Evaluation of Cause of Deaths' Validity Using Outcome Measures from a Prospective, Population Based Cohort Study in Tehran, Iran

OBJECTIVE: The aim of this study was to evaluate the validity of cause of death stated in death certificates in Tehran using outcome measures of the Tehran Lipid and Glucose Study (TLGS), an ongoing prospective cohort study. METHODS: The cohort was established in 1999 in a population of 15005 people, 3 years old and over, living in Tehran; 3551 individuals were added to this population three years later. As part of cohort's outcome measures, deaths occurring in the cohort are investigated by a panel of medical specialists (Cohort Outcome Panel--COP) and underlying cause of death is determined for each death. The cause of death assigned in a deceased's original death certificate was evaluated against the cause of death determined by COP and sensitivity and positive predictive values (PPV) were determined. In addition, determinants of assigning accurate underlying cause of death were determined using logistic regression model. RESULT: A total of 231 death certificates were evaluated. The original death certificates over reported deaths due to neoplasms and underreported death due to circulatory system and transport accidents. Neoplasms with sensitivity of 0.91 and PPV of 0.71 were the most valid category. The disease of circulatory system showed moderate degree of validity with sensitivity of 0.67 and PPV of 0.78. The result of logistic regression indicated if the death certificate is issued by a general practitioner, there is 2.3 (95% CI 1.1, 5.1) times chance of being misclassified compared with when it is issued by a specialist. If the deceased is more than 60 years, the chance of misclassification would be 2.5 times (95% CI of 1.1, 5.9) compared with when the deceased is less than 60 years

The phenotype associated with a large deletion on MECP2

Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22–0.79, P=0.007) and to be currently walking (OR 0.53, 95% CI: 0.26–1.10, P=0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98–3.48, P=0.057) and epilepsy (OR 2.72, 95% CI: 1.38–5.37, P=0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected

Unstaged cancer in the United States: a population-based study

<p>Abstract</p> <p>Background</p> <p>The current study examines unstaged disease for 18 cancer sites in the United States according to the influence of age, sex, race, marital status, incidence, and lethality.</p> <p>Methods</p> <p>Analyses are based on 1,040,381 male and 1,011,355 female incident cancer cases diagnosed during 2000 through 2007. Data were collected by population-based cancer registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program.</p> <p>Results</p> <p>The level of unstaged disease was greater in more lethal cancers (e.g., liver, esophagus, and pancreas) compared with less deadly cancers (i.e., colon, urinary bladder, and female breast). Unstaged disease increased with age and is greater among non-married patients. Blacks compared with whites experienced significantly higher levels of unstaged cancers of the stomach, rectum, colon, skin (melanoma), urinary bladder, thyroid, breast, corpus, cervix, and ovaries, but lower levels of unstaged liver, lung and bronchial cancers. Males compared with females experienced significantly lower levels of unstaged cancers of the liver, pancreas, esophagus, and stomach, but significantly higher levels of unstaged lung and bronchial cancer and thyroid cancer. The percent of unstaged cancer significantly decreased over the study period for 15 of the 18 cancer sites.</p> <p>Conclusion</p> <p>Tumor staging directly affects treatment options and survival, so it is recommended that further research focus on why a decrease in unstaged disease did not occur for all of the cancer sites considered from 2000 to 2007, and why there are differential levels of staging between whites and blacks, males and females for several of the cancer sites.</p

Genetic Structure of the Polymorphic Metrosideros (Myrtaceae) Complex in the Hawaiian Islands Using Nuclear Microsatellite Data

Five species of Metrosideros (Myrtaceae) are recognized in the Hawaiian Islands, including the widespread M. polymorpha, and are characterized by a multitude of distinctive, yet overlapping, habit, ecological, and morphological forms. It remains unclear, despite several previous studies, whether the morphological variation within Hawaiian Metrosideros is due to hybridization, genetic polymorphism, phenotypic plasticity, or some combination of these processes. The Hawaiian Metrosideros complex has become a model system to study ecology and evolution; however this is the first study to use microsatellite data for addressing inter-island patterns of variation from across the Hawaiian Islands.Ten nuclear microsatellite loci were genotyped from 143 individuals of Metrosideros. We took advantage of the bi-parental inheritance and rapid mutation rate of these data to examine the validity of the current taxonomy and to investigate whether Metrosideros plants from the same island are more genetically similar than plants that are morphologically similar. The Bayesian algorithm of the program structure was used to define genetic groups within Hawaiian Metrosideros and the closely related taxon M. collina from the Marquesas and Austral Islands. Several standard and nested AMOVAs were conducted to test whether the genetic diversity is structured geographically or taxonomically.The results suggest that Hawaiian Metrosideros have dynamic gene flow, with genetic and morphological diversity structured not simply by geography or taxonomy, but as a result of parallel evolution on islands following rampant island-island dispersal, in addition to ancient chloroplast capture. Results also suggest that the current taxonomy requires major revisions in order to reflect the genetic structure revealed in the microsatellite data

A monoclonal antibody raised against bacterially expressed MPV17 sequences shows peroxisomal, endosomal and lysosomal localisation in U2OS cells

Recessive mutations in the MPV17 gene cause mitochondrial DNA depletion syndrome, a fatal infantile genetic liver disease in humans. Loss of function in mice leads to glomerulosclerosis and sensineural deafness accompanied with mitochondrial DNA depletion. Mutations in the yeast homolog Sym1, and in the zebra fish homolog tra cause interesting, but not obviously related phenotypes, although the human gene can complement the yeast Sym1 mutation. The MPV17 protein is a hydrophobic membrane protein of 176 amino acids and unknown function. Initially localised in murine peroxisomes, it was later reported to be a mitochondrial inner membrane protein in humans and in yeast. To resolve this contradiction we tested two new mouse monoclonal antibodies directed against the human MPV17 protein in Western blots and immunohistochemistry on human U2OS cells. One of these monoclonal antibodies showed specific reactivity to a protein of 20 kD absent in MPV17 negative mouse cells. Immunofluorescence studies revealed colocalisation with peroxisomal, endosomal and lysosomal markers, but not with mitochondria. This data reveal a novel connection between a possible peroxisomal/endosomal/lysosomal function and mitochondrial DNA depletion

Drosophila as a Model for MECP2 Gain of Function in Neurons

Methyl-CpG-binding protein 2 (MECP2) is a multi-functional regulator of gene expression. In humans loss of MECP2 function causes classic Rett syndrome, but gain of MECP2 function also causes mental retardation. Although mouse models provide valuable insight into Mecp2 gain and loss of function, the identification of MECP2 genetic targets and interactors remains time intensive and complicated. This study takes a step toward utilizing Drosophila as a model to identify genetic targets and cellular consequences of MECP2 gain-of function mutations in neurons, the principle cell type affected in patients with Rett-related mental retardation. We show that heterologous expression of human MECP2 in Drosophila motoneurons causes distinct defects in dendritic structure and motor behavior, as reported with MECP2 gain of function in humans and mice. Multiple lines of evidence suggest that these defects arise from specific MECP2 function. First, neurons with MECP2-induced dendrite loss show normal membrane currents. Second, dendritic phenotypes require an intact methyl-CpG-binding domain. Third, dendritic defects are amended by reducing the dose of the chromatin remodeling protein, osa, indicating that MECP2 may act via chromatin remodeling in Drosophila. MECP2-induced motoneuron dendritic defects cause specific motor behavior defects that are easy to score in genetic screening. In sum, our data show that some aspects of MECP2 function can be studied in the Drosophila model, thus expanding the repertoire of genetic reagents that can be used to unravel specific neural functions of MECP2. However, additional genes and signaling pathways identified through such approaches in Drosophila will require careful validation in the mouse model

STAT5 Is an Ambivalent Regulator of Neutrophil Homeostasis

BACKGROUND: Although STAT5 promotes survival of hematopoietic progenitors, STAT5-/- mice develop mild neutrophilia. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that in STAT5-/- mice, liver endothelial cells (LECs) autonomously secrete high amounts of G-CSF, allowing myeloid progenitors to overcompensate for their intrinsic survival defect. However, when injected with pro-inflammatory cytokines, mutant mice cannot further increase neutrophil production, display a severe deficiency in peripheral neutrophil survival, and are therefore unable to maintain neutrophil homeostasis. In wild-type mice, inflammatory stimulation induces rapid STAT5 degradation in LECs, G-CSF production by LECs and other cell types, and then sustained mobilization and expansion of long-lived neutrophils. CONCLUSION: We conclude that STAT5 is an ambivalent factor. In cells of the granulocytic lineage, it exerts an antiapoptotic function that is required for maintenance of neutrophil homeostasis, especially during the inflammatory response. In LECs, STAT5 negatively regulates granulopoiesis by directly or indirectly repressing G-CSF expression. Removal of this STAT5-imposed brake contributes to induction of emergency granulopoiesis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Correção da magnitude da mortalidade por câncer do colo do útero no Brasil, 1996-2005

OBJETIVO: Desenvolver uma metodologia para correção da magnitude dos óbitos por câncer do colo do útero no Brasil. MÉTODOS: Os dados sobre os 9.607.177 óbitos foram obtidos do Sistema de Informação sobre Mortalidade, para o período de 1996 a 2005. Para a correção do sub-registro, foram utilizados os fatores de expansão gerados pelo Projeto Carga Global de Doença no Brasil - 1998. Para correção das categorias de diagnósticos desconhecidos, incompletos ou mal definidos de óbitos, foi aplicada redistribuição proporcional. Os dados ausentes de idade foram corrigidos por imputação. As correções foram aplicadas por Unidade Federativa e os resultados apresentados para o Brasil, região e áreas geográficas (capital, demais municípios das regiões metropolitanas e interior) por meio do percentual de variabilidade da magnitude das taxas, antes e após a correção dos óbitos. O comportamento das correções foi analisado por modelo de regressão linear multivariada com termos de interação entre região do País e área geográfica. RESULTADOS: As taxas corrigidas de mortalidade por câncer do colo do útero no Brasil mostraram um acréscimo de 103,4%, variando de 35% para as capitais da região Sul a 339% para o interior da região Nordeste. A redistribuição dos óbitos por câncer de útero sem especificação de localização anatômica promoveu os maiores acréscimos na magnitude das taxas. Os percentuais de correção, segundo ano de ocorrência do óbito, mostraram tendência estacionária no Brasil. CONCLUSÕES: Os resultados permitem concluir que a metodologia proposta foi adequada para corrigir a magnitude das taxas de mortalidade por câncer do colo do útero no País, mostrando que a mortalidade por esse câncer é ainda maior do que o observado nos informes oficiais.OBJETIVO: Desarrollar una metodología para corrección de la magnitud de los óbitos por cáncer de colon uterino en Brasil. MÉTODOS: Los datos sobre los 9.607.177 óbitos fueron obtenidos del Sistema de Información sobre Mortalidad de Brasil, para el período de 1996 a 2005. Para la corrección del sub-registro, fueron utilizados los factores de expansión generados por el Proyecto Carga Global de Enfermedad en Brasil-1998. Para la corrección de las categorías de diagnósticos desconocidos, incompletos o mal definidos de óbitos, fue aplicada la metodología de redistribución proporcional. Los datos ausentes de edad fueron corregidos por imputación. Las correcciones fueron aplicadas por Unidad Federativa y los resultados son presentados para Brasil, región y áreas geográficas (capital, demás municipios de las regiones metropolitanas e interior) por medio del porcentaje de variabilidad de la magnitud de las tasas, antes y después de la corrección de los óbitos. El comportamiento de las correcciones fue analizado por modelo de regresión linear multivariada con términos de interacción entre región del país y área geográfica. RESULTADOS: Las tasas corregidas de mortalidad por cáncer de colon uterino en Brasil mostraron un aumento de 103,4%, variando de 35% para las capitales de la región Sur a 339% para el interior de la región Noreste. La redistribución de los óbitos por cáncer uterino sin especificación de localización anatómica promovió los mayores aumentos en la magnitud de las tasas. Los porcentajes de corrección, según año de ocurrencia de óbito, mostraron tendencia estacionaria en Brasil. CONCLUSIONES: Los resultados permiten concluir que la metodología propuesta fue adecuada para corregir la magnitud de las tasas de mortalidad por cáncer de colon uterino en Brasil, muestreando que la mortalidad por ese cáncer es aún mayor a lo observado en los informes oficiales.OBJECTIVE: To develop a methodology for correction of reported cervical cancer deaths in Brazil. METHODS: Data on 9,607,177 cancer deaths were obtained from the Brazilian National Mortality Database for the period between 1996 and 2005. For correction of underreporting of deaths, factors generated by the Global Burden of Disease Study in Brazil-1998 were used. Proportional distribution was used in order to correct the categories of unknown, incomplete or ill-defined death diagnosis. The corrections were applied to each Brazilian state and the results were presented for Brazil nationwide, macroregions, and geographical areas (capital, other cities of metropolitan areas and interior cities) as percent variability of cervical mortality rates before and after correction. Corrections were analyzed by multivariate linear regression with interaction terms between macroregion and geographical area. RESULTS: After correction, cervical cancer mortality rates showed an increment of 103% nationwide, ranging between 35% (Southern region capitals) and 339% (Northeastern region interior cities). The reallocation of cervical cancer deaths not otherwise specified resulted in greater mortality rate increments. The percent correction by year of death revealed steady trends nationwide. CONCLUSIONS: The study results showed that the proposed methodology was appropriate for the correction of cervical cancer mortality rates in Brazil. It evidenced that cervical cancer mortality is even higher than that reported