral exchange had occurred between both populations in Flanders as well as across international borders. Furthermore, evidence was found suggestive of subtypes 1a and 3a predominantly circulating in subpopulations of Flemish IDUs, exhibiting different degrees of travelling/migration behaviour. Secondly, through coalescent-based analysis the viral epidemic history of the hepatitis C subtype 1a and 3a epidemics was inferred. Evidence was found for different dynamic forces driving both epidemics. Moreover, results suggested that the hepatitis C subtype 3a epidemic has reached a steady state, while the hepatitis C 1a epidemic has not, which therefore might become the predominant subtype among IDUs.


Assuntos
Surtos de Doenças , Transmissão de Doença Infecciosa , Genes Virais , Hepacivirus/genética , Hepatite C/epidemiologia , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adulto , Sequência de Bases , Bélgica/epidemiologia , DNA Viral/genética , Emigração e Imigração , Hepacivirus/classificação , Hepatite C/transmissão , Humanos , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Abuso de Substâncias por Via Intravenosa/virologia , Viagem
6.
J Leukoc Biol ; 83(1): 220-2, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17962369

RESUMO

Fas (TNFRSF6/Apo-1/CD95) is a type I transmembrane receptor, which mediates apoptosis. Fas gene mutations, aberrant transcripts, and abundant expression of Fas have been reported in adult T cell leukemia (ATL). To further elucidate the role of Fas in ATL pathogenesis, we investigated whether the -670 FAS promoter A/G polymorphism (STAT1-binding site) might contribute to susceptibility and clinical outcome in ATL. Thirty-one patients with ATL, 33 healthy, human T lymphotropic virus type 1-infected individuals, and 70 healthy, uninfected controls were genotyped for the FAS -670 polymorphism by PCR-restriction fragment-length polymorphism. The AA genotype was significantly over-represented in ATL patients in comparison with healthy controls (P=0.006), as well as asymptomatics (P=0.037), corresponding to an odds ratio (OR) of 3.79 [95% confidence intervals (CI; 1.28-11.41)] and 4.58 [95% CI (1.13-20.03)], respectively. The AA group also comprised significantly more aggressive (acute and lymphoma) clinical subtypes [P=0.012; OR=8.40; 95% CI (1.60-44.12)]. In addition, we observed a statistically significant association between GG genotype and survival (log rank test, P=0.032). Finally, IFN-gamma-induced but not basal FAS mRNA levels were increased significantly (P=0.049) in PBMCs from AA versus GG individuals, demonstrating the IFN-dependent functionality of the -670 polymorphism. In conclusion, our results demonstrate that a functional Fas promoter polymorphism is significantly associated to susceptibility, clinical manifestation, and survival in ATL.


Assuntos
Predisposição Genética para Doença/genética , Leucemia de Células T/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Receptor fas/genética , Seguimentos , Genótipo , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Humanos , Interferon gama/farmacologia , Leucemia de Células T/diagnóstico , Leucemia de Células T/virologia , Leucócitos Mononucleares/efeitos dos fármacos , RNA Mensageiro/genética , Fatores de Risco , Taxa de Sobrevida , Receptor fas/imunologia
7.
Psychooncology ; 16(9): 851-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17219399

RESUMO

Since 2000 the MRISC study evaluates the psychological consequences of regular breast cancer surveillance for women at increased risk for hereditary breast cancer. Coping style may influence these psychological consequences. In a cohort of 357 women at increased risk for hereditary breast cancer, the impact of coping styles on the course, divided into level and trend of psychological distress (general and breast cancer specific) was examined, around two consecutive surveillance appointments. With structural equation modelling we found passive coping to be associated with higher levels of both general and breast cancer specific distress. Seeking social support, expression of emotions and thinking comforting thoughts were associated with lower levels of psychological distress. Coping style was not associated with the trend of psychological distress around the two surveillance appointments. It is recommendable to take coping styles into account when counselling these high-risk women.


Assuntos
Adaptação Psicológica , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Cooperação do Paciente/estatística & dados numéricos , Adulto , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Mamografia , Pessoa de Meia-Idade , Vigilância da População , Prevalência , Apoio Social , Inquéritos e Questionários
8.
Eur J Cancer ; 43(1): 95-103, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17095208

RESUMO

The levels and course of psychological distress before and after prophylactic mastectomy (PM) and/or prophylactic salpingo-oophorectomy (PSO) were studied in a group of 78 women. General distress was measured through the hospital anxiety and depression scale (HADS), cancer-related distress using the impact of events scale (IES). Measurement moments were baseline (2-4 weeks prior to prophylactic surgery), and 6 and 12 months post-surgery. After PM, anxiety and cancer-related distress were significantly reduced, whereas no significant changes in distress scores were observed after PSO. At one year after prophylactic surgery, a substantial amount of women remained at clinically relevant increased levels of cancer-related distress and anxiety. We conclude that most women can undergo PM and/or PSO without developing major emotional distress. More research is needed to further define the characteristics of the women who continue to have clinically relevant increased scores after surgery, in order to offer them additional counselling.


Assuntos
Neoplasias da Mama/patologia , Tubas Uterinas/cirurgia , Mastectomia/psicologia , Neoplasias Ovarianas/psicologia , Ovariectomia/psicologia , Estresse Psicológico/etiologia , Adulto , Ansiedade/etiologia , Aprendizagem da Esquiva , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Transtorno Depressivo/etiologia , Feminino , Predisposição Genética para Doença/psicologia , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia
9.
Neurology ; 66(4): 494-8, 2006 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-16505300

RESUMO

BACKGROUND: Alexander disease is most commonly associated with macrocephaly and, on MRI, a leukoencephalopathy with frontal preponderance. The disease is caused by mutation of the GFAP gene. Clinical and MRI phenotypic variation have been increasingly recognized. METHODS: The authors studied seven patients with Alexander disease, diagnosed based on mutations in the GFAP gene, who presented unusual MRI findings. The authors reviewed clinical history, MRI abnormalities, and GFAP mutations. RESULTS: All patients had juvenile disease onset with signs of brainstem or spinal cord dysfunction. None of the patients had a macrocephaly. The MRI abnormalities were dominated by medulla and spinal cord abnormalities, either signal abnormalities or atrophy. One patient had only minor cerebral white matter abnormalities. A peculiar finding was the presence of a kind of garland along the ventricular wall in four patients. Three patients had an unusual GFAP mutation, one of which was a duplication mutation of two amino acids, and one an insertion deletion. CONCLUSION: Signal abnormalities or atrophy of the medulla or spinal cord on MRI are sufficient to warrant DNA analysis for Alexander disease. Ventricular garlands constitute a new sign of the disease. Unusual phenotypes of Alexander disease are found among patients with late onset and protracted disease course.


Assuntos
Doença de Alexander/patologia , Encéfalo/anormalidades , Ventrículos Cerebrais/patologia , Proteína Glial Fibrilar Ácida/genética , Bulbo/anormalidades , Medula Espinal/anormalidades , Adolescente , Adulto , Doença de Alexander/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Bulbo/patologia , Mutação , Medula Espinal/patologia
10.
Breast ; 15(5): 673-6, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16556497

RESUMO

Magnetic resonance imaging (MRI) of the breasts is a promising screening modality for early detection in women at increased breast cancer risk. We investigated the subjective experiences with MRI and the preferences for MRI, mammography or clinical breast examination in 178 high-risk women adhering to a breast cancer surveillance programme. MRI was reported to cause limited discomfort. About 44% preferred MRI as a screening test (mammography: 14%). MRI provided the most reassurance of breast cancer being absent in case of a favourable test result. MRI seems to be acceptable as a screening test for women at increased breast cancer risk and is preferred by them over mammography.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Imageamento por Ressonância Magnética/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Neoplasias da Mama/patologia , Diagnóstico Precoce , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Imageamento por Ressonância Magnética/psicologia , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Países Baixos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Vigilância da População , Estudos Prospectivos , Inquéritos e Questionários
11.
Br J Cancer ; 91(1): 69-76, 2004 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-15199386

RESUMO

The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample (n=334) showed significant changes over time. The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population.


Assuntos
Neoplasias da Mama/diagnóstico , Predisposição Genética para Doença , Nível de Saúde , Programas de Rastreamento , Qualidade de Vida , Estresse Psicológico , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Imageamento por Ressonância Magnética , Mamografia/efeitos adversos , Pessoa de Meia-Idade , Dor , Fatores de Risco
12.
Mol Biol Evol ; 21(3): 603-11, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14739252

RESUMO

The evolutionary rate of the human T-cell lymphotropic virus type-1 (HTLV-1) is considered to be very low, in strong contrast to the related human retrovirus HIV. However, current estimates of the HTLV-1 rate rely on the anthropological calibration of phylogenies using assumed dates of human migration events. To obtain an independent rate estimate, we analyzed two variable regions of the HTLV-1 genome (LTR and env) from eight infected families. Remarkable genetic stability was observed, as only two mutations in LTR (756 bp) and three mutations in env (522 bp) occurred within the 16 vertical transmission chains, including one ambiguous position in each region. The evolutionary rate in HTLV-1 was then calculated using a maximum-likelihood approach that used the highest and lowest possible times of HTLV-1 shared ancestry, given the known transmission histories. The rates for the LTR and env regions were 9.58 x 10(-8)-1.25 x 10(-5) and 7.84 x 10(-7) -2.33 x 10(-5)nucleotide substitutions per site per year, respectively. A more precise estimate was obtained for the combined LTR-env data set, which was 7.06 x 10(-7)-1.38 x 10(-5)substitutions per site per year. We also note an interesting correlation between the occurrence of mutations in HTLV-1 and the age of the individual infected.


Assuntos
Evolução Biológica , Vírus Linfotrópico T Tipo 1 Humano/genética , Transmissão Vertical de Doenças Infecciosas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Infecções por HTLV-I/transmissão , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Filogenia , Distribuição de Poisson
13.
J Inherit Metab Dis ; 26(2-3): 309-18, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12889669

RESUMO

In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.


Assuntos
Cromossomos Humanos X , Ligação Genética , Proteínas de Membrana Transportadoras/genética , Erros Inatos do Metabolismo/genética , Proteínas do Tecido Nervoso/genética , Transporte Biológico , Creatina/deficiência , Creatina/metabolismo , Feminino , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores
14.
Community Genet ; 6(4): 235-41, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-15331869

RESUMO

BACKGROUND: The Magnetic Resonance Imaging Screening study evaluates the efficacy and psychological impact of a surveillance program for women at increased risk for hereditary or familial breast cancer in the Netherlands. Surveillance consists of biannual physical examination, annual mammography, annual MRI and monthly breast self-examination (BSE). OBJECTIVE: To examine the association between psychological distress and reported BSE frequency. METHODS: Two months prior to surveillance demographics, BSE frequency, general distress (Hospital Anxiety and Depression Scale and the somatic scale of the Symptom Checklist-90) and breast cancer-specific distress (Impact of Event Scale) were assessed in 316 women (mean age 40.5 years, range 21-63 years). RESULTS: The majority (57%) reported performing monthly BSE. Ten percent reported never performing BSE, 20% less frequently than once a month and 13% at least once a week. Women below the age of 40 who examined their breasts more frequently than recommended (i.e. at least once a week) were shown to be significantly more distressed than the other women in the sample (p = 0.03). These women represented 15% of all the women below the age of 40 years in our study sample. CONCLUSION: Higher breast cancer-specific distress scores were observed among younger women who examined their breasts at least once a week. It is important for physicians to be aware of this hypervigilant behaviour, especially since it is correlated with breast cancer-specific distress.


Assuntos
Atitude Frente a Saúde , Neoplasias da Mama/genética , Autoexame de Mama/estatística & dados numéricos , Predisposição Genética para Doença/psicologia , Estresse Psicológico/etiologia , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/psicologia , Autoexame de Mama/psicologia , Coleta de Dados , Feminino , Humanos , Pessoa de Meia-Idade
15.
FEMS Microbiol Lett ; 205(1): 147-50, 2001 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-11728729

RESUMO

The enzyme Hbp (hemoglobin protease) of the pathogenic Escherichia coli strain EB1 has been purified to homogeneity by gel filtration chromatography. The purified protein is capable of binding heme and shows hemoglobin protease activity. Our method of purification is applicable not only to Hbp but also to other autotransporter proteins and will contribute to a better understanding of the function-structure relationship of this family of proteins.


Assuntos
Endopeptidases/isolamento & purificação , Escherichia coli/enzimologia , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/isolamento & purificação , Meios de Cultivo Condicionados/química , Endopeptidases/química , Escherichia coli/crescimento & desenvolvimento , Heme/metabolismo , Dados de Sequência Molecular , Coelhos
17.
J Acquir Immune Defic Syndr ; 27(5): 499-505, 2001 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-11511828

RESUMO

OBJECTIVE: We evaluated the prevalence of HIV-1 non-clade B over time in a formerly clade B-restricted area. Protease and reverse transcriptase regions of the pol gene were used for phylogenetic and recombination analysis and for clade assignment to HIV-1 A-D, F-H, J, and K strains of the M group. METHODS: The pol gene of 349 HIV-1 patients belonging to the Italian Cohort Naive for Antiretrovirals (ICONA) were genotypically analyzed to study the prevalence of antiretroviral-associated resistance mutations. All HIV-1 pol sequences and 32 HIV reference strains were analyzed, including the reference strains for the major HIV-1 subtypes. The non-clade B sequences according to the HIV-1 Subtyping Tool program were further studied by a bootscan analysis (SimPlot) to investigate the likelihood of recombination between subtypes. RESULTS: Phylogenetic analysis detected 19 of 349 (5.4%) non-clade B subtypes. The proportions of patients carrying non-clade B virus before and after 1997 were 1.9% and 8.4%, respectively (p =.008). Among whites, heterosexual infection and female gender were significantly associated with the presence of non-clade B subtypes (p =.001 and.005, respectively). Non-clade B HIV-1 was harbored by 14.5% of the heterosexuals who were found to be HIV-1 positive after 1997, 60% of whom were women. Bootscan analysis identified four strains as F, two as A, one as C, one as G, and 11 (57.9 %) as non-clade B recombinant subtypes. CONCLUSION: Detection of HIV-1 subtypes and intersubtype recombinants in a previously clade B-homogeneous area indicates that the HIV-1 epidemic is evolving in Italy and that heterosexuals and women are at increased risk of infection with non-clade B HIV-1 subtypes. Sequences inferred from the pol gene yield to establish the subtype of circulating HIV-1 strains. As a consequence, genotyping of pol gene for testing resistance to antiretrovirals warrants concomitant surveillance of non-clade B subtypes.


Assuntos
Genes pol/genética , Infecções por HIV/epidemiologia , HIV-1/classificação , HIV-1/genética , Heterossexualidade , Adulto , Feminino , Infecções por HIV/virologia , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , Prevalência , RNA Viral/sangue , Recombinação Genética , Análise de Sequência de DNA
18.
Am J Hum Genet ; 68(6): 1497-500, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11326334

RESUMO

We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in SLC6A8, which has been mapped to Xq28.


Assuntos
Proteínas de Transporte/genética , Códon sem Sentido/genética , Creatina/deficiência , Deficiências do Desenvolvimento/genética , Ligação Genética/genética , Proteínas de Membrana Transportadoras , Cromossomo X/genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Criança , Mapeamento Cromossômico , Creatina/análise , Creatina/sangue , Creatina/urina , Feminino , Fibroblastos , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Dados de Sequência Molecular , Hipotonia Muscular/genética , Linhagem , Síndrome
19.
Mol Biol Evol ; 18(4): 661-71, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11264418

RESUMO

To investigate the origin of the African PTLV-I virus, we phylogenetically analyzed the available HTLV-I and STLV-I strains. We also attempted to date the presumed interspecies transmissions that resulted in the African HTLV-I subtypes. Molecular-clock analysis was performed using the Tamura-Nei substitution model and gamma distributed rate heterogeneity based on the maximum-likelihood topology of the combined long-terminal-repeat and env third-codon-position sequences. Since the molecular clock was not rejected and no evidence for saturation was found, a constant rate of evolution at these positions for all 33 HTLV-I and STLV-I strains was reasonably assumed. The spread of PTLV-I in Africa is estimated to have occurred at least 27,300 +/- 8,200 years ago. Using the available strains, the HTLV-If subtype appears to have emerged within the last 3,000 years, and the HTLV-Ia, HTLV-Ib, HTLV-Id, and HTLV-Ie subtypes appear to have diverged between 21,100 and 5,300 years ago. Interspecies transmissions, most probably simian to human, must have occurred around that time and probably continued later. When the synonymous and nonsynonymous substitution ratios were compared, it was clear that purifying selection was the driving force for PTLV-I evolution in the env gene, irrespective of the host species. Due to the small number of strains in some of the investigated groups, these data on selective pressure should be taken with caution.


Assuntos
Evolução Molecular , Genes env/genética , Repetição Terminal Longa de HIV/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 de Símios/genética , África , Animais , Bases de Dados Factuais , Vírus Linfotrópico T Tipo 1 Humano/classificação , Humanos , Funções Verossimilhança , Filogenia , Primatas/genética , Vírus Linfotrópico T Tipo 1 de Símios/classificação , Fatores de Tempo
20.
Mol Pharmacol ; 57(1): 116-24, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10617686

RESUMO

The peptoid CGP64222 has been previously demonstrated to inhibit the human immunodeficiency virus (HIV) Tat/transactivation response element complex formation. It has previously been shown that CGP64222 selectively inhibits HIV-1 long terminal repeat-driven gene expression and HIV-1(LAV) replication in lymphocytes. Here, we show that CGP64222 inhibits the replication of a wide range of laboratory strains of HIV-1 and HIV-2 in MT-4 cells. However, CGP64222 proved inactive in MT-4 cells against HIV-1 strains that are resistant to the bicyclams. The bicyclams are known to specifically interact with CXC-chemokine receptor 4, the main coreceptor used by T-tropic HIV strains to enter the cells. Mechanism of action studies revealed that CGP64222 can inhibit the HIV replicative cycle, also through a selective interaction with the CXC-chemokine receptor 4 coreceptor.


Assuntos
Fármacos Anti-HIV/farmacologia , Produtos do Gene tat/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Oligopeptídeos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Anticorpos Monoclonais/imunologia , Ligação Competitiva , Transporte Biológico , Cálcio/metabolismo , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Relação Dose-Resposta a Droga , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Produtos do Gene tat/genética , Produtos do Gene tat/metabolismo , Genes tat/efeitos dos fármacos , Transcriptase Reversa do HIV/efeitos dos fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/fisiologia , HIV-2/efeitos dos fármacos , HIV-2/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Peptoides , Receptores CXCR4/imunologia , Ativação Transcricional/efeitos dos fármacos , Transfecção , Células Tumorais Cultivadas , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana
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