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1.
Global Health ; 15(Suppl 1): 76, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31775788

RESUMO

The structural perspective outlined here sheds light on some of the fundamental challenges involved in achieving Universal Health Care (UHC) in this twenty-first-century era of trade and financialized capitalism. This commentary explores connections between the structure of twenty-first-century capitalism and challenges to achieving UHC, discussing three features of today's capitalism: financialized capitalism; trade, intangibles and global value chains; and inequality (as exacerbated by the first two features). The final section discusses the various opportunities for reform to facilitate UHC-from tinkering with the status quo, to deeper regulatory reform and fundamental structural change.

2.
Am J Hum Genet ; 105(3): 606-615, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474318

RESUMO

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

3.
Am J Hum Genet ; 104(6): 1040-1059, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079900

RESUMO

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.

5.
Am J Hum Genet ; 104(1): 139-156, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372

RESUMO

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.


Assuntos
Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Ligação Proteica/genética , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Síndrome
6.
Am J Med Genet A ; 170(10): 2644-51, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27240540

RESUMO

Baraitser-Winter cerebrofrontofacial syndrome is caused by heterozygous missense mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1. Recently, we characterized the large cohort of 41 patients presenting with this condition. Our series contained 34 patients with mutations in ACTB and only nine with ACTG1 mutations. Here, we report on seven unrelated patients with six mutations in ACTG1-four novel and two previously reported. Only one of seven patients was clinically diagnosed with this disorder and underwent ACTB/ACTG1 targeted sequencing, four patients were screened as a part of the large lissencephaly cohort and two were tested with exome sequencing. Retrospectively, facial features were compatible with the diagnosis but significantly milder than previously reported in four patients, and non-specific in one. The pattern of malformations of cortical development was highly similar in four of six patients with available MRI images and encompassed frontal predominant pachygyria merging with the posterior predominant band heterotopia. Two remaining patients showed mild involvement consistent with bilaterally simplified gyration over the frontal lobes. Taken together, we expand the clinical spectrum of the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome demonstrating the mild end of the facial and brain manifestations. © 2016 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Actinas/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Mutação de Sentido Incorreto , Biomarcadores , Encéfalo/patologia , Pré-Escolar , Análise Mutacional de DNA , Exoma , Facies , Feminino , Estudos de Associação Genética , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Fenótipo
7.
Am J Med Genet A ; 161A(8): 1833-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23813913

RESUMO

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Encéfalo/anormalidades , Transtornos do Comportamento Infantil/patologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Cromossomos Humanos Par 17/genética , Duplicação Gênica , Proteínas Associadas aos Microtúbulos/genética , Adolescente , Adulto , Encéfalo/patologia , Criança , Transtornos do Comportamento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo
8.
Am J Hum Genet ; 92(2): 210-20, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23332918

RESUMO

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.


Assuntos
Éxons/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas/química , Proteínas/genética , Deleção de Sequência/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Facies , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fenótipo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Supressão Genética , Síndrome , Adulto Jovem , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética
9.
Hum Mutat ; 33(4): 728-40, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22290657

RESUMO

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.


Assuntos
Transtornos Dismórficos Corporais/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos Mentais/genética , Fatores de Transcrição SOXD/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 12 , Feminino , Humanos , Masculino
10.
Hum Genet ; 131(1): 145-56, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21800092

RESUMO

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.


Assuntos
Agenesia do Corpo Caloso/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Genes/fisiologia , Microcefalia/genética , Convulsões/genética , Anormalidades Múltiplas , Adolescente , Agenesia do Corpo Caloso/patologia , Biomarcadores/metabolismo , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Convulsões/patologia , Síndrome
11.
J Genet Couns ; 20(5): 432-41, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21618060

RESUMO

Down syndrome is one of the most common conditions encountered in the genetics clinic. Due to improvements in healthcare, educational opportunities, and community inclusion over the past 30 years, the life expectancy and quality of life for individuals with Down syndrome have significantly improved. As prenatal screening and diagnostic techniques have become more enhanced and widely available, genetic counselors can expect to frequently provide information and support following a new diagnosis of Down syndrome. This guideline was written for genetic counselors and other healthcare providers regarding the communication of a diagnosis of Down syndrome to ensure that families are consistently given up-to-date and balanced information about the condition, delivered in a supportive and respectful manner.


Assuntos
Síndrome de Down/diagnóstico , Aconselhamento Genético , Diagnóstico Pré-Natal , Síndrome de Down/fisiopatologia , Humanos , Qualidade de Vida , Recursos Humanos
12.
Am J Hum Genet ; 87(3): 354-64, 2010 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20727516

RESUMO

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development.


Assuntos
Calcinose/complicações , Calcinose/genética , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/genética , Proteínas de Membrana/genética , Mutação/genética , Junções Íntimas/genética , Animais , Sequência de Bases , Calcinose/líquido cefalorraquidiano , Calcinose/patologia , Córtex Cerebral/patologia , Cromossomos Humanos Par 5/genética , Consanguinidade , Análise Mutacional de DNA , Regulação da Expressão Gênica , Homozigoto , Humanos , Hibridização In Situ , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Malformações do Desenvolvimento Cortical/líquido cefalorraquidiano , Malformações do Desenvolvimento Cortical/patologia , Proteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , Ocludina , Software
13.
Dev Biol ; 314(2): 443-56, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18199433

RESUMO

During pancreatic development insulin(+) cells co-express the transcription factors MafB and Pax6, and transition from a MafA(-) to MafA(+) state. To examine the role of Pax6 and MafB in the development of beta-cells, we analyzed embryonic pancreata from Pax6- and MafB-deficient mice. Pax6 deficiency, as manifest in the Pax6(Sey-Neu) allele, reduced not only the number of cells expressing insulin or glucagon, but also the number of MafB, PDX-1 and MafA expressing cells. We show that MafB can directly activate expression of insulin and glucagon, and a MafB protein engineered to contain N248S mutation in the MafB (kr(ENU)) results in significantly reduced activation. Furthermore, pancreata from MafB deficient (kr(ENU)/kr(ENU)) mice exhibited reduced number of cells expressing insulin, glucagon, PDX-1 and MafA, with only a minor reduction in MafB expressing cells. MafB deficiency does not affect endocrine specification but does affect the lineage commitment of the endocrine cells and their maturation. Similar to Pax6 deficient mice, MafB deficient mice showed reductions both in insulin and glucagon expressing cells and in the ability of MafB and PDX-1 expressing cells to activate expression of these hormones. However, MafB deficient mice exhibited no effect on Pax6 expression. These results suggest that MafB may function as a downstream mediator of Pax6 in regulating the specification of insulin and glucagon expressing cells. Interestingly, the remaining insulin(+) cells in these knockouts preferentially express Hb9, suggesting the existence of an alternate pathway for the generation of insulin expressing cells, even in the absence of Pax6 and MafB function. Thus, Pax6 acts upstream of MafB, which in turn may trigger the expression of insulin and regulate the PDX-1 and MafA expression required for beta-cell maturation.


Assuntos
Proteínas do Olho/fisiologia , Proteínas de Homeodomínio/fisiologia , Células Secretoras de Insulina/fisiologia , Fator de Transcrição MafB/deficiência , Fator de Transcrição MafB/fisiologia , Fatores de Transcrição Box Pareados/fisiologia , Proteínas Repressoras/fisiologia , Animais , Embrião de Mamíferos/fisiologia , Proteínas do Olho/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteínas de Homeodomínio/genética , Insulina/deficiência , Insulina/genética , Luciferases/genética , Fator de Transcrição MafB/genética , Camundongos , Camundongos Knockout , Mutagênese , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/deficiência , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética
14.
Am J Med Genet A ; 143A(5): 430-42, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17236194

RESUMO

Prader-Willi syndrome (PWS) is caused by loss of function of paternally expressed genes in the 15q11-q13 region and a paucity of data exists on transcriptome variation. To further characterize genetic alterations in this classic obesity syndrome using whole genome microarrays to analyze gene expression, microarray and quantitative RT-PCR analysis were performed using RNA isolated from lymphoblastoid cells from PWS male subjects (four with 15q11-q13 deletion and three with UPD) and three age and cognition matched nonsyndromic comparison males. Of more than 47,000 probes examined in the microarray, 23,383 were detectable and 323 had significantly different expression in the PWS lymphoblastoid cells relative to comparison cells, 14 of which were related to neurodevelopment and function. As expected, there was no evidence of expression of paternally expressed genes from the 15q11-q13 region (e.g., SNRPN) in the PWS cells. Alterations in expression of serotonin receptor genes (e.g., HTR2B) and genes involved in eating behavior and obesity (ADIPOR2, MC2R, HCRT, OXTR) were noted. Other genes of interest with reduced expression in PWS subjects included STAR (a key regulator of steroid synthesis) and SAG (an arrestin family member which desensitizes G-protein-coupled receptors). Quantitative RT-PCR for SAG, OXTR, STAR, HCRT, and HTR2B using RNA isolated from their lymphoblastoid cells and available brain tissue (frontal cortex) from separate individuals with PWS and control subjects and normalized to GAPD gene expression levels validated our microarray gene expression data. Our analysis identified previously unappreciated changes in gene expression which may contribute to the clinical manifestations seen in PWS.


Assuntos
Genoma Humano , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Encéfalo/crescimento & desenvolvimento , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 5 , Feminino , Impressão Genômica , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Obesidade/genética , Receptores de GABA/genética , Serotonina/metabolismo , Dissomia Uniparental/genética
15.
Brief Funct Genomic Proteomic ; 4(2): 178-85, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16102272

RESUMO

Comparative genomics has emerged as a valuable tool for locating genes, transcription factor motifs and other putative control regions. There are, however, issues that keep comparative genomics from being a straightforward process. These caveats fall into three categories: database, computational and biological. In this review paper, these caveats will be discussed and illustrated using related case studies. The National Center for Biotechnology Information and University of California Santa Cruz genome databases were used, and VISTA, LAGAN and zPicture were used as comparison tools. Based on these caveats, a tiered approach to carrying out comparative genomic studies is presented.


Assuntos
Biologia Computacional/métodos , Genômica/métodos , Algoritmos , Animais , DNA Complementar/metabolismo , Proteínas de Ligação a DNA/genética , Bases de Dados Factuais , Bases de Dados Genéticas , Éxons , Genoma , Genoma Humano , Humanos , Interleucina-10/metabolismo , Íntrons , Fator de Transcrição MafB , Camundongos , Proteínas Oncogênicas/genética , Software , Fatores de Transcrição/genética
16.
BMC Med Inform Decis Mak ; 5: 6, 2005 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-15766382

RESUMO

BACKGROUND: The rapid growth of online publications such as the Medline and other sources raises the questions how to get the relevant information efficiently. It is important, for a bench scientist, e.g., to monitor related publications constantly. It is also important, for a clinician, e.g., to access the patient records anywhere and anytime. Although time-consuming, this kind of searching procedure is usually similar and simple. Likely, it involves a search engine and a visualization interface. Different words or combination reflects different research topics. The objective of this study is to automate this tedious procedure by recording those words/terms in a database and online sources, and use the information for an automated search and retrieval. The retrieved information will be available anytime and anywhere through a secure web server. RESULTS: We developed such a database that stored searching terms, journals and et al., and implement a piece of software for searching the medical subject heading-indexed sources such as the Medline and other online sources automatically. The returned information were stored locally, as is, on a server and visible through a Web-based interface. The search was performed daily or otherwise scheduled and the users logon to the website anytime without typing any words. The system has potentials to retrieve similarly from non-medical subject heading-indexed literature or a privileged information source such as a clinical information system. The issues such as security, presentation and visualization of the retrieved information were thus addressed. One of the presentation issues such as wireless access was also experimented. A user survey showed that the personalized online searches saved time and increased and relevancy. Handheld devices could also be used to access the stored information but less satisfactory. CONCLUSION: The Web-searching software or similar system has potential to be an efficient tool for both bench scientists and clinicians for their daily information needs.


Assuntos
Bases de Dados Bibliográficas/estatística & dados numéricos , Armazenamento e Recuperação da Informação/métodos , Redes Neurais (Computação) , Interface Usuário-Computador , Eficiência , Humanos , Internet , MEDLINE/estatística & dados numéricos , Medical Subject Headings , Sistemas On-Line , Software
17.
Cancer Genet Cytogenet ; 157(1): 67-9, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15676150

RESUMO

Uterine leiomyomata are benign, smooth-muscle tumors. The tumors are very common, affecting approximately 10-15 million women in the United States annually. Uterine leiomyomata are often asymptomatic, but may cause symptoms that range in severity from mild abdominal discomfort to uterine prolapse. Several different chromosomal aberrations have been found in the tumor tissue. Because of the common occurrence of this tumor and the potential severity of associated sequelae, research delineating the different molecular subtypes is needed. Deletions on the long arm of chromosome 7 are believed to be the most common genetic anomaly in uterine leiomyoma. The size of the deletion varies, which makes it difficult to identify the genes that, upon deletion, contribute to tumor growth. The smallest previously defined interval was >12,000 kb. We have narrowed a minimal region to an interval of <500 kb.


Assuntos
Cromossomos Humanos Par 7 , Leiomioma/genética , Neoplasias Uterinas/genética , Feminino , Humanos
18.
Percept Mot Skills ; 99(3 Pt 1): 909-12, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15648487

RESUMO

275 undergraduate university students were asked to complete a battery concerning their health complaints, perceived stress, strenuous physical activity, and personality ("Big Five" traits). An hierarchical regression showed that Stress and Strenuous Physical Activity Participation, but not Personality, predicted the Number of Health Complaints in this sample. Also, there was a significant interaction for Stress by Strenuous Activity indicating individuals who did not frequently engage in strenuous leisure-time physical activity reported more health complaints than those who did. This finding corroborates the notion that physical activity (or fitness) may serve to attenuate the relation between stress and health complaints.


Assuntos
Atitude Frente a Saúde , Nível de Saúde , Atividade Motora , Personalidade , Estresse Psicológico/psicologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Inquéritos e Questionários
19.
J Clin Endocrinol Metab ; 87(12): 5461-4, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12466337

RESUMO

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/- SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/- 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.


Assuntos
Hiperfagia/etiologia , Obesidade/etiologia , Hormônios Peptídicos/sangue , Síndrome de Prader-Willi/complicações , Adulto , Ingestão de Alimentos/fisiologia , Jejum/sangue , Feminino , Grelina , Humanos , Fome/fisiologia , Masculino , Concentração Osmolar , Síndrome de Prader-Willi/sangue , Síndrome de Prader-Willi/fisiopatologia , Valores de Referência
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