33 resultados para Human development index (HDI)
Resumo:
The Wilms' tumor gene, WT1, encodes a zinc finger transcription factor which functions as a tumor suppressor. Defects in the WT1 gene can result in the development of nephroblastoma. WT1 is expressed during development, primarily in the metanephric kidney, the mesothelial lining of the abdomen and thorax, and the developing gonads. WT1 expression is tightly regulated and is essential for renal development. The WT1 gene encodes a protein with a proline-rich N-terminus which functions as a transcriptional repressor and C-terminus contains 4 zinc fingers that mediate DNA binding. WT1 represses transcription from a number of growth factors and growth factor receptors. WT1 mRNA undergoes alternative splicing at two sites, resulting in 4 mRNA species and polypeptide products. Exon 5, encoding 17 amino acids is alternatively spliced, and is located between the transcriptional repression domain and the DNA binding domain. The second alternative splice is the terminal 9 nucleotides of zinc finger 3, encoding the tripeptide Lys-Thr-Ser (KTS). The presence or absence of KTS within the zinc fingers of WT1 alters DNA binding.^ I have investigated transcriptional regulation of WT1, characterizing two means of repressing WT1 transcription. I have cloned a transcriptional silencer of the WT1 promoter which is located in the third intron of the WT1 gene. The silencer is 460 bp in length and contains an Alu repeat. The silencer functions in cells of non-renal origin.^ I have found that WT1 protein can autoregulate the WT1 promoter. Using the autoregulation of the WT1 promoter as a functional assay, I have defined differential consensus DNA binding motifs of WT1 isoforms lacking and containing the KTS tripeptide insertion. With these refined consensus DNA binding motifs, I have identified two additional targets of WT1 transcriptional repression, the proto-oncogenes bcl-2 and c-myc.^ I have investigated the ability of the alternatively spliced exon 5 to influence cell growth. In cell proliferation assays, isoforms of WT1 lacking exon 5 repress cell growth. WT1 isoforms containing exon 5 fail to repress cell growth to the same extent, but alter the morphology of the cells. These experiments demonstrate that the alternative splice isoforms of WT1 have differential effects on the function of WT1. These findings suggest a role for the alternative splicing of WT1 in metanephric development. ^
Resumo:
Formation of cartilage and bone involves sequential processes in which undifferentiated mesenchyme aggregates into primordial condensations which subsequently grow and differentiate, resulting in morphogenesis of the adult skeleton. While much has been learned about the structural molecules which comprise cartilage and bone, little is known about the nuclear factors which regulate chondrogenesis and osteogenesis. MHox is a homeobox-containing gene which is expressed in the mesenchyme of facial, limb, and vertebral skeletal precursors during mouse embryogenesis. MHox expression has been shown to require epithelial-derived signals, suggesting that MHox may regulate the epithelial-mesenchymal interactions required for skeletal organogenesis. To determine the functions of MHox, we generated a loss-of-function mutation in the MHox gene. Mice homozygous for a mutant MHox allele exhibit defects of skeletogenesis, involving the loss or malformation of craniofacial, limb and vertebral skeletal structures. The affected skeletal elements are derived from the cranial neural crest, as well as somitic and lateral mesoderm. Analysis of the mutant phenotype during ontogeny demonstrated a defect in the formation or growth of chondrogenic and osteogenic precursors. These findings provide evidence that MHox regulates the formation of preskeletal condensations from undifferentiated mesenchyme. In addition, generation of mice doubly mutant for the MHox and S8 homeobox genes reveal that these two genes interact to control formation of the limb and craniofacial skeleton. Mice carrying mutant alleles for S8 and MHox exhibit an exaggeration of the craniofacial and limb phenotypes observed in the MHox mutant mouse. Thus, MHox and S8 are components of a combinatorial genetic code controlling generation of the skeleton of the skull and limbs. ^
Resumo:
PAX6 is a transcription activator that regulates eye development in animals ranging from Drosophila to human. The C-terminal region of PAX6 is proline/serine/threonine-rich (PST) and functions as a potent transactivation domain when attached to a heterologous DNA-binding domain of the yeast transcription factor, GAL4. The PST region comprises 152 amino acids encoded by four exons. The transactivation function of the PST region has not been defined and characterized in detail by in vitro mutagenesis. I dissected the PST domain in two independent systems, a heterologous system using a GAL4 DNA-binding site and the native system of PAX6. In both systems, the results show consistently that all four constituent exons of the PST domain are responsible for the transactivation function. The four exon fragments act cooperatively to stimulate transcription, although none of them can function individually as an independent transactivation domain. Combinations of two or more exon fragments can reconstitute substantial transactivation activity when fused to the DNA-binding domain of GAL4, but they surprisingly do not produce much activity in the context of native PAX6 even though the mutant PAX6 proteins are stable and their DNA-binding function remains unaffected. I conclude that the PAX6 protein contains an unusually large transactivation domain that is evolutionarily conserved to a high degree, and that its full transactivation activity relies on the cooperative action of the four exon fragments.^ Most PAX6 mutations detected in patients with aniridia result in truncations of the protein. Some of the truncation mutations occur in the PST region of PAX6, resulting in mutant proteins that retain their DNA-binding ability but have no significant transactivation activity. It is not clear whether such mutants are true loss-of-function or dominant-negative mutants. I show that these mutants are dominant-negative if they are coexpressed with wild-type PAX6 in cultured cells and that the dominant-negative effects result from enhanced DNA-binding ability of these mutants due to removal of the PST domain. These mutants are able to repress the wild-type PAX6 activity not only at target genes with paired domain binding sites but also at target genes with homeodomain binding sites.^ Mutations in the human PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, autosomal dominant keratitis, and familial foveal dysplasia. The various phenotypes may arise from different mutations in the same gene. To test this theory, I performed a functional analysis of two missense mutations in the paired domain: the R26G mutation reported in a case of Peters' anomaly, and the I87R mutation identified in a patient with aniridia. While both the R26 and the I87 positions are conserved in the paired boxes of all known PAX genes, X-ray crystallography has shown that only R26 makes contact with DNA. I found that the R26G mutant failed to bind a subset of paired domain binding sites but, surprisingly, bound other sites and successfully transactivated promoters containing those sites. In contrast, the I87R mutant had lost the ability to bind DNA at all tested sites and failed to transactivate promoters. My data support the haploinsufficiency hypothesis of aniridia, and the hypothesis that R26G is a hypomorphic allele. ^
Resumo:
Left ventricular mass (LVM) is a strong predictor of cardiovascular disease (CVD) in adults. However, normal growth of LVM in healthy children is not well understood, and previous results on independent effects of body size and body fatness on LVM have been inconsistent. The purpose of this study was (1) to establish the normal growth curve of LVM from age 8 to age 18, and evaluate the determinants of change in LVM with age, and (2) to assess the independent effects of body size and body fatness on LVM.^ In Project HeartBeat!, 678 healthy children aged 8, 11 and 14 years at baseline were enrolled and examined at 4-monthly intervals for up to 4 years. A synthetic cohort with continuous observations from age 8 to 18 years was constructed. A total of 4608 LVM measurements was made from M-mode echocardiography. The multilevel linear model was used for analysis.^ Sex-specific trajectories of normal growth of LVM from age 8 to 18 was displayed. On average, LVM was 15 g higher in males than females. Average LVM increased linearly in males from 78 g at age 8 to 145 g at age 18. For females, the trajectory was curvilinear, nearly constant after age 14. No significant racial differences were found. After adjustment for the effects of body size and body fatness, average LVM decreased slightly from age 8 to 18, and sex differences in changes of LVM remained constant.^ The impact of body size on LVM was examined by adding to a basic LVM-sex-age model one of 9 body size indicators. The impact of body fatness was tested by further introducing into each of the 9 LVM models (with one or another of the body size indicators) one of 4 body fatness indicators, yielding 36 models with different body size and body fatness combinations. The results indicated that effects of body size on LVM can be distinguished between fat-free body mass and fat body mass, both being independent, positive predictors. The former is the stronger determinant. When a non-fat-free body size indicator is used as predictor, the estimated residual effect of body fatness on LVM becomes negative. ^
Resumo:
Placental formation and genomic imprinting are two important features of embryonic development in placental mammals. Genetic studies have demonstrated that imprinted genes play a prominent role in regulating placental formation. In marsupials, mice and humans, the paternally derived X chromosome is preferentially inactivated in the placental tissues of female embryos. This special form of genomic imprinting may have evolved under the same selective forces as autosomal imprinted genes. This chromosomal imprinting phenomenon predicts the existence of maternally expressed X-linked genes that regulate placental development.^ In this study, an X-linked homeobox gene, designated Esx1 has been isolated. During embryogenesis, Esx1 was expressed in a subset of placental tissues and regulates formation of the chorioallantoic placenta. Esx1 acted as an imprinted gene. Heterozygous female mice that inherit an Esx1-null allele from their father developed normally. However, heterozygous females that inherit the Esx1 mutation from their mother were born 20% smaller than normal and had an identical phenotype to hemizygous mutant males and homozygous mutant females. Surprisingly, although Esx1 mutant embryos were initially comparable in size to wild-type controls at 13.5 days post coitum (E13.5) their placentas were significantly larger (51% heavier than controls). Defects in the morphogenesis of the labyrinthine layer were observed as early as E11.5. Subsequently, vascularization abnormalities developed at the maternal-fetal interface, causing fetal growth retardation. These results identify Esx1 as the first essential X-chromosome-imprinted regulator of placental development that influences fetal growth and may have important implications in understanding human placental insufficiency syndromes such as intrauterine growth retardation (IUGR). ^
Resumo:
Objectives. Cardiovascular disease (CVD) including CVD secondary to diabetes type II, a significant health problem among Mexican American populations, originates in early childhood. This study seeks to determine risk factors available to the health practitioner that can identify the child at potential risk of developing CVD, thereby enabling early intervention. ^ Design. This is a secondary analysis of cross-sectional data of matched Mexican American parents and children selected from the HHANES, 1982–1984. ^ Methods. Parents at high risk for CVD were identified based on medical history, and clinical and physical findings. Factor analysis was performed on children's skinfold thicknesses, height, weight, and systolic and diastolic blood pressures, in order to produce a limited number of uncorrelated child CVD risk factors. Multiple regression analyses were then performed to determine other CVD markers associated with these Factors, independently for mothers and fathers. ^ Results. Factor analysis of children's measurements revealed three uncorrelated latent variables summarizing the children's CVD risk: Factor1: ‘Fatness’, Factor2: ‘Size and Maturity’, and Factor3: ‘Blood Pressure’, together accounting for the bulk of variation in children's measurements (86–89%). Univariate analyses showed that children from high CVD risk families did not differ from children of low risk families in occurrence of high blood pressure, overweight, biological maturity, acculturation score, or social and economic indicators. However, multiple regression using the factor scores (from factor analysis) as dependent variables, revealed that higher CVD risk in parents, was significantly associated with increased fatness and increased blood pressure in the children. Father's CVD risk status was associated with higher levels of body fat in his children and higher levels of blood pressure in sons. Mother's CVD risk status was associated with higher blood pressure levels in children, and occurrence of obesity in the mother associated with higher fatness levels in her children. ^ Conclusion. Occurrence of cardiovascular disease and its risk factors in parents of Mexican American children, may be used to identify children at potentially higher risk for developing CV disease in the future. Obesity in mothers appears to be an important marker for the development of higher levels of body fatness in children. ^
Resumo:
Neural tube defects (NTDs) are malformations of the developing brain and spinal cord; the most common are anencephaly and spina bifida. Evidence from many populations suggests that 50% of NTDs can be prevented through daily consumption of folic acid. A recent study has reported that folic acid may not protect populations of Mexican descent. This finding has serious implications for women living along the US-Mexico border. Not only is risk high in these Mexican American women compared with other US women; they also differ markedly in supplemental folic acid and dietary folate consumption, and in NTD-related risks (e.g., obesity, diabetes). This case-control study investigated whether folic acid supplements and dietary folate reduces NTDs in Mexican Americans. Cases included liveborn, stillborn, electively and spontaneously aborted NTD-affected fetuses and infants occurring in the 14-county Texas-Mexico border. Controls were randomly selected from unaffected live births, frequency matched to cases by hospital and year. An in-person interview of 110 case and 113 control mothers solicited data on folic acid supplements, dietary folate, and other covariates. Consumption of folic acid-containing vitamins before conception was only 5% for both case and control women. Taking vitamins the trimester before conception had no apparent effect, after adjusting for covariates [odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.3–3.4]. Combining folate from vitamins and diet showed a 20% risk reduction for women consuming at least 400 μg of folate daily [OR = 0.8, 95% CI = 0.5–1.5]; however, this estimate is statistically indistinguishable from the null. Although consistent with an inherent ineffectiveness of supplemental folic acid, that so few women consumed multivitamins during the critical time severely limited the assessment of folic acid in this population. A reduced folate response in Mexican descent women may be due to a genetic heterogeneity for metabolizing folate. Alternatively, folate intakes may be insufficient to overcome other underlying risk factors. In conclusion, determining whether folic acid reduces NTD risk in Mexican American women requires further study in populations with higher folic acid exposures. Meanwhile, we should pursue all recommended prevention strategies to reduce risk, including motivating Mexican American women of childbearing age to take folic acid routinely. ^
Resumo:
Neural tube defects (NTDs) are the most common severely disabling birth defects in the United States, with a frequency of approximately 1–2 of every 1,000 births. This text includes the identification and evaluation of candidate susceptibility genes that confer risk for the development of neural tube defects (NTDs). The project focused on isolated meningomyelocele, also termed spina bifida (SB). ^ Spina bifida is a complex disease with multifactorial inheritance, therefore the subject population (consisting of North American Caucasians and Hispanics of Mexicali-American descent) was composed of 459 simplex SB families who were tested for genetic associations utilizing the transmission disequilibrium test (TDT), a nonparametric linkage technique. Three categories of candidate genes were studied, including (1) human equivalents of genes determined in mouse models to cause NTDs, (2) HOX and PAX genes, and (3) the MTHFR gene involved in the metabolic pathway of folate. ^ The C677T variant of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene was the first mutation in this gene to be implicated as a risk factor for NTDs. Our evaluation of the MTHFR gene provides evidence that maternal C677T homozygosity is a risk factor for upper level spina bifida defects in Hispanics [OR = 2.3, P = 0.02]. This observed risk factor is of great importance due to the high prevalence of this homozygous genotype in the Hispanic population. Additionally, maternal C677T/A1298C compound heterozygosity is a risk factor for upper level spina bifida defects in non-Hispanic whites [OR = 3.6, P = 0.03]. ^ For TDT analysis, our total population of 1128 subjects were genotyped for 54 markers from within and/or flanking the 20 candidate genes/gene regions of interest. Significant TDT findings were obtained for 3 of the 54 analyzed markers: d20s101 flanking the PAX1 gene (P = 0.019), d1s228 within the PAX7 gene (P = 0.011), and d2s110 within the PAX8 gene (P = 0.013). These results were followed-up by testing the genes directly for mutations utilizing single-strand conformational analysis (SSCA) and direct sequencing. Multiple variations were detected in each of these PAX genes; however, these variations were not passed from parent to child in phase with the positively transmitted alleles. Therefore, these variations do not contribute to the susceptibility of spina bifida, but rather are previously unreported single nucleotide polymorphisms. ^
Resumo:
In June 1995 a case-control study was initiated by the Texas Department of Health among Mexican American women residing in the fourteen counties of the Texas-Mexico border. Case-women had carried infants with neural tube defect. Control-women had given birth to infants without neural tube defects. The case-control protocol included a general questionnaire which elicited information regarding illnesses experienced and antibiotics taken from three months prior to conception to three months after conception. An assessment of the associations between periconceptional diarrhea and the risk of neural tube defects indicated that the unadjusted association of diarrhea and risk of neural tube defect was significant (OR = 3.3, CI = 1.4–7.6). The unadjusted association of use of oral antimicrobials and risk of neural tube defect was also significant (OR = 3.4, CI = 1.6–7.3). These associations persisted among women who had no fever during the periconceptional period and were present irrespective of folate intake. Diarrhea was associated with an increased risk of NTD independent of use of antimicrobials. The converse was also true; antimicrobials were associated with an increased risk of NTD independent of diarrhea. Further research regarding these potentially modifiable risk factors is warranted. Replication of these findings could result in interventions in addition to folate supplementation. ^
Resumo:
Background. Increasing rates of maternal employment highlight the need for non-maternal child care for infants at an earlier age. Several studies have shown that employment induced maternal depression or psychological distress is associated with the child's socio-emotional and cognitive development. However, separation anxiety, a common phenomenon observed among employed mothers during early years, has seldom been studied. Therefore, the purpose of this study was to evaluate the role of maternal separation anxiety in the child's cognitive development.^ Methods. Data were obtained from Phase I (birth to 36 months) of the National Institute of Child Health and Human Development, Study of Early Child Care and Youth Development (NICHD SECCYD). Bivariate and multivariate analyses were performed to determine the association between separation anxiety groups and child outcomes. Multivariate analysis was also used to examine the mediating and/or moderating effect of sensitivity and moderating effect of difficult temperament.^ Results. Separation anxiety showed a negative association with the Bracken, attachment security, maternal sensitivity and psychological state. Children whose mothers never reported high levels of separation anxiety showed higher levels of school readiness and attachment security compared to those whose mothers experienced high levels of separation anxiety at least once. There was a significant interaction between separation anxiety and maternal sensitivity for the Bracken and attachment security indicating the moderating effect of sensitivity. Maternal sensitivity was also found to partially mediate the association between high levels of separation anxiety and school readiness or attachment security. However, the interaction between difficult temperament and separation anxiety was not significant for any of the child outcomes. ^ Conclusions. High levels of separation anxiety have a negative impact on school readiness, attachment security, maternal sensitivity and psychological state. In addition, mothers who experience high levels of separation anxiety but are sensitive during the mother-child interaction have children with high school readiness and attachment security compared to those who are less sensitive.^ Keywords. Maternal separation anxiety, School readiness. ^
Resumo:
High prevalence of overweight and obesity among preschool children in the low income population is consistently documented in research with one of every seven low-income, preschool-aged children classified as obese. Parental feeding practices have the potential to be contributing factors to the obesity epidemic. However, the impact of parental feeding practices on obesity in preschool age children has not been well explored. The purpose of this study was to determine relationships between the parental feeding practices of using dessert, sweets or candy as a reward for finishing foods, restricting dessert if the child does not finish their plate at dinner, asking the child to consume everything on their plate at dinner, and having family dinners to obesity in low income, preschool age children.^ A cross-sectional secondary data analysis was completed using the STATA 11 statistical software. Descriptive statistics were completed to summarize demographic and BMI data of participants, as well as parental feeding behavior variables. Pearson’s correlation was implemented to determine a correlation between parental feeding behavior variables and BMI z scores. Predictive relationships between the variables were explored through multivariable linear regression analysis. Regression analyses were also completed factoring in the confounders of gender, age, and ethnicity.^ Results revealed (1) no significant correlations or predictive trends between the use of rewards, forced consumption, or family dinner and BMI in low income preschool age children, and (2) a significant negative correlation and predictive trend between restriction of desserts and BMI in low income preschool age children. Since the analysis supported the null hypothesis for the practices of reward use, forced consumption, and family dinner, these practices are not considered risk factors for obese level BMIs. The inverse association found for practice of restriction and BMI suggests it is unnecessary to discourage parents from using restriction. Limitations of the study included the sample size, reliability of the answers provided on the Healthy Home Survey by participant guardians, and generalizability of the sample to the larger population.^
Resumo:
Most studies related to diarrhea have been focused narrowly on the etiological and pathophysiological factors involved in inducing the disease. Such studies have often failed to consider other facets contributing to and possibly prolonging the problem, namely: socio-economic conditions, educational opportunities and attainments, cultural characteristics and beliefs, and the political administration and its commitment towards fulfilling its moral and ethical obligations in responding to and fostering human development.^ This study utilized the diagnostic approach of the PRECEDE model. The acronym stands for the predisposing reinforcing, and enabling constructs in educational diagnosis and evaluation. The constituents of this model were identified by utilizing participant observation field methods, traditionally applied by ethnographers to collect data describing the multiple facets of a culture, and linguistic anthropology used to capture and define characteristic semantics and viewpoints. The household study sample was randomly selected from a defined list of households known to have at least one child less than five years of age. An open-ended questionnaire format was used to interview the 115 mothers in the selected households sample.^ Kalama, the study community, is characteristically an agricultural village, situated in the Governorate of Kaliobia and located approximately 25 Km (about 15.5 miles) from the capital, Cairo, Egypt. The 1986 census indicates a population size of 13,328 people in 4,818 households. There were 65 deaths occurring among children less than five years in 1986. The causes of death were primarily related to diarrhea, followed by upper respiratory infections, congenital anomalies and birth injuries.^ This study outlines (a) practices related to the management of diarrhea, including the administration of foods and drinks during such episodes; (b) influences of governmental policies; and (c) recommended strategies for overcoming barriers and promoting effective diarrhea intervention programs. ^
Resumo:
Using data from the Hispanic Health and Nutrition Examination Survey, 1982-1984 (HHANES) of the Nutritional Center for Health Statistics (NCHS), the heights, weights and arm circumferences of 217 Mexican-American children ranging in age from six to sixty months were examined to assess whether birth weight, parental stature, and economic status greatly influenced growth patterns of Mexican-American children living with both parents.^ Heights, weights, and arm circumferences were converted to standardized values of height-for-age, weight-for-age, and arm circumference-for-age using norms developed for Anglo-American children (NCHS, 1977).^ Correlation and contingency table analysis were performed to test hypotheses concerning factors found associated with the stature of children in earlier studies.^ While relationships among childhood stature and birth weight, parental stature, and economic status were in the expected direction, few were statistically significant due to the small number of cases in the analyses. Reliable conclusions concerning these relationships require a much longer sample of families. ^
Resumo:
The growth patterns of weight from birth through the first twelve months of life among rural Taiwanese infants were investigated with the following objectives: (i) compare each of the parameters of the Count model estimated for infants who were nutritionally at risk with those for a reference population from the United States; and (ii) within the Taiwanese infants, account for the variance in the growth patterns in the first and second six months of life on the basis of selected ecological factors.^ The significance between group differences were observed in the patterns of the weight growth in both linear growth and in the timing and the direction of velocity changes. A significant decline in growth velocity was observed among Taiwanese infants at about the fourth month of life. The decline is in keeping with a recent proposal made by J. C. Waterlow regarding the timing of change in growth velocity among nutritionally at risk populations in developing countries. The growth course of a nutritionally at risk infant during the first three months is apparently protected by the nurturance of the mother and innate biological properties of the infant.^ A highly significant portion of the growth variance in the second six months of life was accounted for by exogenous factors and biological factors related to the infant. Conversely, none of the growth variance in the first six months of life was accounted for by predictor variables. The most potent determinant of growth in the second six months of life was seasonality which represents a multiple environmental event.^ The model parameters estimated from the Count model represent different aspect of physical growth; yet the correlation coefficients between parameters b and c are high (r > .80). Clearly, the biological interpretation of the model parameters requires analysis of the whole function in the specific context of a given age period. ^