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1.
Int J Pharm ; 586: 119591, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32640268

RESUMO

The main objective of this work was to explore the potential of coupling hot-melt extrusion (HME) to Fused Filament Fabrication (FFF), also known as Extrusion-Based Additive Manufacturing (EBAM) or 3D Printing, in order to manufacture 3D printed tablets with different release behavior from plasticizer-free filament matrices. The suitability of different thermoplastic polymers towards FFF was investigated, and a link between the mechanical properties of filaments produced by HME and the feeding performance into the FFF printer was established. Model drugs with different aqueous solubility (metoprolol tartrate and theophylline anhydrous) were processed with hydrophilic and hydrophobic polymers, and the influence of the formulation, drug concentration and applied process settings on the release kinetics was investigated. Filaments with up to 40% drug load were successfully extruded with a smooth surface and a diameter of 1.75 ± 0.05 mm. However, filaments with high brittleness and low toughness were broken by the feeding gears. In contrast, none of the filaments were squeezed aside by the gears, which indicated that they were sufficiently stiff as indicated by the high Young's moduli of all formulations. For all formulations, the release from the tablets with 50% infill degree was faster as compared to the tablets with 100% infill degree. Theophylline (20% w/w) release from Kollicoat® IR matrix was completed within 40 min from 50% infill tablets. In contrast, 80% metoprolol tartrate was released from the hydrophobic Capa® 6506 polymer within 24hrs from 50% infill 3D tablets containing 40% w/w MPT.


Assuntos
Polímeros , Tecnologia Farmacêutica , Liberação Controlada de Fármacos , Humanos , Impressão Tridimensional , Solubilidade , Comprimidos
2.
Pharmacogenomics J ; 12(5): 425-31, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21606947

RESUMO

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.


Assuntos
Substituição de Aminoácidos/genética , Doença das Coronárias/genética , Mutação , Fosfolipases A2/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase , Alelos , Doença das Coronárias/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Genética Populacional , Homozigoto , Humanos , Inibidores de Fosfolipase A2 , Fosfolipases A2/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , População Branca/genética
3.
Br J Cancer ; 102(9): 1371-7, 2010 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-20389299

RESUMO

BACKGROUND: Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction. METHODS: Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study. RESULTS: No polymorphisms were associated with alanine aminotransferase elevation. The Gilbert's uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3-32.2) compared with other genotypes. CONCLUSIONS: The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.


Assuntos
Antineoplásicos/efeitos adversos , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Hiperbilirrubinemia/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Polimorfismo Genético , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Alanina Transaminase/metabolismo , Antineoplásicos/uso terapêutico , Bilirrubina/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Genótipo , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Hiperbilirrubinemia/epidemiologia , Hiperbilirrubinemia/etiologia , Indazóis , Neoplasias Renais/cirurgia , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico
4.
Tissue Antigens ; 76(1): 48-56, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20403135

RESUMO

The first Crohn's disease (CD) susceptibility gene identified was CARD15, which is a member of the emerging NOD-like receptor (NLR) family. These function as intracellular cystosolic pattern recognition receptors (PRRs) and play a central role in the innate immune response. We studied other members of the NLR family using a gene-wide haplotype tagging approach in a well-characterised collection of 547 CD patients and 465 controls. Four single nucleotide polymorphisms (SNPs) in NLRP3 had P values < 0.05 and are in high linkage disequilibrium (LD) with each other (r(2) > 0.90 for all four SNPs). rs4925648 and rs10925019 were the most strongly associated with CD susceptibility (P = 0.001, odds ratio (OR) 1.62, 95% CI 1.2-2.18; and P = 6.5 x 10(-4), OR 1.65, 95% CI 1.23-2.19, respectively). rs1363758 located in NLRP11 was associated with CD susceptibility [P = 0.002 (1.64, 1.19-2.25)], which was weakly confirmed in an independent case-cohort collection on joint analysis [P = 0.05, (1.28, 1-1.64)]. On sub-phenotype analysis, an interesting association between NLRP1 and skin extra-intestinal manifestations and colonic, inflammatory CD was identified. None of these results was replicated in the Wellcome Trust Case Control Consortium study and therefore need replication in a further large cohort.


Assuntos
Doença de Crohn/genética , Proteínas Adaptadoras de Sinalização NOD/genética , Adolescente , Adulto , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
5.
Diabetologia ; 52(4): 600-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19139842

RESUMO

AIMS/HYPOTHESIS: Several susceptibility genes for type 2 diabetes have been discovered recently. Individually, these genes increase the disease risk only minimally. The goals of the present study were to determine, at the population level, the risk of diabetes in individuals who carry risk alleles within several susceptibility genes for the disease and the added value of this genetic information over the clinical predictors. METHODS: We constructed an additive genetic score using the most replicated single-nucleotide polymorphisms (SNPs) within 15 type 2 diabetes-susceptibility genes, weighting each SNP with its reported effect. We tested this score in the extensively phenotyped population-based cross-sectional CoLaus Study in Lausanne, Switzerland (n = 5,360), involving 356 diabetic individuals. RESULTS: The clinical predictors of prevalent diabetes were age, BMI, family history of diabetes, WHR, and triacylglycerol/HDL-cholesterol ratio. After adjustment for these variables, the risk of diabetes was 2.7 (95% CI 1.8-4.0, p = 0.000006) for individuals with a genetic score within the top quintile, compared with the bottom quintile. Adding the genetic score to the clinical covariates improved the area under the receiver operating characteristic curve slightly (from 0.86 to 0.87), yet significantly (p = 0.002). BMI was similar in these two extreme quintiles. CONCLUSIONS/INTERPRETATION: In this population, a simple weighted 15 SNP-based genetic score provides additional information over clinical predictors of prevalent diabetes. At this stage, however, the clinical benefit of this genetic information is limited.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Suíça/epidemiologia , População Branca/estatística & dados numéricos
6.
Am J Med Genet B Neuropsychiatr Genet ; 150B(3): 425-9, 2009 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-18712713

RESUMO

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.


Assuntos
Família , Aconselhamento Genético , Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Humanos , Proteína Huntingtina , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Penetrância , Venezuela , Adulto Jovem
7.
Rheumatology (Oxford) ; 47(12): 1761-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18835879

RESUMO

OBJECTIVES: The heritability of RA has been estimated to be approximately 55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. METHODS: Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404-carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. RESULTS: Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. CONCLUSIONS: The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.


Assuntos
Artrite Reumatoide/genética , Proteínas de Ligação a DNA/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Técnicas Imunoenzimáticas , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Proteínas dos Microfilamentos , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
8.
Pharmacogenomics J ; 8(3): 186-95, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17505501

RESUMO

One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.


Assuntos
Alanina Transaminase/sangue , Anticoagulantes/efeitos adversos , Azetidinas/efeitos adversos , Benzilaminas/efeitos adversos , Fígado/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Estudos Retrospectivos
9.
J Med Genet ; 44(1): 44-50, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17018562

RESUMO

BACKGROUND: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations. OBJECTIVE: To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela. METHODS: Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B). RESULTS: The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes. CONCLUSIONS: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.


Assuntos
Doença de Huntington/epidemiologia , Doença de Huntington/genética , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/genética , Transativadores/genética , Idade de Início , Apolipoproteínas E/genética , Desoxirribonucleases/genética , Frequência do Gene , Humanos , Proteína Huntingtina , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas de Ligação a Poli-ADP-Ribose , Receptores de Ácido Caínico/genética , Fatores de Elongação da Transcrição , Expansão das Repetições de Trinucleotídeos/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina Tiolesterase/genética , Venezuela , Receptor de GluK2 Cainato
10.
Behav Genet ; 36(6): 947-50, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16804748

RESUMO

Transmission distortion refers to deviation from the normal 50:50 transmission of alleles from parents to offspring. Identification of genomic regions which undergo distortion is necessary for the correct interpretation of linkage and association studies, since tests of linkage using affected relative pairs and family based tests of association will yield spurious results in the presence of transmission distortion. With the increasing availability of genome-wide high density SNP data (e.g. from the International HapMap project), identification of these loci is now a real possibility. Here we present an analytical formula which demonstrates that the power to detect transmission distortion is a simple function of the number of heterozygous parents in the sample and the level of distortion at the locus. Our results indicate that whilst it will be possible to identify loci undergoing major levels of distortion using tens or hundreds of trios, large sample sizes in the order of tens of thousands of trios will be necessary to detect minor levels of distortion with appreciable power. The corollary is that genome-wide searches are unlikely to identify loci where the level of distortion is small, although they may serve to identify interesting regions worthy of follow up.


Assuntos
Desequilíbrio de Ligação/genética , Relações Pais-Filho , Gêmeos/genética , Adulto , Criança , Feminino , Humanos , Masculino , Modelos Genéticos , Reprodutibilidade dos Testes
11.
J Child Psychol Psychiatry ; 46(10): 1045-56, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16178928

RESUMO

BACKGROUND: There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy. METHODS: We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs. RESULTS: We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage. CONCLUSIONS: Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Dislexia/epidemiologia , Dislexia/genética , Ligação Genética/genética , Adolescente , Criança , Colorado/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Análise Multivariada , Análise de Regressão , Irmãos
12.
Genet Epidemiol ; 27(4): 442-50, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15543640

RESUMO

A dense set of 5,000 SNPs on a 10-Mb region of human chromosome 20 has been typed on samples of African Americans, East Asians, and United Kingdom Caucasians. There are departures from Hardy-Weinberg equilibrium beyond the level at which markers are often discarded because of possible genotyping errors. The observation that markers showing such departures are often close together on the chromosome confirms the result that Hardy-Weinberg tests at two loci are correlated to an extent that depends on the linkage disequilibrium between those two markers. Linkage disequilibrium can be described by the composite linkage disequilibrium coefficient, the parameter that determines the behavior of case-control allelic tests of association. A useful preliminary investigation of datasets of this type is provided by counting the numbers of distinct multi-locus genotypes in windows of a few markers.


Assuntos
Alelos , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 20/genética , Genética Populacional , Desequilíbrio de Ligação/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Negro ou Afro-Americano/genética , Povo Asiático/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/epidemiologia , Genoma Humano , Genótipo , Haplótipos , Humanos , Modelos Estatísticos , População Branca/genética
13.
Gut ; 52(4): 541-6, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12631666

RESUMO

BACKGROUND AND AIMS: Genetic variation in the chromosome 5q31 cytokine cluster (IBD5 risk haplotype) has been associated with Crohn's disease (CD) in a Canadian population. We studied the IBD5 risk haplotype in both British and Japanese cohorts. Disease associations have also been reported for CARD15/NOD2 and TNF variants. Complex interactions between susceptibility loci have been shown in animal models, and we tested for potential gene-gene interactions between the three CD associated loci. METHODS: Family based association analyses were performed in 457 British families (252 ulcerative colitis, 282 CD trios) genotyped for the IBD5 haplotype, common CARD15, and TNF-857 variants. To test for possible epistatic interactions between variants, transmission disequilibrium test analyses were further stratified by genotype at other loci, and novel log linear analyses were performed using the haplotype relative risk model. Case control association analyses were performed in 178 Japanese CD patients and 156 healthy controls genotyped for the IBD5 haplotype. RESULTS: The IBD5 haplotype was associated with CD (p=0.007), but not with UC, in the British Caucasian population. The CARD15 variants and IBD5 haplotype showed additive main effects, and in particular no evidence for epistatic interactions was found. Variants from the IBD5 haplotype were extremely rare in the Japanese. CONCLUSIONS: The IBD5 risk haplotype is associated with British CD. Genetic variants predisposing to CD show heterogeneity and population specific differences.


Assuntos
Cromossomos Humanos Par 5/genética , Doença de Crohn/genética , Epistasia Genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular , Adulto , Canadá , Proteínas de Transporte/genética , Estudos de Casos e Controles , Colite Ulcerativa/etnologia , Colite Ulcerativa/genética , Doença de Crohn/etnologia , Feminino , Genótipo , Haplótipos , Humanos , Japão , Masculino , Proteína Adaptadora de Sinalização NOD2 , Fator de Necrose Tumoral alfa/genética , Reino Unido
14.
Nat Genet ; 33(3): 382-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12590262

RESUMO

Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins.


Assuntos
Cromossomos Humanos Par 19/genética , Haplótipos/genética , Recombinação Genética , Alelos , Mapeamento Cromossômico , DNA/genética , Evolução Molecular , Frequência do Gene , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
16.
Heart ; 88(4): 397-400, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12231601

RESUMO

OBJECTIVE: To evaluate the load dependence of effective regurgitant orifice area (ROA) in an animal model of chronic aortic regurgitation. METHODS: Eight sheep were studied 10-20 weeks after the surgical creation of aortic regurgitation. After baseline studies, 500 ml of blood, angiotensin II, and nitroprusside were infused sequentially. Electromagnetic flow meters were used as reference standards to determine aortic regurgitation volume. The time-velocity integral was acquired using the continuous wave Doppler method. RESULTS: Baseline aortic regurgitant volume varied from 8 ml (regurgitant fraction 28%) to 29 ml (59%), with a mean (SD) value of 17 (8) ml; mean ROA was 0.15 (0.05) cm2. During angiotensin II infusion, aortic regurgitation volume (20 (8) ml) and mean diastolic aortoventricular pressure gradient (62 (18) mm Hg) increased by 26 (16)% and 48 (64)%, respectively (p < 0.01 for both). ROA did not change (0.16 (0.06) cm(2), p = 0.15). During nitroprusside infusion, aortic regurgitant volume (13 (7) ml, p = 0.05) and diastolic pressure gradient (25 (13) mm Hg, p < 0.05) decreased. ROA did not change (0.15 (0.05) cm2). When analysing 32 stages together, aortic regurgitant volume (r = 0.78, p < 0.01) and regurgitant fraction (r = 0.55, p < 0.01) correlated well with ROA. However, diastolic pressure gradient (r = 0.28) was not significantly correlated with ROA. CONCLUSIONS: In an animal model of chronic aortic regurgitation, ROA did not change with load alterations.


Assuntos
Insuficiência da Valva Aórtica/fisiopatologia , Angiotensina II/farmacologia , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Transfusão de Sangue , Doença Crônica , Ecocardiografia Doppler/métodos , Hemodinâmica , Nitroprussiato/farmacologia , Análise de Regressão , Ovinos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
17.
Ann Hum Genet ; 66(Pt 3): 211-21, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12174212

RESUMO

Regression analysis of a quantitative trait as a function of a single diallelic polymorphism has been extended to allelic association by composite likelihood under the Malecot model for multiple markers. We applied the method to 10 single nucleotide polymorphisms (SNPs) spanning 27 kb of the angiotensin-I converting enzyme (ACE) gene in British families, localising a causal SNP between G2530A and 4656(CT)3/2 in the 3' region, at a distance of 21.6+/-0.9 kb from the most proximal SNP T-5491C. Neither they nor the I/D polymorphism is causal. To clarify genetic parameters we applied combined segregation, linkage and association analysis. Stronger evidence for the 3' region was obtained, with significant evidence of a lesser 5' effect as reported in French and Nigerian families. However, rigorous confirmation requires that the causal SNPs be identified. Both Malecot and parametric analysis appear to have high power by comparison with alternative methods for localizing oligogenes and their causal polymorphisms.


Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 17 , Herança Multifatorial , Locos de Características Quantitativas , Humanos , Escore Lod , Modelos Genéticos , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Análise de Regressão
19.
J Am Coll Cardiol ; 38(4): 1195-202, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11583903

RESUMO

OBJECTIVES: We aimed to validate a new flow convergence (FC) method that eliminated the need to locate the regurgitant orifice and that could be performed semiautomatedly. BACKGROUND: Complex and time-consuming features of previously validated color Doppler methods for determining mitral regurgitant volume (MRV) have prevented their widespread clinical use. METHODS: Thirty-nine different hemodynamic conditions in 12 sheep with surgically created flail leaflets inducing chronic mitral regurgitation were studied with two-dimensional (2D) echocardiography. Color Doppler M-mode images along the centerline of the accelerating flow towards the mitral regurgitation orifice were obtained. The distance between the two first aliasing boundaries (interaliasing distance [IAD]) was measured and the FC radius was mathematically derived according to the continuity equation (R(calc) = IAD/(1 - radicalv(1)/v(2)), v(1) and v(2) being the aliasing velocities). The conventional 2D FC radius was also measured (R(meas)). Mitral regurgitant volume was then calculated according to the FC method using both R(calc) and R(meas). Aortic and mitral electromagnetic (EM) flow probes and meters were balanced against each other to determine the reference standard MRV. RESULTS: Mitral regurgitant volume calculated from R(calc) and R(meas) correlated well with EM-MRV (y = 0.83x + 5.17, r = 0.90 and y = 1.04x + 0.91, r = 0.91, respectively, p < 0.001 for both). However, both methods resulted in slight overestimation of EM-MRV (Delta was 3.3 +/- 2.1 ml for R(calc) and 1.3 +/- 2.3 ml for R(meas)). CONCLUSIONS: Good correlation was observed between MRV derived from R(calc) (IAD method) and EM-MRV, similar to that observed with R(meas) (conventional FC method) and EM-MRV. The R(calc) using the IAD method has an advantage over conventional R(meas) in that it does not require spatial localization of the regurgitant orifice and can be performed semiautomatedly.


Assuntos
Insuficiência da Valva Mitral/fisiopatologia , Modelos Animais , Ultrassonografia Doppler em Cores , Animais , Velocidade do Fluxo Sanguíneo , Insuficiência da Valva Mitral/diagnóstico por imagem , Modelos Cardiovasculares , Ovinos
20.
Behav Genet ; 31(2): 219-30, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11545538

RESUMO

We describe a family-based sample of individuals with reading disability collected as part of a quantitative trait loci (QTL) mapping study. Eighty-nine nuclear families (135 independent sib-pairs) were identified through a single proband using a traditional discrepancy score of predicted/actual reading ability and a known family history. Eight correlated psychometric measures were administered to each sibling, including single word reading, spelling, similarities, matrices, spoonerisms, nonword and irregular word reading, and a pseudohomophone test. Summary statistics for each measure showed a reduced mean for the probands compared to the co-sibs, which in turn was lower than that of the population. This partial co-sib regression back to the mean indicates that the measures are influenced by familial factors and therefore, may be suitable for a mapping study. The variance of each of the measures remained largely unaffected, which is reassuring for the application of a QTL approach. Multivariate genetic analysis carried out to explore the relationship between the measures identified a common factor between the reading measures that accounted for 54% of the variance. Finally the familiality estimates (range 0.32-0.73) obtained for the reading measures including the common factor (0.68) supported their heritability. These findings demonstrate the viability of this sample for QTL mapping, and will assist in the interpretation of any subsequent linkage findings in an ongoing genome scan.


Assuntos
Dislexia/genética , Característica Quantitativa Herdável , Criança , Mapeamento Cromossômico , Feminino , Humanos , Inteligência/genética , Masculino , Modelos Genéticos , Testes Neuropsicológicos , Fenótipo , Fatores Sexuais
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