Identification, characterization, and DNA sequence of a functional "double" groES-like chaperonin from chloroplasts of higher plants.
Chloroplasts of higher plants contain a nuclear-encoded protein that is a functional homolog of the Escherichia coli chaperonin 10 (cpn10; also known as groES). In pea (Pisum sativum), chloroplast cpn10 was identified by its ability to (i) assist bacterial chaperonin 60 (cpn60; also known as groEL) in the ATP-dependent refolding of chemically denatured ribulose-1,5-bisphosphate carboxylase and (ii) form a stable complex with bacterial cpn60 in the presence of Mg.ATP. The subunit size of the pea protein is approximately 24 kDa--about twice the size of bacterial cpn10. A cDNA encoding a spinach (Spinacea oleracea) chloroplast cpn10 was isolated, sequenced, and expressed in vitro. The spinach protein is synthesized as a higher molecular mass precursor and has a typical chloroplast transit peptide. Surprisingly, however, attached to the transit peptide is a single protein, comprised of two distinct cpn10 molecules in tandem. Moreover, both halves of this "double" cpn10 are highly conserved at a number of residues that are present in all cpn10s that have been examined. Upon import into chloroplasts the spinach cpn10 precursor is processed to its mature form of approximately 24 kDa. N-terminal amino acid sequence analysis reveals that the mature pea and spinach cpn10 are identical at 13 of 21 residues.


Anti-infectious antibodies and autoimmune-associated autoantibodies in patients with type I diabetes mellitus and their close family members.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease with complex interactions between genetic and environmental factors. We compared antibody levels to various infectious agents and of autoimmune-associated autoantibodies between Colombian T1DM patients, their close family members and healthy controls. Significantly lower levels of antibodies against several infectious agents were detected in the T1DM patients. These included Helicobacter pylori (P = 0.01), cytomegalovirus (P = 0.001), Epstein-Barr virus (P = 0.02) and Toxoplasma (P = 0.001). T1DM patients had significantly higher levels of IgG-anti-gliadin antibodies (P = 0.001) and IgG-antitissue transglutaminase antibodies (P = 0.03), and a borderline association with anticentromere antibodies (P = 0.06). The lower level of antibodies against infectious agents in T1DM patients may be related to their younger ages, but may also point to a protective role of those infections in T1DM development in susceptible individuals. Our results confirm the association between T1DM and celiac disease. A possible association with anticentromere antibody needs further studies.


Comparison of endorectal magnetic resonance imaging, guided prostate biopsy and digital rectal examination in the preoperative anatomical localization of prostate cancer.
We compared the accuracy of endorectal magnetic resonance imaging (erMRI), transrectal ultrasound (TRUS) guided biopsy and digital rectal examination (DRE) for detecting the location of cancer in the prostate gland and seminal vesicles. This is a retrospective study of 106 consecutive patients with prostate cancer who were referred for erMRI before radical prostatectomy. Step-section pathological data and erMRI were available in 90 patients, DRE data were available on 86 and individually labeled sextant core biopsies were available in 45. T1 and T2-weighted erMRI was interpreted by a single reader, who scored the likelihood of tumor on a 5-point scale in each seminal vesicle and in 12 locations in the prostate gland. MR spectroscopy data were not used for erMRI interpretation. One pathologist reviewed whole mount serial sections of radical prostatectomy specimens. The area under ROC curves was used to evaluate accuracy. The area under ROC curves for tumor localization was higher for erMRI than for DRE at the prostatic apex (0.72 vs 0.66), mid gland (0.80 vs 0.69) and base (0.83 vs 0.69). It was likewise higher for erMRI than for TRUS biopsy in the mid gland (0.75 vs 0.68) and base (0.81 vs 0.61) but not in the apex (0.67 vs 0.70). On mixed model analysis erMRI significantly increased the accuracy of prostate cancer localization by DRE or TRUS biopsy (each p <0.0001). For prostate cancer localization erMRI contributes significant incremental value to DRE or TRUS biopsy findings (each p <0.0001).


Phosphorylation of G Protein-Coupled Receptors: From the Barcode Hypothesis to the Flute Model.
Seven transmembrane G protein-coupled receptors (GPCRs) are often phosphorylated at the C terminus and on intracellular loops in response to various extracellular stimuli. Phosphorylation of GPCRs by GPCR kinases and certain other kinases can promote the recruitment of arrestin molecules. The arrestins critically regulate GPCR functions not only by mediating receptor desensitization and internalization, but also by redirecting signaling to G protein-independent pathways via interactions with numerous downstream effector molecules. Accumulating evidence over the past decade has given rise to the phospho-barcode hypothesis, which states that ligand-specific phosphorylation patterns of a receptor direct its distinct functional outcomes. Our recent work using unnatural amino acid incorporation and fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy led to the flute model, which provides preliminary insight into the receptor phospho-coding mechanism, by which receptor phosphorylation patterns are recognized by an array of phosphate-binding pockets on arrestin and are translated into distinct conformations. These selective conformations are recognized by various effector molecules downstream of arrestin. The phospho-barcoding mechanism enables arrestin to recognize a wide range of phosphorylation patterns of GPCRs, contributing to their diverse functions.


Conversion from dopamine agonists to pramipexole. An open-label trial in 227 patients with advanced Parkinson's disease.
Pramipexole is a nonergoline dopamine agonist with D2 and preferential D3 dopamine receptor activity. This selective activity may result in clinically different effects. Small clinical trials indicate that overnight switching from one agonist to another can be performed safely. Objective To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinson's disease (PD). To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinson's disease (PD). Patients with advanced PD and motor complications not optimally controlled by levodopa and a stable dose of bromocriptine, pergolide or ropinirole were converted to pramipexole overnight. Clinical assessments were performed just prior to conversion and after 2, 6 and 12 weeks of treatment, when an optimal dose of pramipexole was achieved. Two hundred and seventeen patients were included in the trial. One hundred and twenty five were converted from pergolide to pramipexole, 58 from bromocriptine and 34 from ropinirole. After 12 weeks, the average dose of pramipexole was 2.8, 2.9 and 3.4 mg/d in patients converted from bromocriptine, pergolide, and ropinirole, respectively. UPDRS II, III and IV scores were reduced by 26-30% in all patients (p<0.0001). Mean levodopa dose was slightly reduced in all groups (p: NS). No serious or unexpected side effects were reported. The dose equivalences calculated from this trial were: bromocriptine:pramipexole 6.9:1, pergolide:pramipexole 0.9:1, ropinirole:pramipexole 1.5:1. Switching from bromocriptine, pergolide or ropinirole to pramipexole in an overnight schedule is safe. The observed clinical improvement may be related to a placebo effect, to the use of low doses of dopamine agonists or to a direct effect of pramipexole.


The possible mechanisms of the human microbiome in allergic diseases.
In the present paper, we discuss the importance of the microbiome in allergic disease. In this review paper, the data from the Medline (PubMed) and search engine of Kirikkale University were systematically searched for all relevant articles in June 15th, 2015 for the past 30 years. The keywords of "microbiome", "dysbiosis", "allergy", "allergic rhinitis", "allergic disease", "mechanisms" and "treatment" were used alone or together. In this paper, microbiomes were presented in terms of "Definition", "Influence of \the human microbiome on health", "The microbiome and allergic diseases", and "Modulation of the gut microbiota in terms of treatment and prevention". Microbiological dysbiosis is also reviewed. The microbiome is the genetic material of all microbes (bacteria, fungi, protozoa, and viruses) that live on or in the human body. Microbes outnumber human cells in a 10:1 ratio. Most microbes live in the gut, particularly the large intestine. Changes in the immune function of the respiratory tract are (at least in theory) linked to the immunomodulatory activity of the gut microbiota via the concept of a "common mucosal response". The gut microbiota shapes systemic immunity, thus affecting the lung mucosa. Alternatively, changes in the gut microbiota may reflect alterations in the oropharyngeal microbiota, which may in turn directly affect the lung microbiota and host immune responses via microaspiration. Dysbiosis is defined as qualitative and quantitative changes in the intestinal flora; and modern diet and lifestyle, antibiotics, psychological and physical stress result in alterations in bacterial metabolism, as well as the overgrowth of potentially pathogenic microorganisms. All immune system components are directly or indirectly regulated by the microbiota. The nature of microbial exposure early in life appears to be important for the development of robust immune regulation; disruption of either the microbiota or the host response can trigger chronic inflammation. Dysbiosis is also an important clinical entity. Antibiotics, psychological and physical stress, and dietary factors contribute to intestinal dysbiosis.


Why homeodynamics, not homeostasis?
Ideas of homeostasis derive from the concept of the organism as an open system. These ideas can be traced back to Heraclitus. Hopkins, Bernard, Hill, Cannon, Weiner and von Bertalanffy developed further the mechanistic basis of turnover of biological components, and Schoenheimer and Rittenberg were pioneers of experimental approaches to the problems of measuring pool sizes and dynamic fluxes. From the second half of the twentieth century, a biophysical theory mainly founded on self-organisation and Dynamic Systems Theory allowed us to approach the quantitative and qualitative analysis of the organised complexity that characterises living systems. This combination of theoretical framework and more refined experimental techniques revealed that feedback control of steady states is a mode of operation that, although providing stability, is only one of many modes and may be the exception rather than the rule. The concept of homeodynamics that we introduce here offers a radically new and all-embracing concept that departs from the classical homeostatic idea that emphasises the stability of the internal milieu toward perturbation. Indeed, biological systems are homeodynamic because of their ability to dynamically self-organise at bifurcation points of their behaviour where they lose stability. Consequently, they exhibit diverse behaviour; in addition to monotonic stationary states, living systems display complex behaviour with all its emergent characteristics, i.e., bistable switches, thresholds, waves, gradients, mutual entrainment, and periodic as well as chaotic behaviour, as evidenced in cellular phenomena such as dynamic (supra)molecular organisation and flux coordination. These processes may proceed on different spatial scales, as well as across time scales, from the very rapid processes within and between molecules in membranes to the slow time scales of evolutionary change. It is dynamic organisation under homeodynamic conditions that make possible the organised complexity of life.


Efficacy of a Urinary Bladder Matrix for Treating Wound Dehiscence With Hardware Exposure in a Patient With Rheumatoid Arthritis.
This case report explores an effective treatment modality in a medically complicated patient, with considerable wound dehiscence refractory to treatment with negative pressure wound therapy (NPWT). A 35-year-old woman with a past medical history of hypothyroidism, osteoporosis, and rheumatoid arthritis treated with tumor necrosis factor (TNF) alpha inhibitors and disease-modifying antirheumatic drugs presented to the clinic following right great toe arthrodesis, metatarsal neck osteotomies, extensor tendon lengthening, and capsulotomy of the second, third, fourth, and fifth toes 2 weeks prior, with wound dehiscence of the right great toe and subsequent exposure of surgical hardware, complicated by infection. At the 2-week postop, a urinary bladder matrix was placed on the wound following failed NPWT, which was in place for 10 days. At the 3-month follow-up, the wound was closed and without any drainage. Patient reported a significant reduction in pain (visual analogue scale: 3) with adherence to weight-bearing restrictions. Wound healing was accomplished without removal of the exposed deep hardware in a patient with comorbidities and post-surgical wound dehiscence.


SU-E-T-485: Validation of Acuros XB Dose Calculations in SBRT Lung Planning with Monte Carlo Methods.
The Acuros XB (AXB) Advanced Dose algorithm (Varian Medical Systems) represents a dramatic shift in clinical photon dose calculation methodology from pencil-beam superposition/convolution methods. Early studies evaluating the accuracy of the algorithm in lung have found good agreement with both measurement and Monte Carlo based dose calculations. In this study, a dosimetric validation of Acuros is performed for clinical SBRT lung planning cases using Monte Carlo (MC) calculations as a benchmark. MC simulations using BEAMnrc/DOSXYZnrc were carried out for 8 AXB calculated 6/10 MV arc plans delivered on a TrueBeamTM STx linac in high-dose-rate flattening filter free mode. Clinical planning constraints were applied in each case with plans normalized to achieve 95% PTV coverage. Metrics used in the evaluation include: maximum and minimum GTV/PTV dose, PTV isodose coverage, conformity and dose profile comparisons. To understand the impact of moving toward to AXB calculations in SBRT lung planning, calculations using the Analytical Anisotropic Algorithm (AAA) are presented for each plan. For both 6 and 10MV energies, consistent mean GTV dose and PTV isodose coverage was observed for AXB and MC calculations. GTV mean dose was observed to deviate by <2% for all cases. Isodose coverage for MC simulations ranged from 92%-98%. AAA was also in agreement with MC simulations within the GTV to within 2%. AXB and MC maximum and minimum PTV dose differences were larger (up to 9%) but not of clinical concern. In several cases, AXB exhibited a significant improvement in dose calculation accuracy in the lung region surrounding the GTV over AAA, particularly with lung densities < 0.1 g/cc. AcurosXB provides increased accuracy in modelling dose deposition for SBRT lung over AAA and is found to be in good agreement with MC calculations.


Biochemical characterization of the cell-biomaterial interface by quantitative proteomics.
Surface topography and texture of cell culture substrata can affect the differentiation and growth of adherent cells. The biochemical basis of the transduction of the physical and mechanical signals to cellular responses is not well understood. The lack of a systematic characterization of cell-biomaterial interaction is the major bottleneck. This study demonstrated the use of a novel subcellular fractionation method combined with quantitative MS-based proteomics to enable the robust and high-throughput analysis of proteins at the adherence interface of Madin-Darby canine kidney cells. This method revealed the enrichment of extracellular matrix proteins and membrane and stress fibers proteins at the adherence surface, whereas it shows depletion of extracellular matrix belonging to the cytoplasmic, nucleus, and lateral and apical membranes. The asymmetric distribution of proteins between apical and adherence sides was also profiled. Apart from classical proteins with clear involvement in cell-material interactions, proteins previously not known to be involved in cell attachment were also discovered.


Different learned coordinate frames for planning trajectories and final positions in reaching.
We previously reported that the kinematics of reaching movements reflect the superimposition of two separate control mechanisms specifying the hand's spatial trajectory and its final equilibrium position. We now asked whether the brain maintains separate representations of the spatial goals for planning hand trajectory and final position. One group of subjects learned a 30 degrees visuomotor rotation about the hand's starting point while performing a movement reversal task ("slicing") in which they reversed direction at one target and terminated movement at another. This task required accuracy in acquiring a target mid-movement. A second group adapted while moving to -- and stabilizing at -- a single target ("reaching"). This task required accuracy in specifying an intended final position. We examined how learning in the two tasks generalized both to movements made from untrained initial positions and to movements directed toward untrained targets. Shifting initial hand position had differential effects on the location of reversals and final positions: Trajectory directions remained unchanged and reversal locations were displaced in slicing whereas final positions of both reaches and slices were relatively unchanged. Generalization across directions in slicing was consistent with a hand-centered representation of desired reversal point as demonstrated previously for this task whereas the distributions of final positions were consistent with an eye-centered representation as found previously in studies of pointing in three-dimensional space. Our findings indicate that the intended trajectory and final position are represented in different coordinate frames, reconciling previous conflicting claims of hand-centered (vectorial) and eye-centered representations in reach planning.


Hierarchical assembly of metal nanoparticles, quantum dots and organic dyes using DNA origami scaffolds.
The self-assembly of nanoscale elements into three-dimensional structures with precise shapes and sizes is important in fields such as nanophotonics, metamaterials and biotechnology. Short molecular linkers have previously been used to create assemblies of nanoparticles, but the approach is limited to small interparticle distances, typically less than 10 nm. Alternatively, DNA origami can precisely organize nanoscale objects over much larger length scales. Here we show that rigid DNA origami scaffolds can be used to assemble metal nanoparticles, quantum dots and organic dyes into hierarchical nanoclusters that have a planet-satellite-type structure. The nanoclusters have a tunable stoichiometry, defined distances of 5-200 nm between components, and controllable overall sizes of up to 500 nm. We also show that the nanoscale components can be positioned along the radial DNA spacers of the nanostructures, which allows short- and long-range interactions between nanoparticles and dyes to be studied in solution. The approach could, in the future, be used to construct efficient energy funnels, complex plasmonic architectures, and porous, nanoengineered scaffolds for catalysis.


Reprogrammable, Reprocessible, and Self-Healable Liquid Crystal Elastomer with Exchangeable Disulfide Bonds.
A liquid crystal elastomer (LCE) can be regarded as an integration of mesogenic molecules into a polymer network. The LCE can generate large mechanical actuation when subjected to various external stimuli. Recently, it has been extensively explored to make artificial muscle and multifunctional devices. However, in the commonly adopted two-step crosslinking method for synthesizing monodomain LCEs, the LCE needs to be well-cross-linked in the first step before stretching, which increases the disorder of mesogenic molecules in the final state of the LCE and makes it very challenging to fabricate the LCE of complex shapes. In this article, we developed a new LCE with disulfide bonds, which can be reprogrammed from the polydomain state to the monodomain state either through heating or UV illumination, owing to the rearrangement of the polymer network induced by the metathesis reaction of disulfide bonds. In addition, the newly developed LCE can be easily reprocessed and self-healed by heating. Because of the excellent reprogrammability as well as reprocessability of the LCE, we further fabricated LCE-based active micropillar arrays through robust imprint lithography, which can be hardly achieved using the LCE prepared previously. Finally, we showed an excellent long-term durability of the newly developed LCE.


Challenges in Estimating the Effectiveness of COVID-19 Vaccination Using Observational Data.
The COVID-19 vaccines were developed and rigorously evaluated in randomized trials during 2020. However, important questions, such as the magnitude and duration of protection, their effectiveness against new virus variants, and the effectiveness of booster vaccination, could not be answered by randomized trials and have therefore been addressed in observational studies. Analyses of observational data can be biased because of confounding and because of inadequate design that does not consider the evolution of the pandemic over time and the rapid uptake of vaccination. Emulating a hypothetical "target trial" using observational data assembled during vaccine rollouts can help manage such potential sources of bias. This article describes 2 approaches to target trial emulation. In the sequential approach, on each day, eligible persons who have not yet been vaccinated are matched to a vaccinated person. The single-trial approach sets a single baseline at the start of the rollout and considers vaccination as a time-varying variable. The nature of the confounding depends on the analysis strategy: Estimating "per-protocol" effects (accounting for vaccination of initially unvaccinated persons after baseline) may require adjustment for both baseline and "time-varying" confounders. These issues are illustrated by using observational data from 2 780 931 persons in the United Kingdom aged 70 years or older to estimate the effect of a first dose of a COVID-19 vaccine. Addressing the issues discussed in this article should help authors of observational studies provide robust evidence to guide clinical and policy decisions.


Pragmatic exercise intervention for people with multiple sclerosis (ExIMS trial): study protocol for a randomised controlled trial.
Exercise is an effective intervention for improving function, mobility and health-related quality of life in people with multiple sclerosis (PwMS). Questions remain however, regarding the effectiveness of pragmatic exercise interventions for evoking tangible and sustained increases in physical activity and long-term impact on important health outcomes in PwMS. Furthermore, dose-response relationships between exercise and health outcomes have not previously been reported in PwMS. These issues, and improved knowledge of cost effectiveness, are likely to influence key decisions of health policy makers regarding the implementation of exercise therapy as part of the patient care pathway for PwMS. Hence, the primary aim of this study is to investigate whether a 12-week tapered programme of supervised exercise, incorporating cognitive-behavioural techniques to facilitate sustained behaviour change, is effective for evoking improvements in physical activity and key health outcomes in PwMS over 9 months of follow-up. A total of 120 PwMS will be randomised (1:1) to either a 12-week pragmatic exercise therapy intervention or usual care control group. Participants will be included on the basis of a clinical diagnosis of MS, with an expanded disability status score (EDSS) between 1 and 6.5. Outcome measures, to be assessed before and after the intervention and 6 months later, will include physical activity, clinical and functional measures and health-related quality of life. In addition, the cost effectiveness of the intervention will be evaluated and dose-response relationships between physical activity and the primary/secondary outcomes in those with mild and more severe disease will be explored.


Global gene expression profiling of Bacillus subtilis in response to ammonium and tryptophan starvation as revealed by transcriptome and proteome analysis.
The global gene expression profile of Bacillus subtilis in response to ammonium and tryptophan starvation was analyzed using transcriptomics and proteomics which gained novel insights into these starvation responses. The results demonstrate that both starvation conditions induce specific, overlapping and general starvation responses. The TnrA regulon, the glutamine synthetase (glnA) as well as the sigma(L)-dependent bkd and roc operons were most strongly and specifically induced after ammonium starvation. These are involved in the uptake and utilization of ammonium and alternative nitrogen sources such as amino acids, gamma-aminobutyrate, nitrate/nitrite, uric acid/urea and oligopeptides. In addition, several carbon catabolite-controlled genes (e.g. acsA, citB), the alpha-acetolactate synthase/-decarboxylase alsSD operon and several aminotransferase genes were specifically induced after ammonium starvation. The induction of sigma(F)- and sigma(E)-dependent sporulation proteins at later time points in ammonium-starved cells was accompanied by an increased sporulation frequency. The specific response to tryptophan starvation includes the TRAP-regulated tryptophan biosynthesis genes, some RelA-dependent genes (e.g. adeC, ald) as well as spo0E. Furthermore, we recognized overlapping responses between ammonium and tryptophan starvation (e.g. dat, maeN) as well as the common induction of the CodY and sigma(H) general starvation regulons and the RelA-dependent stringent response. Many genes encoding proteins of so far unknown functions could be assigned to specifically or commonly induced genes.


Are dispersion corrections accurate outside equilibrium? A case study on benzene.
Modern approaches to modelling dispersion forces are becoming increasingly accurate, and can predict accurate binding distances and energies. However, it is possible that these successes reflect a fortuitous cancellation of errors at equilibrium. Thus, in this work we investigate whether a selection of modern dispersion methods agree with benchmark calculations across several potential-energy curves of the benzene dimer to determine if they are capable of describing forces and energies outside equilibrium. We find the exchange-hole dipole moment (XDM) model describes most cases with the highest overall agreement with reference data for energies and forces, with many-body dispersion (MBD) and its fractionally ionic (FI) variant performing essentially as well. Popular approaches, such as Grimme-D and van der Waals density functional approximations (vdW-DFAs) underperform on our tests. The meta-GGA M06-L is surprisingly good for a method without explicit dispersion corrections. Some problems with SCAN+rVV10 are uncovered and briefly discussed.


Assessing bias, precision, and agreement in method comparison studies.
Recently, a new estimation procedure has been developed to assess bias and precision of a new measurement method, relative to a reference standard. However, the author did not develop confidence bands around the bias and standard deviation curves. Therefore, the goal in this paper is to extend this methodology in several important directions. First, by developing simultaneous confidence bands for the various parameters estimated to allow formal comparisons between different measurement methods. Second, by proposing a new index of agreement. Third, by providing a series of new graphs to help the investigator to assess bias, precision, and agreement between the two measurement methods. The methodology requires repeated measurements on each individual for at least one of the two measurement methods. It works very well to estimate the differential and proportional biases, even with as few as two to three measurements by one of the two methods and only one by the other. The repeated measurements need not come from the reference standard but from either measurement methods. This is a great advantage as it may sometimes be more feasible to gather repeated measurements with the new measurement method.


Recreational music-making modulates immunological responses and mood states in older adults.
Given that previous studies have shown that recreational music-making has benefits for younger individuals, we explored two questions. (1) Could a recreational music-making protocol improve mood and modulate immunological responses in a direction opposite to that associated with chronic stress in older adults? (2) Would the protocol affect older and younger participants differently? Two groups of volunteers demarcated at age 65 years underwent identical one-hour recreational music-making interventions. Pre-and post-intervention data were collected using blood samples and mood state questionnaires. Data from 27 older and 27 younger volunteers were analyzed for cytokine production levels, natural killer cell activity, plasma catecholamines, and numbers of T cells, T cell subsets, B cells, and natural killer cells. Exercise expenditure was also recorded. In the older group, we found significant increases in the number of lymphocytes, T cells, CD4+ T cells, memory T cells, and production of interferon-gamma and interleukin-6. In the younger group, modulation was non-significant. Worthy of note was the specific immunological changes in the direction opposite to that expected with chronic stress in the older group. The increase in Th1 cytokine IFN-gamma and unchanged Th2 cytokine IL-4 and IL-10 levels in the older group suggests a shift to a Th1-dominant status, a shift opposite to that expected with stress. However, the immunological changes were not statistically different between the two groups. Mood states improved in both groups, but were also not statistically different between groups. Although no statistically significant difference was found between the two age groups, the improvement in immunological profile and mood states in the older group and the low level of energy required for participation suggest this music-making protocol has potential as a health improvement strategy for older individuals.


Dye-sensitized solar cells employing a single film of mesoporous TiO2 beads achieve power conversion efficiencies over 10%.
Dye-sensitized solar cells employing mesoporous TiO(2) beads have demonstrated longer electron diffusion lengths and extended electron lifetimes over Degussa P25 titania electrodes due to the well interconnected, densely packed nanocrystalline TiO(2) particles inside the beads. Careful selection of the dye to match the dye photon absorption characteristics with the light scattering properties of the beads have improved the light harvesting and conversion efficiency of the bead electrode in the dye-sensitized solar cell. This has resulted in a solar to electric power conversion efficiency (PCE) of greater than 10% (10.6% for Ru(II)-based dye C101 and 10.7% using C106) for the first time using a single screen-printed titania layer cell construction (that is, without an additional scattering layer).


Three different potassium channels in human atrium. Contribution to the basal potassium conductance.
We applied the cell-attached and inside-out patch-clamp technique under symmetrical isotonic potassium conditions on single human (and guinea pig) atrial cells. The human cells were isolated by a modified method to that described earlier. Our aim was twofold: 1) to study the single-channel characteristics of potassium channels in human atrial single cells, present under basal conditions (iK1 and iK(ATP] or when stimulated with 10(-5) M acetylcholine; and 2) to calculate the contribution of these three channel types to the total basal potassium conductance in human atrial cells, and to compare the results with data on guinea pig atrial cells under the same conditions. We found that in human cells 58% of the patches (n = 42/74) contained acetylcholine-sensitive potassium channels: their conductance was 42 +/- 1.2 pS and mean open time (tau o) was 1.7 +/- 0.5 msec. They showed sporadic openings in the absence of agonist, and activation by acetylcholine was G-protein dependent. In 16% of the patches (n = 7/44), adenosine (10(-4) M) activated the same channels, but the activity was lower than when stimulated by acetylcholine. In 18% of the patches (n = 9/51), an iK1 channel was present (conductance, 27 pS; tau o, 8.7 msec), whereas in the cell-attached mode, ATP-dependent channels were never seen. However, they were present in half of the inside-out patches on washout of ATPi (conductance, 73 pS; tau o, 1.4 msec). The basal potassium conductance (i.e., in the absence of any exogenous hormone or neurotransmitter) was mainly due to iK1 channels in both human and guinea pig cells, a finding that is in contrast with previous reports. However, the potassium current that is induced by acetylcholine is much higher in guinea pig than in human isolated cells; a fraction of it would suffice to fully determine the resting potassium conductance in guinea pig atrial cells, whereas it can play only a modulatory role in human cells. This difference could be important in species-specific autonomic modulation and antiarrhythmic drug action.


The characterization of multiple novel paramyxoviruses highlights the diverse nature of the subfamily Orthoparamyxovirinae.
The subfamily Orthoparamyxovirinae is a group of single-stranded, negative-sense RNA viruses that contains many human, animal, and zoonotic pathogens. While there are currently only forty-two recognized species in this subfamily, recent research has revealed that much of its diversity remains to be characterized. Using a newly developed nested PCR-based screening assay, we report here the discovery of fifteen orthoparamyxoviruses in rodents and shrews from Belgium and Guinea, thirteen of which are believed to represent new species. Using a combination of nanopore and sanger sequencing, complete genomes could be determined for almost all these viruses, enabling a detailed evaluation of their genome characteristics. While most viruses are thought to belong to the rapidly expanding genus Jeilongvirus, we also identify novel members of the genera Narmovirus, Henipavirus, and Morbillivirus. Together with other recently discovered orthoparamyxoviruses, both henipaviruses and the morbillivirus discovered here appear to form distinct rodent-/shrew-borne clades within their respective genera, clustering separately from all currently classified viruses. In the case of the henipaviruses, a comparison of the different members of this clade revealed the presence of a secondary conserved open reading frame, encoding for a transmembrane protein, within the F gene, the biological relevance of which remains to be established. While the characteristics of the viruses described here shed further light on the complex evolutionary origin of paramyxoviruses, they also illustrate that the diversity of this group of viruses in terms of genome organization appears to be much larger than previously assumed.


Evolution of cranial telescoping in echolocating whales (Cetacea: Odontoceti).
Odontocete (echolocating whale) skulls exhibit extreme posterior displacement and overlapping of facial bones, here referred to as retrograde cranial telescoping. To examine retrograde cranial telescoping across 40 million years of whale evolution, we collected 3D scans of whale skulls spanning odontocete evolution. We used a sliding semilandmark morphometric approach with Procrustes superimposition and PCA to capture and describe the morphological variation present in the facial region, followed by Ancestral Character State Reconstruction (ACSR) and evolutionary model fitting on significant components to determine how retrograde cranial telescoping evolved. The first PC score explains the majority of variation associated with telescoping and reflects the posterior migration of the external nares and premaxilla alongside expansion of the maxilla and frontal. The earliest diverging fossil odontocetes were found to exhibit a lesser degree of cranial telescoping than later diverging but contemporary whale taxa. Major shifts in PC scores and centroid size are identified at the base of Odontoceti, and early burst and punctuated equilibrium models best fit the evolution of retrograde telescoping. This indicates that the Oligocene was a period of unusually high diversity and evolution in whale skull morphology, with little subsequent evolution in telescoping.


Filling-Enforced Magnetic Dirac Semimetals in Two Dimensions.
Filling-enforced Dirac semimetals, or those required at specific fillings by the combination of crystalline and time-reversal symmetries, have been proposed in numerous materials. However, Dirac points in these materials are not generally robust against breaking or modifying time-reversal symmetry. We present a new class of two-dimensional Dirac semimetal protected by the combination of crystal symmetries and a special, antiferromagnetic time-reversal symmetry. Systems in this class of magnetic layer groups, while having broken time-reversal symmetry, still respect the operation of time-reversal followed by a half-lattice translation. In contrast to 2D time-reversal-symmetric Dirac semimetal phases, this magnetic Dirac phase is capable of hosting just a single isolated Dirac point at the Fermi level, one that can be stabilized solely by symmorphic crystal symmetries. We find that this Dirac point represents a new quantum critical point, existing at the boundary between Chern insulating, antiferromagnetic topological crystalline insulating, and trivial insulating phases, and we discuss its relationship with condensed matter fermion doubling theorems. We present density functional theoretic calculations which demonstrate the presence of these 2D magnetic Dirac points in FeSe monolayers and discuss the implications for engineering quantum phase transitions in these materials.


Alzheimer's disease-associated disability: an ICF approach.
The aim of the study is to provide a description of dementia-associated disability in Alzheimer's disease (AD) patients through the International Classification of Functioning, Disability and Health (ICF). Twenty-six AD patients at different stages of disease participated in the study. Mini Mental State Examination (MMSE) and Global Deterioration Scale (GDS) were used to stage the degree of cognitive impairment and the stage of disease, respectively. All subjects were classified using the ICF categories in the more detailed four-level version. Correlation between compromised ICF items and both MMSE and GDS scores were calculated through Spearman Rho test. Mental functions were impaired in all the subjects examined. Data on activity and participation showed that not only domestic life, self care, and mobility but also communication and interaction and social relationships are compromised in AD patients. Three main areas appeared as the most relevant facilitators: products and technology, support and relationship and services, systems and policies. ICF codes were generally correlated with both MMSE and GDS: subjects who appeared more compromised on MMSE and GDS showed higher impairment of functions, activity limitation, and participation restriction.Conclusion. ICF is a useful tool to describe health status in AD patients in that it underlines important aspects of daily living generally not considered by activity of daily living scales such as communication, social relationships, and recreation and leisure.


Endoscopic and Open Release Similarly Safe for the Treatment of Carpal Tunnel Syndrome. A Systematic Review and Meta-Analysis.
The Endoscopic Release of Carpal Tunnel Syndrome (ECTR) is a minimal invasive approach for the treatment of Carpal Tunnel Syndrome. There is scepticism regarding the safety of this technique, based on the assumption that this is a rather "blind" procedure and on the high number of severe complications that have been reported in the literature. To evaluate whether there is evidence supporting a higher risk after ECTR in comparison to the conventional open release. We searched MEDLINE (January 1966 to November 2013), EMBASE (January 1980 to November 2013), the Cochrane Neuromuscular Disease Group Specialized Register (November 2013) and CENTRAL (2013, issue 11 in The Cochrane Library). We hand-searched reference lists of included studies. We included all randomized or quasi-randomized controlled trials (e.g. study using alternation, date of birth, or case record number) that compare any ECTR with any OCTR technique. Safety was assessed by the incidence of major, minor and total number of complications, recurrences, and re-operations.The total time needed before return to work or to return to daily activities was also assessed. We synthesized data using a random-effects meta-analysis in STATA. We conducted a sensitivity analysis for rare events using binomial likelihood. We judged the conclusiveness of meta-analysis calculating the conditional power of meta-analysis. ECTR is associated with less time off work or with daily activities. The assessment of major complications, reoperations and recurrence of symptoms does not favor either of the interventions. There is an uncertain advantage of ECTR with respect to total minor complications (more transient paresthesia but fewer skin-related complications). Future studies are unlikely to alter these findings because of the rarity of the outcome. The effect of a learning curve might be responsible for reduced recurrences and reoperations with ECTR in studies that are more recent, although formal statistical analysis failed to provide evidence for such an association. I.


Prevalence and Severity of Off-Centering During Diagnostic CT: Observations From 57,621 CT scans of the Chest, Abdomen, and/or Pelvis.
To determine distances between patient centroid and gantry isocenter during CT imaging of the chest, abdomen, and/or pelvis, and to evaluate differences based on patient gender, scan region, patient position, and gantry aperture. A water phantom and an anthropomorphic phantom were imaged in the centered position in the CT gantry and at several off-centered positions. Additionally, data from 57,621 adult chest, abdomen, and/or pelvic CT acquisitions were evaluated. Data were analyzed with an analysis of variance using the centroid-to-isocenter data as the dependent variable and the other parameters as independent variables. The majority of patient acquisitions (83.7% (48271/57621)) were performed with the patient's centroid positioned below isocenter (mean 1.7 cm below isocenter (SD 1.8 cm); range 12.1 cm below to 7.8 cm above isocenter). Off-centering in the x-axis was less severe (mean 0.01 cm left of isocenter (SD 1.6 cm)). Distance between centroid and isocenter in the y-axis did not differ as a function of sex but did differ based on scan region, patient position, and gantry aperture. Off-centering is common during CT imaging and has been previously demonstrated to impact dose and image quality.


Experiences and Views of Medicine Information Among the General Public in Thailand.
Written and electronic medicine information are important for improving patient knowledge and safe use of medicines. Written medicine information in Thailand is mostly in the form of printed package inserts (PIs), designed for health professionals, with few medicines having patient information leaflets (PILs). The aim of this study was to determine practices, needs and expectations of Thai general public about written and electronic medicine information and attitudes towards PILs. Cross-sectional survey, using self-completed questionnaires, was distributed directly to members of the general public in a large city, during January to March 2019. It explored experiences of using information, expectations, needs and attitudes, the latter measured using a 10-item scale. Differences between sub-groups were assessed, applying the Bonferroni correction to determine statistical significance. Of the total 851 questionnaires distributed, 550 were returned (64.2%). The majority of respondents (88%) had received PIs, but only a quarter (26.2%) had received PILs. Most respondents (78.5%) had seen medicine information in online form. High educational level and income increased the likelihood of receiving PILs and electronic information. The majority of respondents (88.5%) perceived PILs as useful, but 70% considered they would still need information about medicines from health professionals. Indication, drug name and precautions were the most frequently read information in PIs and perceived as needed in PILs. Three-quarters of respondents would read electronic information if it were available, with more who had received a PIL having previously searched for such information compared to those who had not. All respondents had positive overall attitudes towards PILs. Experiences of receiving PILs and electronic medicine information in Thailand are relatively limited. However, the general public considered PILs as a useful source of medicine information. Electronic medicine information was desired and should be developed to be an additional source of information for consumers.


A 'Healthy Islands' framework for climate change in the Pacific.
Small Pacific Island countries (PICs) are among the most vulnerable countries in the world to the anticipated detrimental health effects of climate change. The assessment of health vulnerabilities and planning adaptation strategies to minimize the impacts of climate change on health tests traditional health governance structures and depends on strong linkages and partnerships between actors involved in these vital processes. This article reviews the actors, processes and contexts of the climate change and health vulnerability assessment and adaptation planning project carried out by the World Health Organization and health sector partners in three island countries in the Micronesian region of the Pacific throughout 2010 and 2011: Federated States of Micronesia, Marshall Islands and Palau. Despite their shared history and cultural characteristics, the findings and implications of this article are considered to have substantial relevance and potential application to other PICs. The modified 'Healthy Islands' framework for climate change and health adaptation presented in this article draws upon real-world experience and governance theory from both the health and climate change literature and, for the first time, places health systems adaptation within the vision for 'Healthy Islands' in the Pacific region.


Approaches to catheter ablation for persistent atrial fibrillation.
Catheter ablation is less successful for persistent atrial fibrillation than for paroxysmal atrial fibrillation. Guidelines suggest that adjuvant substrate modification in addition to pulmonary-vein isolation is required in persistent atrial fibrillation. We randomly assigned 589 patients with persistent atrial fibrillation in a 1:4:4 ratio to ablation with pulmonary-vein isolation alone (67 patients), pulmonary-vein isolation plus ablation of electrograms showing complex fractionated activity (263 patients), or pulmonary-vein isolation plus additional linear ablation across the left atrial roof and mitral valve isthmus (259 patients). The duration of follow-up was 18 months. The primary end point was freedom from any documented recurrence of atrial fibrillation lasting longer than 30 seconds after a single ablation procedure. Procedure time was significantly shorter for pulmonary-vein isolation alone than for the other two procedures (P<0.001). After 18 months, 59% of patients assigned to pulmonary-vein isolation alone were free from recurrent atrial fibrillation, as compared with 49% of patients assigned to pulmonary-vein isolation plus complex electrogram ablation and 46% of patients assigned to pulmonary-vein isolation plus linear ablation (P=0.15). There were also no significant differences among the three groups for the secondary end points, including freedom from atrial fibrillation after two ablation procedures and freedom from any atrial arrhythmia. Complications included tamponade (three patients), stroke or transient ischemic attack (three patients), and atrioesophageal fistula (one patient). Among patients with persistent atrial fibrillation, we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01203748.).


Mushroom extract protects against hydrogen peroxide-induced toxicity in hepatic and neuronal human cultured cells.
Hydrogen peroxide is an oxidative stress agent that is associated with depletion of intracellular glutathione and inhibition of antioxidant enzymes in different cell lines. Consumption of antioxidant-rich foods reduces cellular oxidative stress and its related health problems. This study aimed to assess the antioxidant properties of mushroom, Agaricus bisporous cultivar extract, against hydrogen peroxide induced oxidative stress in cultured human hepatic (HepG2) and neuronal (SH-SY5Y) cells. In this study, hydrogen peroxide caused significant oxidative stress in HepG2 and SH-SY5Y cells as demonstrated by glutathione depletion, impairment of total antioxidant capacity and inhibition of antioxidant enzymes (glutathione peroxidase, catalase and superoxide dismutase). Agaricusbisporous extract ameliorated the observed hydrogen peroxide-induced oxidative cellular insult as indicated by restoring the activity of glutathione and the assayed antioxidant enzymes to control levels. The results suggest that mushroom extract as antioxidant properties and protects against the oxidative stress induced by hydrogen peroxide-in cultured human hepatic and neuronal cells.


Microgel particles containing methacrylic acid: pH-triggered swelling behaviour and potential for biomaterial application.
pH-responsive microgels are crosslinked polymer particles that swell when the pH approaches the pK(a) of the ionic monomer incorporated within the particles. In recent work from our group it was demonstrated that the mechanical properties of degenerated intervertebral discs (IVDs) could be restored to normal values by injection of poly(EA/MAA/BDDA) (ethylacrylate, methacrylic acid and butanediol diacrylate) microgel dispersions [J.M. Saunders, T. Tong, C.L. Le Maitre, T.J. Freemont, B.R. Saunders, Soft Matter 3 (2007) 486]. In this work we report the pH dependent swelling and rheological properties of poly(MMA/MAA/EGDMA) (methylmethacrylate and ethyleneglycol dimethacrylate) microgel dispersions. This system was investigated because it contains monomers that are already used as biomaterials. The poly(MMA/MAA/EGDMA) particles exhibit pH-triggered volume swelling ratios of up to ca. 250. The swelling onset for these particles occurs at pH values greater than ca. 6.0. A pK(a) for these particles of ca. 6.7 is consistent with titration and swelling data. Fluid-to-gel phase diagrams for concentrated poly(MMA/MAA/EGDMA) dispersions were determined as a function of polymer volume fraction and pH using tube-inversion measurements. The rheological properties for the gelled microgel dispersions were investigated using dynamic rheology measurements. The elastic modulus data for the poly(MMA/MAA/EGDMA) gelled dispersions were compared to data for poly(EA/MAA/BDDA) microgels. A similar pH-dependence for the elastic modulus was apparent. The maximum elastic modulus was achieved at a pH of about 7.0. The elastic modulus is an exponentially increasing function of polymer volume fraction at pH 7.0. Preliminary cell challenge experimental data are reported that indicate that gelled poly(MMA/MAA/EGDMA) microgel dispersions are biocompatible with cells from human intervertebral discs. However, the duration over which these experiments could be performed was limited by gradual redispersion of the gelled microgel dispersions. Based on the results presented it is suggested that poly(MMA/MAA/EGDMA) microgel would be a good candidate as a biomaterial for structural support of soft connective tissues.


Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade.
Itk, a Tec family tyrosine kinase, acts downstream of Lck and phosphatidylinositol 3'-kinase to facilitate T cell receptor (TCR)-dependent calcium influxes and increases in extracellular-regulated kinase activity. Here we demonstrate interactions between Itk and crucial components of TCR-dependent signaling pathways. First, the inositide-binding pocket of the Itk pleckstrin homology domain directs the constitutive association of Itk with buoyant membranes that are the primary site of TCR activation and are enriched in both Lck and LAT. This association is required for the transphosphorylation of Itk. Second, the Itk proline-rich region binds to Grb2 and LAT. Third, the Itk Src homology (SH3) 3 and SH2 domains interact cooperatively with Syk-phosphorylated SLP-76. Notably, SLP-76 contains a predicted binding motif for the Itk SH2 domain and binds to full-length Itk in vitro. Finally, we show that kinase-inactive Itk can antagonize the SLP-76-dependent activation of NF-AT. The inhibition of NF-AT activation depends on the Itk pleckstrin homology domain, proline-rich region, and SH2 domain. Together, these observations suggest that multivalent interactions recruit Itk to LAT-nucleated signaling complexes and facilitate the activation of LAT-associated phospholipase Cgamma1 by Itk.


Directional bias of neurons in V1 and V2 of strabismic monkeys: temporal-to-nasal asymmetry?
Strabismus that develops shortly after birth is known to cause temporal-to-nasal eye movement asymmetries under monocular viewing. The neural mechanisms underlying this deficit are not well understood. In the current study, the hypothesis that this eye movement anomaly reflects a similar asymmetry in the directional response properties of neurons in the early stages of cortical processing was examined. Strabismus was simulated with optical methods in infant monkeys between 4 and 14 weeks of age. When the monkeys were mature, microelectrode recording experiments were conducted in the primary visual cortex (V1) and visual area 2 (V2). After the spatial frequency of sine wave-grating stimuli for each neuron was optimized, each neuron's responsiveness to 24 directions of stimulus movement was measured. The preferred direction and the strength of directional bias were determined by a vector summation method: There was not an overabundance of neurons in V1 or V2 of strabismic monkeys preferring the temporal-to-nasal direction of stimulus movement. However, the average directional bias was significantly reduced in these strabismic monkeys. Interocular suppression was highly prevalent, and this suppression was stronger and more common in neurons dominated by the ipsilateral eye. The results suggest that the eye movement asymmetries in strabismic subjects do not result from similar asymmetries in the directional properties of V1 or V2 neurons, but rather reflect impoverished cortical signals to the brain stem nuclei that control eye movements.


Influence of stage classification, tumor differentiation and mode of invasion against clinical and histopathological effects on low dose sequential methotrexate and 5-fluorouracil administration as neo-adjuvant chemotherapy for oral squamous cell carcinoma.
We report on the influences of stage classification, tumor differentiation and mode of invasion against clinical and histopathological effects associated with low dose sequential methotrexate (MTX) and 5-fluorouracil (5-FU) (MF therapy) as neo-adjuvant chemotherapy in oral cancer. The oral cancer of 22 patients was treated as follows: MTX (75 mg/body) was administrated by intravenous infusion for 1 hour, followed by 5-FU (500 mg/body) intravenous infusion for 2 hours on Day 1, MTX (75 mg/body) intravenous infusion for 1 hour on Day 4, and parenteral dose of leucovorin on Day 2 and Day 5. The MF therapy of 1-5 courses was performed weekly or every 2 weeks. The clinical response rate was lower in stage IV than in the other stages. There was no difference in the rate of tumor differentiation by WHO grade classification, I and II. The rate was higher in grade 1, 2 and 3 than in grade 4C and 4D due to mode of invasion. The histological response rate was higher in stage I and II than in stage III and IV. The response rate was higher in grade II than in grade I, but was higher in grade 1 and 2 than in grade 3 and 4C. However, the response rate in grade 4D was good (66.7%; 2/3). Histological response was demonstrated only in partial or complete response cases of the clinical response. MF therapy was suggested to be effective for histological response regardless of stage classification, tumor differentiation and mode of invasion, although its success rate was low in stage III, IV (stage classification), grade I (tumor differentiation), grade 3 and 4C (mode of invasion).


A magic pill? A qualitative analysis of patients' views on the role of antidepressant therapy in inflammatory bowel disease (IBD).
Studies with healthy volunteers have demonstrated that antidepressants can improve immunoregulatory activity and thus they may have a potential to positively impact the disease course in inflammatory bowel disease (IBD), a chronic and incurable condition. However, patients' views on the role of antidepressants in the management of their IBD are unknown. Thus, this study aimed to explore patients' experiences and opinions regarding the effect of antidepressants on IBD course before possibly undertaking future treatment trials with antidepressants. Semi-structured in-depth interviews with open-ended questions were conducted with a randomly selected sample of IBD patients recruited at the Australian public hospital IBD clinic and currently receiving antidepressants. A qualitative content analysis was undertaken to summarise patients' responses. A Visual Analogue Scale was used to provide a quantitative assessment of patients' experiences with antidepressants. Overall, 15 IBD sufferers currently on antidepressants (nine females, six males) were interviewed. All 15 reported a positive response to antidepressants reporting they improved their quality of life, with minimal side-effects. Five patients (33.3%) felt the antidepressant had specifically improved their IBD course. Three patients noted how they believed the reduction in feelings of stress mediated the positive influence of the antidepressant on IBD course. Ten patients (66.7%) felt the antidepressants had not specifically influenced their IBD. Nine patients (60.0%) had a generally positive attitude towards antidepressants, four patients (26.7%) were ambivalent, and two patients (13.3%) held a negative view towards antidepressants. Twelve patients (80.0%) stated that they would be willing to participate in clinical trials. Antidepressants seem to be well tolerated by IBD patients. One third of patients reported an observable improvement of their IBD under the influence of this treatment. The positive attitude towards antidepressants in these participants may make the conduct of clinical trials to further assess for any specific role on IBD course feasible. However, due to a small sample size, a qualitative nature of this study and in light of the results of studies on other populations indicating reluctance to taking antidepressants at least in some patients, these results should be interpreted with caution until confirmed in quantitative studies.


Attention Stabilizes Representations in the Human Hippocampus.
Attention and memory are intricately linked, but how attention modulates brain areas that subserve memory, such as the hippocampus, is unknown. We hypothesized that attention may stabilize patterns of activity in human hippocampus, resulting in distinct but reliable activity patterns for different attentional states. To test this prediction, we utilized high-resolution functional magnetic resonance imaging and a novel "art gallery" task. On each trial, participants viewed a room containing a painting, and searched a stream of rooms for a painting from the same artist (art state) or a room with the same layout (room state). Bottom-up stimulation was the same in both tasks, enabling the isolation of neural effects related to top-down attention. Multivariate analyses revealed greater pattern similarity in all hippocampal subfields for trials from the same, compared with different, attentional state. This stability was greater for the room than art state, was unrelated to univariate activity, and, in CA2/CA3/DG, was correlated with behavior. Attention therefore induces representational stability in the human hippocampus, resulting in distinct activity patterns for different attentional states. Modulation of hippocampal representational stability highlights the far-reaching influence of attention outside of sensory systems.


Skeletal muscle atrophy during short-term disuse: implications for age-related sarcopenia.
Situations such as the recovery from injury and illness can lead to enforced periods of muscle disuse or unloading. Such circumstances lead to rapid skeletal muscle atrophy, loss of functional strength and a multitude of related negative health consequences. The elderly population is particularly vulnerable to the acute challenges of muscle disuse atrophy. Any loss of skeletal muscle mass must be underpinned by a chronic imbalance between muscle protein synthesis and breakdown rates. It is recognized that muscle atrophy during prolonged (>10 days) disuse is brought about primarily by declines in post-absorptive and post-prandial muscle protein synthesis rates, without a clear contribution from changes in muscle protein breakdown. Few data are available on the impact of short-term disuse (<10 days) on muscle protein turnover in humans. However, indirect evidence indicates that considerable muscle atrophy occurs during this early phase, and is likely attributed to a rapid increase in muscle protein breakdown accompanied by the characteristic decline in muscle protein synthesis. Short-term disuse atrophy is of particular relevance in the development of sarcopenia, as it has been suggested that successive short periods of muscle disuse, due to sickness or injury, accumulate throughout an individual's lifespan and contributes considerably to the net muscle loss observed with aging. Research is warranted to elucidate the physiological and molecular basis for rapid muscle loss during short periods of disuse. Such mechanistic insight will allow the characterization of nutritional, exercise and/or pharmacological interventions to prevent or attenuate muscle loss during periods of disuse and therefore aid in the treatment of age-related sarcopenia.


Will you accept the government's friend request? Social networks and privacy concerns.
Participating in social network websites entails voluntarily sharing private information, and the explosive growth of social network websites over the last decade suggests shifting views on privacy. Concurrently, new anti-terrorism laws, such as the USA Patriot Act, ask citizens to surrender substantial claim to privacy in the name of greater security. I address two important questions regarding individuals' views on privacy raised by these trends. First, how does prompting individuals to consider security concerns affect their views on government actions that jeopardize privacy? Second, does the use of social network websites alter the effect of prompted security concerns? I posit that prompting individuals to consider security concerns does lead to an increased willingness to accept government actions that jeopardize privacy, but that frequent users of websites like Facebook are less likely to be swayed by prompted security concerns. An embedded survey experiment provides support for both parts of my claim.


Evaluating Pennsylvania Pharmacists' Provision of Community-based Patient Care Services to Develop a Statewide Practice Network.
To identify and describe Pennsylvania pharmacists who currently provide or are interested in providing community-based patient care services and are interested in joining a statewide practice network. Cross-sectional survey. February to June 2009 in Pennsylvania. 1700 pharmacists. Mailed and electronic survey. Number and geographic location of pharmacists providing or interested in providing community-based patient care in Pennsylvania. Description of patient care documentation methods; physical space; services provided; perceived barriers to providing patient care; training needs; and interest in joining a statewide practice network. The final analysis included data from 1700 pharmacists. Approximately one-third of pharmacists (n=554) were providing patient care services to community-based patients. Most were routinely documenting (67.5%) and many had a semi-private or private space to provide care. MTM and immunizations were the most common services provided. Respondents reported the most significant barrier to providing MTM, diabetes education, and smoking cessation education was time constraints, whereas training was a barrier for immunization provision. Most pharmacists were not being compensated for patient care services. Of the 869 pharmacists interested in joining a statewide network, those providing care were more interested in joining than those who were not (70.8% vs. 43.8%, p < 0.001). CONCLUSION: Pennsylvania pharmacists are interested in providing community-based patient care services and joining a statewide practice network focused on providing community-based patient care services. This research serves as a foundation for building a pharmacist practice network in Pennsylvania.


Effect of Olfactory Stimulation by L-Menthol on Laboratory-Induced Dyspnea in COPD.
Inhalation of L-menthol as a transient receptor potential melastatin 8 agonist induces a cooling sensation in the airway. This cooling sensation induced through olfactory stimulation by L-menthol (OSM) alleviates dyspnea in healthy humans. Therefore, we investigated effects of OSM on the neural respiratory drive (NRD) and multidimensional aspects of dyspnea induced by inspiratory resistive loaded breathing in COPD. In total, 28 patients with COPD and 14 control participants were included in this randomized, single-blinded, placebo-controlled, crossover study. OSM was administered using an L-menthol-scented patch, whereas placebo was administered using olfactory stimulation by strawberry-scented patch: placebo (OSP). Sham condition was measured by breathing through a face mask without a OSP. Dyspnea was evoked by breathing through the inspiratory resistance of 20 or 30 cm H2O/L/s and measured using the Multidimensional Dyspnea Profile. NRD was estimated using the electromyogram activities of the parasternal intercostal muscles. Compared with sham and OSP, OSM did not alter the breathing pattern/timing and NRD during inspiratory resistive loading; however, it significantly alleviated the physical and mental breathing effort, air hunger, breathing discomfort, anxiety, and fear during inspiratory resistive loaded breathing in patients with COPD. However, although OSM reduced the air hunger, mental breathing effort, and unpleasantness, no significant improvement on affective dimension of dyspnea by OSM was observed in control participants. Our findings suggest that OSM activated the sense of inspiratory flow that achieved dyspnea relief in patients with COPD. UMIN Clinical Trials Registry (UMIN-CTR); No.: UMIN000033822; URL: https://www.umin.ac.jp/ctr/index.htm.


Structural divergence of chromosomes between malaria vectors Anopheles lesteri and Anopheles sinensis.
Anopheles lesteri and Anopheles sinensis are two major malaria vectors in China and Southeast Asia. They are dramatically different in terms of geographical distribution, host preference, resting habitats, and other traits associated with ecological adaptation and malaria transmission. Both species belong to the Anopheles hyrcanus group, but the extent of genetic differences between them is not well understood. To provide an effective way to differentiate between species and to find useful markers for population genetics studies, we performed a comparative cytogenetic analysis of these two malaria vectors. Presented here is a standard cytogenetic map for An. lesteri, and a comparative analysis of chromosome structure and gene order between An. lesteri and An. sinensis. Our results demonstrate that much of the gene order on chromosomes X and 2 was reshuffled between the two species. However, the banding pattern and the gene order on chromosome 3 appeared to be conserved. We also found two new polymorphic inversions, 2Lc and 3Rb, in An. lesteri, and we mapped the breakpoints of these two inversions on polytene chromosomes. Our results demonstrate the extent of structural divergence of chromosomes between An. lesteri and An. sinensis, and provide a new taxonomic cytogenetic tool to distinguish between these two species. Polymorphic inversions of An. lesteri could serve as markers for studies of the population structure and ecological adaptations of this major malaria vector.


Bolaamphiphiles bearing bipyridine as mesogenic core: rational exploitation of molecular architectures for controlled self-assembly.
A bolaamphiphile (5,5-B2NBr8) bearing a functional bipyridine moiety as the mesogenic core is reported for the first time. 5,5-B2NBr8 was found to self-assemble into uniform fibrous structure in aqueous solution, when the concentration was higher than cmc. Analogues of 5,5-B2NBr8 with structural differences in chain length, headgroup, mesogenic core, and substituted position were synthesized, elucidating that small variances of the molecular structure could lead to dramatic changes of the resulting assemblies. For example, compound 4,4-B2NBr8 showed only spherical colloidal aggregates rather than fibers as 5,5-B2NBr8 did, while the only difference between them was the position at which the alkyl chains were attached onto bipyridine. A probable model for the fibrous structure of 5,5-B2NBr8 was proposed. Moreover, exploiting the coordination capacity of bipyridine, assembly and disassembly of 5,5-B2NBr8 could be reversibly controlled through the addition of EDTA and Cu(II), respectively.


Improve your Galaxy text life: The Query Tabular Tool.
Galaxy provides an accessible platform where multi-step data analysis workflows integrating disparate software can be run, even by researchers with limited programming expertise. Applications of such sophisticated workflows are many, including those which integrate software from different 'omic domains (e.g. genomics, proteomics, metabolomics). In these complex workflows, intermediate outputs are often generated as tabular text files, which must be transformed into customized formats which are compatible with the next software tools in the pipeline. Consequently, many text manipulation steps are added to an already complex workflow, overly complicating the process and decreasing usability, especially for non-expert bench researchers focused on obtaining results. In some cases, limitations to existing text manipulation are such that desired analyses can only be carried out using highly sophisticated processing steps beyond the reach of most users. As a solution, we have developed the Query Tabular Galaxy tool, which leverages a SQLite database generated from tabular input data. This database can be queried and manipulated to produce transformed and customized tabular outputs compatible with downstream processing steps. Regular expressions can also be utilized for even more sophisticated manipulations, such as find and replace and other filtering actions. Using several Galaxy-based multi-omic workflows as an example, we demonstrate how the Query Tabular tool dramatically streamlines and simplifies the creation of multi-step analyses, efficiently enabling complicated textual manipulations and processing. This tool should find broad utility for users of the Galaxy platform seeking to develop and use sophisticated workflows involving text manipulation on tabular outputs.


Season and outdoor temperature in relation to detection and control of hypertension in a large rural Chinese population.
In many Western populations, blood pressure varies moderately with season and outdoor temperature. Relatively little is known about effects of seasonal changes in blood pressure on the detection and control of hypertension in general populations, especially in low- and middle-income countries. We analysed cross-sectional data of 57 375 (42% men) participants aged 30-79 (mean 52.3) years who were enrolled during 2004-08, as part of the China Kadoorie Biobank, from a rural county in the south-east costal Zhejiang Province. Analyses related daily mean outdoor temperature, obtained from local Meteorological Bureau, to mean systolic (SBP) and diastolic blood pressure (DBP), rate of newly detected hypertension and, among those with self-reported physician-diagnosed hypertension, rate of adequate blood pressure control, using multiple linear and logistic regression models. The overall mean blood pressure was 135.9 mmHg for SBP and 80.5 mmHg for DBP. Daily outdoor temperature ranged between -2.9 and 33.7°C, with July being the hottest month (mean 29.4°C) and January the coldest (mean 4.0°C). Comparing January (the coldest month) with July (the warmest), the differences in the adjusted SBP/DBP were 19.2/7.7 mmHg. Each 10°C lower ambient temperature was associated with 6.9/2.9 mmHg higher SBP/DBP,14.1% higher prevalence of newly detected hypertension and, among those with pre-diagnosed hypertension, 13.0% lower hypertension control rate. In rural China, lower outdoor temperature is strongly associated with higher mean blood pressure and hypertension prevalence as well as poorer hypertension control, and should be considered when conducting population-based hypertension surveys and providing treatment for hypertensive patients.


Information content of optical vortex fields.
We study, experimentally as well as theoretically, the spatial coherence function and the Wigner distribution function for one-dimensional projections of optical vortices of different orders. The information entropy derived from the spatial coherence functions has been used to quantify the information content of the vortices and compared with those obtained for the Gaussian beam. The experimental results verify the theoretical findings of Agarwal and Banerji [Opt. Lett. 27, 800 (2002)].


The multisensory perception of flavor.
Following on from ecological theories of perception, such as the one proposed by [Gibson, J. J. (1966). The senses considered as perceptual systems. Boston: Houghton Mifflin] this paper reviews the literature on the multisensory interactions underlying the perception of flavor in order to determine the extent to which it is really appropriate to consider flavor perception as a distinct perceptual system. We propose that the multisensory perception of flavor may be indicative of the fact that the taxonomy currently used to define our senses is simply not appropriate. According to the view outlined here, the act of eating allows the different qualities of foodstuffs to be combined into unified percepts; and flavor can be used as a term to describe the combination of tastes, smells, trigeminal, and tactile sensations as well as the visual and auditory cues, that we perceive when tasting food.


Conflicting selection on the timing of germination in a natural population of Arabidopsis thaliana.
The timing of germination is a key life-history trait that may strongly influence plant fitness and that sets the stage for selection on traits expressed later in the life cycle. In seasonal environments, the period favourable for germination and the total length of the growing season are limited. The optimal timing of germination may therefore be governed by conflicting selection through survival and fecundity. We conducted a field experiment to examine the effects of timing of germination on survival, fecundity and overall fitness in a natural population of the annual herb Arabidopsis thaliana in north-central Sweden. Seedlings were transplanted at three different times in late summer and in autumn covering the period of seed germination in the study population. Early germination was associated with low seedling survival, but also with high survival and fecundity among established plants. The advantages of germinating early more than balanced the disadvantage and selection favoured early germination. The results suggest that low survival among early germinating seeds is the main force opposing the evolution of earlier germination and that the optimal timing of germination should vary in space and time as a function of the direction and strength of selection acting during different life-history stages.


New developments in transplant proteomics.
Despite modern immunosuppression, renal allograft rejection remains a major contributor to graft loss. Novel biomarkers may help improve posttransplant outcomes through the early detection and treatment of rejection. Our objective is to provide an overview of proteomics, review recent discovery-based rejection studies, and explore innovative approaches in biomarker development. Urine MMP7 was identified as a biomarker of subclinical and clinical rejection using two-dimensional liquid chromatography tandem-mass spectrometry (LC-MS/MS) and improved the overall diagnostic discrimination of urine CXCL10 : Cr alone for renal allograft inflammation. A novel peptide signature to classify stable allografts from acute rejection, chronic allograft injury, and polyoma virus (BKV) nephropathy was identified using isobaric tag for relative and absolute quantitation (TRAQ) and label-free MS, with independent validation by selected reaction monitoring mass spectrometry (SRM-MS). Finally, an in-depth exploration of peripheral blood mononuclear cells identified differential proteoform expression in healthy transplants versus rejection. There is still much in the human proteome that remains to be explored, and further integration of renal, urinary, and exosomal data may offer deeper insight into the pathophysiology of rejection. Functional proteomics may be more biologically relevant than protein/peptide quantity alone, such as assessment of proteoforms or activity-based protein profiling. Discovery-based studies have identified potential biomarker candidates, but external validation studies are required.


Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.
Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c(+) antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c(+) cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c(+) cells regained the ability to efficiently cross-present antigen and prime CD8(+) T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8(+) T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8(+) T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors.


Evaluation of a new approach to the treatment of lymphedema resulting from breast cancer therapy.
The aim of this study was to evaluate a new form of intensive treatment for arm lymphedema. A prospective study of 66 patients with breast cancer-related lymphedema was performed. The ages of the patients ranged from 35 to 83 years old with a mean of 58.8 years. Diagnosis of lymphedema was made by physical examination and water-displacement volumetry (a difference of ≥ 200 mL between arms). All the patients were submitted to clinical treatment in an outpatient setting which involved a once-weekly session of 3 to 4h of manual and mechanical lymph drainage, myolymphokinetic activities and exercising using facilitating apparatuses and the use of a medical compression sleeve. Monthly volumetry evaluations were routinely performed. The Student t-test was employed for statistical analysis with an alpha level of 5% (p<0.05) being considered significant. The mean follow-up time between cancer treatment and this study was 12.3 months. A significant reduction in the size of the arms was observed for all patients. The mean difference between the lymphedematous and normal arms of all patients was 553.8 mL at the start of treatment and a mean reduction of 70.1% (388.7 mL) of the edema was achieved (p=0.0001). In our experience, this model of treatment appeared efficacious in decreasing and maintaining the reduction in volume of arm in breast cancer-related lymphedema.


Prevalence of Dental Caries in Children of Age 5 to 13 Years in District of Vaishali, Bihar, India.
Dental caries is the most common type of oral health problem globally. It is known to have multifactorial etiology with a number of variables that influence the prevalence of the condition. The present study was carried out in the district of Vaishali, Bihar, India, with an aim to determine the prevalence of dental caries in children of 5 to 13 years. It was a descriptive type of epidemiological study and the design adopted for the study was cross-sectional. No active intervention and follow-up examinations were performed. A total of 1,000 children of 5 to 13 year age group were examined for the study. The study population was categorized based on age, sex, location, and socioeconomic status. The examination procedure and criteria were those recommended by the World Health Organization (WHO). The data obtained from the survey were subjected to statistical evaluation using the Statistical Package for the Social Sciences (SPSS) software. Test for significance was done with the help of analysis of variance (ANOVA) and chi-square test. The difference in the caries prevalence between the age groups and between the socioeconomic level was very highly significant (p = 0.000). There was a statistically significant difference observed in the prevalence of caries between the sexes (p = 0.016) as well as between urban and rural (p = 0.018). It is expected that the data obtained with the help of this survey will prove to be very useful to the concerned authorities in handling dental caries which is a biosocial disease rooted in the technology and economy of our society.How to cite this article: Goenka P, Dutta S, Marwah N, Sarawgi A, Nirwan M, Mishra P. Prevalence of Dental Caries in Children of Age 5 to 13 Years in District of Vaishali, Bihar, India. Int J Clin Pediatr Dent 2018;11(5):359-364.


The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression.
The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.


Neuro-fuzzy technology as a predictor of parathyroid hormone level in hemodialysis patients.
Measuring the plasma parathyroid hormone (PTH) concentration is crucial to evaluate renal bone disease in patients with renal failure. Although frequent measurement is needed to avoid inadequate prescription of phosphate binders and vitamin D preparations, artificial intelligence can repeatedly perform the forecasting tasks and may be a satisfactory substitute for laboratory tests. Neuro-fuzzy technology represents a promising forecasting application in clinical medicine. We therefore constructed a coactive neuro-fuzzy inference system (CANFIS) to predict plasma PTH concentrations in hemodialysis patients. The CANFIS was constructed with clinical parameters (patient age, plasma albumin, calcium, phosphorus, alkaline phosphatase, and calcium-phosphorus product) from a cohort of hemodialysis patients, and plasma PTH concentration measured by radioimmunoassay (RIA) was the supervised outcome. The accuracy of the CANFIS was prospectively compared with RIA in another hospital. Plasma PTH concentrations measured by RIA and predicted by CANFIS were 179.04 +/- 38.18 ng/l and 179.34 +/- 37.76 ng/l, respectively (p = 0.15). The CANFIS was able to precisely estimate plasma PTH concentrations in hemodialysis patients. These results suggest that the neuro-fuzzy technology, based on limited clinical parameters, is an excellent alternative to RIA for accurately predicting plasma PTH concentration in hemodialysis patients.


Children lose confidence in their potential to "be scientists," but not in their capacity to "do science".
Over the course of middle childhood, children's interest and beliefs about their own capacities for success in science often decline. This pernicious decline is especially evident among underrepresented groups, including girls, members of some racial and ethnic minorities, and children from lower socioeconomic backgrounds. The present research (N = 306, ages 6-11) found that while children lose interest and feelings of efficacy about their potential to "be scientists" across middle childhood, they maintain more robust interest and efficacy about "doing science." These patterns were confirmed in both longitudinal and cross-sectional analyses; effects were stable or increased across time and age. Mediation analyses revealed that the positive effect of action framing is partially accounted for by children's views that the group of people who do science is more inclusive than the category of scientists. These findings suggest that using action-focused language to encourage children in science is more inclusive and may lead to more science engagement across middle childhood than language that emphasizes scientists as an identity category. Implications for educational practices will be discussed.


Acute renal injury by tetraethyl orthosilicate in mice: ultrastructure, histochemistry and X-ray microanalysis.
Tetraethyl orthosilicate (Si(OC2H5)4, or TEOS) is a silicon-containing compound which has widespread industrial applications and which has been documented as biohazardous. The histopathological features and mechanism of TEOS toxicity in the kidney of ICR mice were investigated in a light and electron microscopy study, which included energy dispersive X-ray microanalysis. TEOS was given to mice as intraperitoneal injection of approximately 1,670 mg/kg body weight in experiments based on a 24 h time-scale. Tissues were examined after sampling either immediately on death if this occurred within 24 h or, in the case of surviving animals, after sacrifice at 24 h. Renal injury was considered to be the most probable cause of death, on the basis of the following main findings: 1) acute tubular necrosis (glomerular lesions were absent); 2) a dense deposit of silicon over the microvilli of dead tubular epithelial cells; 3) an abundant aggregation of hydroxyapatite crystals containing calcium in the cytoplasm and mitochondria of the dead tubular epithelial cells; and 4) abundant myelinosomes and some hydroxyapatite crystals in the cytoplasm of viable proximal convoluted tubule epithelial cells. It was speculated that silicon compounds may bind to the plasma membranes of the proximal convoluted tubule epithelial cell microvilli and damage or interfere with membrane calcium channels. The resulting calcium ion imbalance may play a role in the subsequent progression of acute tubular necrosis by TEOS.


Label-free, high-throughput measurements of dynamic changes in cell nuclei using angle-resolved low coherence interferometry.
Accurate measurements of nuclear deformation, i.e., structural changes of the nucleus in response to environmental stimuli, are important for signal transduction studies. Traditionally, these measurements require labeling and imaging, and then nuclear measurement using image analysis. This approach is time-consuming, invasive, and unavoidably perturbs cellular systems. Light scattering, an emerging biophotonics technique for probing physical characteristics of living systems, offers a promising alternative. Angle-resolved low-coherence interferometry (a/LCI), a novel light scattering technique, was developed to quantify nuclear morphology for early cancer detection. In this study, a/LCI is used for the first time to noninvasively measure small changes in nuclear morphology in response to environmental stimuli. With this new application, we broaden the potential uses of a/LCI by demonstrating high-throughput measurements and by probing aspherical nuclei. To demonstrate the versatility of this approach, two distinct models relevant to current investigations in cell and tissue engineering research are used. Structural changes in cell nuclei due to subtle environmental stimuli, including substrate topography and osmotic pressure, are profiled rapidly without disrupting the cells or introducing artifacts associated with traditional measurements. Accuracy > or = 3% is obtained for the range of nuclear geometries examined here, with the greatest deviations occurring for the more complex geometries. Given the high-throughput nature of the measurements, this deviation may be acceptable for many biological applications that seek to establish connections between morphology and function.


Insights Into the Metabolic Aspects of Aortic Stenosis With the Use of Magnetic Resonance Imaging.
Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.


Utility of liver allograft biopsy obtained at procurement.
Extended-donor criteria (EDC) liver allografts potentiate the role of procurement biopsy in organ utilization. To expedite allocation, histologic evaluation is routinely performed upon frozen-section (FS) specimens by local pathologists. This descriptive study compares FS reports by local pathologists with permanent-section (PS) evaluation by dedicated hepatopathologists, identifies histologic characteristics underrepresented by FS evaluation, and evaluates the efficacy of a biopsy decision analysis based on organ visualization. Fifty-two liver transplants using EDC allografts evaluated by FS with PS were studied. Pathologic worksheets created by an organ procurement organization were applied in 34 FS. PS analysis included 7 staining procedures for 8 histologic criteria. PS from 56 additional allografts determined not to require donor biopsy were also analyzed. A high correlation was observed between FS and PS. Underestimation of steatosis by FS was associated with allograft dysfunction. Surgical assessment of cholestasis, congestion, and steatosis was accurate whereas inflammation, necrosis, and fibrosis were underestimated in allografts suffering parenchymal injury. In conclusion, the correlation between FS and PS is high, and significant discrepancies are rare. Biopsy is not a prerequisite for EDC utilization but is suggested in hepatitis C, hypernatremia, donation after cardiac death, or multiple EDC indications. Implementation of a universal FS worksheet could standardize histologic reporting and facilitate data collection, allocation, and research.


Assessment of the relationship between water insecurity, hygiene practices, and incidence of diarrhea among children from rural households of the Menoua Division, West Cameroon.
The objectives of a cross-sectional, semi-quantitative study were to: i) assess the prevalence of water insecurity and its association with water access-related behaviors such as time, distance, and sources of water; ii) identify major themes of concern raised in reference to anxiety, water quality/quantity, and perceived health risk domains of water insecurity, and; iii) examine the relationship between water insecurity, hygiene practices, and diarrheal incidence among children in rural areas of the Menoua Division in the Western Region of Cameroon In-person interviews were conducted with 18 years or older women living with at least one child between 2 and 5 years old (n=134). Participants spent on average 17±12 minutes walking to a drinking water source. Prevalence of water insecurity was 58%, and it was associated with a lower hygiene score among caretakers, i.e., hygiene score of water secure: 9.2±1.2 vs. insecure:8.2±2.2, F(1, 132)=8.096, P<0.01). Overall, the incidence of diarrhea among children was 18%, and it was significantly higher among water insecure households (79%) compared with secure households (21%, P=0.02). In conclusion, access to improved sources of water is an issue in rural areas. Addressing water insecurity is critical in promoting optimal health and development of children due to its association with poor hygiene practices among caretakers.


Cyr61 is involved in neutrophil infiltration in joints by inducing IL-8 production by fibroblast-like synoviocytes in rheumatoid arthritis.
It is well known that neutrophils play very important roles in the development of rheumatoid arthritis (RA) and interleukin (IL)-8 is a critical chemokine in promoting neutrophil migration. We previously showed that increased production of Cyr61 by fibroblast-like synoviocytes (FLS) in RA promotes FLS proliferation and Th17 cell differentiation, thus Cyr61 is a pro-inflammatory factor in RA pathogenesis. In this study, we explored the role of Cyr61 in neutrophil migration to the joints of RA patients. RA FLS were treated with Cyr61 and IL-8 expression was analyzed by real-time PCR and ELISA. The migration of neutrophils recruited by the culture supernatants was determined by the use of a chemotaxis assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as a control. Arthritis severity was determined by visual examination of the paws and joint destruction was determined by hematoxylin-eosin (H&E) staining. Signal transduction pathways in Cyr61-induced IL-8 production were investigated by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay or chromatin immunoprecipitation (ChIP) assay. We found that Cyr61 induced IL-8 production by RA FLS in an IL-1β and TNF-α independent pathway. Moreover, we identified that Cyr61-induced IL-8-mediated neutrophil migration in vitro. Using a CIA animal model, we found that treatment with anti-Cyr61 mAb led to a reduction in MIP-2 (a counterpart of human IL-8) expression and decrease in neutrophil infiltration, which is consistent with an attenuation of inflammation in vivo. Mechanistically, we showed that Cyr61 induced IL-8 production in FLS via AKT, JNK and ERK1/2-dependent AP-1, C/EBPβ and NF-κB signaling pathways. Our results here reveal a novel role of Cyr61 in the pathogenesis of RA. It promotes neutrophil infiltration via up-regulation of IL-8 production in FLS. Taken together with our previous work, this study provides further evidence that Cyr61 plays a key role in the vicious cycle formed by the interaction between infiltrating neutrophils, proliferated FLS and activated Th17 cells in the development of RA.