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Understanding how seizures spread throughout the brain is an important problem in the treatment of epilepsy, especially for implantable devices that aim to avert focal seizures before they spread to, and overwhelm, the rest of the brain. This paper presents an analysis of the speed of propagation in a computational model of seizure-like activity in a 2-dimensional recurrent network of integrate-and-fire neurons containing both excitatory and inhibitory populations and having a difference of Gaussians connectivity structure, an approximation to that observed in cerebral cortex. In the same computational model network, alternative mechanisms are explored in order to simulate the range of seizure-like activity propagation speeds (0.1–100 mm/s) observed in two animal-slice-based models of epilepsy: (1) low extracellular , which creates excess excitation and (2) introduction of gamma-aminobutyric acid (GABA) antagonists, which reduce inhibition. Moreover, two alternative connection topologies are considered: excitation broader than inhibition, and inhibition broader than excitation. It was found that the empirically observed range of propagation velocities can be obtained for both connection topologies. For the case of the GABA antagonist model simulation, consistent with other studies, it was found that there is an effective threshold in the degree of inhibition below which waves begin to propagate. For the case of the low extracellular model simulation, it was found that activity-dependent reductions in inhibition provide a potential explanation for the emergence of slowly propagating waves. This was simulated as a depression of inhibitory synapses, but it may also be achieved by other mechanisms. This work provides a localised network understanding of the propagation of seizures in 2-dimensional centre-surround networks that can be tested empirically. [ABSTRACT FROM AUTHOR]

Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures. Adult Noda epileptic rats (NER, >12-week-old) exhibit spontaneously generalized tonic-clonic convulsion about once a day. To pursue the involvement of synaptic Zn2+ signal in susceptibility to spontaneous seizures, in the present study, the effect of zinc chelators on epileptogenesis was examined using adult NER. Clioquinol (CQ) and TPEN are lipophilic zinc chelotors, transported into the brain and reduce the levels of synaptic Zn2+. The incidence of tonic-clonic convulsion was markedly increased after i.p. injection of CQ (30–100 mg/kg) and TPEN (1 mg/kg). The basal levels of extracellular Zn2+ measured by ZnAF-2 were decreased before tonic-clonic convulsion was induced with zinc chelators. The hippocampal electroencephalograms during CQ (30 mg/kg)-induced convulsions were similar to those during sound-induced convulsions in NER reported previously. Exocytosis of hippocampal mossy fibers, which was measured with FM4-64, was significantly increased in hippocampal slices from CQ-injected NER that did not show tonic-clonic convulsion yet. These results indicate that the abnormal excitability of mossy fibers is induced prior to epileptic seizures by injection of zinc chelators into NER. The incidence of tonic-clonic convulsion induced with CQ (30 mg/kg) was significantly reduced by co-injection with aminooxyacetic acid (5–10 mg/kg), an anticonvulsant drug enhancing GABAergic activity, which did not affect locomotor activity. The present paper demonstrates that the abnormal excitability in the brain, especially in mossy fibers, which is potentially associated with the insufficient GABAergic neuron activity, may be a factor to reduce the threshold for epileptogenesis in NER. [ABSTRACT FROM AUTHOR]

Advances in next-generation sequencing technologies have enabled the identification of multiple rare single nucleotide polymorphisms involved in diseases or traits. Several strategies for identifying rare variants that contribute to disease susceptibility have recently been proposed. An important feature of many of these statistical methods is the pooling or collapsing of multiple rare single nucleotide variants to achieve a reasonably high frequency and effect. However, if the pooled rare variants are associated with the trait in different directions, then the pooling may weaken the signal, thereby reducing its statistical power. In the present paper, we propose a backward support vector machine (BSVM)-based variant selection procedure to identify informative disease-associated rare variants. In the selection procedure, the rare variants are weighted and collapsed according to their positive or negative associations with the disease, which may be associated with common variants and rare variants with protective, deleterious, or neutral effects. This nonparametric variant selection procedure is able to account for confounding factors and can also be adopted in other regression frameworks. The results of a simulation study and a data example show that the proposed BSVM approach is more powerful than four other approaches under the considered scenarios, while maintaining valid type I errors. [ABSTRACT FROM AUTHOR]

Developing appropriate risk messages during challenging situations like public health outbreaks is complicated. The focus of this paper is on how First Nations and Metis people in Manitoba, Canada, responded to the public health management of pandemic H1N1, using a focus group methodology (n = 23 focus groups). Focus group conversations explored participant reactions to messaging regarding the identification of H1N1 virus risk groups, the H1N1 vaccine and how priority groups to receive the vaccine were established. To better contextualize the intentions of public health professionals, key informant interviews (n = 20) were conducted with different health decision makers (e.g., public health officials, people responsible for communications, representatives from some First Nations and Metis self-governing organizations). While risk communication practice has improved, ‘one size’ messaging campaigns do not work effectively, particularly when communicating about who is most ‘at-risk’. Public health agencies need to pay more attention to the specific socio-economic, historical and cultural contexts of First Nations and Metis citizens when planning for, communicating and managing responses associated with pandemic outbreaks to better tailor both the messages and delivery. More attention is needed to directly engage First Nations and Metis communities in the development and dissemination of risk messaging. [ABSTRACT FROM AUTHOR]

The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer’s disease (AD), and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3×Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD. [ABSTRACT FROM AUTHOR]

Background: Triatoma dimidiata is among the main vectors of Chagas disease in Latin America. However, and despite important advances, there is no consensus about the taxonomic status of phenotypically divergent T. dimidiata populations, which in most recent papers are regarded as subspecies. Methodology and Findings: A total of 126 cyt b sequences (621 bp long) were produced for specimens from across the species range. Forty-seven selected specimens representing the main cyt b clades observed (after a preliminary phylogenetic analysis) were also sequenced for an ND4 fragment (554 bp long) and concatenated with their respective cyt b sequences to produce a combined data set totalling 1175 bp/individual. Bayesian and Maximum-Likelihood phylogenetic analyses of both data sets (cyt b, and cyt b+ND4) disclosed four strongly divergent (all pairwise Kimura 2-parameter distances >0.08), monophyletic groups: Group I occurs from Southern Mexico through Central America into Colombia, with Ecuadorian specimens resembling Nicaraguan material; Group II includes samples from Western-Southwestern Mexico; Group III comprises specimens from the Yucatán peninsula; and Group IV consists of sylvatic samples from Belize. The closely-related, yet formally recognized species T. hegneri from the island of Cozumel falls within the divergence range of the T. dimidiata populations studied. Conclusions: We propose that Groups I–IV, as well as T. hegneri, should be regarded as separate species. In the Petén of Guatemala, representatives of Groups I, II, and III occur in sympatry; the absence of haplotypes with intermediate genetic distances, as shown by multimodal mismatch distribution plots, clearly indicates that reproductive barriers actively promote within-group cohesion. Some sylvatic specimens from Belize belong to a different species – likely the basal lineage of the T. dimidiata complex, originated ∼8.25 Mya. The evidence presented here strongly supports the proposition that T. dimidiata is a complex of five cryptic species (Groups I–IV plus T. hegneri) that play different roles as vectors of Chagas disease in the region. [ABSTRACT FROM AUTHOR]

Background: Swallowing dysfunction (also known as dysphagia), which results in a deterioration of nutritional intake, slows rehabilitation and causes aspiration pneumonia, is very common following neurological impairments. Although videofluorographic (VF) examination is widely used for detecting aspiration, an objective and non-invasive method for assessing swallowing function has yet to be established because of a lack of adequate devices and protocols. In this paper, a bend sensor whose resistance is altered by bending was introduced to monitor swallowing-related laryngeal movement. Methods: Six healthy male volunteers were recruited in the present study. Specific time points on the signal waveform produced by the bend sensor were defined to describe laryngeal movement by differential analysis. Additionally, the physiological significance of the obtained waveform was confirmed by analyzing the sequential correlations between the signal waveform from the bend sensor and hyoid bone kinetics simultaneously recorded by VF. Results: Seven time points were successfully defined on the signal waveform to reference laryngeal movement. Each time point was well correlated with certain VF events, with evidence of no significant time lags, and there were positive correlations between waveform time points and matched VF events. Furthermore, obvious similarities were noticed between the duration of each phase on the signal waveform and the duration of the matched hyoid bone activity. Conclusions: The present monitoring system using a bend sensor might be useful for observing the temporal aspects of laryngeal movement during swallowing, and it was well coordinated with hyoid bone movement. [ABSTRACT FROM AUTHOR]

Plasma sterilization offers a faster, less toxic and versatile alternative to conventional sterilization methods. Using a relatively small, low temperature, atmospheric, dielectric barrier discharge surface plasma generator, we achieved ≥6 log reduction in concentration of vegetative bacterial and yeast cells within 4 minutes and ≥6 log reduction of Geobacillus stearothermophilus spores within 20 minutes. Plasma sterilization is influenced by a wide variety of factors. Two factors studied in this particular paper are the effect of using different dielectric substrates and the significance of the amount of liquid on the dielectric surface. Of the two dielectric substrates tested (FR4 and semi-ceramic (SC)), it is noted that the FR4 is more efficient in terms of time taken for complete inactivation. FR4 is more efficient at generating plasma as shown by the intensity of spectral peaks, amount of ozone generated, the power used and the speed of killing vegetative cells. The surface temperature during plasma generation is also higher in the case of FR4. An inoculated FR4 or SC device produces less ozone than the respective clean devices. Temperature studies show that the surface temperatures reached during plasma generation are in the range of 30°C–66°C (for FR4) and 20°C–49°C (for SC). Surface temperatures during plasma generation of inoculated devices are lower than the corresponding temperatures of clean devices. pH studies indicate a slight reduction in pH value due to plasma generation, which implies that while temperature and acidification may play a minor role in DBD plasma sterilization, the presence of the liquid on the dielectric surface hampers sterilization and as the liquid evaporates, sterilization improves. [ABSTRACT FROM AUTHOR]

Background: Carcinomas make up the majority of cancers. Their accurate and specific diagnoses are of great significance for the improvement of patients' curability. Methodology/Principal Findings: In this paper, we report an effectual example of the in vivo fluorescence molecular imaging of carcinomas with extremely high specificity based on whole cell-SELEX aptamers. Firstly, S6, an aptamer against A549 lung carcinoma cells, was adopted and labeled with Cy5 to serve as a molecular imaging probe. Flow cytometry assays revealed that Cy5-S6 could not only specifically label in vitro cultured A549 cells in buffer, but also successfully achieve the detection of ex vivo cultured target cells in serum. When applied to in vivo imaging, Cy5-S6 was demonstrated to possess high specificity in identifying A549 carcinoma through a systematic comparison investigation. Particularly, after Cy5-S6 was intravenously injected into nude mice which were simultaneously grafted with A549 lung carcinoma and Tca8113 tongue carcinoma, a much longer retention time of Cy5-S6 in A549 tumor was observed and a clear targeted cancer imaging result was presented. On this basis, to further promote the application to imaging other carcinomas, LS2 and ZY8, which are two aptamers selected by our group against Bel-7404 and SMMC-7721 liver carcinoma cells respectively, were tested in a similar way, both in vitro and in vivo. Results showed that these aptamers were even effective in differentiating liver carcinomas of different subtypes in the same body. Conclusions/Significance: This work might greatly advance the application of whole cell-SELEX aptamers to carcinomas-related in vivo researches. [ABSTRACT FROM AUTHOR]

The rapid detection and identification of infectious disease pathogens is a critical need for healthcare in both developed and developing countries. As we gain more insight into the genomic basis of pathogen infectivity and drug resistance, point-of-care nucleic acid testing will likely become an important tool for global health. In this paper, we present an inexpensive, handheld, battery-powered instrument designed to enable pathogen genotyping in the developing world. Our Microfluidic Biomolecular Amplification Reader (µBAR) represents the convergence of molecular biology, microfluidics, optics, and electronics technology. The µBAR is capable of carrying out isothermal nucleic acid amplification assays with real-time fluorescence readout at a fraction of the cost of conventional benchtop thermocyclers. Additionally, the µBAR features cell phone data connectivity and GPS sample geotagging which can enable epidemiological surveying and remote healthcare delivery. The µBAR controls assay temperature through an integrated resistive heater and monitors real-time fluorescence signals from 60 individual reaction chambers using LEDs and phototransistors. Assays are carried out on PDMS disposable microfluidic cartridges which require no external power for sample loading. We characterize the fluorescence detection limits, heater uniformity, and battery life of the instrument. As a proof-of-principle, we demonstrate the detection of the HIV-1 integrase gene with the µBAR using the Loop-Mediated Isothermal Amplification (LAMP) assay. Although we focus on the detection of purified DNA here, LAMP has previously been demonstrated with a range of clinical samples, and our eventual goal is to develop a microfluidic device which includes on-chip sample preparation from raw samples. The µBAR is based entirely around open source hardware and software, and in the accompanying online supplement we present a full set of schematics, bill of materials, PCB layouts, CAD drawings, and source code for the µBAR instrument with the goal of spurring further innovation toward low-cost genetic diagnostics. [ABSTRACT FROM AUTHOR]

In this study, we describe a novel porcine parechovirus-like virus (tentatively named PLV-CHN) from healthy piglets in China using 454 high-throughput sequencing. The complete genome of the virus comprises 6832 bp, encoding a predicted polyprotein of 2132 amino acids that is most similar to Ljungan virus (32% identity). A similar virus that belongs to a novel Picornaviridae genus, named swine pasivirus 1 (SPaV-1), was reported during the preparation of this paper. Sequence analysis revealed that PLV-CHN and SPaV1 shared 82% nucleotide identity and 89% amino acid identity. Further genomic and phylogenetic analyses suggested that both SPaV1 and PLV-CHN shared similar genomic characteristics and belong to the same novel Picornaviridae genus. A total of 36 (20.0%) fecal samples from 180 healthy piglets were positive for PLV-CHN by RT-PCR, while no fecal samples from 100 healthy children and 100 children with diarrhea, and no cerebrospinal fluid samples from 196 children with suspected viral encephalitis, was positive for the virus. However, Western blot and enzyme-linked immunosorbent assays using recombinant PLV-CHN VP1 polypeptide as an antigen showed a high seroprevalence of 63.5% in the healthy population. When grouped by age, the antibody-positivity rates showed that the majority of children under 12 years of age have been infected by the virus. It was suggested that PLV-CHN, SPaV1, or an as-yet-uncharacterized virus can infect humans early in life. Thus, investigation of the role of this novel virus is vital. [ABSTRACT FROM AUTHOR]

Background: Increasing active travel (primarily walking and cycling) has been widely advocated for reducing obesity levels and achieving other population health benefits. However, the strength of evidence underpinning this strategy is unclear. This study aimed to assess the evidence that active travel has significant health benefits. Methods: The study design was a systematic review of (i) non-randomised and randomised controlled trials, and (ii) prospective observational studies examining either (a) the effects of interventions to promote active travel or (b) the association between active travel and health outcomes. Reports of studies were identified by searching 11 electronic databases, websites, reference lists and papers identified by experts in the field. Prospective observational and intervention studies measuring any health outcome of active travel in the general population were included. Studies of patient groups were excluded. Results: Twenty-four studies from 12 countries were included, of which six were studies conducted with children. Five studies evaluated active travel interventions. Nineteen were prospective cohort studies which did not evaluate the impact of a specific intervention. No studies were identified with obesity as an outcome in adults; one of five prospective cohort studies in children found an association between obesity and active travel. Small positive effects on other health outcomes were found in five intervention studies, but these were all at risk of selection bias. Modest benefits for other health outcomes were identified in five prospective studies. There is suggestive evidence that active travel may have a positive effect on diabetes prevention, which may be an important area for future research. Conclusions: Active travel may have positive effects on health outcomes, but there is little robust evidence to date of the effectiveness of active transport interventions for reducing obesity. Future evaluations of such interventions should include an assessment of their impacts on obesity and other health outcomes. [ABSTRACT FROM AUTHOR]

The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889–90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics. [ABSTRACT FROM AUTHOR]

We consider the recently introduced edge-based compartmental models (EBCM) for the spread of susceptible-infected-recovered (SIR) diseases in networks. These models differ from standard infectious disease models by focusing on the status of a random partner in the population, rather than a random individual. This change in focus leads to simple analytic models for the spread of SIR diseases in random networks with heterogeneous degree. In this paper we extend this approach to handle deviations of the disease or population from the simplistic assumptions of earlier work. We allow the population to have structure due to effects such as demographic features or multiple types of risk behavior. We allow the disease to have more complicated natural history. Although we introduce these modifications in the static network context, it is straightforward to incorporate them into dynamic network models. We also consider serosorting, which requires using dynamic network models. The basic methods we use to derive these generalizations are widely applicable, and so it is straightforward to introduce many other generalizations not considered here. Our goal is twofold: to provide a number of examples generalizing the EBCM method for various different population or disease structures and to provide insight into how to derive such a model under new sets of assumptions. [ABSTRACT FROM AUTHOR]

Background: Predicting type-1 Human Immunodeficiency Virus (HIV-1) protease cleavage site in protein molecules and determining its specificity is an important task which has attracted considerable attention in the research community. Achievements in this area are expected to result in effective drug design (especially for HIV-1 protease inhibitors) against this life-threatening virus. However, some drawbacks (like the shortage of the available training data and the high dimensionality of the feature space) turn this task into a difficult classification problem. Thus, various machine learning techniques, and specifically several classification methods have been proposed in order to increase the accuracy of the classification model. In addition, for several classification problems, which are characterized by having few samples and many features, selecting the most relevant features is a major factor for increasing classification accuracy. Results: We propose for HIV-1 data a consistency-based feature selection approach in conjunction with recursive feature elimination of support vector machines (SVMs). We used various classifiers for evaluating the results obtained from the feature selection process. We further demonstrated the effectiveness of our proposed method by comparing it with a state-of-the-art feature selection method applied on HIV-1 data, and we evaluated the reported results based on attributes which have been selected from different combinations. Conclusion: Applying feature selection on training data before realizing the classification task seems to be a reasonable data-mining process when working with types of data similar to HIV-1. On HIV-1 data, some feature selection or extraction operations in conjunction with different classifiers have been tested and noteworthy outcomes have been reported. These facts motivate for the work presented in this paper. Software availability: The software is available at http://ozyer.etu.edu.tr/c-fs-svm.rar. The software can be downloaded at esnag.etu.edu.tr/software/hiv_cleavage_site_prediction.rar; you will find a readme file which explains how to set the software in order to work. [ABSTRACT FROM AUTHOR]

In the USA, the relationship between the legal availability of guns and the firearm-related homicide rate has been debated. It has been argued that unrestricted gun availability promotes the occurrence of firearm-induced homicides. It has also been pointed out that gun possession can protect potential victims when attacked. This paper provides a first mathematical analysis of this tradeoff, with the goal to steer the debate towards arguing about assumptions, statistics, and scientific methods. The model is based on a set of clearly defined assumptions, which are supported by available statistical data, and is formulated axiomatically such that results do not depend on arbitrary mathematical expressions. According to this framework, two alternative scenarios can minimize the gun-related homicide rate: a ban of private firearms possession, or a policy allowing the general population to carry guns. Importantly, the model identifies the crucial parameters that determine which policy minimizes the death rate, and thus serves as a guide for the design of future epidemiological studies. The parameters that need to be measured include the fraction of offenders that illegally possess a gun, the degree of protection provided by gun ownership, and the fraction of the population who take up their right to own a gun and carry it when attacked. Limited data available in the literature were used to demonstrate how the model can be parameterized, and this preliminary analysis suggests that a ban of private firearm possession, or possibly a partial reduction in gun availability, might lower the rate of firearm-induced homicides. This, however, should not be seen as a policy recommendation, due to the limited data available to inform and parameterize the model. However, the model clearly defines what needs to be measured, and provides a basis for a scientific discussion about assumptions and data. [ABSTRACT FROM AUTHOR]

T-STAR (testis-signal transduction and activation of RNA) is an RNA binding protein, containing an SH3-binding domain and thus potentially playing a role in integration of cell signaling and RNA metabolism. The specific function of T-STAR is unknown and its implication in cancer is poorly characterized. Expression of T-STAR has been reported in human testis, muscle and brain tissues, and is associated with a growth-inhibitory role in immortalized fibroblasts. The aim of this paper was to investigate the functional role of T-STAR through (i) survival analysis of patients with primary invasive breast cancer and (ii) experimental evaluation of the effect of T-STAR on breast cancer cell growth. T-STAR protein expression was analysed by immunohistochemistry (IHC) in tissue microarrays with tumors from 289 patients with primary invasive breast cancer, and correlations to clinicopathological characteristics, recurrence-free and overall survival (RFS and OS) and established tumor markers such as HER2 and ER status were evaluated. In addition, the function of T-STAR was investigated using siRNA-mediated knock-down and overexpression of the gene in six breast cancer cell lines. Of the tumors analysed, 86% showed nuclear T-STAR expression, which was significantly associated with an improved RFS and strongly associated with positive HER2 status and negative hormone receptor status. Furthermore, experimental data showed that overexpression of T-STAR decreased cellular growth while knock-down increased it, as shown both by thymidine incorporation and metabolic activity. In summary, we demonstrate that T-STAR protein expression correlates with an improved RFS in primary breast cancer. This is supported by functional data, indicating that T-STAR regulation is of importance both for breast cancer biology and clinical outcome but future studies are needed to determine a potential role in patient stratification. [ABSTRACT FROM AUTHOR]

We report here identification and validation of the first papillomavirus encoded microRNAs expressed in human cervical lesions and cell lines. We established small RNA libraries from ten human papillomavirus associated cervical lesions including cancer and two human papillomavirus harboring cell lines. These libraries were sequenced using SOLiD 4 technology. We used the sequencing data to predict putative viral microRNAs and discovered nine putative papillomavirus encoded microRNAs. Validation was performed for five candidates, four of which were successfully validated by qPCR from cervical tissue samples and cell lines: two were encoded by HPV 16, one by HPV 38 and one by HPV 68. The expression of HPV 16 microRNAs was further confirmed by in situ hybridization, and colocalization with p16INK4A was established. Prediction of cellular target genes of HPV 16 encoded microRNAs suggests that they may play a role in cell cycle, immune functions, cell adhesion and migration, development, and cancer. Two putative viral target sites for the two validated HPV 16 miRNAs were mapped to the E5 gene, one in the E1 gene, two in the L1 gene and one in the LCR region. This is the first report to show that papillomaviruses encode their own microRNA species. Importantly, microRNAs were found in libraries established from human cervical disease and carcinoma cell lines, and their expression was confirmed in additional tissue samples. To our knowledge, this is also the first paper to use in situ hybridization to show the expression of a viral microRNA in human tissue. [ABSTRACT FROM AUTHOR]

Antigenic characterization based on serological data, such as Hemagglutination Inhibition (HI) assay, is one of the routine procedures for influenza vaccine strain selection. In many cases, it would be impossible to measure all pairwise antigenic correlations between testing antigens and reference antisera in each individual experiment. Thus, we have to combine and integrate the HI tables from a number of individual experiments. Measurements from different experiments may be inconsistent due to different experimental conditions. Consequently we will observe a matrix with missing data and possibly inconsistent measurements. In this paper, we develop a new mathematical model, which we refer to as Joint Matrix Completion and Filtering, for HI data integration. In this approach, we simultaneously handle the incompleteness and uncertainty of observations by assuming that the underlying merged HI data matrix has low rank, as well as carefully modeling different levels of noises in each individual table. An efficient blockwise coordinate descent procedure is developed for optimization. The performance of our approach is validated on synthetic and real influenza datasets. The proposed joint matrix completion and filtering model can be adapted as a general model for biological data integration, targeting data noises and missing values within and across experiments. [ABSTRACT FROM AUTHOR]

Although the starvation response of the model multicellular organism Caenorhabditis elegans is a subject of much research, there is no convenient phenotypic readout of caloric restriction that can be applicable to large numbers of worms. This paper describes the distribution of mass densities of populations of C. elegans, from larval stages up to day one of adulthood, using isopycnic centrifugation, and finds that density is a convenient, if complex, phenotypic readout in C. elegans. The density of worms in synchronized populations of wildtype N2 C. elegans grown under standard solid-phase culture conditions was normally distributed, with distributions peaked sharply at a mean of 1.091 g/cm3 for L1, L2 and L3 larvae, 1.087 g/cm3 for L4 larvae, 1.081 g/cm3 for newly molted adults, and 1.074 g/cm3 at 24 hours of adulthood. The density of adult worms under starvation stress fell well outside this range, falling to a mean value of 1.054 g/cm3 after eight hours of starvation. This decrease in density correlated with the consumption of stored glycogen in the food-deprived worms. The density of the worms increased when deprived of food for longer durations, corresponding to a shift in the response of the worms: worms sacrifice their bodies by retaining larvae, which consume the adults from within. Density-based screens with the drug Ivermectin on worms cultured on single plates resulted in a clear bimodal (double-peaked) distribution of densities corresponding to drug exposed and non-exposed worms. Thus, measurements of changes in density could be used to conduct screens on the effects of drugs on several populations of worms cultured on single plates. [ABSTRACT FROM AUTHOR]

Aims: The matrix metalloproteinase (MMP) 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs) ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL) by inserting a gelatinase cleavable peptide (PVGLIG) between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. Materials and Methods: mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs) prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. Results: The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel) as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. Conclusion: The results in this study preliminarily demonstrated the effectiveness of gelatinase-responsive targeting strategy and the prospect of this intelligent nano-drug delivery system though further studies are needed. [ABSTRACT FROM AUTHOR]

Age at infection with hepatitis B virus (HBV) is a known risk factor for chronic HBV infection. However, in addition, there is some evidence that early age at infection further increases the risk of primary liver cancer beyond its association with increased risk of chronic infection. This systematic review of observational studies assesses the association between age at initiation of chronic HBV infection and liver cirrhosis, hepatocellular carcinoma, and their predictors including indicators of ongoing viral replication and hepatic damage. The review includes birth order and maternal HBV serology as proxies for age at infection. Electronic searches in two English-language (Medline and Embase, until Jan 2012) and two Chinese-language (CNKI and SinoMed, until Sep 2012) databases without language restriction and manual search through reference lists identified 7,077 papers, of which 19 studies of 21 outcomes (8 primary liver cancer, 1 liver cirrhosis, 10 viral replication and 2 liver inflammation) are included. One study directly examined the age at infection in a longitudinal cohort, 12 assessed maternal sero-status and 6 investigated birth order. The direction of associations in all studies was in accordance with our hypothesis that earlier age at infection is associated with worse outcomes in addition to its effect of increasing the probability of chronic HBV infection. This has implications for the control of hepatitis B. [ABSTRACT FROM AUTHOR]

Over the past three decades, L-proline has become recognized as an important metabolite for trypanosomatids. It is involved in a number of key processes, including energy metabolism, resistance to oxidative and nutritional stress and osmoregulation. In addition, this amino acid supports critical parasite life cycle processes by acting as an energy source, thus enabling host-cell invasion by the parasite and subsequent parasite differentiation. In this paper, we demonstrate that L-proline is oxidized to Δ1-pyrroline-5-carboxylate (P5C) by the enzyme proline dehydrogenase (TcPRODH, E.C. 1.5.99.8) localized in Trypanosoma cruzi mitochondria. When expressed in its active form in Escherichia coli, TcPRODH exhibits a Km of 16.58±1.69 µM and a Vmax of 66±2 nmol/min mg. Furthermore, we demonstrate that TcPRODH is a FAD-dependent dimeric state protein. TcPRODH mRNA and protein expression are strongly upregulated in the intracellular epimastigote, a stage which requires an external supply of proline. In addition, when Saccharomyces cerevisiae null mutants for this gene (PUT1) were complemented with the TcPRODH gene, diminished free intracellular proline levels and an enhanced sensitivity to oxidative stress in comparison to the null mutant were observed, supporting the hypothesis that free proline accumulation constitutes a defense against oxidative imbalance. Finally, we show that proline oxidation increases cytochrome c oxidase activity in mitochondrial vesicles. Overall, these results demonstrate that TcPRODH is involved in proline-dependant cytoprotection during periods of oxidative imbalance and also shed light on the participation of proline in energy metabolism, which drives critical processes of the T. cruzi life cycle. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) is one of the most variable and gene-dense regions of the human genome. Most studies of the MHC, and associated regions, focus on minor variants and HLA typing, many of which have been demonstrated to be associated with human disease susceptibility and metabolic pathways. However, the detection of variants in the MHC region, and diagnostic HLA typing, still lacks a coherent, standardized, cost effective and high coverage protocol of clinical quality and reliability. In this paper, we presented such a method for the accurate detection of minor variants and HLA types in the human MHC region, using high-throughput, high-coverage sequencing of target regions. A probe set was designed to template upon the 8 annotated human MHC haplotypes, and to encompass the 5 megabases (Mb) of the extended MHC region. We deployed our probes upon three, genetically diverse human samples for probe set evaluation, and sequencing data show that ∼97% of the MHC region, and over 99% of the genes in MHC region, are covered with sufficient depth and good evenness. 98% of genotypes called by this capture sequencing prove consistent with established HapMap genotypes. We have concurrently developed a one-step pipeline for calling any HLA type referenced in the IMGT/HLA database from this target capture sequencing data, which shows over 96% typing accuracy when deployed at 4 digital resolution. This cost-effective and highly accurate approach for variant detection and HLA typing in the MHC region may lend further insight into immune-mediated diseases studies, and may find clinical utility in transplantation medicine research. This one-step pipeline is released for general evaluation and use by the scientific community. [ABSTRACT FROM AUTHOR]

Background: India, with a population of more than 1.21 billion, has the highest maternal mortality in the world (estimated to be 56000 in 2010); and adolescent (aged 15–19) mortality shares 9% of total maternal deaths. Addressing the maternity care needs of adolescents may have considerable ramifications for achieving the Millennium Development Goal (MDG)–5. This paper assesses the socioeconomic differentials in accessing full antenatal care and professional attendance at delivery by adolescent mothers (aged 15–19) in India during 1990–2006. Methods and Findings: Data from three rounds of the National Family Health Survey of India conducted during 1992–93, 1998–99, and 2005–06 were analyzed. The Cochran-Armitage and Chi-squared test for linear and non-linear time trends were applied, respectively, to understand the trend in the proportion of adolescent mothers utilizing select maternity care services during 1990–2006. Using pooled multivariate logistic regression models, the probability of select maternal healthcare utilization among women by key socioeconomic characteristics was appraised. After adjusting for potential socio-demographic and economic characteristics, the likelihood of adolescents accessing full antenatal care increased by only 4% from 1990 to 2006. However, the probability of adolescent women availing themselves of professional attendance at delivery increased by 79% during the same period. The study also highlights the desolate disparities in maternity care services among adolescents across the most and the least favoured groups. Conclusion: Maternal care interventions in India need focused programs for rural, uneducated, poor adolescent women so that they can avail themselves of measures to delay child bearing, and for better antenatal consultation and delivery care in case of pregnancy. This study strongly advocates the promotion of a comprehensive ‘adolescent scheme’ along the lines of ‘Continuum of Maternal, Newborn and Child health Care’ to address the unmet need of reproductive and maternal healthcare services among adolescent women in India. [ABSTRACT FROM AUTHOR]

Background: Nearly half of births in low-income countries occur without a skilled attendant, and even fewer mothers and babies have postnatal contact with providers who can deliver preventive or curative services that save lives. Community-based maternal and newborn care programs with postnatal home visits have been tested in Bangladesh, Malawi, and Nepal. This paper examines coverage and content of home visits in pilot areas and factors associated with receipt of postnatal visits. Methods: Using data from cross-sectional surveys of women with live births (Bangladesh 398, Malawi: 900, Nepal: 615), generalized linear models were used to assess the strength of association between three factors - receipt of home visits during pregnancy, birth place, birth notification - and receipt of home visits within three days after birth. Meta-analytic techniques were used to generate pooled relative risks for each factor adjusting for other independent variables, maternal age, and education. Findings: The proportion of mothers and newborns receiving home visits within three days after birth was 57% in Bangladesh, 11% in Malawi, and 50% in Nepal. Mothers and newborns were more likely to receive a postnatal home visit within three days if the mother received at least one home visit during pregnancy (OR2.18, CI1.46–3.25), the birth occurred outside a facility (OR1.48, CI1.28–1.73), and the mother reported a CHW was notified of the birth (OR2.66, CI1.40–5.08). Checking the cord was the most frequently reported action; most mothers reported at least one action for newborns. Conclusions: Reaching mothers and babies with home visits during pregnancy and within three days after birth is achievable using existing community health systems if workers are available; linked to communities; and receive training, supplies, and supervision. In all settings, programs must evaluate what community delivery systems can handle and how to best utilize them to improve postnatal care access. [ABSTRACT FROM AUTHOR]

This paper aims to study the abnormal patterns of brain glucose metabolism co-variations in Alzheimer disease (AD) and Mild Cognitive Impairment (MCI) patients compared to Normal healthy controls (NC) using the Alzheimer Disease Neuroimaging Initiative (ADNI) database. The local cerebral metabolic rate for glucose (CMRgl) in a set of 90 structures belonging to the AAL atlas was obtained from Fluro-Deoxyglucose Positron Emission Tomography data in resting state. It is assumed that brain regions whose CMRgl values are significantly correlated are functionally associated; therefore, when metabolism is altered in a single region, the alteration will affect the metabolism of other brain areas with which it interrelates. The glucose metabolism network (represented by the matrix of the CMRgl co-variations among all pairs of structures) was studied using the graph theory framework. The highest concurrent fluctuations in CMRgl were basically identified between homologous cortical regions in all groups. Significant differences in CMRgl co-variations in AD and MCI groups as compared to NC were found. The AD and MCI patients showed aberrant patterns in comparison to NC subjects, as detected by global and local network properties (global and local efficiency, clustering index, and others). MCI network’s attributes showed an intermediate position between NC and AD, corroborating it as a transitional stage from normal aging to Alzheimer disease. Our study is an attempt at exploring the complex association between glucose metabolism, CMRgl covariations and the attributes of the brain network organization in AD and MCI. [ABSTRACT FROM AUTHOR]

Background: In Sub-Saharan Africa, policy changes have begun to pave the way for community distribution of injectable contraceptives but sustaining such efforts remains challenging. Combining social marketing with community-based distribution provides an opportunity to recover some program costs and compensate workers with proceeds from contraceptive sales. This paper proposes a model for increasing access to injectable contraceptives in rural settings by using community-based distributers as social marketing agents and incorporating financing systems to improve sustainability. Methods: This intervention was implemented in three districts of the Central Zone of Tigray, Ethiopia and program data has been collected from November 2011 through October 2012. A total of 137 Community Based Reproductive Health Agents (CBRHAs) were trained to provide injectable contraceptives and were provided with a loan of 25 injectable contraceptives from a drug revolving fund, created with project funds. The price of a single dose credited to a CBRHA was 3 birr ($0.17) and they provide injections to women for 5 birr ($0.29), determined with willingness-to-pay data. Social marketing was used to create awareness and generate demand. Both quantitative and qualitative methods were used to examine important feasibility aspects of the intervention. Results: Forty-four percent of CBRHAs were providing family planning methods at the time of the training and 96% believed providing injectable contraceptives would improve their services. By October 2012, 137 CBRHAs had successfully completed training and provided 2541 injections. Of total injections, 47% were provided to new users of injectable contraceptives. Approximately 31% of injections were given for free to the poorest women, including adolescents. Conclusions: Insights gained from the first year of implementation of the model provide a framework for further expansion in Tigray, Ethiopia. Our experience highlights how program planners can tailor interventions to match family planning preferences and create more sustainable contraceptive service provision with greater impact. [ABSTRACT FROM AUTHOR]

Background: Tobacco smoking (TS) and illicit drug use (IDU) are of public health concerns especially in developing countries, including Bangladesh. This paper aims to (i) identify the determinants of TS and IDU, and (ii) examine the association of TS with IDU among young slum dwellers in Bangladesh. Methodology/Principal Findings: Data on a total of 1,576 young slum dwellers aged 15–24 years were extracted for analysis from the 2006 Urban Health Survey (UHS), which covered a nationally representative sample of 13,819 adult men aged 15–59 years from slums, non-slums and district municipalities of six administrative regions in Bangladesh. Methods used include frequency run, Chi-square test of association and multivariable logistic regression. The overall prevalence of TS in the target group was 42.3%, of which 41.4% smoked cigarettes and 3.1% smoked bidis. The regression model for TS showed that age, marital status, education, duration of living in slums, and those with sexually transmitted infections were significantly (p<0.001 to p<0.05) associated with TS. The overall prevalence of IDU was 9.1%, dominated by those who had drug injections (3.2%), and smoked ganja (2.8%) and tari (1.6%). In the regression model for IDU, the significant (p<0.01 to p<0.10) predictors were education, duration of living in slums, and whether infected by sexually transmitted diseases. The multivariable logistic regression (controlling for other variables) revealed significantly (p<0.001) higher likelihood of IDU (OR = 9.59, 95% CI = 5.81–15.82) among users of any form of TS. The likelihood of IDU increased significantly (p<0.001) with increased use of cigarettes. Conclusions/Significance: Certain groups of youth are more vulnerable to TS and IDU. Therefore, tobacco and drug control efforts should target these groups to reduce the consequences of risky lifestyles through information, education and communication (IEC) programs. [ABSTRACT FROM AUTHOR]

This paper describes an automatic algorithm that uses a geometry-driven optimization approach to restore the shape of three-dimensional (3D) left ventricular (LV) models created from magnetic resonance imaging (MRI) data. The basic premise is to restore the LV shape such that the LV epicardial surface is smooth after the restoration and that the general shape characteristic of the LV is not altered. The Maximum Principle Curvature () and the Minimum Principle Curvature () of the LV epicardial surface are used to construct a shape-based optimization objective function to restore the shape of a motion-affected LV via a dual-resolution semi-rigid deformation process and a free-form geometric deformation process. A limited memory quasi-Newton algorithm, L-BFGS-B, is then used to solve the optimization problem. The goal of the optimization is to achieve a smooth epicardial shape by iterative in-plane and through-plane translation of vertices in the LV model. We tested our algorithm on 30 sets of LV models with simulated motion artifact generated from a very smooth patient sample, and 20 in vivo patient-specific models which contain significant motion artifacts. In the 30 simulated samples, the Hausdorff distances with respect to the Ground Truth are significantly reduced after restoration, signifying that the algorithm can restore geometrical accuracy of motion-affected LV models. In the 20 in vivo patient-specific models, the results show that our method is able to restore the shape of LV models without altering the general shape of the model. The magnitudes of in-plane translations are also consistent with existing registration techniques and experimental findings. [ABSTRACT FROM AUTHOR]

Designs of the double sampling (DS) chart are traditionally based on the average run length (ARL) criterion. However, the shape of the run length distribution changes with the process mean shifts, ranging from highly skewed when the process is in-control to almost symmetric when the mean shift is large. Therefore, we show that the ARL is a complicated performance measure and that the median run length (MRL) is a more meaningful measure to depend on. This is because the MRL provides an intuitive and a fair representation of the central tendency, especially for the rightly skewed run length distribution. Since the DS chart can effectively reduce the sample size without reducing the statistical efficiency, this paper proposes two optimal designs of the MRL-based DS chart, for minimizing (i) the in-control average sample size (ASS) and (ii) both the in-control and out-of-control ASSs. Comparisons with the optimal MRL-based EWMA and Shewhart charts demonstrate the superiority of the proposed optimal MRL-based DS chart, as the latter requires a smaller sample size on the average while maintaining the same detection speed as the two former charts. An example involving the added potassium sorbate in a yoghurt manufacturing process is used to illustrate the effectiveness of the proposed MRL-based DS chart in reducing the sample size needed. [ABSTRACT FROM AUTHOR]

The fact that smoking is bad for people’s health has become common knowledge, yet a substantial amount of people still smoke. Previous studies that sought to better understand this phenomenon have found that smoking is associated with the tendency to take risk in other areas of life as well. The current paper explores factors that may underlie this tendency. An experimental analysis shows that smokers are more easily tempted by immediate high rewards compared to nonsmokers. Thus the salience of risky alternatives that produce large rewards most of the time can direct smokers to make bad choices even in an abstract situation such as the Iowa Gambling Task. These findings suggest that the risk taking behavior associated with smoking is not related to the mere pursuit of rewards but rather reflects a tendency to yield to immediate temptation. [ABSTRACT FROM AUTHOR]

Background: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. Methods and Results: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i)As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13–0.67 and 0.20,0.09–0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50–0.93 and 0.55,0.28–1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57–0.92 and 0.43,0.22–0.83). ii)Mothers interested in probiotics or research or reporting infants’ adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9–13.1%) to 4.6%(−1.4–+10.5%), and OR from 0.40(0.18–0.91) to 0.56(0.26–1.21). Other findings were unchanged. Conclusions: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. Trial Registration: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children. [ABSTRACT FROM AUTHOR]

Experimental research in adult attachment theory is faced with the challenge to adequately activate the adult attachment system. In view of the multitude of methods employed for this purpose so far, this paper suggests to further make use of the methodological advantages of semantic priming. In order to enable the use of such a paradigm in a German speaking context, a set of German words belonging to the semantic categories ‘interpersonal closeness’, ‘interpersonal distance’ and ‘neutral’ were identified and their semantics were validated combining production- and rating method. 164 university students answered corresponding online-questionnaires. Ratings were analysed using analysis of variance (ANOVA) and cluster analysis from which three clearly distinct groups emerged. Beyond providing validated stimulus- and target words which can be used to activate the adult attachment system in a semantic priming paradigm, the results of this study point at important links between attachment and stress which call for further investigation in the future. [ABSTRACT FROM AUTHOR]

A major barrier for a broad applicability of brain-computer interfaces (BCIs) based on electroencephalography (EEG) is the large number of EEG sensor electrodes typically used. The necessity for this results from the fact that the relevant information for the BCI is often spread over the scalp in complex patterns that differ depending on subjects and application scenarios. Recently, a number of methods have been proposed to determine an individual optimal sensor selection. These methods have, however, rarely been compared against each other or against any type of baseline. In this paper, we review several selection approaches and propose one additional selection criterion based on the evaluation of the performance of a BCI system using a reduced set of sensors. We evaluate the methods in the context of a passive BCI system that is designed to detect a P300 event-related potential and compare the performance of the methods against randomly generated sensor constellations. For a realistic estimation of the reduced system's performance we transfer sensor constellations found on one experimental session to a different session for evaluation. We identified notable (and unanticipated) differences among the methods and could demonstrate that the best method in our setup is able to reduce the required number of sensors considerably. Though our application focuses on EEG data, all presented algorithms and evaluation schemes can be transferred to any binary classification task on sensor arrays. [ABSTRACT FROM AUTHOR]

Background: Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India. Methods: Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens. Results: Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification. Conclusions: 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB. Trial Registration: Clinical Trials Registry of India CTRI/2012/10/003060 [ABSTRACT FROM AUTHOR]

: The brain is able to maintain a stable perception although the visual stimuli vary substantially on the retina due to geometric transformations and lighting variations in the environment. This paper presents a theory for achieving basic invariance properties already at the level of receptive fields. Specifically, the presented framework comprises (i) local scaling transformations caused by objects of different size and at different distances to the observer, (ii) locally linearized image deformations caused by variations in the viewing direction in relation to the object, (iii) locally linearized relative motions between the object and the observer and (iv) local multiplicative intensity transformations caused by illumination variations. The receptive field model can be derived by necessity from symmetry properties of the environment and leads to predictions about receptive field profiles in good agreement with receptive field profiles measured by cell recordings in mammalian vision. Indeed, the receptive field profiles in the retina, LGN and V1 are close to ideal to what is motivated by the idealized requirements. By complementing receptive field measurements with selection mechanisms over the parameters in the receptive field families, it is shown how true invariance of receptive field responses can be obtained under scaling transformations, affine transformations and Galilean transformations. Thereby, the framework provides a mathematically well-founded and biologically plausible model for how basic invariance properties can be achieved already at the level of receptive fields and support invariant recognition of objects and events under variations in viewpoint, retinal size, object motion and illumination. The theory can explain the different shapes of receptive field profiles found in biological vision, which are tuned to different sizes and orientations in the image domain as well as to different image velocities in space-time, from a requirement that the visual system should be invariant to the natural types of image transformations that occur in its environment. [ABSTRACT FROM AUTHOR]

Segmentation of brain MR images plays an important role in longitudinal investigation of developmental, aging, disease progression changes in the cerebral cortex. However, most existing brain segmentation methods consider multiple time-point images individually and thus cannot achieve longitudinal consistency. For example, cortical thickness measured from the segmented image will contain unnecessary temporal variations, which will affect the time related change pattern and eventually reduce the statistical power of analysis. In this paper, we propose a 4D segmentation framework for the adult brain MR images with the constraint of cortical thickness variations. Specifically, we utilize local intensity information to address the intensity inhomogeneity, spatial cortical thickness constraint to maintain the cortical thickness being within a reasonable range, and temporal cortical thickness variation constraint in neighboring time-points to suppress the artificial variations. The proposed method has been tested on BLSA dataset and ADNI dataset with promising results. Both qualitative and quantitative experimental results demonstrate the advantage of the proposed method, in comparison to other state-of-the-art 4D segmentation methods. [ABSTRACT FROM AUTHOR]

Externally generated visual motion signals can cause the illusion of self-motion in space (vection) and corresponding visually evoked postural responses (VEPR). These VEPRs are not simple responses to optokinetic stimulation, but are modulated by the configuration of the environment. The aim of this paper is to explore what factors modulate VEPRs in a high quality virtual reality (VR) environment where real and virtual foreground objects served as static visual, auditory and haptic reference points. Data from four experiments on visually evoked postural responses show that: 1) visually evoked postural sway in the lateral direction is modulated by the presence of static anchor points that can be haptic, visual and auditory reference signals; 2) real objects and their matching virtual reality representations as visual anchors have different effects on postural sway; 3) visual motion in the anterior-posterior plane induces robust postural responses that are not modulated by the presence of reference signals or the reality of objects that can serve as visual anchors in the scene. We conclude that automatic postural responses for laterally moving visual stimuli are strongly influenced by the configuration and interpretation of the environment and draw on multisensory representations. Different postural responses were observed for real and virtual visual reference objects. On the basis that automatic visually evoked postural responses in high fidelity virtual environments should mimic those seen in real situations we propose to use the observed effect as a robust objective test for presence and fidelity in VR. [ABSTRACT FROM AUTHOR]

Background: This paper reports day-to-day data for from a one-week intervention phase, part of a 9-weeks randomised parallel study with patient having major depression (data from weekly visits have been reported). Wake therapy (sleep deprivation) has an established antidepressant effect with onset of action within hours. Deterioration on the following night’s sleep is, however, common, and we used daily light therapy and sleep time stabilisation as a preventive measure. In particular, we evaluated the day-to-day acute effect of and tolerance to sleep deprivation and examined predictors of response. Methods: Patients were assessed at psychiatric inpatient wards. In the wake group (n = 36), patients did three wake therapies in combination with light therapy each morning together with sleep time stabilisation. In the exercise group (n = 38), patients did daily exercise. Hamilton subscale scores were primary outcome (not blinded), secondary outcome was self-assessment data from the Preskorn scale and sleep. Results: Patients in the wake therapy group had an immediate, large, stable, and statistically significant better antidepressant effect than patients in the exercise group with response rates at day5 of 75.0%/25.1% and remission rates of 58.6%/6.0%, respectively. The response and remission rates were diminished at day8 with response rates of 41.9%/10.1% and remission rates of 19.4%/4.7%, respectively. Patients and ward personnel found the method applicable with few side effects. Positive diurnal variation (mood better in the evening) predicted a larger response to wake therapy. In the wake group napping on days after intervention predicted greater deterioration on day8. Conclusions: The intervention induced an acute antidepressant response without relapse between wake nights but with a diminishing effect after intervention. Development is still needed to secure maintenance of response. Avoiding napping in the days after wake therapy is important. Trial Registration: Clinical trials.gov NCT00149110 [ABSTRACT FROM AUTHOR]

Several studies have reported that interactions of mothers with preterm infants show differential characteristics compared to that of mothers with full-term infants. Interaction of preterm dyads is often reported as less harmonious. However, observations and explanations concerning the underlying mechanisms are inconsistent. In this work 30 preterm and 42 full-term mother-infant dyads were observed at one year of age. Free play interactions were videotaped and coded using a micro-analytic coding system. The video records were coded at one second resolution and studied by a novel approach using network analysis tools. The advantage of our approach is that it reveals the patterns of behavioral transitions in the interactions. We found that the most frequent behavioral transitions are the same in the two groups. However, we have identified several high and lower frequency transitions which occur significantly more often in the preterm or full-term group. Our analysis also suggests that the variability of behavioral transitions is significantly higher in the preterm group. This higher variability is mostly resulted from the diversity of transitions involving non-harmonious behaviors. We have identified a maladaptive pattern in the maternal behavior in the preterm group, involving intrusiveness and disengagement. Application of the approach reported in this paper to longitudinal data could elucidate whether these maladaptive maternal behavioral changes place the infant at risk for later emotional, cognitive and behavioral disturbance. [ABSTRACT FROM AUTHOR]

Objective: Excess mortality from diseases and medical conditions (natural death) in persons with psychiatric disorders has been extensively reported. Even in the Nordic countries with well-developed welfare systems, register based studies find evidence of an excess mortality. In recent years, cardiac mortality and death by diseases of the circulatory system has seen a decline in all the Nordic countries, but a recent paper indicates that women and men in Denmark, Finland, and Sweden, who had been hospitalised for a psychotic disorder, had a two to three-fold increased risk of dying from a cardiovascular disease. The aim of this study was to compare the mortality by diseases of the circulatory system among patients with bipolar disorder or schizophrenia in the three Nordic countries Denmark, Sweden, and Finland. Furthermore, the aim was to examine and compare life expectancy among these patients. Cause specific Standardized Mortality Rates (SMRs) were calculated for each specific subgroup of mortality. Life expectancy was calculated using Wiesler’s method. Results: The SMR for bipolar disorder for diseases of the circulatory system was approximately 2 in all countries and both sexes. SMR was slightly higher for people with schizophrenia for both genders and in all countries, except for men in Denmark. Overall life expectancy was much lower among persons with bipolar disorder or schizophrenia, with life expectancy being from 11 to 20 years shorter. Conclusion: Our data show that persons in the Nordic countries with schizophrenia or bipolar disorder have a substantially reduced life expectancy. An evaluation of the reasons for these increased mortality rates should be prioritized when planning healthcare in the coming years. [ABSTRACT FROM AUTHOR]

Network medicine has been applied successfully to elicit the structure of large-scale molecular interaction networks. Its main proponents have claimed that this approach to integrative medical investigation should make it possible to identify functional modules of interacting molecular biological units as well as interactions themselves. This paper takes a significant step in this direction. Based on a large-scale analysis of the nervous system molecular medicine literature, this study analyzes and visualizes the complex structure of associations between diseases on the one hand and all types of molecular substances on the other. From this analysis it then identifies functional co-association groups consisting of several types of molecular substances, each consisting of substances that exhibit a pattern of frequent co-association with similar diseases. These groups in turn exhibit interlinking in a complex pattern, suggesting that such complex interactions between functional molecular modules may play a role in disease etiology. We find that the patterns exhibited by the networks of disease – molecular substance associations studied here correspond well to a number of recently published research results, and that the groups of molecular substances identified by statistical analysis of these networks do appear to be interesting groups of molecular substances that are interconnected in identifiable and interpretable ways. Our results not only demonstrate that networks are a convenient framework to analyze and visualize large-scale, complex relationships among molecular networks and diseases, but may also provide a conceptual basis for bridging gaps in experimental and theoretical knowledge. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is the main cause of blindness in the developed world. The etiology of AMD is multifactorial due to the interaction between genetic and environmental factors. IL-8 has a role in inflammation and angiogenesis; we report the genetic characterization of IL-8 allele architecture and evaluate the role of SNPs or haplotypes in the susceptibility to wet AMD, case-control study. Methods: Case-control study including 721 AMD patients and 660 controls becoming from Italian population. Genotyping was carried out by Real Time-PCR. Differences in the frequencies were estimated by the chi-square test. Direct sequencing was carried out by capillary electrophoresis trough ABI3130xl. Results: rs2227306 showed a p–value of 4.15*10−5 and an Odds Ratio (OR) for T allele of 1.39 [1.19–1.62]. After these positive results, we sequenced the entire IL-8 regulatory and coding regions of 60 patients and 30 controls stratified for their genotype at rs2227306. We defined two different haplotypes involving rs4073 (A/T), rs2227306 (C/T), rs2227346 (C/T) and rs1126647 (A/T): A-T-T-T (p-value: 2.08*10−9; OR: 1.68 [1.43–1.97]) and T-C-C-A (p-value: 7.07*10−11; OR: 0.60 [0.51–0.70]). To further investigate a potential functional role of associated haplotypes, we performed an expression study on RNA extracted from whole blood of 75 donors to verify a possible direct correlation between haplotype and gene expression, failing to reveal significant differences. Conclusions: These results suggest a possible secondary role of IL-8 gene in the development of the disease. This paper outlines the importance of association between inflammation and AMD. Moreover IL-8 is a new susceptibility genomic biomarker of AMD. [ABSTRACT FROM AUTHOR]

Aim: To investigate the personality in very preterm individuals (VPT; gestational age, GA, <32 weeks) at adult age in two cohorts born in 1974–76 and 1980–82, respectively, and to illuminate the effect of increased survival rates and the clinical implications of deviations in personality. Method: Demographic data were extracted for all individuals born in Denmark in 1974–76 and 1980–82. From each period one index-group each comprising 150 individuals with the lowest gestational age was selected. Thereafter two control groups born at term were matched by gender, age and residential area. Personality was assessed with the short version of NEO PI-R, and psychiatric diagnoses were obtained from the Danish Psychiatric Central Research Register. Results: Of all the individuals born <32 weeks of gestation in 1980–82 67% were alive in 2006 vs. 43% of those born in 1974–76 (p<0.0001). A total of 433 individuals participated in the study, 76% of the VPT groups (n = 227, mean GA = 27.9) and 69% of the control groups (n = 206). There were no significant differences on personality scores between the two VPT groups. Compared to the control groups, the combined VPT groups scored higher on neuroticism (p = 0.005) and agreeableness (p = 0.012), but lower on extraversion (p = 0.002). Psychiatric disorder was strongly associated with higher scores on neuroticism and lower scores on extraversion. Interpretation: Improved survival of VPT infants was not associated with increased deviances in the personality as adults. The personality traits in VPT individuals differ moderately from those of term born controls. High scores in neuroticism and low scores in extraversion were associated with increased risk psychiatric disorders. VPT adults also showed signs of positive adaptation in the form of an agreeable and confident attitude towards others. What this paper adds: The much improved survival rate in very preterm infants during the early years of active neonatology was not associated with increased risk of personality deviation. There are signs of positive adaptation in the form of increased agreeableness in young adults born very preterm. [ABSTRACT FROM AUTHOR]

France implemented a comprehensive smoke-free law in two phases: Phase 1 (February 2007) banned smoking in workplaces, shopping centres, airports, train stations, hospitals, and schools; Phase 2 (January 2008) banned smoking in hospitality venues (bars, restaurants, hotels, casinos, nightclubs). This paper evaluates France’s smoke-free law based on the International Tobacco Control Policy Evaluation Project in France (the ITC France Project), which conducted a cohort survey of approximately 1,500 smokers and 500 non-smokers before the implementation of the laws (Wave 1) and two waves after the implementation (Waves 2 and 3). Results show that the smoke-free law led to a very significant and near-total elimination of observed smoking in key venues such as bars (from 94–97% to 4%) and restaurants (from 60–71% to 2–3%) at Wave 2, which was sustained four years later (6–8% in bars; 1–2% in restaurants). The reduction in self-reported smoking by smoking respondents was nearly identical to the effects shown in observed smoking. Observed smoking in workplaces declined significantly after the law (from 41–48% to 18–20%), which continued to decline at Wave 3 (to 14–15%). Support for the smoke-free laws increased significantly after their implementation and continued to increase at Wave 3 (p<.001 among smokers for bars and restaurants; p<.001 among smokers and p = .003 for non-smokers for workplaces). The findings demonstrate that smoke-free policies that are implemented in ways consistent with the Guidelines for Article 8 of the WHO Framework Convention on Tobacco Control (WHO FCTC) lead to substantial and sustained reductions in indoor smoking while also leading to high levels of support by the public. Moreover, contrary to arguments by opponents of smoke-free laws, smoking in the home did not increase after the law was implemented and prevalence of smoke-free homes among smokers increased from 23.2% before the law to 37.2% 5 years after the law. [ABSTRACT FROM AUTHOR]

This paper is dedicated to the memory of our wonderful colleague Professor Alfredo Colonna, who passed away the same day of its acceptance. Fatty liver accumulation, inflammatory process and insulin resistance appear to be crucial in non-alcoholic fatty liver disease (NAFLD), nevertheless emerging findings pointed an important role also for iron overload. Here, we investigate the molecular mechanisms of hepatic iron metabolism in the onset of steatosis to understand whether its impairment could be an early event of liver inflammatory injury. Rats were fed with control diet or high fat diet (HFD) for 5 or 8 weeks, after which liver morphology, serum lipid profile, transaminases levels and hepatic iron content (HIC), were evaluated. In liver of HFD fed animals an increased time-dependent activity of iron regulatory protein 1 (IRP1) was evidenced, associated with the increase in transferrin receptor-1 (TfR1) expression and ferritin down-regulation. Moreover, ferroportin (FPN-1), the main protein involved in iron export, was down-regulated accordingly with hepcidin increase. These findings were indicative of an increased iron content into hepatocytes, which leads to an increase of harmful free-iron also related to the reduction of hepatic ferritin content. The progressive inflammatory damage was evidenced by the increase of hepatic TNF-α, IL-6 and leptin, in parallel to increased iron content and oxidative stress. The major finding that emerged of this study is the impairment of iron homeostasis in the ongoing and sustaining of liver steatosis, suggesting a strong link between iron metabolism unbalance, inflammatory damage and progression of disease. [ABSTRACT FROM AUTHOR]

The objectives of this paper are to predict life years lost associated with obesity-related diseases (ORDs) for U.S. non-smoking adults, and to examine the relationship between those ORDs and mortality. Data from the National Health Interview Survey, 1997–2000, were used. We employed mixed proportional hazard models to estimate the association between those ORDs and mortality and used simulations to project life years lost associated with the ORDs. We found that obesity-attributable comorbidities are associated with large decreases in life years and increases in mortality rates. The life years lost associated with ORDs is more marked for younger adults than older adults, for blacks than whites, for males than females, and for the more obese than the less obese. Using U.S. non-smoking adults aged 40 to 49 years as an example to illustrate percentage of the life years lost associated with ORDs, we found that the mean life years lost associated with ORDs for U.S. non-smoking black males aged 40 to 49 years with a body mass index above 40 kg/m2 was 5.43 years, which translates to a 7.5% reduction in total life years. White males of the same age range and same degree of obesity lost 5.23 life years on average – a 6.8% reduction in total life years, followed by black females (5.04 years, a 6.5% reduction in life years), and white females (4.7 years, a 5.8% reduction in life years). Overall, ORDs increased chances of dying and lessened life years by 0.2 to 11.7 years depending on gender, race, BMI classification, and age. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity (PA) typically declines throughout pregnancy. Low levels of PA are associated with excessive weight gain and subsequently increase risk of pre-eclampsia, gestational diabetes mellitus, hypertension disorders, delivery by caesarean section and stillbirth. Systematic reviews on PA during pregnancy have not explored the efficacy of behaviour change techniques or related theory in altering PA behaviour. This systematic review evaluated the content of PA interventions to reduce the decline of PA in pregnant women with a specific emphasis on the behaviour change techniques employed to elicit this change. Search and Review Methodology: Literature searches were conducted in eight databases. Strict inclusion and exclusion criteria were employed. Two reviewers independently evaluated each intervention using the behaviour change techniques (BCT) taxonomy to identify the specific behaviour change techniques employed. Two reviewers independently assessed the risk of bias using the guidelines from the Cochrane Collaboration. Overall quality was determined using the GRADE approach. Findings: A total of 1140 potentially eligible papers were identified from which 14 studies were selected for inclusion. Interventions included counselling (n = 6), structured exercise (n = 6) and education (n = 2). Common behaviour change techniques employed in these studies were goal setting and planning, feedback, repetition and substitution, shaping knowledge and comparison of behaviours. Regular face-to-face meetings were also commonly employed. PA change over time in intervention groups ranged from increases of 28% to decreases of 25%. In 8 out of 10 studies, which provided adequate data, participants in the intervention group were more physically active post intervention than controls. Conclusions and Implications: Physical activity interventions incorporating behaviour change techniques help reduce the decline in PA throughout pregnancy. Range of behaviour change techniques can be implemented to reduce this decline including goals and planning, shaping knowledge and comparison of outcomes. A lack of high quality interventions hampers conclusions of intervention effectiveness. [ABSTRACT FROM AUTHOR]

Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer′s disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention. [ABSTRACT FROM AUTHOR]