Human and rabbit inter-species comparison of ionic mechanisms of arrhythmic risk: A simulation study.
Experimental studies of pro-arrhythmic mechanisms are scarcely performed in humans due to the limited availability of human cardiomyocytes. Subsequently, extrapolation of animal experimental research to humans is widely extended. Our aim is to systematically compare the ionic mechanisms of the main cellular biomarkers of arrhythmic risk between human and rabbit using computer simulations. For this purpose four stimulation protocols were applied to the Mahajan et al. rabbit ventricular action potential (AP) model for control conditions and for ± 15 and ± 30% variations in the ionic current conductances of the main repolarization currents to quantify cellular biomarkers. Sensitivity of every simulated biomarker to every parameter modification was compared to that obtained for human in our previous work. Our results show that the ionic mechanisms involved in AP triangulation, systolic intracellular calcium concentration and AP duration (APD) accommodation to abrupt changes of pacing rate are very similar in both species. Unfortunately, significant differences were found in the ionic mechanisms related to APD, restitution properties and rate dependence of intracellular calcium and sodium concentrations. In conclusion, extrapolation of experimental research in rabbit to humans is limited by the existence of species dependent ionic mechanisms. In addition, this analysis is very useful for understanding and improvement of mathematical models.


Imaging of cell/substrate contacts on polymers by total internal reflection fluorescence microscopy.
A simplified model of total internal reflection fluorescence (TIRF) emission of fluorescently labeled cell membranes [Reichert, W. M.; Truskey, G. A. J. Cell Sci. 1990, 96, 219-230] was used to determine the topography of the cell membrane in apposition to a polymer-coated surface. The homopolymer substrates were spun cast films of hydrophilic poly(hydroxyethyl methacrylate) (polyHEMA) or hydrophobic poly(ethyl methacrylate) (polyEMA). Bovine aortic endothelial cells (BAEC) on preadsorbed fibronectin polymer substrates were either plated for 24 h, fixed, labeled, and examined by TIRF microscopy (TIRFM) and phase-contrast microscopy or plated for 2 h and tested for their adhesion strength in a parallel-plate flow chamber. BAEC attached to polyHEMA showed no evidence of focal contact formation. However, BAEC attached to polyEMA were well spread and showed an array of focal contacts. TIRFM data were transformed to construct a detailed topographical map of relative cell/substrate separation distances. Virtually all of the BAEC plated to polyHEMA were sheared from the surface when subjected to a 50 dyn/cm2 burst of laminar flow, whereas only 10% of the BAEC were sheared from the polyEMA surface. These data suggest that the polyHEMA and polyEMA surface properties (e.g., hydrophobicity) correlate with the presence of BAEC focal contacts and the BAEC attachment strength.


Being Poorer Than the Rest of the Neighborhood: Relative Deprivation and Problem Behavior of Youth.
According to the neighborhood effects hypothesis, there is a negative relation between neighborhood wealth and youth's problem behavior. It is often assumed that there are more problems in deprived neighborhoods, but there are also reports of higher rates of behavioral problems in more affluent neighborhoods. Much of this literature does not take into account relative wealth. Our central question was whether the economic position of adolescents' families, relative to the neighborhood in which they lived, was related to adolescents' internalizing and externalizing problem behavior. We used longitudinal data for youth between 12-16 and 16-20 years of age, combined with population register data (N = 926; 55% females). We employ between-within models to account for time-invariant confounders, including parental background characteristics. Our findings show that, for adolescents, moving to a more affluent neighborhood was related to increased levels of depression, social phobia, aggression, and conflict with fathers and mothers. This could be indirect evidence for the relative deprivation mechanism, but we could not confirm this, and we did not find any gender differences. The results do suggest that future research should further investigate the role of individuals' relative position in their neighborhood in order not to overgeneralize neighborhood effects and to find out for whom neighborhoods matter.


Effect of Ag Thin Films on the Photoluminescence of ZnO Films.
The Ag-coated ZnO films were deposited on glass substrates using magnetron sputtering technique. Atomic Force Microscopy was employed to characterize the surface and the profile roughness of Ag-coated ZnO films. X-ray diffraction and X-ray photoelectron were used respectively to analyze the crystalline and chemical state of survey samples. The influence of capping Ag on the photoluminescence intensities of ZnO films has been investigated. The photoluminescence spectra were found to change as the deposited Ag varied with different deposition times and annealing temperatures. Relationships between the fabrication, characterization and performance of Ag-coated ZnO films are established. The results indicate that the diffusion of Ag into ZnO films and the upward bending of the energy band near the interface of ZnO/Ag led to the decrease of ultraviolet intensities of Ag-coated ZnO films. Due to the density of surface states on the bending of energy band, it is crucial to control the surface morphology of metal/ZnO for the enhancement of light emission.


Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES).
Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.


Impact of tissue correction strategy on GABA-edited MRS findings.
Tissue composition impacts the interpretation of magnetic resonance spectroscopy metabolite quantification. The goal of applying tissue correction is to decrease the dependency of metabolite concentrations on the underlying voxel tissue composition. Tissue correction strategies have different underlying assumptions to account for different aspects of the voxel tissue fraction. The most common tissue correction is the CSF-correction that aims to account for the cerebrospinal fluid (CSF) fraction in the voxel, in which it is assumed there are no metabolites. More recently, the α-correction was introduced to account for the different concentrations of GABA+in gray matter and white matter. In this paper, we show that the selected tissue correction strategy can alter the interpretation of results using data from a healthy aging cohort with GABA+ measurements in a frontal and posterior voxel. In a frontal voxel, we show an age-related decline in GABA+ when either no tissue correction (R2 = 0.25, p < 0.001) or the CSF-correction is applied (R2 = 0.08, p < 0.01). When applying the α-correction to the frontal voxel data, we find no relationship between age and GABA+ (R2 = 0.02, p = 0.15). However, with the α-correction we still find that cognitive performance is correlated with GABA+ (R2 = 0.11, p < 0.01). These data suggest that in healthy aging, while there is normal atrophy in the frontal voxel, GABA+ in the remaining tissue is not decreasing on average. This indicates that the selection of tissue correction can significantly impact the interpretation of MRS results.


Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts.
The antral follicle count (AFC) and anti-Müllerian hormone (AMH) both represent age-related follicular decline quite accurately, although long-term follow-up studies are still lacking. The best ovarian reserve test would need only a single, cycle-independent measurement to be representative. To compare the inter- and intra-cycle stability of AFC and AMH, we used age-adjusted intra-class correlation coefficients (ICCs). To measure inter-cycle stability across a number of up to four menstrual cycles, we used data, prospectively collected for the purpose of an other study, from 77 regularly cycling, infertile women aged 24-40 years. AMH and AFC values were measured on cycle day 3. To study intra-cycle variability, we used data from a prospective cohort study of 44 regularly cycling volunteers, aged 25-46 years and measured AMH and assessed the AFC (2-10 mm) every 1-3 cycle days. Between menstrual cycles, AFC and AMH varied between 0 and 25 follicles (median 10), and 0.3 and 27.1 ng/ml (median 4.64). The difference in age-adjusted ICC between AMH [ICC, 0.89 (95% CI, 0.84-0.94)] and AFC [ICC, 0.71 (95% CI, 0.63-0.77)] was 0.18 (95% CI, 0.12-0.27). For the intra-cycle variation, 0-43 antral follicles (median 7) were counted per volunteer. The difference in age-adjusted ICC between AMH [ICC, 0.87 (95% CI, 0.82-0.91)] and AFC [ICC, 0.69 (95% CI, 0.46-0.82)] was 0.18 (95% CI, 0.034-0.42). Serum AMH demonstrated less individual intra- and inter-cycle variation than AFCs and may therefore be considered a more reliable and robust means of assessing ovarian reserve in subfertile women.


The Clock Genes Are Involved in The Deterioration of Atopic Dermatitis after Day-and-Night Reversed Physical Stress in NC/Nga Mice.
In modern society, irregular lifestyles are a problem. It is well known that Atopic Dermatitis (AD) occurs during physical stress in people with an irregular lifestyle. We evaluated the influence that day-and-night reversal physical stress has on AD. Six-week-old specific-pathogen-free and conventional NC/Nga male mice were used. For the day-and-night reversal procedure, the mice ran on a treadmill at a slow speed of 10 m/min for 12 h (between 8:00 and 20:00). Then, between 20:00 and 8:00, we put the mice in a dark place. This treatment was repeated every day for two weeks. The behavioral circadian rhythm of the mice was evaluated with the open field test. Then, the mice were sacrificed and histological examinations of the tissues, the expression of peptide hormones, corticosterone, Immunoglobulin E, histamine, and cytokines was performed using an enzyme-linked immunosorbent assay. In the treadmill-treated conventional NC/Nga mice, AD symptoms were deteriorated compared with the non-treated conventional NC/Nga mice. The levels of Period (Per) 2, Clock, and brain and muscle arnt-like protein 1 (Bmal1) in the skin were increased constantly in the treadmill-treated conventional mice. Furthermore, the expression of Retinoic Acid-related Orphan Receptor (ROR)α, which activates Bmal1, was increased in the treadmill-treated conventional mice compared with the non-treated conventional mice. In addition, when non-treated conventional mice were administrated by the agonist of RORα, AD symptoms were deteriorated similar to treadmill-treated conventional mice. In the day-and-night reversal mice, the clock genes were increased constantly, indicating that this is a factor that deteriorated AD.


Study of layer-by-layer self-assembled viscoelastic films on thickness-shear mode resonator surfaces.
We describe quartz crystal electroacoustic admittance studies in thickness shear mode resonators loaded with self-assembled multilayers composed of alternate layers of glucose oxidase (GOx) and poly(allylamine) covalently attached to [Os(bpy)2ClPyCOH]- , (PAH-Os), deposited on a 3-mercaptopropanesulfonic acid (MPS)-modified gold on the quartz crystal. The complex acoustic impedance parameters, R(S) and X(LS) of a lumped-element Butterworth-Van Dyke (BVD) resonator have been determined for organized thin films of different thickness obtained by varying the number of enzyme layers, n, in (PAH-Os)n(GOx)n structures. The ellipsometric film thickness and mass for dry enzyme multilayer films and films in contact with water were evaluated, and the average film density was estimated. By combination of the estimated film thickness and density, the expression for the surface mechanical impedance of the lumped-element modified resonator (Granstaff and Martin model), and the liquid density and viscosity, we simulate the layer-by-layer film growth on the basis of the measured electroacoustic impedance. The complex impedance X(LS) and R(S) increase with film thickness and the enzyme films can be regarded as acoustically thin in the reduced state for films thinner than 600 nm. We have also measured electroacoustic parameters for PAH-Os/GOx self-assembled multilayers under electrochemical perturbation in a buffer electrolytic solution. The electrostatically self-assembled multilayers behaved as lossy viscoelastic films at 10 MHz with G'f and G''f on the order of 10(6) Pa. The films became viscoelastic upon oxidation to Os(III), resulting in an increase of R(S) and X(LS) in the oxidized state with the number of (PAH-Os)(GOx) bilayers due to film swelling and an increase in the shear moduli during oxidation.


RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation.
The RAD51 paralogues act in the homologous recombination (HR) pathway of DNA repair. Human RAD51C (hRAD51C) participates in branch migration and Holliday junction resolution and thus is important for processing HR intermediates late in the DNA repair process. Evidence for early involvement of RAD51 during DNA repair also exists, but its function in this context is not understood. In this study, we demonstrate that RAD51C accumulates at DNA damage sites concomitantly with the RAD51 recombinase and is retained after RAD51 disassembly, which is consistent with both an early and a late function for RAD51C. RAD51C recruitment depends on ataxia telangiectasia mutated, NBS1, and replication protein A, indicating it functions after DNA end resection but before RAD51 assembly. Furthermore, we find that RAD51C is required for activation of the checkpoint kinase CHK2 and cell cycle arrest in response to DNA damage. This suggests that hRAD51C contributes to the protection of genome integrity by transducing DNA damage signals in addition to engaging the HR machinery.


Host-pathogen interactions between the human innate immune system and Candida albicans-understanding and modeling defense and evasion strategies.
The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.


Using a Dedicated Interventional Pulmonology Practice Decreases Wait Time Before Treatment Initiation for New Lung Cancer Diagnoses.
While there is significant mortality and morbidity with lung cancer, early stage diagnoses carry a better prognosis. As lung cancer screening programs increase with more pulmonary nodules detected, expediting definitive treatment initiation for newly diagnosed patients is imperative. The objective of our analysis was to determine if the use of a dedicated interventional pulmonology practice decreases time delay from new diagnosis of lung cancer or metastatic disease to the chest to treatment initiation. Retrospective chart analysis was done of 87 consecutive patients with a new diagnosis of primary lung cancer or metastatic cancer to the chest from our interventional pulmonology procedures. Demographic information and time intervals from abnormal imaging to procedure and to treatment initiation were recorded. Patients were older (mean age 69) and former or current smokers (72%). A median of 27 days (1-127 days) passed from our diagnostic biopsy to treatment initiation. A median of 53 total days (2-449 days) passed from abnormal imaging to definitive treatment. Endobronchial ultrasound-guided transbronchial needle aspiration was the most commonly used diagnostic procedure (59%), with non-small cell lung cancer the majority diagnosis (64%). For surgical patients, all biopsy-negative lymph nodes from our procedures were cancer-free at surgical excision. Compared to prior reports from international and United States cohorts, obtaining a tissue biopsy diagnosis through a gatekeeper interventional pulmonology practice decreases median delay from abnormal imaging to treatment initiation. This finding has the potential to positively impact patient outcomes and requires further evaluation.


Vocal tract characteristics in Parkinson's disease.
Voice tremor is strongly linked to the Parkinson's disease speech-voice symptom complex. Little is known about the underlying anatomic source(s) of voice tremor when it occurs. We review recent literature addressing this issue. Additionally we report findings from a study we conducted employing rating of vocal tract structures viewed using nasolaryngoscopy during vocal and nonspeech tasks. In Parkinson's disease, using laryngeal electromyography, tremor has not been identified in muscles in the vocal folds even when perceived auditorily. Preliminary findings using nasolaryngoscopy suggest that Parkinson's disease voice tremor is not associated with the vocal folds and may involve the palate, the global larynx, and the arytenoids. Tremor in the vertical larynx on /a/, and tremor in the arytenoid cartilages on /s/ differentiated patients with Parkinson's disease from neurologically healthy controls. Visual reliable detection of tremor when it is absent or borderline present, is challenging. Parkinson's disease voice tremor is likely to be related to oscillatory movement in structures across the vocal tract rather than just the vocal folds. To progress clinical practice, more refined tools for the visual rating of tremor would be beneficial. How far voice tremor represents a functionally significant factor for speakers would also add to the literature.


Enhancement of in vitro cytopathogenicity by Acanthamoeba spp. following acquisition of bacterial endosymbionts.
Approximately one in five isolates of Acanthamoeba spp. recovered from clinical and environmental sources are found to harbor obligate, uncultured bacterial endosymbionts of unknown clinical significance. To investigate their possible role in amoebic pathogenesis, four uninfected amoebic strains were exposed to four different endosymbionts, from which 12 stably-infected host-symbiont pairs resulted. Standardized inocula of amoebae with and without endosymbionts were placed on fibroblast monolayers to examine for cytopathic effects (CPEs). Eight to 10 days were required for monolayer effacement by endosymbiont-free amoebae; 5-8 days for amoebae containing Gram-negative rod endosymbionts; and 3 days for two amoebic isolates infected with a Chlamydia-like endosymbiont. All endosymbiont-infected amoebae produced a statistically significant enhancement in CPEs in comparison to uninfected amoebae; endosymbionts alone on monolayers produced no CPEs. This report provides evidence that obligate bacterial endosymbionts are able to enhance amoebic pathogenic potential in vitro by some as-yet unknown mechanism.


Australian women's awareness of ovarian cancer symptoms, risk and protective factors, and estimates of own risk.
To examine Australian women's perceived risk of ovarian cancer, reasons for perceived risk levels, and knowledge of ovarian cancer symptoms at two timepoints (2003 and 2007). A computer-assisted telephone (CATI) survey of 2,954 Australian women with no history of ovarian cancer was conducted. Approximately 60% of women perceived their risk of ovarian cancer was similar to other women of their age; 10% indicated an increased risk, and 30% indicated a lower risk. These figures were similar in 2003 and 2007. Logistic regression found that lower income, increased age, being born overseas, and being retired were significantly associated with lower perceived risk (accounted for only 7.5% of the variance). Common reasons for higher perceived risk included family history of ovarian/other cancers, increasing age, and having had other types of cancer or health problems. Reasons for lower than average risk included absence of family history, having a hysterectomy, and having regular Pap smears (indicating confusion between ovarian and cervical cancer). There appeared to be substantial confusion in women's understanding of ovarian cancer symptoms; this was similar in 2003 and 2007. The observed misperceptions and confusion regarding ovarian cancer symptoms and risk factors suggest ongoing public education campaigns are needed to improve knowledge and awareness.


One-Pot, Large-Scale Synthesis of Organic Color Center-Tailored Semiconducting Carbon Nanotubes.
Organic color center-tailored semiconducting single-walled carbon nanotubes are a rising family of synthetic quantum emitters that display bright defect photoluminescence molecularly tunable for imaging, sensing, and quantum information processing. A major advance in this area would be the development of a high-yield synthetic route that is capable of producing these materials well exceeding the current μg/mL scale. Here, we demonstrate that adding a chlorosulfonic acid solution of raw carbon nanotubes, sodium nitrite, and an aniline derivative into water readily leads to the synthesis of organic color center-tailored nanotubes. This unexpectedly simple one-pot reaction is highly scalable (yielding hundreds of milligrams of materials in a single run), efficient (reaction completes in seconds), and versatile (achieved the synthesis of organic color centers previously unattainable). The implanted organic color centers can be easily tailored by choosing from the more than 40 aniline derivatives that are commercially available, including many fluoroaniline and aminobenzoic acid derivatives, and that are difficult to convert into diazonium salts. We found this chemistry works for all the nanotube chiralities investigated. The synthesized materials are neat solids that can be directly dispersed in either water or an organic solvent by a surfactant or polymer depending on the specific application. The nanotube products can also be further sorted into single chirality-enriched fractions with defect-specific photoluminescence that is tunable over ∼1100 to ∼1550 nm. This one-pot chemistry thus provides a highly scalable synthesis of organic color centers for many potential applications that require large quantities of materials.


Past dust and GAS/FUME exposure and COPD in Chinese: the Guangzhou Biobank Cohort Study.
The impact of occupational dust and gas/fume exposure on chronic obstructive pulmonary disease (COPD) in developing countries has not been quantified. We examined the relationship between past dust and fume exposure and prevalence of COPD and respiratory symptoms in a cross-sectional analysis of a large Chinese population sample. Participants in the Guangzhou Biobank Cohort Study (n = 8216; 27.3% men, mean age 61.9 ± 6.8 years) had spirometry and a structured interview including exposures, symptoms, and lifestyle. Self-reported intensity and duration of dust and gas/fume exposure was used to derive cumulative exposure. COPD was diagnosed from spirometry using lower limit of normal based on prediction equations. COPD was associated with high exposure to dust or gas/fume (exposed: 87/1206 v non-exposed: 191/3853; adjusted odds ratio: 1.41; 95% confidence interval (CI) 1.06, 1.87) with no evidence of effect modification by smoking. Respiratory symptoms were associated with exposures to dust and gas/fume, with adjusted odds ratios for chronic cough/phlegm of 1.57 (1.13, 2.17) and 1.39 (1.20, 1.60) for dyspnoea. The overall population attributable fraction for COPD due to occupational exposure was 10.4% (95% CI -0.9%, 19.5%). Occupational dust and gas/fume exposure is associated with an increased prevalence of COPD in this Chinese sample, independent of smoking. The population attributable fraction in Chinese is similar to that in Western populations.


Improving the accuracy and efficiency of identity-by-descent detection in population data.
Segments of indentity-by-descent (IBD) detected from high-density genetic data are useful for many applications, including long-range phase determination, phasing family data, imputation, IBD mapping, and heritability analysis in founder populations. We present Refined IBD, a new method for IBD segment detection. Refined IBD achieves both computational efficiency and highly accurate IBD segment reporting by searching for IBD in two steps. The first step (identification) uses the GERMLINE algorithm to find shared haplotypes exceeding a length threshold. The second step (refinement) evaluates candidate segments with a probabilistic approach to assess the evidence for IBD. Like GERMLINE, Refined IBD allows for IBD reporting on a haplotype level, which facilitates determination of multi-individual IBD and allows for haplotype-based downstream analyses. To investigate the properties of Refined IBD, we simulate SNP data from a model with recent superexponential population growth that is designed to match United Kingdom data. The simulation results show that Refined IBD achieves a better power/accuracy profile than fastIBD or GERMLINE. We find that a single run of Refined IBD achieves greater power than 10 runs of fastIBD. We also apply Refined IBD to SNP data for samples from the United Kingdom and from Northern Finland and describe the IBD sharing in these data sets. Refined IBD is powerful, highly accurate, and easy to use and is implemented in Beagle version 4.


Atmospheric refraction effects on optical-infrared sensor performance in a littoral-maritime environment.
During a number of transmission experiments over littoral waters, quantitative measurements of atmospheric refraction phenomena were carried out to determine the range performance of optical-IR sensors. Examples of distortion and intensity gain generated by spatial variations of the atmospheric refractive index are shown. A high-precision ray-tracing model has been developed for better understanding of the phenomena and to satisfy the requirements for accuracy of the meteorological data used in refraction models. The output of the model includes the propagation function, the intensity gain, and details of the ray curvature and of the optical phase behavior along the path between the target and the observer. Examples of measured transmission data and their interpretation are presented.


Supporting the psychological needs of teenagers and young adults during cancer treatment: a literature review.
The developmental period of the teenage years and young adulthood can be a challenging time for most. Experiencing a diagnosis of cancer during this time inevitably presents further challenges and concerns. Identifying such issues can help to provide better ways of understanding the patients' experience and their needs, offering nurses insight to enhance care and support for teenagers and young adults (TYAs) undergoing cancer treatments. To explore the literature regarding the psychological issues faced by TYAs during cancer treatment to inform nursing practice. A systematic search of electronic databases was conducted using predetermined search terms which yielded relevant articles. Applying an inclusion and exclusion criteria identified six articles that were deemed appropriate to explore the focus question. A thematic analysis identified three main themes and five sub-themes: anxieties about treatment, concerns regarding the impact on life (feeling restricted and different, the benefits of being sick, facing uncertainty) and coping strategies (positive thinking and problem solving, support). Teenagers and young adults face a unique set of psychological concerns and challenges during cancer treatment, resulting in the development of specific coping strategies. These strategies should be promoted by nurses, ensuring patients are supported throughout their cancer journey.


Adapting an Ergosterol Extraction Method with Marine Yeasts for the Quantification of Oceanic Fungal Biomass.
Ergosterol has traditionally been used as a proxy to estimate fungal biomass as it is almost exclusively found in fungal lipid membranes. Ergosterol determination has been mostly used for fungal samples from terrestrial, freshwater, salt marsh- and mangrove-dominated environments or to describe fungal degradation of plant matter. In the open ocean, however, the expected concentrations of ergosterol are orders of magnitude lower than in terrestrial or macrophyte-dominated coastal systems. Consequently, the fungal biomass in the open ocean remains largely unknown. Recent evidence based on microscopy and -omics techniques suggests, however, that fungi contribute substantially to the microbial biomass in the oceanic water column, highlighting the need to accurately determine fungal biomass in the open ocean. We performed ergosterol extractions of an oceanic fungal isolate (Rhodotorula sphaerocarpa) with biomass concentrations varying over nine orders of magnitude. While after the initial chloroform-methanol extraction ~87% of the ergosterol was recovered, a second extraction recovered an additional ~10%. Testing this extraction method on samples collected from the open Atlantic Ocean, we successfully determined ergosterol concentrations as low as 0.12 pM. Thus, this highly sensitive method is well suited for measuring fungal biomass from open ocean waters, including deep-sea environments.


Mathematical modeling of the eukaryotic heat-shock response: dynamics of the hsp70 promoter.
The heat-shock response in humans and other eukaryotes is a highly conserved genetic network that coordinates the cellular response to protein damage and is essential for adaptation and survival of the stressed cell. It involves an immediate and transient activation of heat-shock transcription factor-1 (HSF1) which results in the elevated expression of genes encoding proteins important for protein homeostasis including molecular chaperones and components of the protein degradative machinery. We have developed a mathematical model of the critical steps in the regulation of HSF1 activity to understand how chronic exposure to a stress signal is converted into specific molecular events for activation and feedback regulated attenuation of HSF1. The model is utilized to identify the most sensitive steps in HSF1 activation and to evaluate how these steps affect the expression of molecular chaperones. This analysis allows the formulation of hypotheses about the differences between the heat-shock responses in yeast and humans and generates a model with predictive abilities relevant to diseases associated with the accumulation of damaged and aggregated proteins including cancer and neurodegenerative diseases.


Antibody response after immunization with the gangliosides GM1, GM2, GM3, GD2 and GD3 in the mouse.
The gangliosides GM2, GD2 and GD3 are differentiation antigens expressed on the cell surface of human melanomas and other cancers of neuroectodermal origin. We have compared the antibody response after vaccination with gangliosides GM1, GM2, GM3, GD2 and GD3 in the mouse. Purified gangliosides were injected subcutaneously alone or attached to Salmonella minnesota mutant R595 after pretreatment of the mice with low-dose cyclophosphamide. Spontaneous GM1 antibodies, but not antibodies against the other gangliosides, were detected in many mice, the incidence increasing with age. Purified gangliosides injected alone (in saline) induced no antibody response. R595/GM1 and R595/GD3 vaccination induced consistent high-titer antibody responses. R595/GM2 and R595/GD2 induced occasional antibody responses, and R595/GM3 induced no antibody response. Comparison of the antibody responses induced against these gangliosides in the mouse with those in man reveals that GM1, GM3 and GD2 have a similar immunogenicity in both species while the relative immunogenicity of GM2 and GD3 is reversed. To understand better the basis for these differences, the antibody responses against the five gangliosides in man and the mouse were compared with their known expression in normal tissues. No correlation was detected between ganglioside expression in normal brain and immunogenicity, consistent with this being a cloistered site. The antibody responses did correlate inversely with expression in normal non-brain human and murine tissues. Variations between species of ganglioside immunogenicity may reflect variations in ganglioside expression in normal tissues.


New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients.
Accurate stage determination is crucial in the choice of treatment for patients suffering from sleeping sickness, also known as human African trypanosomiasis (HAT). Current staging methods, based on the counting of white blood cells (WBC) and the detection of parasites in the cerebrospinal fluid (CSF) have limited accuracy. We hypothesized that immune mediators reliable for staging T. b. gambiense HAT could also be used to stratify T. b. rhodesiense patients, the less common form of HAT.A population comprising 85 T. b. rhodesiense patients, 14 stage 1 (S1) and 71 stage 2 (S2) enrolled in Malawi and Uganda, was investigated. The CSF levels of IgM, MMP-9, CXCL13, CXCL10, ICAM-1, VCAM-1, neopterin and B2MG were measured and their staging performances evaluated using receiver operating characteristic (ROC) analyses.IgM, MMP-9 and CXCL13 were the most accurate markers for stage determination (partial AUC 88%, 86% and 85%, respectively). The combination in panels of three molecules comprising CXCL13-CXCL10-MMP-9 or CXCL13-CXCL10-IgM significantly increased their staging ability to partial AUC 94% (p value < 0.01).The present study highlighted new potential markers for stage determination of T. b. rhodesiense patients. Further investigations are needed to better evaluate these molecules, alone or in panels, as alternatives to WBC to make reliable choice of treatment.


SPINE 2: a system for collaborative structural proteomics within a federated database framework.
We present version 2 of the SPINE system for structural proteomics. SPINE is available over the web at http://nesg.org. It serves as the central hub for the Northeast Structural Genomics Consortium, allowing collaborative structural proteomics to be carried out in a distributed fashion. The core of SPINE is a laboratory information management system (LIMS) for key bits of information related to the progress of the consortium in cloning, expressing and purifying proteins and then solving their structures by NMR or X-ray crystallography. Originally, SPINE focused on tracking constructs, but, in its current form, it is able to track target sample tubes and store detailed sample histories. The core database comprises a set of standard relational tables and a data dictionary that form an initial ontology for proteomic properties and provide a framework for large-scale data mining. Moreover, SPINE sits at the center of a federation of interoperable information resources. These can be divided into (i) local resources closely coupled with SPINE that enable it to handle less standardized information (e.g. integrated mailing and publication lists), (ii) other information resources in the NESG consortium that are inter-linked with SPINE (e.g. crystallization LIMS local to particular laboratories) and (iii) international archival resources that SPINE links to and passes on information to (e.g. TargetDB at the PDB).


First Report of Basal Stem Rot of Apple Cactus (Cereus peruvianus monstruosus) Caused by Fusarium oxysporum in Italy.
During the summer of 2010, 20% of 7,000 4-month-old plants of apple cactus (Cereus peruvianus monstruosus) showed symptoms of a basal stem rot in a commercial nursery located in Liguria (northern Italy). Affected plants showed yellow orange-to-pale brown color from the crown level to the stem apex and a water-soaked rot was observed on the stem starting from the base. Brown discoloration was observed in the vascular system. Eventually stems bent, plants collapsed and died, and affected tissues dried out. A Fusarium sp. was consistently and readily isolated from symptomatic tissue on Komada selective medium. Isolates were purified and subcultured on potato dextrose agar (PDA). Single-spore cultures on PDA, Spezieller Nährstoffarmer agar (SNA) (3), and carnation leaf-piece agar (CLA) (2) were incubated at 26 ± 1°C (12-h fluorescent light, 12-h dark). On PDA, cultures produced a thick growth of white-to-pink mycelium and pale pink pigments in the agar. On SNA, cultures produced short monophialides with unicellular, ovoid-elliptical microconidia measuring 4.3 to 8.2 × 2.3 to 3.8 (average 6.0 × 2.8) μm. Chlamydospores were abundant, single or paired, terminal and intercalary, rough walled, and 6 to 8 μm in diameter. On CLA, cultures produced orange sporodochia with macroconidia that were 3 to 4 septate, nearly straight with a foot-shaped basal cell and a short apical cell, and measured 31.1 to 51.5 × 4.4 to 3.5 (average 43.2 × 3.8) μm. Such characteristics are typical of Fusarium oxysporum (3). Amplification of the ITS (internal transcribed spacer) of the rDNA using primers ITS1/ITS4 (4) yielded a 498-bp band. Sequencing and BLASTn analysis of this band showed an E-value of 0.0 with F. oxysporum. The nucleotide sequence has been assigned GenBank Accession No. JF422071. To confirm pathogenicity, five 6-month-old healthy plants of C. peruvianus monstruosus were inoculated by dipping roots in a conidial suspension (2.4 × 106 CFU/ml) of F. oxysporum isolated from affected plants. Inoculum was obtained from pure cultures of three single-spore isolates grown for 10 days on casein hydrolysate liquid medium. Roots were not wounded before the inoculation. Plants were transplanted into pots filled with steam-sterilized substrate (sphagnum peat/perlite/pine bark/clay 50:20:20:10). Five noninoculated plants served as a control. Plants were placed in a climatic chamber at 25 ± 1°C (12-h fluorescent light, 12 h-dark). Basal stem rot and vascular discoloration in the crown and stem developed within 30 days on each inoculated plant. Noninoculated plants remained healthy. F. oxysporum was consistently isolated from symptomatic plants. The pathogenicity test was conducted twice. F. oxysporum has been reported on Cereus spp. in the United States (1). To our knowledge, this is the first report of F. oxysporum on C. peruvianus monstruosus in Italy as well as in Europe. Currently, this disease is present in a few nurseries in Liguria. References: (1) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St Paul, MN, 1989. (2) N. L. Fisher et al. Phytopathology 72:151, 1982. (3) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell, Ames, IA, 2006. (4) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.


Wide-Band Color Imagery Restoration for RGB-NIR Single Sensor Images.
Multi-spectral RGB-NIR sensors have become ubiquitous in recent years. These sensors allow the visible and near-infrared spectral bands of a given scene to be captured at the same time. With such cameras, the acquired imagery has a compromised RGB color representation due to near-infrared bands (700⁻1100 nm) cross-talking with the visible bands (400⁻700 nm). This paper proposes two deep learning-based architectures to recover the full RGB color images, thus removing the NIR information from the visible bands. The proposed approaches directly restore the high-resolution RGB image by means of convolutional neural networks. They are evaluated with several outdoor images; both architectures reach a similar performance when evaluated in different scenarios and using different similarity metrics. Both of them improve the state of the art approaches.


High epitope expression levels increase competition between T cells.
Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs) or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response.


The antagonistic modulation of Arp2/3 activity by N-WASP, WAVE2 and PICK1 defines dynamic changes in astrocyte morphology.
Astrocytes exhibit a complex, branched morphology, allowing them to functionally interact with numerous blood vessels, neighboring glial processes and neuronal elements, including synapses. They also respond to central nervous system (CNS) injury by a process known as astrogliosis, which involves morphological changes, including cell body hypertrophy and thickening of major processes. Following severe injury, astrocytes exhibit drastically reduced morphological complexity and collectively form a glial scar. The mechanistic details behind these morphological changes are unknown. Here, we investigate the regulation of the actin-nucleating Arp2/3 complex in controlling dynamic changes in astrocyte morphology. In contrast to other cell types, Arp2/3 inhibition drives the rapid expansion of astrocyte cell bodies and major processes. This intervention results in a reduced morphological complexity of astrocytes in both dissociated culture and in brain slices. We show that this expansion requires functional myosin II downstream of ROCK and RhoA. Knockdown of the Arp2/3 subunit Arp3 or the Arp2/3 activator N-WASP by siRNA also results in cell body expansion and reduced morphological complexity, whereas depleting WAVE2 specifically reduces the branching complexity of astrocyte processes. By contrast, knockdown of the Arp2/3 inhibitor PICK1 increases astrocyte branching complexity. Furthermore, astrocyte expansion induced by ischemic conditions is delayed by PICK1 knockdown or N-WASP overexpression. Our findings identify a new morphological outcome for Arp2/3 activation in restricting rather than promoting outwards movement of the plasma membrane in astrocytes. The Arp2/3 regulators PICK1, and N-WASP and WAVE2 function antagonistically to control the complexity of astrocyte branched morphology, and this mechanism underlies the morphological changes seen in astrocytes during their response to pathological insult.


Toxic keratopathy associated with abuse of low-dose anesthetic: a case report.
To describe the clinical course and treatment of toxic keratopathy associated with abuse of topical anesthetic at a very low concentration, 0.05%. Case report. A 47-year-old female systemic lupus erythematosus (SLE) patient with blurred vision and irritated right eye was referred to the ophthalmology department of our hospital. Under slit-lamp microscope, a 5.5 x 4.5 mm central corneal epithelial defect with underlying infiltrative and opaque stroma was noted in her right eye. Two weeks before, a corneal ulcer was diagnosed, and oxybuprocaine 0.05% (Lacrimin, Santen, Osaka, Japan) eye drops were prescribed 4 times daily but used every 5 to 10 minutes because the right eye was severely irritated. She was admitted immediately under the impression of toxic corneal ulcer. Preservative-free lubricants and prophylactic topical antibiotics 4 times daily were applied. Therapeutic soft contact lens was started after no infective agents were detected. Two weeks later, the stromal infiltration subsided, and the corneal epithelium was slowly healing, but superficial punctate epithelial defects at the lesion site persisted for another 6 months. The vision of her right eye improved from finger-counting at a 30-cm distance to 20/1200 with correction. Toxic keratopathy may result from abuse of topically administered anesthetics even at a very low concentration, 0.05%. Because this SLE patient has tear problems, we suggest that topical anesthetics must be used very cautiously and never prescribed to patients with dry eyes where the integrity of ocular surface is altered.


Synchronized Northern Hemisphere climate change and solar magnetic cycles during the Maunder Minimum.
The Maunder Minimum (A.D. 1645-1715) is a useful period to investigate possible sun-climate linkages as sunspots became exceedingly rare and the characteristics of solar cycles were different from those of today. Here, we report annual variations in the oxygen isotopic composition (δ(18)O) of tree-ring cellulose in central Japan during the Maunder Minimum. We were able to explore possible sun-climate connections through high-temporal resolution solar activity (radiocarbon contents; Δ(14)C) and climate (δ(18)O) isotope records derived from annual tree rings. The tree-ring δ(18)O record in Japan shows distinct negative δ(18)O spikes (wetter rainy seasons) coinciding with rapid cooling in Greenland and with decreases in Northern Hemisphere mean temperature at around minima of decadal solar cycles. We have determined that the climate signals in all three records strongly correlate with changes in the polarity of solar dipole magnetic field, suggesting a causal link to galactic cosmic rays (GCRs). These findings are further supported by a comparison between the interannual patterns of tree-ring δ(18)O record and the GCR flux reconstructed by an ice-core (10)Be record. Therefore, the variation of GCR flux associated with the multidecadal cycles of solar magnetic field seem to be causally related to the significant and widespread climate changes at least during the Maunder Minimum.


Favorable Effects of Sacubitril/Valsartan on the Peak Atrial Longitudinal Strain in Patients With Chronic Heart Failure and a History of One or More Episodes of Atrial Fibrillation: A Retrospective Cohort Study.
The peak atrial longitudinal strain (PALS) is primarily an index of the reservoir function of atrial chambers. The conceptual basis exists to hypothesize that sacubitril/valsartan improves the expandability of atrial chambers in the reservoir phase of the atrial mechanical cycle, as a consequence of its effect of prolonging the half-life of natriuretic peptides. Therefore in this retrospective study we evaluated the repercussions of the administration of sacubitril/valsartan maintained for at least 12 months on the PALS. In our retrospective study a cohort of 40 patients treated with sacubitril/valsartan has been compared with a second cohort subjected to the conventional treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. A general criterion to be satisfied was the presence of at least one episode of atrial fibrillation (AF) in the history of the enrolled patients. The study population was composed of New York Heart Association (NYHA) class II/III chronic heart failure (CHF) patients, due to the fact that the treating physicians of the patients whose clinical records were used as source of data, complied with the international guidelines that have so far validated sacubitril/valsartan exclusively for the CHF therapy. The aims were to verify whether the 1-year administration of sacubitril/valsartan is effective in improving the PALS, and also ascertain whether the drug is associated with a decreased risk of AF relapses over a mean retrospective observation period of 12 months. Sacubitril/valsartan cohort was proven to benefit from a significant increase in average values of PALS (median: 26.5%; interquartile range (IQR): 22% - 30%), opposed to the much less pronounced increase in PALS found in the conventional therapy cohort (median: 22.5%; IQR: 18% - 25.5%). Additionally, the comparison made by means of one-way analysis of variance regarding the mean changes of PALS values, outlined clearly that the sacubitril/valsartan users had an increase in PALS after 1 year of therapy significantly greater (P < 0.001) compared to the patients taking the conventional drugs. Moreover, a risk significantly higher of AF recurrences (P = 0.001) was identified in the conventional therapy group compared to the sacubitril/valsartan group during a 12-month retrospective observation period. In the present retrospective cohort study a higher increase of PALS has been shown in the cohort treated with sacubitril/valsartan. Moreover, a reduced risk of AF recurrences has been shown in the sacubitril/valsartan users compared to the patients with CHF subjected to conventional treatment.


Protective Function of Ahnak1 in Vascular Healing after Wire Injury.
Vascular remodeling following injury substantially accounts for restenosis and adverse clinical outcomes. In this study, we investigated the role of the giant scaffold protein Ahnak1 in vascular healing after endothelial denudation of the murine femoral artery. The spatiotemporal expression pattern of Ahnak1 and Ahnak2 was examined using specific antibodies and real-time quantitative PCR. Following wire-mediated endothelial injury of Ahnak1-deficient mice and wild-type (WT) littermates, the processes of vascular healing were analyzed. Ahnak1 and Ahnak2 showed a mutually exclusive vascular expression pattern, with Ahnak1 being expressed in the endothelium and Ahnak2 in the medial cells in naïve WT arteries. After injury, a marked increase of Ahnak1- and Ahnak2-positive cells at the lesion site became evident. Both proteins showed a strong upregulation in neointimal cells 14 days after injury. Ahnak1-deficient mice showed delayed vascular healing and dramatically impaired re-endothelialization that resulted in prolonged adverse vascular remodeling, when compared to the WT littermates. The large scaffold and adaptor proteins Ahnak1 and Ahnak2 exhibit differential expression patterns and functions in naïve and injured arteries. Ahnak1 plays a nonredundant protective role in vascular healing.


Herd management and social variables associated with bulk tank somatic cell count in dairy herds in the eastern United States.
The ability to reduce somatic cell counts (SCC) and improve milk quality depends on the effective and consistent application of established mastitis control practices. The US dairy industry continues to rely more on nonfamily labor to perform critical tasks to maintain milk quality. Thus, it is important to understand dairy producer attitudes and beliefs relative to management practices, as well as employee performance, to advance milk quality within the changing structure of the dairy industry. To assess the adoption rate of mastitis control practices in United States dairy herds, as well as assess social variables, including attitudes toward employees relative to mastitis control, a survey was sent to 1,700 dairy farms in Michigan, Pennsylvania, and Florida in January and February of 2013. The survey included questions related to 7 major areas: sociodemographics and farm characteristics, milking proficiency, milking systems, cow environment, infected cow monitoring and treatment, farm labor, and attitudes toward mastitis and related antimicrobial use. The overall response rate was 41% (21% in Florida, 39% in Michigan, and 45% in Pennsylvania). Herd size ranged from 9 to 5,800 cows. Self-reported 3-mo geometric mean bulk tank SCC (BTSCC) for all states was 194,000 cells/mL. Multivariate analysis determined that proven mastitis control practices such as the use of internal teat sealants and blanket dry cow therapy, and not using water during udder preparation before milking, were associated with lower BTSCC. Additionally, farmer and manager beliefs and attitudes, including the perception of mastitis problems and the threshold of concern if BTSCC is above 300,000 cells/mL, were associated with BTSCC. Ensuring strict compliance with milking protocols, giving employees a financial or other penalty if BTSCC increased, and a perceived importance of reducing labor costs were negatively associated with BTSCC in farms with nonfamily employees. These findings highlight the need for a comprehensive approach to managing mastitis, one that includes the human dimensions of management to maintain the practice of scientifically validated mastitis control practices.


Simple derivation of the initial fluid rate for the resuscitation of severely burned adult combat casualties: in silico validation of the rule of 10.
In practice, current burn resuscitation formulas, designed to estimate 24-hour fluid resuscitation needs, provide only a starting point for resuscitation. To simplify this process, we devised the "rule of 10" to derive the initial fluid rate. We performed an in silico study to determine whether the rule of 10 would result in acceptable initial fluid rates for adult patients. A computer application using Java (Sun Microsystems Inc., Santa Clara, CA) generated a set of 100,000 random weights and percentage of total body surface area (%TBSA) values with distributions matching the model characteristics with which the initial fluid rate was calculated using the rule of 10. The initial rate for 100,000 simulations was compared with initial rates calculated by using either the modified Brooke (MB, 2 mL/kg/%TBSA) or the Parkland (PL, 4 mL/kg/%TBSA) formulas. Analysis of calculated initial fluid rates using the rule of 10 showed that 87.8% (n = 87,840) of patients fell between the initial rates derived by the MB and the PL formulas. Less than 12% (n = 11,502) of patients had rule of 10 derived initial rates below the MB. Among these patients, the median difference of the initial rate was 14 mL/hr (range, 2-212 mL/hr). Among those who had initial rule of 10 calculated rates greater than the PL formula (<1%, n = 658), the median difference in rate was 33 mL/hr (range, 1-213 mL/hr), with a mean %TBSA of 21% +/- 1% and mean weight of 130 kg +/- 11 kg. For the majority of adult burn patients, the rule of 10 approximates the initial fluid rate within acceptable ranges.


Interlocking oppressions: the effect of a comorbid physical disability on perceived stigma and discrimination among mental health consumers in Canada.
People living with mental health problems often face stigma and discrimination; however, there is a lack of research that examines how comorbid conditions affect this perceived stigma. This study sought to determine whether people who have a comorbid physical and psychiatric disability experience more stigma than those with only a psychiatric disability. It also looked at how perceived stigma and discrimination affect physical and mental health. A secondary analysis on data from interviews with 336 former and current clients of the mental health system in a mid-size Canadian city in 2005 was performed. Of these, 203 (60.4%) reported they had a psychiatric disability, 112 (33.0%) reported that they had a physical disability, with 74 reporting both a psychiatric and a physical disability. People with a self-reported psychiatric disability and a self-reported comorbid physical disability faced more overall perceived discrimination/stigma (P = 0.04), than those with a psychiatric disability alone. Perceived discrimination/stigma was positively correlated with psychiatric problem severity (P = 0.02), and negatively correlated with self-rated general health (P < 0.001), physical condition (P < 0.001), emotional well-being (P < 0.001) and life satisfaction (P < 0.001). These results bring to light the aggravating effect of a physical disability on the perceived stigma for those living with a mental illness, and also strengthen the knowledge that stigma and discrimination have a negative impact on health. Healthcare providers should recognise this negative impact and screen for these comorbid conditions. Policy-makers should take measures such as improving access to housing and employment services to help reduce stigma and discrimination against this particularly vulnerable group.


Formation of reactive oxygen and nitrogen species in the presence of pinosylvin - an analogue of resveratrol.
Formation of reactive oxygen species in neutrophils of rats with adjuvant arthritis and generation of nitric oxide in RAW 264.7 macrophages were analysed in the presence of pinosylvin. The method of chemiluminescence was used for the detection of reactive oxygen species in blood of rats with adjuvant arthritis. Pinosylvin (50 mg/kg, daily, p.o.) and methotrexate (0.4 mg/kg, twice a week, p.o.) were applied separately or in a combination over a period of 28 days from the day of immunisation. Adjuvant arthritis was accompanied by a significantly increased number of neutrophils, by elevated concentration of oxidants in blood and by excessive responsiveness of neutrophils to stimulation with PMA. In rats treated with methotrexate, all these changes were significantly reduced and the inhibition became more pronounced when methotrexate was applied in the combination with pinosylvin; the monotherapy with pinosylvin did not induce any detectable changes in the parameters tested. Under in vitro conditions, pinosylvin inhibited formation of nitric oxide (NO) in macrophages, as demonstrated by the decreased concentration of nitrite - the end-product of NO metabolism (assessed by Griess' method), by the reduced expression of inducible NO synthase (detected by Western blot), and by the failure of pinosylvin to scavenge nitric oxide (measured amperometrically in cell-free system). The observed ability of pinosylvin to decrease concentration of reactive oxygen and nitrogen species, along with its capacity to enhance the efficacy of methotrexate in arthritis treatment may shed more light into the pharmacological potential of this prospective natural substance.


Short mitochondrial ARF triggers Parkin/PINK1-dependent mitophagy.
Parkinson disease (PD) is a complex neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Multiple genes have been associated with PD, including Parkin and PINK1. Recent studies have established that the Parkin and PINK1 proteins function in a common mitochondrial quality control pathway, whereby disruption of the mitochondrial membrane potential leads to PINK1 stabilization at the mitochondrial outer surface. PINK1 accumulation leads to Parkin recruitment from the cytosol, which in turn promotes the degradation of the damaged mitochondria by autophagy (mitophagy). Most studies characterizing PINK1/Parkin mitophagy have relied on high concentrations of chemical uncouplers to trigger mitochondrial depolarization, a stimulus that has been difficult to adapt to neuronal systems and one unlikely to faithfully model the mitochondrial damage that occurs in PD. Here, we report that the short mitochondrial isoform of ARF (smARF), previously identified as an alternate translation product of the tumor suppressor p19ARF, depolarizes mitochondria and promotes mitophagy in a Parkin/PINK1-dependent manner, both in cell lines and in neurons. The work positions smARF upstream of PINK1 and Parkin and demonstrates that mitophagy can be triggered by intrinsic signaling cascades.


Relative contribution of various chronic diseases and multi-morbidity to potential disability among Dutch elderly.
The amount of time spent living with disease greatly influences elderly people's wellbeing, disability and healthcare costs, but differs by disease, age and sex. We assessed how various single and combined diseases differentially affect life years spent living with disease in Dutch elderly men and women (65+) over their remaining life course. Multistate life table calculations were applied to age and sex-specific disease prevalence, incidence and death rates for the Netherlands in 2007. We distinguished congestive heart failure, coronary heart disease (CHD), breast and prostate cancer, colon cancer, lung cancer, diabetes, COPD, stroke, dementia and osteoarthritis. Across ages 65, 70, 75, 80 and 85, CHD caused the most time spent living with disease for Dutch men (from 7.6 years at age 65 to 3.7 years at age 85) and osteoarthritis for Dutch women (from 11.7 years at age 65 to 4.8 years at age 85). Of the various co-occurrences of disease, the combination of diabetes and osteoarthritis led to the most time spent living with disease, for both men (from 11.2 years at age 65 to 4.9 -years at age 85) and women (from 14.2 years at age 65 to 6.0 years at age 85). Specific single and multi-morbid diseases affect men and women differently at different phases in the life course in terms of the time spent living with disease, and consequently, their potential disability. Timely sex and age-specific interventions targeting prevention of the single and combined diseases identified could reduce healthcare costs and increase wellbeing in elderly people.


Uniparental disomy and human disease: an overview.
Uniparental disomy (UPD) refers to the situation in which both homologues of a chromosomal region/segment have originated from only one parent. This can involve the entire chromosome or only a small segment. As a consequence of UPD, or uniparental duplication/deficiency of part of a chromosome, there are two types of developmental risk: aberrant dosage of genes regulated by genomic imprinting and homozygosity of a recessive mutation. UPD models generated by reciprocal and Robertsonian translocation heterozygote intercrosses have been a powerful tool to investigate genomic imprinting in mice, whereas novel UPD patients such as those with cystic fibrosis and Prader-Willi syndrome, triggered the clarification of recessive diseases and genomic imprinting disorders in human. Newly developed genomic technologies as well as conventional microsatellite marker methods have been contributing to the functional and mechanistic investigation of UPD, leading to not only the acquisition of clinically valuable information, but also the further clarification of diverse genetic processes and disease pathogenesis.


The origins and evolution of chromosomes, dosage compensation, and mechanisms underlying venom regulation in snakes.
Here we use a chromosome-level genome assembly of a prairie rattlesnake (Crotalus viridis), together with Hi-C, RNA-seq, and whole-genome resequencing data, to study key features of genome biology and evolution in reptiles. We identify the rattlesnake Z Chromosome, including the recombining pseudoautosomal region, and find evidence for partial dosage compensation driven by an evolutionary accumulation of a female-biased up-regulation mechanism. Comparative analyses with other amniotes provide new insight into the origins, structure, and function of reptile microchromosomes, which we demonstrate have markedly different structure and function compared to macrochromosomes. Snake microchromosomes are also enriched for venom genes, which we show have evolved through multiple tandem duplication events in multiple gene families. By overlaying chromatin structure information and gene expression data, we find evidence for venom gene-specific chromatin contact domains and identify how chromatin structure guides precise expression of multiple venom gene families. Further, we find evidence for venom gland-specific transcription factor activity and characterize a complement of mechanisms underlying venom production and regulation. Our findings reveal novel and fundamental features of reptile genome biology, provide insight into the regulation of snake venom, and broadly highlight the biological insight enabled by chromosome-level genome assemblies.


Osteopontin Promotes Protective Antigenic Tolerance against Experimental Allergic Airway Disease.
In the context of inflammation, osteopontin (Opn) is known to promote effector responses, facilitating a proinflammatory environment; however, its role during antigenic tolerance induction is unknown. Using a mouse model of asthma, we investigated the role of Opn during antigenic tolerance induction and its effects on associated regulatory cellular populations prior to disease initiation. Our experiments demonstrate that Opn drives protective antigenic tolerance by inducing accumulation of IFN-β-producing plasmacytoid dendritic cells, as well as regulatory T cells, in mediastinal lymph nodes. We also show that, in the absence of TLR triggers, recombinant Opn, and particularly its SLAYGLR motif, directly induces IFN-β expression in Ag-primed plasmacytoid dendritic cells, which renders them extra protective against induction of allergic airway disease upon transfer into recipient mice. Lastly, we show that blockade of type I IFNR prevents antigenic tolerance induction against experimental allergic asthma. Overall, we unveil a new role for Opn in setting up a tolerogenic milieu boosting antigenic tolerance induction, thus leading to prevention of allergic airway inflammation. Our results provide insight for the future design of immunotherapies against allergic asthma.


Estimating prevalences of sensitive problems from nonsensitive data.
Accurate and regularly updated prevalences are critical to guide both prevention and policy. However, despite their impact on public health, the prevalence of behavioral and mental health problems such as child maltreatment and intimate partner violence (IPV) are collected infrequently (e.g., once per decade or less). The purpose of this study is to test the viability of using nonsensitive, dynamic variables to estimate prevalences of sensitive behavioral problems. Several archival data sets of partner and child maltreatment are used. Data sets are randomly divided into development and cross-validation subsets. Sequential, backward, stepwise logistic regression is used to derive estimation equations, which are then tested in the cross-validation subset. The results indicate that estimated prevalences are close to the measured prevalences. Confidence intervals (95%) are approximately the same as those that pertain to measured prevalences (± 1%-2%). In situations where it is either too expensive or too sensitive to assess a population regularly on a problem of interests, it appears as if policy makers and prevention planners can use regularly collected, nonsensitive data to estimate accurately the prevalence of unmeasured, sensitive outcomes.


Phase II Trial of Angiotensin-(1-7) for the Treatment of Patients with Metastatic Sarcoma.
Background. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous antiangiogenic hormone with anticancer activity. In a phase I study of Ang-(1-7), two of three patients with metastatic sarcoma experienced disease stabilization. This phase II study examined clinical and biomarker outcomes for patients with metastatic sarcoma. Methods. Ang-(1-7) was administered by subcutaneous injection at a dose of 20 mg daily. If excessive toxicities occurred in the first cohort, a dose deescalation cohort was allowed. Blood samples were obtained to measure changes in biomarkers. Results. Treatment was well-tolerated and the dose deescalation cohort was not required. Plasma PlGF concentrations following treatment were not statistically significantly changed. A significant increase in plasma Ang-(1-7) was observed at 4 hours after injection. The median progression-free survival was 2.7 months (95% CI; 1.4 to 4.1 months), and the median overall survival was 10.2 months (95% CI; 5.3 to 18.3 months). Two patients with vascular sarcomas demonstrated prolonged disease stabilization of 10 months (hemangiopericytoma) and 19 months (epithelioid hemangioendothelioma). Conclusions. Ang-(1-7) at a dose of 20 mg daily was well-tolerated. This prospective phase II study failed to confirm the PlGF biomarker effect identified in the prior phase I study. Prolonged disease stabilization in hemangiopericytoma and epithelioid hemangioendothelioma may warrant further investigation.


Treating Negative Symptoms in Schizophrenia: an Update.
Interest in the negative symptoms of schizophrenia has increased rapidly over the last several decades, paralleling a growing interest in functional, in addition to clinical, recovery, and evidence underscoring the importance negative symptoms play in the former. Efforts continue to better define and measure negative symptoms, distinguish their impact from that of other symptom domains, and establish effective treatments as well as trials to assess these. Multiple interventions have been the subject of investigation, to date, including numerous pharmacological strategies, brain stimulation, and non-somatic approaches. Level and quality of evidence vary considerably, but to this point, no specific treatment can be recommended. This is particularly problematic for individuals burdened with negative symptoms in the face of mild or absent positive symptoms. Presently, clinicians will sometimes turn to interventions that are seen as more "benign" and in line with routine clinical practice. Strategies include use of atypical antipsychotics, ensuring the lowest possible antipsychotic dose that maintains control of positive symptoms (this can involve a shift from antipsychotic polypharmacy to monotherapy), possibly an antidepressant trial (given diagnostic uncertainty and the frequent use of these drugs in schizophrenia), and non-somatic interventions (e.g., cognitive behavioral therapy, CBT). The array and diversity of strategies currently under investigation highlight the lack of evidence-based treatments and our limited understanding regarding negative symptoms underlying etiology and pathophysiology. Their onset, which can precede the first psychotic break, also means that treatments are delayed. From this perspective, identification of biomarkers and/or endophenotypes permitting earlier diagnosis and intervention may serve to improve treatment efficacy as well as outcomes.


Construction of High-Density Genetic Maps and Detection of QTLs Associated With Huanglongbing Tolerance in Citrus.
Huanglongbing (HLB), or citrus greening, is the most devastating disease in citrus worldwide. Commercial citrus varieties including sweet orange (Citrus sinensis) are highly susceptible to HLB, and trifoliate orange (Poncirus trifoliata, a close Citrus relative) is widely considered resistant or highly tolerant to HLB. In this study, an intergeneric F1 population of sweet orange and trifoliate orange was genotyped by Genotyping-by-Sequencing, and high-density SNP-based genetic maps were constructed separately for trifoliate orange and sweet orange. The two genetic maps exhibited high synteny and high coverage of the citrus genome. Progenies of the F1 population and their parents were planted in a replicated field trial, exposed to intense HLB pressure for 3 years, and then evaluated for susceptibility to HLB over 2 years. The F1 population exhibited a wide range in severity of HLB foliar symptom and canopy damage. Genome-wide QTL analysis based on the phenotypic data of foliar symptom and canopy damage in 2 years identified three clusters of repeatable QTLs in trifoliate orange linkage groups LG-t6, LG-t8 and LG-t9. Co-localization of QTLs for two traits was observed within all three regions. Additionally, one cluster of QTLs in sweet orange (linkage group LG-s7) was also detected. The majority of the identified QTLs each explained 18-30% of the phenotypic variation, indicating their major role in determining HLB responses. These results show, for the first time, a quantitative genetic nature yet the presence of major loci for the HLB tolerance in trifoliate orange. The results suggest that sweet orange also contains useful genetic factor(s) for improving HLB tolerance in commercial citrus varieties. Findings from this study should be very valuable and timely to researchers worldwide as they are hastily searching for genetic solutions to the devastating HLB crisis through breeding, genetic engineering, or genome editing.


Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action.
Infection is a dynamic biological process underpinned by a complex interplay between the pathogen and the host. Microbes from all domains of life, including bacteria, viruses, fungi, and protozoan parasites, have the capacity to cause infection. Infection is sensed by the host, which often leads to activation of the inflammasome, a cytosolic macromolecular signaling platform that mediates the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and cleavage of the pore-forming protein gasdermin D, leading to pyroptosis. Host-mediated sensing of the infection occurs when pathogens inject or carry pathogen-associated molecular patterns (PAMPs) into the cytoplasm or induce damage that causes cytosolic liberation of danger-associated molecular patterns (DAMPs) in the host cell. Recognition of PAMPs and DAMPs by inflammasome sensors, including NLRP1, NLRP3, NLRC4, NAIP, AIM2, and Pyrin, initiates a cascade of events that culminate in inflammation and cell death. However, pathogens can deploy virulence factors capable of minimizing or evading host detection. This review presents a comprehensive overview of the mechanisms of microbe-induced activation of the inflammasome and the functional consequences of inflammasome activation in infectious diseases. We also explore the microbial strategies used in the evasion of inflammasome sensing at the host-microbe interaction interface.


Evaluating the validity of anger regulation problems, interpersonal style, and disturbed mental state for predicting inpatient violence.
Research has been conducted to try to identify risk factors to help predict which patients will be violent during psychiatric hospitalization. Despite the relatively large amount of research conducted, it is difficult to draw any firm conclusions, as the studies vary considerably in study design, methods used, and choice of outcome measures. Studies also tend to focus on risk prediction, even though risk management is the primary aim of clinical practice in mental health services and few studies have focused on a theoretical basis for understanding violence. This study assessed the predictive validity of brief assessment scales in a sample of 94 forensic inpatients who had been inpatient for a median of 521 days, to test the hypotheses that anger regulation problems, interpersonal style, and disturbed mental state would be linked to increased violence risk in a forensic hospital during a hospital stay. The outcome variables for this study were physical violence against another and/or clear threats of physical violence. The results of this study provide support for the hypotheses, and this remained the case after controlling for age, gender, length of stay, and presence of major mental disorder. The findings should not only assist clinicians with assessment and management of risk but also support the reconceptualizing of risk prediction research to reflect the task of clinical risk management.


The preliminary experience in the emergency department of a newly opened penitentiary institution hospital in Turkey.
Emergency cases become a widespread problem in prisons across Turkey. The opening of a new prison hospital in January 2012 within the catchment of Silivri Penitentiary Institution gave a unique opportunity to treat the inmates quickly. The study was to conduct an extensive review for documentation of prisoners' healthcare problems leading to emergency admission following the first year after the opening of Penitentiary Institution Hospital and point to decrease redundant hospital transfers of this individual cohort. A cross-sectional study was carried out where 12,325 visits to the Silivri Penitentiary Institution Hospital for emergency visits from the period of 1(st) January 2012 to the 31(st) December 2012 were identified from electronic medical records. After obtaining consent from the local IRB, data including details of the type, cause and nature of the complaints of the illnesses were processed. In the 12-month period, there were 12,325 visits to the emergency department, of which 4328 for surgical conditions (35.1%), 2684 for medical disorders (21.8%), 1867 for sports injuries (15.2%), 1327 for Ear Nose Throat (ENT) problems (10.8%), 827 for psychiatric disorders (6.70%), 396 for violence injury (3.2%), 169 for self harm (1.4%), and 727 for miscellaneous (5.8%). The most common cause of emergency visits was sports injuries, followed by non-specific abdominal pain and ENT problems. Eighteen prisoners re-attended 243 times, ranging from 8 visits to a maximum of 56 visits. Inmates in prison have a wide range of complaints, and sometimes these complaints do not suggest an illness. Prison population exhibited substantially higher prevalence rates of diseases than the civilian population. We conclude that this new healthcare system in prisons will prevent redundant hospital transfers and guarantee detainees have access to the same health care that is offered to non-detained population.


Persistence of aquatic insects across managed landscapes: effects of landscape permeability on re-colonization and population recovery.
Human practices in managed landscapes may often adversely affect aquatic biota, such as aquatic insects. Dispersal is often the limiting factor for successful re-colonization and recovery of stressed habitats. Therefore, in this study, we evaluated the effects of landscape permeability, assuming a combination of riparian vegetation (edge permeability) and other vegetation (landscape matrix permeability), and distance between waterbodies on the colonization and recovery potential of weakly flying insects. For this purpose, we developed two models, a movement and a population model of the non-biting midge, Chironomus riparius, an aquatic insect with weak flying abilities. With the movement model we predicted the outcome of dispersal in a landscape with several linear water bodies (ditches) under different assumptions regarding landscape-dependent movement. Output from the movement model constituted the probabilities of encountering another ditch and of staying in the natal ditch or perishing in the landscape matrix, and was used in the second model. With this individual-based model of midge populations, we assessed the implications for population persistence and for recovery potential after an extreme stress event. We showed that a combination of landscape attributes from the movement model determines the fate of dispersing individuals and, once extrapolated to the population level, has a big impact on the persistence and recovery of populations. Population persistence benefited from low edge permeability as it reduced the dispersal mortality which was the main factor determining population persistence and viability. However, population recovery benefited from higher edge permeability, but this was conditional on the low effective distance that ensured fewer losses in the landscape matrix. We discuss these findings with respect to possible landscape management scenarios.


Camera augmented mobile C-arm (CAMC): calibration, accuracy study, and clinical applications.
Mobile C-arm is an essential tool in everyday trauma and orthopedics surgery. Minimally invasive solutions, based on X-ray imaging and coregistered external navigation created a lot of interest within the surgical community and started to replace the traditional open surgery for many procedures. These solutions usually increase the accuracy and reduce the trauma. In general, they introduce new hardware into the OR and add the line of sight constraints imposed by optical tracking systems. They thus impose radical changes to the surgical setup and overall procedure. We augment a commonly used mobile C-arm with a standard video camera and a double mirror system allowing real-time fusion of optical and X-ray images. The video camera is mounted such that its optical center virtually coincides with the C-arm's X-ray source. After a one-time calibration routine, the acquired X-ray and optical images are coregistered. This paper describes the design of such a system, quantifies its technical accuracy, and provides a qualitative proof of its efficiency through cadaver studies conducted by trauma surgeons. In particular, it studies the relevance of this system for surgical navigation within pedicle screw placement, vertebroplasty, and intramedullary nail locking procedures. The image overlay provides an intuitive interface for surgical guidance with an accuracy of < 1 mm, ideally with the use of only one single X-ray image. The new system is smoothly integrated into the clinical application with no additional hardware especially for down-the-beam instrument guidance based on the anteroposterior oblique view, where the instrument axis is aligned with the X-ray source. Throughout all experiments, the camera augmented mobile C-arm system proved to be an intuitive and robust guidance solution for selected clinical routines.


Personal meanings in the construction of need for total knee replacement surgery.
This study explores patients' personal meanings of knee osteoarthritis (OA) and total knee replacement (TKR). Personal meanings are important because decisions regarding the need for TKR do not seem to be explained by symptoms alone. A total of 18 semi-structured interviews were conducted with a purposive sample of respondents who were listed for TKR at one UK specialist orthopaedic hospital, and who had lower than average disease burden according to standard quantitative criteria. Data were analysed using interpretive phenomenological analysis. Several themes related to need for TKR emerged: adoption of the medical model, a person's social network, pain, functional loss, feelings of vulnerability, dependency, low mood and fatigue, ideas related to disease progression and expectations of TKR. Results suggest that the decision to undergo TKR is not related to symptoms alone, but to personal meanings. Some of these personal meanings may not be useful in accurately assessing the need for TKR, and may result in mis-targeting of treatment. It is important for health professionals to explore and tackle personal meanings when considering treatment. In particular, it may be important to consider gender differences that may influence when men and women are listed for TKR. For example: women may be less likely to discuss treatment options with their doctor; they may be more likely to have heard negative examples of TKR from friends or family; they may be more likely to discuss pain and mobility issues than activities requiring higher function; and they may be more likely to discuss the effect on their mood and the emotional impact of OA.


Vaccine-mediated protection against Campylobacter-associated enteric disease.
Campylobacter coli and Campylobacter jejuni are responsible for 400 million to 500 million cases of enteric disease each year and represent the most common cause of bacterial gastroenteritis worldwide. Despite its global importance, Campylobacter vaccine development has been hampered by the lack of animal models that recapitulate human disease pathogenesis. Here, we describe a naturally occurring Campylobacter-associated diarrhea model in outdoor-housed rhesus macaques. Using this model, we developed novel next-generation H2O2-based Campylobacter vaccines that induced strong antibacterial antibodies to multiple Campylobacter proteins including flagellin and provided up to 83% protection against severe C. coli-associated diarrhea. Whole-genome sequencing of circulating Campylobacter strains revealed little to no homology within lipooligosaccharide or capsular polysaccharide loci with the Campylobacter vaccine strains used in these studies, indicating that vaccine-mediated immunity was not restricted to a single homologous serotype. Together, these results demonstrate an important advance in vaccine development and a new approach to reducing Campylobacter-associated enteric disease.


Detection of pristine gas two billion years after the Big Bang.
In the current cosmological model, only the three lightest elements were created in the first few minutes after the Big Bang; all other elements were produced later in stars. To date, however, heavy elements have been observed in all astrophysical environments. We report the detection of two gas clouds with no discernible elements heavier than hydrogen. These systems exhibit the lowest heavy-element abundance in the early universe, and thus are potential fuel for the most metal-poor halo stars. The detection of deuterium in one system at the level predicted by primordial nucleosynthesis provides a direct confirmation of the standard cosmological model. The composition of these clouds further implies that the transport of heavy elements from galaxies to their surroundings is highly inhomogeneous.


Resident and facility characteristics associated with care-need level deterioration in long-term care welfare facilities in Japan.
To determine the resident and facility characteristics associated with residents' care-need level deterioration in long-term care welfare facilities in Japan. A nationally representative sample of 358 886 residents who lived in 3774 long-term care welfare facilities for at least 1 year from October 2012 was obtained from long-term care insurance claims data. Facility characteristics were linked with a survey of institutions and establishments for long-term care in 2012. We used a multilevel logistic regression according to the inclusion and exclusion of lost to follow-up to define the resident and facility characteristics associated with resident care-need level deteriorations (lost to follow-up: the majority were hospitalized residents or had died; were treated as deterioration in the including loss to follow-up model). Adjusting for the covariates, at the resident level, older age and lower care-need level at baseline were more likely to show deterioration in the care-need level. At the facility level, metropolitan facilities, unit model (all private room settings) and mixed-model facilities (partly private room settings) were less likely to experience care-need level deterioration. A higher proportion of registered nurses among all nurses was negatively related to care-need level deterioration only in the model including lost to follow-up. A higher proportion of registered dietitians among all dietitians and the facilities in business for fewer years were negatively associated with care-need level deterioration only in the model excluding lost to follow-up. The present study could help identify residents who are at risk of care-need level deterioration, and could contribute to improvements in provider quality performance and enhance competence in the market. Geriatr Gerontol Int 2018; 18: 758-766.


Psychiatric outcomes after pediatric sports-related concussion.
The objectives of this study were twofold: (1) to examine the prevalence of emotional symptoms among children and adolescents with a sports-related concussion (SRC) who were referred to a multidisciplinary pediatric concussion program and (2) to examine the prevalence, clinical features, risk factors, and management of postinjury psychiatric outcomes among those in this clinical population. The authors conducted a retrospective chart review of all patients with SRC referred to a multidisciplinary pediatric concussion program between September 2013 and October 2014. Clinical assessments carried out by a single neurosurgeon included clinical history, physical examination, and Post-Concussion Symptom Scale (PCSS) scoring. Postinjury psychiatric outcomes were defined as a subjective worsening of symptoms of a preinjury psychiatric disorder or new and isolated suicidal ideation or diagnosis of a novel psychiatric disorder (NPD). An NPD was defined as a newly diagnosed psychiatric disorder that occurred in a patient with or without a lifetime preinjury psychiatric disorder after a concussion. Clinical resources, therapeutic interventions, and clinical and return-to-play outcomes are summarized. One hundred seventy-four patients (mean age 14.2 years, 61.5% male) were included in the study. At least 1 emotional symptom was reported in 49.4% of the patients, and the median emotional PCSS subscore was 4 (interquartile range 1-8) among those who reported at least 1 emotional symptom. Overall, 20 (11.5%) of the patients met the study criteria for a postinjury psychiatric outcome, including 14 patients with an NPD, 2 patients with isolated suicidal ideation, and 4 patients with worsening symptoms of a preinjury psychiatric disorder. Female sex, a higher initial PCSS score, a higher emotional PCSS subscore, presence of a preinjury psychiatric history, and presence of a family history of psychiatric illness were significantly associated with postinjury psychiatric outcomes. Interventions for patients with postinjury psychiatric outcomes included pharmacological therapy alone in 2 patients (10%), cognitive behavioral therapy alone in 4 (20%), multimodal therapy in 9 (45%), and no treatment in 5 (25%). Overall, 5 (25%) of the patients with postinjury psychiatric disorders were medically cleared to return to full sports participation, whereas 5 (25%) were lost to follow-up and 9 (45%) remained in treatment by the multidisciplinary concussion program at the end of the study period. One patient who was asymptomatic at the time of initial consultation committed suicide. Emotional symptoms were commonly reported among pediatric patients with SRC referred to a multidisciplinary pediatric concussion program. In some cases, these symptoms contributed to the development of an NPD, isolated suicidal ideation, and worsening symptoms of a preexisting psychiatric disorder. Future research is needed to clarify the prevalence, pathophysiology, risk factors, and evidence-based management of postinjury psychiatric outcomes after pediatric SRC. Successful management of these patients requires prompt recognition and multidisciplinary care by experts with clinical training and experience in concussion and psychiatry.


Mapping central α-helix linker mediated conformational transition pathway of calmodulin via simple computational approach.
The effects of intrinsic structural flexibility of calmodulin protein on the mechanism of its allosteric conformational transition are investigated in this article. Using a novel in silico approach, the conformational transition pathways of intact calmodulin as well as the isolated N- and C- terminal domains are identified and energetically characterized. It is observed that the central α-helix linker amplifies the structural flexibility of intact Ca(2+)-free calmodulin, which might facilitate the transition of the two domains. As a result, the global conformational transition of Ca(2+)-free calmodulin is initiated by the barrierless transition of two domains and proceeds through the barrier associated unwinding and bending of the central α-helix linker. The binding of Ca(2+) cations to calmodulin further increases the structural flexibility of the C-terminal domain and results in a downhill transition pathway of which all regions transit in a concerted manner. On the other hand, the separation of the N- and C-terminal domains from calmodulin protein loses the mediating function of central α-helix linker, leading to more difficult conformational transitions of both domains. The present study provides novel insights into the correlation of the integrity of protein, the structural flexibility, and the mechanism of conformational transition of proteinlike calmodulin.


Effects of temperature and pH on the contraction and aggregation of microgels in aqueous suspensions.
Chemically cross-linked poly(N-isopropylacrylamide) (PNIPAM) microgels and PNIPAM with different amounts of acrylic acid groups (PNIPAM-co-PAA) were synthesized and the temperature-induced aggregation behaviors of aqueous suspensions of these microgels were investigated mainly with the aid of dynamic light scattering (DLS) and turbidimetry. The DLS results show that the particles at all conditions shrink at temperatures up to approximately the lower critical solution temperature (LCST), but the relative contraction effect is larger for the microgels without acid groups or for microgels with added anionic surfactant (SDS). A significant depression of the cloud point is found in suspensions of PNIPAM with very low concentrations of SDS. The compression of the microgels cannot be traced from the turbidity results, but rather the values of the turbidity increase in this temperature interval. This phenomenon is discussed in the framework of a theoretical model. At temperatures above LCST, the size of the microgels without attached charged groups in a very dilute suspension is unaffected by temperature, while the charged particles (pH 7 and 11) continue to collapse with increasing temperature over the entire domain. In this temperature range, low-charged particles of higher concentration and particles containing acrylic acid groups at low pH (pH 2) aggregate, and macroscopic phase separation is approached at higher temperatures. This study demonstrates how the stabilization of microgels can be affected by factors such as polymer concentration, addition of ionic surfactant to particles without charged acid groups, amount of charged groups in the polymer, and pH.


Scaling up priority health interventions in Tanzania: the human resources challenge.
The international community has set ambitious goals (Millennium Development Goals) to improve health in developing countries by 2015. Effective and often cheap interventions exist to achieve these goals. In the mainland of Tanzania, one of the poorest countries of the world, we explored the human resources challenges of expanding the coverage of such priority interventions. We projected human resources for health (HRH) availability using a standard approach and estimated human resource requirements using a novel method (QTP) that produces estimates by task-specific skill categories and explicitly considers productivity. In this paper, we present the findings of the case study in Tanzania and discuss the strengths and weaknesses of the QTP model. On the whole, the HRH challenge of expanding priority interventions in mainland Tanzania is daunting. HRH requirements exceed by far the estimates of HRH availability for 2015. The scaling up of the HIV/AIDS related intervention cluster, in particular the treatment and care of people living with HIV/AIDS, was the primary driver of increases in HRH requirements between the study's base year, 2002, and 2015, and thus of the overall imbalance. Scenario analysis points to three key areas for change in HRH policy and practice to reduce future imbalances: the increment-attrition balance, staff and service productivity, and the match between task-specific skill and occupational categories. However, even in an optimistic scenario, human resource availability will limit the extent to which priority interventions can be expanded in the mainland of Tanzania, and the government will not be able to avoid adjusting the globally set targets for service coverage and health outcomes to local realities and priorities.