Tuberculosis treatment in a refugee and migrant population: 20 years of experience on the Thai-Burmese border.

Although tuberculosis (TB) is a curable disease, it remains a major global health problem and an important cause of morbidity and mortality among vulnerable populations, including refugees and migrants

Phenotypic Behavior of Caveolin-3 Mutations That Cause Autosomal Dominant Limb Girdle Muscular Dystrophy (LGMD-1C) RETENTION OF LGMD-1C CAVEOLIN-3 MUTANTS WITHIN THE GOLGI COMPLEX

Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cell types (cardiac and skeletal). Autosomal dominant limb girdle muscular dystrophy (LGMD-1C) in humans is due to mutations within the caveolin-3 gene: (i) a 9-base pair microdeletion that removes three amino acids within the caveolin scaffolding domain (DeltaTFT) or (ii) a missense mutation within the membrane spanning domain (P --> L). The molecular mechanisms by which these two mutations cause muscular dystrophy remain unknown. Here, we investigate the phenotypic behavior of these caveolin-3 mutations using heterologous expression. Wild type caveolin-3 or caveolin-3 mutants were transiently expressed in NIH 3T3 cells. LGMD-1C mutants of caveolin-3 (DeltaTFT or P --> L) were primarily retained at the level of a perinuclear compartment that we identified as the Golgi complex in double-labeling experiments, while wild type caveolin-3 was efficiently targeted to the plasma membrane. In accordance with these observations, caveolin-3 mutants formed oligomers of a much larger size than wild type caveolin-3 and were excluded from caveolae-enriched membrane fractions as seen by sucrose density gradient centrifugation. In addition, these caveolin-3 mutants were expressed at significantly lower levels and had a dramatically shortened half-life of approximately 45-60 min. However, caveolin-3 mutants were palmitoylated to the same extent as wild type caveolin-3, indicating that targeting to the plasma membrane is not required for palmitoylation of caveolin-3. In conclusion, we show that LGMD-1C mutations lead to formation of unstable high molecular mass aggregates of caveolin-3 that are retained within the Golgi complex and are not targeted to the plasma membrane. Consistent with its autosomal dominant form of genetic transmission, we demonstrate that LGMD-1C mutants of caveolin-3 behave in a dominant-negative fashion, causing the retention of wild type caveolin-3 at the level of the Golgi. These data provide a molecular explanation for why caveolin-3 levels are down-regulated in patients with this form of limb girdle muscular dystrophy (LGMD-1C)

Virtopsy in conjoined ischiopagus twins.

PURPOSE OF INVESTIGATION To propose a multidisciplinary protocol for postmortem disclosure of complex fetal malformations, comparing ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and autopsy in a case of conjoined ischiopagus twins. MATERIALS AND METHODS A screening second-trimester ultrasound diagnosed ischiopagus twins at 20 gestational weeks in a 31-year-old woman without any previous ultrasound examination. The couple decided for pregnancy termination. The formalin-fixed fetuses underwent full-body CT, MRI, and autopsy. RESULTS ultrasound accurately diagnosed ischiopagus twins. CT was very accurate in the description of bone components. MRI allowed better visualization of the visceral organs than CT. Only autopsy could disclose the aspect of the two gastrointestinal tracts and the external genitalia. CONCLUSIONS Prenatal ultrasound represents the standard diagnostic exam for conjoined twins. CT-MRI virtual autopsy (virtopsy) may be an option if the couple refuses to authorize necropsy or may be useful to plan a minimally invasive autopsy preserving the external phenotype

Contrasting main selection methods in genetic algorithms

In genetic algorithms selection mechanisms aim to favour reproduction of better individuals imposing a direction on the search process. It does not create new individuals; instead it selects comparatively good individuals from a population and typically does it according to their fitness. The idea is that interacting with other individuals (competition), those with higher fitness have a higher probability to be selected for mating. In that manner, because the fitness of an individual gives a measure of its "goodness", selection introduces the influence of the fitness function to the evolutionary process. Moreover, selection is the only operator of genetic algorithm where the fitness of an individual affects the evolution process. In such a process two important, strongly related, issues exist: selective pressure and population diversity. They are the sides of the same coin: exploitation of information gathered so far versus exploration of the searching space. Selection plays an important role here because strong selective pressure can lead to premature convergence and weak selective pressure can make the search ineffective [14]. Focussing on this equilibrium problem significant research has been done. In this work we introduce the main properties of selection, the usual selection mechanisms and finally show the effect of applying proportional, ranking and tournament selection to a set of well known multimodal testing functions on simple genetic algorithms. These are the most widely used selection mechanisms and each of them has their own features. A description of each method, experiment and statistical analyses of results under different parameter settings are reported.Sistemas InteligentesRed de Universidades con Carreras en Informática (RedUNCI

Improving evolutionary algorithms performance by extending incest prevention

Provision of population diversity is one of the main goals to avoid premature convergence in Evolutionary Algorithms (EAs). In this way the risk of being trapped in local optima is minimised. Eshelman and Shaffer [4] attempted to maintain population diversity by using diverse strategies focusing on mating, recombination and replacement. One of their approaches, called incest prevention, avoided mating of pairs showing similarities based on the parent’s hamming distance. Conventional selection mechanisms does not consider if the members of the new population have common ancestors and consequently due to a finite fixed population size, a loss of genetic diversity can frequently arise. This paper shows an extended approach of incest prevention by maintaining information about ancestors within the chromosome and modifying the selection for reproduction in order to impede mating of individuals belonging to the same “family”, for a predefined number of generations. This novel approach was tested on a set of multimodal functions. Description of experiments and analyses of improved results are also shown.Sistemas InteligentesRed de Universidades con Carreras en Informática (RedUNCI

hypomyelination and congenital cataract neuroimaging features of a novel inherited white matter disorder

BACKGROUND AND PURPOSE: Hypomyelination and congenital cataract (HCC) is an autosomal recessive white matter disease caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. We aimed to describe the neuroimaging features of this novel entity. MATERIALS AND METHODS: A systematic analysis of patients with unclassified leukoencephalopathies admitted to our institutions revealed 10 children with congenital cataract, slowly progressive neurologic impairment, and diffuse white matter abnormalities on neuroimaging. Psychomotor developmental delay was evident after the first year of life. Peripheral neuropathy was demonstrated by neurophysiologic studies in 9 children. The available neuroimaging studies were retrospectively reviewed. RESULTS: In all patients, neuroimaging revealed diffuse involvement of the supratentorial white matter associated with preservation of both cortical and deep gray matter structures. Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content. Deep cerebellar white matter hypomyelination was found in 6 patients. Older patients had evidence of white matter bulk loss and gliosis. Proton MR spectroscopy showed variable findings, depending on the stage of the disease. Sural nerve biopsy revealed hypomyelinated nerve fibers. Mutations in the DRCTNNB1A gene on chromosome 7p15.3, causing complete or severe deficiency of hyccin, were demonstrated in all patients. CONCLUSIONS: HCC is characterized by a combined pattern of primary myelin deficiency and secondary neurodegenerative changes. In the proper clinical setting, recognition of suggestive neuroimaging findings should prompt appropriate genetic investigations

Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders.

Here we review the clinical and translational implications of the caveolin gene family for understanding the pathogenesis of human diseases, including breast and prostate cancers, pulmonary hypertension, cardiomyopathy, diabetes, and muscular dystrophy. Detailed phenotypic analysis of caveolin knockout mice has served to highlight the crucial role of a caveolin deficiency in the pathogenesis of many human disease processes. Mutations in the human caveolin genes are associated with a number of established genetic disorders (such as breast cancer, lipodystrophy, muscular dystrophy, and cardiomyopathy), making the caveolins important and novel targets for drug development. The implementation of new strategies for caveolin replacement therapy-including caveolin mimetic peptides-is ongoing

Caveolin-3 Null Mice Show a Loss of Caveolae, Changes in the Microdomain Distribution of the Dystrophin-Glycoprotein Complex, and T-tubule Abnormalities

Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in caveolin-3 protein expression, i.e. a caveolin-3 deficiency. Here, we created a caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a caveolin-3 deficiency. We show that these mice lack caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level

Novel post-synthetic generation, isomeric resolution, and characterization of Fapy-dG within oligodeoxynucleotides: differential anomeric impacts on DNA duplex properties

Accumulation of damaged guanine nucleobases within genomic DNA, including the imidazole ring opened N6-(2-Deoxy-α,β-D-erythro-pentafuranosyl)-2,6-diamino-4-hydroxy-5-formylamidopyrimidine (Fapy-dG), is associated with progression of age-related diseases and cancer. To evaluate the impact of this mutagenic lesion on DNA structure and energetics, we have developed a novel synthetic strategy to incorporate cognate Fapy-dG site-specifically within any oligodeoxynucleotide sequence. The scheme involves the synthesis of an oligonucleotide precursor containing a 5-nitropyrimidine moiety at the desired lesion site via standard solid-phase procedures. Following deprotection and isolation, the Fapy-dG lesion is generated by catalytic hydrogenation and subsequent formylation. NMR assignment of the Fapy-dG lesion (X) embedded within a TXT trimer reveals the presence of rotameric and anomeric species. The latter have been characterized by synthesizing the tridecamer oligodeoxynucleotide d(GCGTACXCATGCG) harboring Fapy-dG as the central residue and developing a protocol to resolve the isomeric components. Hybridization of the chromatographically isolated fractions with their complementary d(CGCATGCGTACGC) counterpart yields two Fapy-dG·C duplexes that are differentially destabilized relative to the canonical G·C parent. The resultant duplexes exhibit distinct thermal and thermodynamic profiles that are characteristic of α- and β-anomers, the former more destabilizing than the latter. These anomer-specific impacts are discussed in terms of differential repair enzyme recognition, processing and translesion synthesis

Anthropometric study of chainsaw operators

Através deste trabalho, objetivou-se estudar, antropometricamente, os operadores de motosserra no corte florestal de Eucalyptus spp. Os objetivos específicos foram: conhecer os padrões antropométricos dos operadores de motosserra, determinar os limites mínimos e máximos das variáveis estudadas e selecionar variáveis correspondentes à dimensão da motosserra para o operador. A coleta de dados foi realizada na empresa de papel e celulose, localizada no Estado de São Paulo. Foram selecionadas 35 variáveis antropométricas para aplicação no estudo e avaliados 85 operadores de motosserra. Verificou-se que a massa média do operador foi de 67,9 kg. O percentil 50% apresenta o valor de 1,705 m para a variável altura do topo da cabeça. O espaço mínimo para introdução da mão no cabo da motosserra, não deve ser inferior a 0,115 m e a profundidade mínima para introdução da mão no cabo da motosserra também não deve ser inferior a 0,088 m.The general objective of this work was to anthropometrically study the chainsaw operators during the forest harvest of Eucalipytus spp. The specific objectives were to find out the anthropometrics patterns of chainsaw operators; to determine the minimum and maximum limits of the variables studied; and to select variables, which correspond to the dimensions of the chainsaw for the operator. Data collection was done at a pulp and paper enterprise located in the state of São Paulo, Brazil. Thirty-five anthropometrics variables were selected for the study. Eighty-five chainsaw operators (totaling 100% of the operators of the enterprise) were evaluated. The mean weight of the operator was of 67.9 kg. The 50% presented a value of 1.705 m for the variable height of the top of the head. The minimum space for the introduction of the hand in the handler of the chainsaw should not be less than 0.115 m. The minimum depth for the introduction of the hand in the chainsaw handler should not be less than 0.088 m