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1.
Eur J Hosp Pharm ; 28(1): 38-41, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33355282

RESUMO

OBJECTIVES: To develop methods for surface bioburden determination of ampoules and vials to be used in the validation of the disinfection procedures and in routine monitoring of ampoules and vials. METHODS: The surface bioburdens of ampoules and vials are determined before and after disinfection by contact plates and total immersion. RESULTS: The mean surface bioburdens of non-disinfected ampoules and vials taken straight from the original boxes are 2.4 and 5.01 cfu (total immersion; n = 20), and 0.97 and 0.94 cfu (contact plates; n = 60). The mean surface bioburdens of ampules and vials after disinfection by wiping are 1.15 and 7.50 cfu (total immersion; n = 20), and 0.12 and 0.10 cfu (contact plates; n = 60). The high number of cfu on vials (total immersion) indicate hidden cfu around the neck not removable by wiping and not detected by contact plates. Total immersion needs special laboratory facilities and is expensive (about €50 a sample). Therefore, it is less appropriate for use in routine monitoring. However, because of the high recovery, it is the method of choice for the validation of the disinfection procedure. Surface bioburden determination by contact plates is relatively simple. Non-flat surfaces cannot be reached, but the recovery from the touched flat part of the surface is high (around 50%). The recovery from swabs is low (around 10%). Another disadvantage of swabs is the laboratory work after sampling. We therefore advise contact plates for routine monitoring. To get a reliable value of the mean surface bioburden at least 30 samples need to be examined. CONCLUSION: Total immersion is the method of choice for the determination of the effectiveness of a disinfection procedure for ampoules and vials. Contact plate is the method of choice for routine monitoring of the surfaces of ampoules and vials.

2.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
3.
Commun Biol ; 2: 285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396565

RESUMO

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.


Assuntos
Lobo Frontal/crescimento & desenvolvimento , Loci Gênicos , Variação Genética , Lobo Occipital/crescimento & desenvolvimento , Lobo Parietal/crescimento & desenvolvimento , Lobo Temporal/crescimento & desenvolvimento , Lobo Frontal/diagnóstico por imagem , Regulação da Expressão Gênica no Desenvolvimento , Estudo de Associação Genômica Ampla , Genótipo , Hereditariedade , Humanos , Imagem por Ressonância Magnética , Lobo Occipital/diagnóstico por imagem , Tamanho do Órgão/genética , Lobo Parietal/diagnóstico por imagem , Fenótipo , Lobo Temporal/efeitos dos fármacos , Reino Unido
4.
Int J Audiol ; 58(5): 262-268, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30890005

RESUMO

OBJECTIVE: To test the channel discrimination of cochlear implant (CI) users along all contacts of the electrode array and assess whether this is related to speech perception. DESIGN: CI recipients were tested with a custom-made channel discrimination test. They were asked to distinguish a target stimulus from two reference stimuli in a three-alternative forced choice (3AFC) task. The target stimulus was evoked using current steering, with current steering coefficients (α) of 1, 0.5 and 0.25. The test provided a discrimination score (Dα) for each electrode contact along the array. STUDY SAMPLE: Thirty adults implanted with a CI from Advanced Bionics. RESULTS: Large variations in Dα scores were observed, both across the electrode array and between subjects. Statistical analysis revealed a significant channel-to-channel variability in Dα score (p < 0.01). Further, there was a significant relationship between subjects' Dα scores and their speech perception in quiet (p < 0.001). CONCLUSIONS: The large variations in Dα score emphasise the importance of testing pitch discrimination across the complete electrode array. The relationship between Dα score and speech perception indicates that pitch discrimination might be a contributing factor to the performance of individual implant users.


Assuntos
Implantes Cocleares , Nível de Discriminação Sonora , Percepção da Fala , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Ann Rheum Dis ; 78(1): 51-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30309970

RESUMO

QUESTION: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? METHODS: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. RESULTS: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. CONCLUSION: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible. TRIAL REGISTRATION NUMBER: 1574.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Etanercepte/administração & dosagem , Metotrexato/administração & dosagem , Prednisolona/administração & dosagem , Sulfassalazina/administração & dosagem , Adolescente , Artrite Juvenil/sangue , Artrite Juvenil/patologia , Sedimentação Sanguínea/efeitos dos fármacos , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Quimioterapia de Indução , Masculino , Índice de Gravidade de Doença , Método Simples-Cego , Exacerbação dos Sintomas , Fatores de Tempo , Resultado do Tratamento
6.
PeerJ ; 6: e4740, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977664

RESUMO

Background: Craniofacial dysmorphic features are morphological changes of the face and skull which are associated with syndromic conditions. Moyamoya angiopathy is a rare cerebral vasculopathy that can be divided into Moyamoya syndrome, which is associated or secondary to other diseases, and into idiopathic Moyamoya disease. Facial dysmorphism has been described in rare genetic syndromes with associated Moyamoya syndrome. However, a direct relationship between idiopathic Moyamoya disease with dysmorphic facial changes is not known yet. Methods: Landmarks were manually placed on frontal photographs of the face of 45 patients with bilateral Moyamoya disease and 50 matched controls. After procrustes alignment of landmarks a multivariate, penalized logistic regression (elastic-net) was performed on geometric features derived from landmark data to classify patients against controls. Classifiers were visualized in importance plots that colorcode importance of geometric locations for the classification decision. Results: The classification accuracy for discriminating the total patient group from controls was 82.3% (P-value = 6.3×10-11, binomial test, a-priori chance 50.2%) for an elastic-net classifier. Importance plots show that differences around the eyes and forehead were responsible for the discrimination. Subgroup analysis corrected for body mass index confirmed a similar result. Discussion: Results suggest that there is a resemblance in faces of Caucasian patients with idiopathic Moyamoya disease and that there is a difference to matched controls. Replication of findings is necessary as it is difficult to control all residual confounding in study designs such as ours. If our results would be replicated in a larger cohort, this would be helpful for pathophysiological interpretation and early detection of the disease.

7.
Genet Epidemiol ; 39(3): 156-65, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25620726

RESUMO

Integrative omics, the joint analysis of outcome and multiple types of omics data, such as genomics, epigenomics, and transcriptomics data, constitute a promising approach for powerful and biologically relevant association studies. These studies often employ a case-control design, and often include nonomics covariates, such as age and gender, that may modify the underlying omics risk factors. An open question is how to best integrate multiple omics and nonomics information to maximize statistical power in case-control studies that ascertain individuals based on the phenotype. Recent work on integrative omics have used prospective approaches, modeling case-control status conditional on omics, and nonomics risk factors. Compared to univariate approaches, jointly analyzing multiple risk factors with a prospective approach increases power in nonascertained cohorts. However, these prospective approaches often lose power in case-control studies. In this article, we propose a novel statistical method for integrating multiple omics and nonomics factors in case-control association studies. Our method is based on a retrospective likelihood function that models the joint distribution of omics and nonomics factors conditional on case-control status. The new method provides accurate control of Type I error rate and has increased efficiency over prospective approaches in both simulated and real data.


Assuntos
Estudos de Casos e Controles , Epigenômica/métodos , Estudo de Associação Genômica Ampla , Genômica/métodos , Funções Verossimilhança , Modelos Genéticos , Esclerose Múltipla/genética , Humanos , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos
8.
BMC Proc ; 8(Suppl 1 Genetic Analysis Workshop 18Vanessa Olmo): S34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25519382

RESUMO

In this analysis, we investigate the contributions that linkage-based methods, such as identical-by-descent mapping, can make to association mapping to identify rare variants in next-generation sequencing data. First, we identify regions in which cases share more segments identical-by-descent around a putative causal variant than do controls. Second, we use a two-stage mixed-effect model approach to summarize the single-nucleotide polymorphism data within each region and include them as covariates in the model for the phenotype. We assess the impact of linkage disequilibrium in determining identical-by-descent states between individuals by using markers with and without linkage disequilibrium for the first part and the impact of imputation in testing for association by using imputed genome-wide association studies or raw sequence markers for the second part. We apply the method to next-generation sequencing longitudinal family data from Genetic Association Workshop 18 and identify a significant region at chromosome 3: 40249244-41025167 (p-value = 2.3 × 10(-3)).

9.
Thromb Res ; 134(6): 1186-92, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25306186

RESUMO

INTRODUCTION: In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family. MATERIALS AND METHODS: We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls. RESULTS: We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels. CONCLUSIONS: In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.


Assuntos
Moléculas de Adesão Celular/genética , Imunoglobulinas/genética , Polimorfismo de Nucleotídeo Único/genética , Deficiência de Proteína C/epidemiologia , Deficiência de Proteína C/genética , Trombose Venosa/epidemiologia , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Molécula 1 de Adesão Celular , Comorbidade , Células Endoteliais/metabolismo , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Proteína C/análise , Proteína C/genética , Deficiência de Proteína C/sangue , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Adulto Jovem
10.
PLoS Genet ; 8(9): e1002932, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23028347

RESUMO

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes--PRDM16, PAX3, TP63, C5orf50, and COL17A1--in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.


Assuntos
Autoantígenos/genética , Proteínas de Ligação a DNA/genética , Face/anatomia & histologia , Colágenos não Fibrilares/genética , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Padronização Corporal/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Imageamento Tridimensional , Imagem por Ressonância Magnética , Fator de Transcrição PAX3 , Fenótipo , Polimorfismo de Nucleotídeo Único
11.
Genet Epidemiol ; 36(8): 811-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22851506

RESUMO

It is hypothesized that certain alleles can have a protective effect not only when inherited by the offspring but also as noninherited maternal antigens (NIMA). To estimate the NIMA effect, large samples of families are needed. When large samples are not available, we propose a combined approach to estimate the NIMA effect from ascertained nuclear families and twin pairs. We develop a likelihood-based approach allowing for several ascertainment schemes, to accommodate for the outcome-dependent sampling scheme, and a family-specific random term, to take into account the correlation between family members. We estimate the parameters using maximum likelihood based on the combined joint likelihood (CJL) approach. Simulations show that the CJL is more efficient for estimating the NIMA odds ratios as compared to a families-only approach. To illustrate our approach, we used data from a family and a twin study from the United Kingdom on rheumatoid arthritis, and confirmed the protective NIMA effect, with an odds ratio of 0.477 (95% CI 0.264-0.864).


Assuntos
Antígenos/imunologia , Artrite Reumatoide/genética , Família , Estudos de Associação Genética/métodos , Modelos Genéticos , Gêmeos/genética , Alelos , Antígenos/genética , Artrite Reumatoide/imunologia , Feminino , Genótipo , Humanos , Funções Verossimilhança , Mães , Razão de Chances , Penetrância , Reino Unido
12.
Am J Med Genet A ; 155A(9): 2161-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21815261

RESUMO

Computer systems play an important role in clinical genetics and are a routine part of finding clinical diagnoses but make it difficult to fully exploit information derived from facial appearance. So far, automated syndrome diagnosis based on digital, facial photographs has been demonstrated under study conditions but has not been applied in clinical practice. We have therefore investigated how well statistical classifiers trained on study data comprising 202 individuals affected by one of 14 syndromes could classify a set of 91 patients for whom pictures were taken under regular, less controlled conditions in clinical practice. We found a classification accuracy of 21% percent in the clinical sample representing a ratio of 3.0 over a random choice. This contrasts with a 60% accuracy or 8.5 ratio in the training data. Producing average images in both groups from sets of pictures for each syndrome demonstrates that the groups exhibit large phenotypic differences explaining discrepancies in accuracy. A broadening of the data set is suggested in order to improve accuracy in clinical practice. In order to further this goal, a software package is made available that allows application of the procedures and contributions toward an improved data set.


Assuntos
Anormalidades Congênitas/diagnóstico , Diagnóstico por Computador/métodos , Face/anormalidades , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Reconhecimento Automatizado de Padrão/métodos , Fenótipo , Software , Síndrome
13.
Eur J Hum Genet ; 19(11): 1192-7, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21694738

RESUMO

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Desenvolvimento Maxilofacial/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Adulto Jovem
14.
Hum Hered ; 67(4): 226-36, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19172082

RESUMO

Genome wide association studies for complex diseases are typically followed by more focused characterization of the identified genetic region. We propose a latent class model to evaluate a candidate region with several measured markers using observations on families. The main goal is to estimate linkage disequilibrium (LD) between the observed markers and the putative true but unobserved disease locus in the region. Based on this model, we estimate the joint distribution of alleles at the observed markers and the unobserved true disease locus, and a penetrance parameter measuring the impact of the disease allele on disease risk. A family specific random effect allows for varying baseline disease prevalences for different families. We present a likelihood framework for our model and assess its properties in simulations. We apply the model to an Alzheimer data set and confirm previous findings in the ApoE region.


Assuntos
Predisposição Genética para Doença , Desequilíbrio de Ligação , Modelos Genéticos , Apolipoproteínas E/genética , Simulação por Computador , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Funções Verossimilhança
15.
Eur J Med Genet ; 51(1): 44-53, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18054308

RESUMO

Digital image analysis of faces has been demonstrated to be effective in a small number of syndromes. In this paper we investigate several aspects that help bringing these methods closer to clinical application. First, we investigate the impact of increasing the number of syndromes from 10 to 14 as compared to an earlier study. Second, we include a side-view pose into the analysis and third, we scrutinize the effect of geometry information. Picture analysis uses a Gabor wavelet transform, standardization of landmark coordinates and subsequent statistical analysis. We can demonstrate that classification accuracy drops from 76% for 10 syndromes to 70% for 14 syndromes for frontal images. Including side-views achieves an accuracy of 76% again. Geometry performs excellently with 85% for combined poses. Combination of wavelets and geometry for both poses increases accuracy to 93%. In conclusion, a larger number of syndromes can be handled effectively by means of image analysis.


Assuntos
Anormalidades Congênitas/patologia , Face/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Inteligência Artificial , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Lactente , Masculino , Pessoa de Meia-Idade , Software , Síndrome
16.
Hum Genet ; 121(3-4): 369-76, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17297623

RESUMO

A great number of case reports on concordant and discordant twins with oculo-auriculo-vertebral spectrum (OAVS) suggest that there might be an association between reproductive abnormalities, twinning and OAVS. The etiology of OAVS is unknown, but may involve epigenetic dysregulation of the oocyte or early embryo. We collected data on fertility and pregnancy outcome of 72 parents of patients with sporadic OAVS. We also evaluated prospective follow-up data on 3.372 fetuses and children conceived by intracytoplasmatic sperm injection (ICSI). Parental age, duration of menstrual cycle and the incidence of spontaneous abortion was not different when compared to the German population. However, there is an excess of parents who have used assisted reproductive techniques (ART; retrospective P = 0.038, prospective P = 0.023) and an excess of twins among naturally conceived patients with OAVS (P = 0.0025). An excess of ART conceptions and monozygotic twinning in OAVS is compatible with the concept of overripeness ovopathy as proposed by Jongbloet (Maandschr Kindergeneeskd 36:352-367, 1968).


Assuntos
Síndrome de Goldenhar/genética , Pais , Técnicas de Reprodução Assistida , Gêmeos , Adulto , Criança , Feminino , Humanos , Masculino , Gravidez , Gravidez Múltipla , Injeções de Esperma Intracitoplásmicas
17.
Am J Hum Genet ; 79(4): 695-701, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16960805

RESUMO

Waldenstrom macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.


Assuntos
Predisposição Genética para Doença , Genoma Humano , Macroglobulinemia de Waldenstrom/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 4 , Família , Feminino , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Modelos Genéticos , Linhagem
18.
Eur J Hum Genet ; 14(10): 1082-9, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16773127

RESUMO

Clinical evaluation of children with developmental delay continues to present a challenge to the clinicians. In many cases, the face provides important information to diagnose a condition. However, database support with respect to facial traits is limited at present. Computer-based analyses of 2D and 3D representations of faces have been developed, but it is unclear how well a larger number of conditions can be handled by such systems. We have therefore analysed 2D pictures of patients each being affected with one of 10 syndromes (fragile X syndrome; Cornelia de Lange syndrome; Williams-Beuren syndrome; Prader-Willi syndrome; Mucopolysaccharidosis type III; Cri-du-chat syndrome; Smith-Lemli-Opitz syndrome; Sotos syndrome; Microdeletion 22q11.2; Noonan syndrome). We can show that a classification accuracy of >75% can be achieved for a computer-based diagnosis among the 10 syndromes, which is about the same accuracy achieved for five syndromes in a previous study. Pairwise discrimination of syndromes ranges from 80 to 99%. Furthermore, we can demonstrate that the criteria used by the computer decisions match clinical observations in many cases. These findings indicate that computer-based picture analysis might be a helpful addition to existing database systems, which are meant to assist in syndrome diagnosis, especially as data acquisition is straightforward and involves off-the-shelf digital camera equipment.


Assuntos
Diagnóstico por Computador/métodos , Facies , Reconhecimento Automatizado de Padrão , Software , Síndrome , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Lactente , Masculino , Reprodutibilidade dos Testes
19.
Hum Mol Genet ; 13(21): 2547-55, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15385437

RESUMO

Angelman syndrome is a neurogenetic disorder caused by the loss of function of the imprinted UBE3A gene in 15q11-q13. In a small group of patients, the disease is due to an imprinting defect (ID) that silences the maternal UBE3A allele. The presence of a faint maternal band detected by methylation-specific PCR analysis of the SNURF-SNRPN locus in approximately one-third of patients who have an ID but no imprinting center deletion suggested that these patients are mosaics of ID cells and normal cells. In two patients studied, somatic mosaicism was proven by molecular and cellular cloning, respectively. X inactivation studies of cloned fibroblasts from one patient suggest that ID occurred before the blastocyst stage. To quantify the degree of mosaicism, we developed a novel quantitative methylation assay based on real-time PCR. In 24 patients tested, the percentage of normal cells ranged from <1% to 40%. Regression analysis suggests that patients with a higher percentage of normally methylated cells tend to have milder clinical symptoms than patients with a lower percentage. In conclusion, we suggest that the role of mosaic imprinting defects in mental retardation is underestimated.


Assuntos
Síndrome de Angelman/genética , Impressão Genômica , Mosaicismo , Síndrome de Angelman/fisiopatologia , Células Cultivadas , Clonagem Molecular , Ilhas de CpG , Metilação de DNA , Primers do DNA , Compensação de Dosagem (Genética) , Fibroblastos/metabolismo , Proteína do X Frágil de Retardo Mental , Humanos , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/genética , Análise de Regressão , Análise de Sequência de DNA , Pele/citologia
20.
Hum Genet ; 111(3): 270-7, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12215840

RESUMO

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.


Assuntos
Antígenos HLA-DR/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Adulto , Alelos , Estudos de Casos e Controles , Testes Genéticos , Genoma Humano , Alemanha , Cadeias HLA-DRB1 , Humanos , Desequilíbrio de Ligação , Repetições de Microssatélites
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