Improving the health and well-being of women at risk for neural tube defect recurrence

There is growing interest in providing women with internatal care, a package of healthcare and ancillary services that can improve their health during the period after the termination of one pregnancy but before the conception of the next pregnancy. Women who have had a pregnancy affected by a neural tube defect can especially benefit from internatal care because they are at increased risk for recurrence and improvements to their health during the inter-pregnancy period can prevent future negative birth outcomes. The dissertation provides three papers that inform the content of internatal care for women at risk for recurrence by examining descriptive epidemiology to develop an accurate risk profile of the population, assessing whether women at risk for recurrence would benefit from a psychosocial intervention, and determining how to improve health promotion efforts targeting folic acid use.^ Paper one identifies information relevant for developing risk profiles and conducting risk assessments. A number of investigations have found that the risk for neural tube defects differs between non-Hispanic Whites and Hispanics. To understand the risk difference, the descriptive epidemiology of spina bifida and anencephaly was examined for Hispanics and non-Hispanic Whites based on data from the Texas Birth Defects Registry for the years 1999 through 2004. Crude and adjusted birth prevalence ratios and corresponding 95% confidence intervals were calculated between descriptive epidemiologic characteristics and anencephaly and spina bifida for non-Hispanic Whites and for Hispanics. In both race/ethnic groups, anencephaly expressed an inverse relationship with maternal age and a positive linear relationship with parity. Both relationships were stronger in non-Hispanic Whites. Female infants had a higher risk for anencephaly in non-Hispanic Whites. Lower maternal education was associated with increased risk for spina bifida in Hispanics.^ Paper two assesses the need for a psychosocial intervention. For mothers who have children with spina bifida, the transition to motherhood can be stressful. This qualitative study explored the process of becoming a mother to a child with spina bifida focusing particularly on stress and coping in the immediate postnatal environment. Semi-structured interviews were conducted with six mothers who have children with spina bifida. Mothers were asked about their initial emotional and problem-based coping efforts, the quality and kind of support provided by health providers, and the characteristics of their meaning-based coping efforts; questions matched Transactional Model of Stress and Coping (TMSC) constructs. Analysis of the responses revealed a number of modifiable stress and coping transactions, the most salient being: health providers are in a position to address beliefs about self-causality and prevent mothers from experiencing the repercussions that stem from maintaining these beliefs. ^ Paper three identifies considerations when creating health promotion materials targeting folic acid use. A brochure was designed using concepts from the Precaution Adoption Process Model (PAPM). Three focus groups comprising 26 mothers of children with spina bifida evaluated the brochure. One focus group was conducted in Spanish-only, the other two focus groups were conducted in English and Spanish combined. Qualitative analysis of coded transcripts revealed that a brochure is a helpful adjunct. Questions about folic acid support the inclusion of an insert with basic information. There may be a need to develop different educational material for Hispanics so the importance of folic acid is provided in a situational context. Some participants blamed themselves for their pregnancy outcome which may affect their receptivity to messages in the brochure. The women's desire for photographs that affect their perception of threat and their identification with the second role model indicate they belong to PAPM Stage 2 and 3. Participants preferred colorful envelopes, high quality paper, intimidating photographs, simple words, conversational style sentences, and positive messages.^ These papers develop the content of risk assessment, psychosocial intervention, and health promotion components of internatal care as they apply to women at risk for recurrence. The findings provided evidence for considering parity and maternal age when assessing nutritional risk. The two dissimilarities between the two race/ethnic groups, infant sex and maternal education lent support to creating separate risk profiles. Interviews with mothers of children with spina bifida revealed the existence of unmet needs-suggesting that a psychosocial intervention provided as part of internatal care can strengthen and support women's well-being. Segmenting the audience according to race/ethnicity and PAPM stage can improve the relevance of print materials promoting folic acid use.^

An exploratory study of screening practices and barriers for postpartum depression in Texas

Purpose. To evaluate the prevalence of Postpartum Depression (PPD) screening among practicing obstetrician-gynecologists in Texas, and to identify factors and barriers associated with routine depression screening practices.^ Subjects. One hundred and eighty-nine fellows and junior fellows of the Texas Association of Obstetricians & Gynecologists (District XI).^ Methods. A survey questionnaire was developed and sent to 2,028 obstetriciangynecologists, asking about their current screening practices related to PPD. The survey questions were related to the physician's demographics, the patient population, screening practices, barriers to screening, and perceptions about resources in the community. Responses were analyzed to determine associations between these factors and the physician's screening practices. ^ Results. The respondents (n=189) constituted 9.3% of the surveyed population, thus the findings cannot be considered representative of all practicing Ob-Gyns in Texas. However, the following trends were observed. Of the respondents, 85.4% reported routinely screening for PPD, while 14.6% did not. However, of those that screened, only 20.2% used the Edinburgh Postnatal Depression Scale and 7.6% screened with the Postpartum Depression Screening Scale, both validated screening tools. The majority (77.2%) reported using an informal patient interview to screen. For those who did not routinely screen, inadequate training and inadequate resources to screen for PPD were the top two barriers. Physician's age was associated with routine screening practice, as older physicians were less likely to screen routinely. Primary insurance coverage of the patient population was also associated with screening practice; physicians with Medicaid and uninsured patients were less likely to screen routinely. Lastly, physicians that believed that adequate resources existed in their communities for the treatment of PPD were more likely to screen than those that did not.^ Conclusions. The present study is the first attempt at assessing Postpartum Depression screening practices and barriers in Texas. Although the response rate was low, the findings related to informal screening methods and inadequate training indicated that education and training with regards to PPD screening and validated screening tools among Ob-Gyns stand to be improved. Connecting physicians to psychiatric resources may also improve screening rates. This first look at screening practices in Texas serves as a platform for future research in order to gain definitive insight into the diagnosis and treatment of PPD, and ultimately design interventions to improve detection rates and treatment.^

Mouse retinal development: Role of cell adhesion and mechanism of gene regulation

Cell differentiation and pattern formation are fundamental processes in animal development that are under intense investigation. The mouse retina is a good model to study these processes because it has seven distinct cell types, and three well-laminated nuclear layers that form during embryonic and postnatal life. β-catenin functions as both the nuclear effector for the canonical Wnt pathway and a cell adhesion molecule, and is required for the development of various organs. To study the function of β-catenin in retinal development, I used a Cre-loxP system to conditionally ablate β-catenin in the developing retina. Deletion of β-catenin led to disrupted laminar structure but did not affect the differentiation of any of the seven cell types. Eliminating β-catenin did not reduce progenitor cell proliferation, although enhanced apoptosis was observed. Further analysis showed that disruption of cell adhesion was the major cause of the observed patterning defects. Overexpression of β-catenin during retinal development also disrupted the normal retinal lamination and caused a transdifferentiation of neurons into pigmented cells. The results indicate that β-catenin functions as a cell adhesion molecule but not as a Wnt pathway component during retinal neurogenesis, and is essential for lamination but not cell differentiation. The results further imply that retinal lamination and cell differentiation are genetically separable processes. ^ Sonic hedgehog (shh) is expressed in retinal ganglion cells under the control of transcription factor Pou4f2 during retinal development. Previous studies identified a phylogenetically conserved region in the first intron of shh containing a Pou4f2 binding site. Transgenic reporter mice in which reporter gene expression was driven by this region showed that this element can direct gene expression specifically in the retina, but expression was not limited to the ganglion cells. From these data I hypothesized that this element is required for shh expression in the retina but is not sufficient for specific ganglion cell expression. To further test this hypothesis, I created a conditional allele by flanking this region with two loxP sites. Lines carrying this allele will be crossed with retinal-specific Cre lines to remove this element in the retina. My hypothesis predicts that alteration in shh expression and subsequent retinal defects will occur in the retinas of these mice. ^

Obesity during pregnancy on vagal tone, hemoglobin A1c, oxygenation, and perinatal outcomes

Purpose: To examine the effect of obesity and gestational weight gain on heart rate variability (HRV), oxygenation (HbO 2 and SpO2), hemoglobin A1c (HbA1c) and the frequency of pregnancy complications in obese (O) and non-obese (NO) women.^ Design: The study was an observational comparison study with a repeated measures design. ^ Setting: The setting was a low risk prenatal, university clinic located in a large southeastern metropolitan city. ^ Sample: The sample consisted of a volunteer group of 41 pregnant women who were observed at the three time points of 20, 28, and 36 weeks gestation. ^ Analysis: Analysis included general linear modeling with repeated measures to test for group differences with changes over time on vagal response, HbA1c, and oxygenation. Odds ratios were computed to compare the frequency of birth outcomes. ^ Findings: The interaction effect of time between O and NO women on HbO2 was significant. The mean HP, RSA, and HbO2 changed significantly over time within the NO women. The mean HbA 1c increased significantly over time within the O women. Women with excess gestational weight gain had significantly lower heart period than women with weight gain within the IOM recommendations. Obese women were more likely to have Group B streptococcal infections, gestational hypertension, give birth by cesarean or instrument assistance, and have at least one postnatal event. ^ Conclusions: Monitoring HRV, oxygenation, and HbA1c using minimally invasive measures may permit early identification of alterations in autonomic response. Implementation of interventions to promote vagal tone may help to reduce risks for adverse perinatal outcomes related to obesity. Future studies should examine the effect of obesity on the vagal response and perinatal outcomes. ^

Perinatal mortality and quality of care at the National Institute of Perinatology: A 3-year analysis

Quality of medical care has been indirectly assessed through the collection of negative outcomes. A preventable death is one that could have been avoided if optimum care had been offered. The general objective of the present project was to analyze the perinatal mortality at the National Institute of Perinatology (located in Mexico City) by social, biological and some available components of quality of care such as avoidability, provider responsibility, and structure and process deficiencies in the delivery of medical care. A Perinatal Mortality Committee data base was utilized. The study population consisted of all singleton perinatal deaths occurring between January 1, 1988 and June 30, 1991 (n = 522). A proportionate study was designed.^ The population studied mostly corresponded to married young adult mothers, who were residents of urban areas, with an educational level of junior high school or more, two to three pregnancies, and intermediate prenatal care. The mean gestational age at birth was 33.4 $\pm$ 3.9 completed weeks and the mean birthweight at birth was 1,791.9 $\pm$ 853.1 grams.^ Thirty-five percent of perinatal deaths were categorized as avoidable. Postnatal infection and premature rupture of membranes were the most frequent primary causes of avoidable perinatal death. The avoidable perinatal mortality rate was 8.7 per 1000 and significantly declined during the study period (p $<$.05). Preventable perinatal mortality aggregated data suggested that at least part of the mortality decline for amenable conditions was due to better medical care.^ Structure deficiencies were present in 35% of avoidable deaths and process deficiencies were present in 79%. Structure deficiencies remained constant over time. Process deficiencies consisted of diagnosis failures (45.8%) and treatment failures (87.3%), they also remained constant through the years. Party responsibility was as follows: Obstetric (35.4%), pediatric (41.4%), institutional (26.5%), and patient (6.6%). Obstetric responsibility significantly increased during the study period (p $<$.05). Pediatric responsibility declined only for newborns less than 1500 g (p $<$.05). Institutional responsibility remained constant.^ Process deficiencies increased the risk for an avoidable death eightfold (confidence interval 1.7-41.4, p $<$.01) and provider responsibility ninety-fivefold (confidence interval 14.8-612.1, p $<$.001), after adjustment for several confounding variables. Perinatal mortality due to prematurity, barotrauma and nosocomial infection, was highly preventable, but not that due to transpartum asphyxia. Once specific deficiencies in the quality of care have been identified, quality assurance actions should begin. ^

THE BACON CHOW STUDY: THE RELATIONSHIP BETWEEN INFECTIOUS ILLNESS AND GROWTH OF INFANTS

Multiple dietary deficiencies and high rates of infectious illness are major health problems leading to malnutrition and limitation of growth of children in developing countries. Longitudinal studies which provide information on illness incidence and growth velocity are needed in order to untangle the complex interrelationship between nutrition, illness and growth. From 1967 to 1973, researchers led by Dr. Bacon Chow of the Johns Hopkins University School of Hygiene undertook a quasi-experimental prospective study in Suilin Township, Taiwan to determine the effects of a nutritional supplement to the diets of pregnant and lactating women on the growth, development and resistance to disease of their offspring. This dissertation presents results from the analysis of infant morbidity and postnatal growth.^ Maternal nutritional supplementation has no apparent effect on the postnatal growth or morbidity of infants. Significant sex differences exist in growth response to illness and in illness susceptibility. Male infants have more diarrhea and upper respiratory illness. Respiratory illness is positively associated with growth rate in weight in the first semester of life. Diarrhea is significantly negatively associated with growth in length in the second semester. Small-for-date infants are more susceptible to illness in general and have a different pattern of growth response than large-for-date infants.^ Principal components analysis of illness data is shown to be an effective technique for making more precise use of ambiguous morbidity data. Multiple regression with component scores is an accurate method for estimating variance in growth rate predicted by indepenent illness variables. A model is advanced in which initial postnatal growth rate determines subsequent susceptibility to nutritional stress and infection. Initial growth rate is a function of prenatal nutrition, but is not significantly affected by maternal supplementation during gestation or lactation. Critical evaluation is made of nutritional supplementation programs which do not afford disease control.^

GROWTH PATTERNS OF CHILDREN OF MOTHERS WITH EPILEPSY

The extent to which antiepileptic drugs (AED) in utero exposure are related to prenatal and postnatal growth is investigated in an retrospective, cohort study of children of AED treated mothers with epilepsy (N = 89) and children of women without epilepsy (N = 89). The study groups were obtained from a population based health care facility.^ Major finding was that birth head circumference of AED exposed children are significantly smaller than control children, notably male children. Other findings include birth length and weight of exposed children was slightly but not significantly smaller. Postnatal growth as measured by two velocity terms, rate of growth, and deceleration, was not significantly different between exposed and control children for height, weight, and head circumference, indicating no catch up growth. Morphologic defects, neonatal and infant mortality was more frequent in exposed children. Mothers with epilepsy reported significantly fewer spontaneous abortions. ^

Assessing and applying evidence-based interventions at the community level in India as a model policy to reduce neonatal mortality rates in Nigeria

Background. The United Nations' Millennium Development Goal (MDG) 4 aims for a two-thirds reduction in death rates for children under the age of five by 2015. The greatest risk of death is in the first week of life, yet most of these deaths can be prevented by such simple interventions as improved hygiene, exclusive breastfeeding, and thermal care. The percentage of deaths in Nigeria that occur in the first month of life make up 28% of all deaths under five years, a statistic that has remained unchanged despite various child health policies. This paper will address the challenges of reducing the neonatal mortality rate in Nigeria by examining the literature regarding efficacy of home-based, newborn care interventions and policies that have been implemented successfully in India. ^ Methods. I compared similarities and differences between India and Nigeria using qualitative descriptions and available quantitative data of various health indicators. The analysis included identifying policy-related factors and community approaches contributing to India's newborn survival rates. Databases and reference lists of articles were searched for randomized controlled trials of community health worker interventions shown to reduce neonatal mortality rates. ^ Results. While it appears that Nigeria spends more money than India on health per capita ($136 vs. $132, respectively) and as percent GDP (5.8% vs. 4.2%, respectively), it still lags behind India in its neonatal, infant, and under five mortality rates (40 vs. 32 deaths/1000 live births, 88 vs. 48 deaths/1000 live births, 143 vs. 63 deaths/1000 live births, respectively). Both countries have comparably low numbers of healthcare providers. Unlike their counterparts in Nigeria, Indian community health workers receive training on how to deliver postnatal care in the home setting and are monetarily compensated. Gender-related power differences still play a role in the societal structure of both countries. A search of randomized controlled trials of home-based newborn care strategies yielded three relevant articles. Community health workers trained to educate mothers and provide a preventive package of interventions involving clean cord care, thermal care, breastfeeding promotion, and danger sign recognition during multiple postnatal visits in rural India, Bangladesh, and Pakistan reduced neonatal mortality rates by 54%, 34%, and 15–20%, respectively. ^ Conclusion. Access to advanced technology is not necessary to reduce neonatal mortality rates in resource-limited countries. To address the urgency of neonatal mortality, countries with weak health systems need to start at the community level and invest in cost-effective, evidence-based newborn care interventions that utilize available human resources. While more randomized controlled studies are urgently needed, the current available evidence of models of postnatal care provision demonstrates that home-based care and health education provided by community health workers can reduce neonatal mortality rates in the immediate future.^

Targeted Deletion Of Functionally Validated Enhancers Defines Their Role in Mouse Limb Development

Transcriptional enhancers are genomic DNA sequences that contain clustered transcription factor (TF) binding sites. When combinations of TFs bind to enhancer sequences they act together with basal transcriptional machinery to regulate the timing, location and quantity of gene transcription. Elucidating the genetic mechanisms responsible for differential gene expression, including the role of enhancers, during embryological and postnatal development is essential to an understanding of evolutionary processes and disease etiology. Numerous methods are in use to identify and characterize enhancers. Several high-throughput methods generate large datasets of enhancer sequences with putative roles in embryonic development. However, few enhancers have been deleted from the genome to determine their roles in the development of specific structures, such as the limb. Manipulation of enhancers at their endogenous loci, such as the deletion of such elements, leads to a better understanding of the regulatory interactions, rules and complexities that contribute to faithful and variant gene transcription – the molecular genetic substrate of evolution and disease. To understand the endogenous roles of two distinct enhancers known to be active in the mouse embryo limb bud we deleted them from the mouse genome. I hypothesized that deletion of these enhancers would lead to aberrant limb development. The enhancers were selected because of their association with p300, a protein associated with active transcription, and because the human enhancer sequences drive distinct lacZ expression patterns in limb buds of embryonic day (E) 11.5 transgenic mice. To confirm that the orthologous mouse enhancers, mouse 280 and 1442 (M280 and M1442, respectively), regulate expression in the developing limb we generated stable transgenic lines, and examined lacZ expression. In M280-lacZ mice, expression was detected in E11.5 fore- and hindlimbs in a region that corresponds to digits II-IV. M1442-lacZ mice exhibited lacZ expression in posterior and anterior margins of the fore- and hindlimbs that overlapped with digits I and V and several wrist bones. We generated mice lacking the M280 and M1442 enhancers by gene targeting. Intercrosses between M280 -/+ and M1442 -/+, respectively, generated M280 and M1442 null mice, which are born at expected Mendelian ratios and manifest no gross limb malformations. Quantitative real-time PCR of mutant E11.5 limb buds indicated that significant changes in transcriptional output of enhancer-proximal genes accompanied the deletion of both M280 and M1442. In neonatal null mice we observed that all limb bones are present in their expected positions, an observation also confirmed by histology of E18.5 distal limbs. Fine-scale measurement of E18.5 digit bone lengths found no differences between mutant and control embryos. Furthermore, when the developmental progression of cartilaginous elements was analyzed in M280 and M1442 embryos from E13.5-E15.5, transient development defects were not detected. These results demonstrate that M280 and M1442 are not required for mouse limb development. Though M280 is not required for embryonic limb development it is required for the development and/or maintenance of body size – adult M280 mice are significantly smaller than control littermates. These studies highlight the importance of experiments that manipulate enhancers in situ to understand their contribution to development.

Modulation of replicative senescence of skeletal muscle satellite cells by insulin -like growth factor-I (IGF-I)

Growth and regeneration of postnatal skeletal muscle requires a population of mononuclear myogenic cells, called satellite cells to add/replace myonuclei, which are postmitotic. Wedged between the sarcolemma and the basal lamina of the skeletal muscle fiber, these cells function as the stem cells of mature muscle fibers. Like other normal diploid cells, satellite cells undergo cellular senescence. Investigations of aging in both rodents and humans have shown that satellite cell self-renewal capacity decreases with advanced age. As a consequence, this could be a potential reason for the characteristically observed age-associated loss in skeletal muscle mass (sarcopenia). This provided the rationale that any intervention that can further increase the proliferative capacity of these cells should potentially be able to either delay, or even prevent sarcopenia. ^ Using clonogenicity assays to determine a cell's proliferation potential, these studies have shown that IGF-I enhances the doubling potential of satellite cells from aged rodents. Using a transgenic model, where the mice express the IGF-I transgene specifically in their striated muscles, some of the underlying biochemical mechanisms for the observed increase in replicative life span were delineated. These studies have revealed that IGF-I activates the PI3/Akt pathway to mediate downregulation of p27KIP1, which consequently is associated with an increase in cyclin E-cdk2 kinase activity, phosphorylation of pRb, and upregulation of cyclin A protein. However, the beneficial effects of IGF-I on satellite cell proliferative potential appears to be limited as chronic overexpression of IGF-I in skeletal muscles did not protect against sarcopenia in 18-mo old mice, and was associated with an exhaustion of satellite cell replicative reserves. ^ These results have shown that replicative senescence can be modulated by environmental factors using skeletal muscle satellite cells as a model system. A better understanding of the molecular basis for enhancement of proliferative capacity by IGF-I will provide a rational basis for developing more effective counter-measures against physical frailty. However, the implications of these studies are that these beneficial effects of enhanced proliferative potential by IGF-I may only be over a short-term period, and other alternative approaches may need to be considered. ^

(Table 1) Circulating levels of TT3 and TT4, and age, length, girth, and estimated body mass in polar bears (Ursus maritimus) from East Greenland 1999-2001

We investigated the multivariate relationships between adipose tissue residue levels of 48 individual organohalogen contaminants (OHCs) and circulating thyroid hormone (TH) levels in polar bears (Ursus maritimus) from East Greenland (1999-2001, n = 62), using projection to latent structure (PLS) regression for four groupings of polar bears; subadults (SubA), adult females with cubs (AdF_N), adult females without cubs (AdF_S) and adult males (AdM). In the resulting significant PLS models for SubA, AdF_N and AdF_S, some OHCs were especially important in explaining variations in circulating TH levels: polybrominated diphenylether (PBDE)-99, PBDE-100, PBDE-153, polychlorinated biphenyl (PCB)-52, PCB-118, cis-nonachlor, trans-nonachlor, trichlorobenzene (TCB) and pentachlorobenzene (QCB), and both negative and positive relationships with THs were found. In addition, the models revealed that DDTs had a positive influence on total 3,5,3'-triiodothyronine (TT3) in AdF_S, and that a group of 17 higher chlorinated ortho-PCBs had a positive influence on total 3,5,3',5'-tetraiodothyronine (thyroxine, TT4) in AdF_N. TH levels in AdM seemed less influenced by OHCs because of non-significant PLS models. TH levels were also influenced by biological factors such as age, sex, body size, lipid content of adipose tissue and sampling date. When controlling for biological variables, the major relationships from the PLS models for SubA, AdF_N and AdF_S were found significant in partial correlations. The most important OHCs that influenced TH levels in the significant PLS models may potentially act through similar mechanisms on the hypothalamic-pituitary-thyroid (HPT) axis, suggesting that both combined effects by dose and response addition and perhaps synergistic potentiation may be a possibility in these polar bears. Statistical associations are not evidence per se of biological cause-effect relationships. Still, the results of the present study indicate that OHCs may affect circulating TH levels in East Greenland polar bears, adding to the "weight of evidence" suggesting that OHCs might interfere with thyroid homeostasis in polar bears.

Gene Expression Profiling in Limb-Girdle Muscular Dystrophy 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that β-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies

Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons

Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton.

Efecto de un programa de ejercicio físico en la recuperación post-parto. Estudio piloto

Un hecho fi siológico como es el proceso de embarazo y parto, puede condicionar en gran medida la futura salud y calidad de vida de la mujer. La retención del peso gestacional, los episodios de pérdida de orina y la depresión postparto son algunos de los problemas más frecuentes a los que la mujer ha de enfrentarse tras el nacimiento de su bebé. Con este estudio se pretendió valorar si un programa de ejercicio físico supervisado puede favorecer la recuperación del peso pre-gestacional, evitar las pérdidas de orina y mejorar el estado psicológico de la mujer. Para ello se diseñó un trabajo experimental, de tipo aleatorizado, no apareado, controlado y no enmascarado que se ha desarrollado por medio de un proyecto de colaboración entre el Hospital Universitario de Fuenlabrada y la Facultad de Ciencias de la Actividad Física y el Deporte (FCCAFD-INEF) de la Universidad Politécnica de Madrid (UPM). Se seleccionaron dos grupos de mujeres, el grupo de intervención y el grupo de control, que sin contraindicaciones absolutas y con el consentimiento médico para la práctica de actividad física, se encontrasen en los primeros 3 meses del período post-parto. El grupo de intervención llevó a cabo un programa de ejercicio físico de 12 semanas de duración con una frecuencia semanal de tres veces por semana y una duración de una hora por sesión. Las variables medidas fueron: recuperación del peso pregestacional (peso, índice de masa corporal), depresión postnatal, incidencia de los problemas sociales ocasionados por la pérdida de orina y percepción sobre el estado de salud propio. Los resultados muestran una aparente asociación positiva entre el ejercicio físico programado y la percepción del estado de salud propio (15,69 vs 10,08; p=0,03). El resto de variables no presentaron diferencias significativas entre los grupos de estudio.

RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/− mice

Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/− mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/− mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/− mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB-deficient disseminated tumors.