Sleep Disorders and Demand for Medical Services: Evidence from a Population-Based Longitudinal Study

Background: The aim of this study was to investigate whether insomnia and obstructive sleep apnea (OSA) were predictors of hospitalizations or emergency department visits during two years following the Sao Paulo Epidemiologic Sleep Study (EPISONO) sample. Methods and Findings: All participants (n = 1,101) who underwent a baseline evaluation between July and December 2007 were contacted in December 2009 and asked to fill out a questionnaire about body weight changes, number of hospitalizations and visits to the emergency department. Participants lost during the follow-up period represented 3.2 % (n = 35) and 7 subjects had died. Hospitalizations were reported by 116 volunteers (10.5%) and emergency department visits were reported by 136 participants (12.4%). The average body mass index (BMI) did not vary significantly between the first and the second assessment [26.7(95%CI:26.3–27.1) vs. 26.9(26.5–27.4) kg/m2]. After adjusting for confounders, a multiple logistic regression model revealed that female gender [1.4(1.0–1.9)], age $40 years, insomnia diagnosed according to the DSM-IV criteria [1.6(1.0–2.6)], and apneahypopnea index$15 [1.5(1.0–2.2)] were predictors of hospitalizations and/or demand for emergency services. Conclusion: Our study of a probabilistic sample of the Sao Paulo inhabitants shows that over a period of two years, insomnia and OSA were both associated with health impairment. Considering the high prevalence and public health burden of slee

Smoothened-antagonists reverse homogentisic acid-induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria

Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia Hedgehog signaling may also be altered in AKU. Thus, we characterized an AKU cellular model in which healthy chondrocytes were treated with HGA (66μM) to replicate AKU cartilage pathology. We investigated the degree of activation of the Hedgehog signaling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced Hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the Hedgehog pathway

Transition from Positive to Neutral in Mutation Fixation along with Continuing Rising Fitness in Thermal Adaptive Evolution

It remains to be determined experimentally whether increasing fitness is related to positive selection, while stationary fitness is related to neutral evolution. Long-term laboratory evolution in Escherichia coli was performed under conditions of thermal stress under defined laboratory conditions. The complete cell growth data showed common continuous fitness recovery to every 2°C or 4°C stepwise temperature upshift, finally resulting in an evolved E. coli strain with an improved upper temperature limit as high as 45.9°C after 523 days of serial transfer, equivalent to 7,560 generations, in minimal medium. Two-phase fitness dynamics, a rapid growth recovery phase followed by a gradual increasing growth phase, was clearly observed at diverse temperatures throughout the entire evolutionary process. Whole-genome sequence analysis revealed the transition from positive to neutral in mutation fixation, accompanied with a considerable escalation of spontaneous substitution rate in the late fitness recovery phase. It suggested that continually increasing fitness not always resulted in the reduction of genetic diversity due to the sequential takeovers by fit mutants, but caused the accumulation of a considerable number of mutations that facilitated the neutral evolution

Early In Vitro Differentiation of Mouse Definitive Endoderm Is Not Correlated with Progressive Maturation of Nuclear DNA Methylation Patterns

The genome organization in pluripotent cells undergoing the first steps of differentiation is highly relevant to the reprogramming process in differentiation. Considering this fact, chromatin texture patterns that identify cells at the very early stage of lineage commitment could serve as valuable tools in the selection of optimal cell phenotypes for regenerative medicine applications. Here we report on the first-time use of high-resolution three-dimensional fluorescence imaging and comprehensive topological cell-by-cell analyses with a novel image-cytometrical approach towards the identification of in situ global nuclear DNA methylation patterns in early endodermal differentiation of mouse ES cells (up to day 6), and the correlations of these patterns with a set of putative markers for pluripotency and endodermal commitment, and the epithelial and mesenchymal character of cells. Utilizing this in vitro cell system as a model for assessing the relationship between differentiation and nuclear DNA methylation patterns, we found that differentiating cell populations display an increasing number of cells with a gain in DNA methylation load: first within their euchromatin, then extending into heterochromatic areas of the nucleus, which also results in significant changes of methylcytosine/global DNA codistribution patterns. We were also able to co-visualize and quantify the concomitant stochastic marker expression on a per-cell basis, for which we did not measure any correlation to methylcytosine loads or distribution patterns. We observe that the progression of global DNA methylation is not correlated with the standard transcription factors associated with endodermal development. Further studies are needed to determine whether the progression of global methylation could represent a useful signature of cellular differentiation. This concept of tracking epigenetic progression may prove useful in the selection of cell phenotypes for future regenerative medicine applications

Individual identification via electrocardiogram analysis

Background: During last decade the use of ECG recordings in biometric recognition studies has increased. ECG characteristics made it suitable for subject identification: it is unique, present in all living individuals, and hard to forge. However, in spite of the great number of approaches found in literature, no agreement exists on the most appropriate methodology. This study aimed at providing a survey of the techniques used so far in ECG-based human identification. Specifically, a pattern recognition perspective is here proposed providing a unifying framework to appreciate previous studies and, hopefully, guide future research. Methods: We searched for papers on the subject from the earliest available date using relevant electronic databases (Medline, IEEEXplore, Scopus, and Web of Knowledge). The following terms were used in different combinations: electrocardiogram, ECG, human identification, biometric, authentication and individual variability. The electronic sources were last searched on 1st March 2015. In our selection we included published research on peer-reviewed journals, books chapters and conferences proceedings. The search was performed for English language documents. Results: 100 pertinent papers were found. Number of subjects involved in the journal studies ranges from 10 to 502, age from 16 to 86, male and female subjects are generally present. Number of analysed leads varies as well as the recording conditions. Identification performance differs widely as well as verification rate. Many studies refer to publicly available databases (Physionet ECG databases repository) while others rely on proprietary recordings making difficult them to compare. As a measure of overall accuracy we computed a weighted average of the identification rate and equal error rate in authentication scenarios. Identification rate resulted equal to 94.95 % while the equal error rate equal to 0.92 %. Conclusions: Biometric recognition is a mature field of research. Nevertheless, the use of physiological signals features, such as the ECG traits, needs further improvements. ECG features have the potential to be used in daily activities such as access control and patient handling as well as in wearable electronics applications. However, some barriers still limit its growth. Further analysis should be addressed on the use of single lead recordings and the study of features which are not dependent on the recording sites (e.g. fingers, hand palms). Moreover, it is expected that new techniques will be developed using fiducials and non-fiducial based features in order to catch the best of both approaches. ECG recognition in pathological subjects is also worth of additional investigations

Incompatibilities Involving Yeast Mismatch Repair Genes: A Role for Genetic Modifiers and Implications for Disease Penetrance and Variation in Genomic Mutation Rates

Genetic background effects underlie the penetrance of most genetically determined phenotypes, including human diseases. To explore how such effects can modify a mutant phenotype in a genetically tractable system, we examined an incompatibility involving the MLH1 and PMS1 mismatch repair genes using a large population sample of geographically and ecologically diverse Saccharomyces cerevisiae strains. The mismatch repair incompatibility segregates into naturally occurring yeast strains, with no strain bearing the deleterious combination. In assays measuring the mutator phenotype conferred by different combinations of MLH1 and PMS1 from these strains, we observed a mutator phenotype only in combinations predicted to be incompatible. Surprisingly, intragenic modifiers could be mapped that specifically altered the strength of the incompatibility over a 20-fold range. Together, these observations provide a powerful model in which to understand the basis of disease penetrance and how such genetic variation, created through mating, could result in new mutations that could be the raw material of adaptive evolution in yeast populations

Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

Introduction Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. Methods Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. Results Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors

Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation

Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered