The effect of mobile phone text-message reminders on Kenyan health workers' adherence to malaria treatment guidelines: a cluster randomised trial.
Health workers' malaria case-management practices often differ from national guidelines. We assessed whether text-message reminders sent to health workers' mobile phones could improve and maintain their adherence to treatment guidelines for outpatient paediatric malaria in Kenya. From March 6, 2009, to May 31, 2010, we did a cluster-randomised controlled trial at 107 rural health facilities in 11 districts in coastal and western Kenya. With a computer-generated sequence, health facilities were randomly allocated to either the intervention group, in which all health workers received text messages on their personal mobile phones on malaria case-management for 6 months, or the control group, in which health workers did not receive any text messages. Health workers were not masked to the intervention, although patients were unaware of whether they were in an intervention or control facility. The primary outcome was correct management with artemether-lumefantrine, defined as a dichotomous composite indicator of treatment, dispensing, and counselling tasks concordant with Kenyan national guidelines. The primary analysis was by intention to treat. The trial is registered with Current Controlled Trials, ISRCTN72328636. 119 health workers received the intervention. Case-management practices were assessed for 2269 children who needed treatment (1157 in the intervention group and 1112 in the control group). Intention-to-treat analysis showed that correct artemether-lumefantrine management improved by 23·7 percentage-points (95% CI 7·6-40·0; p=0·004) immediately after intervention and by 24·5 percentage-points (8·1-41·0; p=0·003) 6 months later. In resource-limited settings, malaria control programmes should consider use of text messaging to improve health workers' case-management practices. The Wellcome Trust.


Nacre and false nacre (foliated aragonite) in extant monoplacophorans (=Tryblidiida: Mollusca).
Extant monoplacophorans (Tryblidiida, Mollusca) have traditionally been reported as having an internal nacreous layer, thus representing the ancestral molluscan condition. The examination of this layer in three species of Neopilinidae (Rokopella euglypta, Veleropilina zografi, and Micropilina arntzi) reveals that only V. zografi secretes an internal layer of true nacre, which occupies only part of the internal shell surface. The rest of the internal surface of V. zografi and the whole internal surfaces of the other two species examined are covered by a material consisting of lath-like, instead of brick-like, crystals, which are arranged into lamellae. In all cases examined, the crystallographic c-axis in this lamellar material is perpendicular to the surface of laths and the a-axis is parallel to their long dimension. The differences between taxa relate to the frequency of twins, which is much higher in Micropilina. In general, the material is well ordered, particularly towards the margin, where lamellae pile up at a small step size, which is most likely due to processes of crystal competition. Given its morphological resemblance to the foliated calcite of bivalves, we propose the name foliated aragonite for this previously undescribed biomaterial secreted by monoplacophorans. We conclude that the foliated aragonite probably lacks preformed interlamellar membranes and is therefore not a variant of nacre. A review of the existing literature reveals that previous reports of nacre in the group were instead of the aragonitic foliated layer and that our report of nacre in V. zografi is the first undisputed evidence of nacre in monoplacophorans. From the evolutionary viewpoint, the foliated aragonite could easily have been derived from nacre. Assuming that nacre represents the ancestral condition, as in other molluscan classes, it has been replaced by foliated aragonite along the tryblidiidan lineage, although the fossil record does not presently provide evidence as to when this replacement took place.


Expression profiling of non-small cell lung carcinoma identifies metastatic genotypes based on lymph node tumor burden.
This study hypothesized that non-small cell lung carcinoma cells from primary tumors isolated by laser capture microdissection would exhibit gene expression profiles associated with graded lymph node metastatic cell burden. Non-small cell lung carcinoma tumors (n = 15) were classified on the basis of nodal metastatic cell burden by 2 methods, obtaining 3 groups: no metastasis, micrometastasis, and overt metastasis. We then performed microarray analysis on microdissected primary tumor cells and identified gene expression profiles associated with graded nodal tumor burden using a correlation-based selection algorithm coupled with cross-validation analysis. Hierarchical clustering showed the regrouping of tumor specimens; the classification inference was assessed with Fisher's exact test. We verified data for certain genes by using another independent assay. The 15 specimens clustered into 3 groups: cluster A predominated in specimens with overt nodal metastasis; cluster B had more specimens with nodal micrometastases; and cluster C included only specimens without nodal metastases. Cluster assignment was based on a validated 75-gene discriminatory subset. Notably, genes not previously associated with positive non-small cell lung carcinoma lymph node status were encountered in the profiling analysis. Microdissection, combined with microarray analysis, is a potentially powerful method to characterize the molecular profile of tumor cells. The 75-gene expression profiles representative of clusters A and B may define genotypes prone to metastasize. Overall, the 3 groups of tumor specimens clustered separately, suggesting that this approach may identify graded metastatic propensity. Further, genes singled out in clustering may yield insights into underlying metastatic mechanisms and may represent new therapeutic targets.


Self-assembled core-polyethylene glycol-lipid shell nanoparticles demonstrate high stability in shear flow.
A core-polyethylene glycol-lipid shell (CPLS) nanoparticle consists of an inorganic core coated with polyethylene glycol (PEG) polymers, surrounded by a lipid bilayer shell. It can be self-assembled from a PEGylated core with surface-tethered PEG chains, where all the distal ends are covalently bonded to lipid molecules. Upon adding free lipids, a complete lipid bilayer shell can be formed on the surface driven by the hydrophobic nature of lipid tails, leading to the formation of a CPLS nanoparticle. The stability of CPLS nanoparticles in shear flow has been systematically studied through large scale dissipative particle dynamics simulations. CPLS nanoparticles demonstrate higher stability and less deformation in shear flow, compared with lipid vesicles. Burst leakage of drug molecules inside lipid vesicles and CPLS NPs can be induced by the large pores at their tips. These pores are initiated by the maximum stress in the waist region. It further grows along with the tank-treading motion of vesicles or CPLS NPs in shear flow. However, due to the constraints applied by PEG polymers, CPLS NPs are less deformed than vesicles with comparable size under the same flow conditions. Thus, the less deformed CPLS NPs express a smaller maximum stress at waists, demonstrating higher stability. Pore formation at waists, evolving into large pores on vesicles, leads to the burst leakage of drug molecules and complete rupture of vesicles. In contrast, although similar drug leakage in CPLS nanoparticles can occur at high shear rates, pores initiated at moderate shear rates tend to be short-lived and close due to the constraints mediated by PEG polymers. This kind of 'self-healing' capability can be observed over a wide range of shear rates for CPLS nanoparticles. Our results suggest self-assembled CPLS nanoparticles to exhibit high stability during blood circulation without rapid drug leakage. These features make CPLS nanoparticles candidates for a promising drug delivery platform.


Hepatitis C virus recurrence after liver transplantation: biomarkers of disease and fibrosis progression.
End-stage liver disease due to hepatitis C virus infection (HCV) is the principal indication for liver transplantation. In the USA, over a third of available liver allografts are transplanted into recipients with chronic HCV infection. Reinfection of the graft is universal, but the impact of reinfection on short- and long-term liver function is highly variable. HCV infection in liver transplantation recipients is characterized by an accelerated fibrogenesis, with approximately a third of patients developing cirrhosis within 5 years of follow-up. HCV is associated with decreased patient and graft survival when compared with other indications of orthotopic liver transplantation. The mechanisms responsible for the accelerated liver damage in HCV-infected orthotopic liver transplantation recipients remain largely unknown.


Metal-organic molecular cages: applications of biochemical implications.
New well-designed materials are highly demanded with the prospect of versatile properties, offering successful applications as alternates to conventional materials. Major new insights into metal-organic self-assembled structures assisting biochemical purposes have recently emerged. Metal-organic polyhedral cages are highlighted as new research materials to be used for therapeutic, sensing and imaging, purposes etc. This tutorial review covers achievements in the biochemical applications of these multinuclear complexes. Examples of their ability to aid the ionic transport, biomolecular sensing, imaging, and drug delivery are presented.


Comprehensive Retinal Image Analysis for Aggressive Posterior Retinopathy of Prematurity.
Computer aided analysis plays a nontrivial role in assisting the diagnosis of various eye pathologies. In this paper, we propose a framework to help diagnose the presence of Aggressive Posterior Retinopathy Of Prematurity (APROP), a pathology that is characterised by rapid onset and increased tortuosity of blood vessels close to the optic disc (OD). We quantify vessel characteristics that are of clinical relevance to APROP such as tortuosity and the extent of branching i.e., vessel segment count in the defined diagnostic region. We have adapted three vessel segmentation techniques: matched filter response, scale space theory and morphology with local entropy based thresholding. The proposed feature set equips us to build a linear discriminant classifier to discriminate APROP images from clinically healthy images. We have studied 36 images from 21 APROP subjects against a control group of 15 clinically healthy age matched infants. All subjects are age matched ranging from 33-40 weeks of post menstrual age. Experimental results show that we attain 100% recall and 95.45% precision, when the vessel network obtained from morphology is used for feature extraction.


Sparse and Low-rank Tensor Estimation via Cubic Sketchings.
In this paper, we propose a general framework for sparse and low-rank tensor estimation from cubic sketchings. A two-stage non-convex implementation is developed based on sparse tensor decomposition and thresholded gradient descent, which ensures exact recovery in the noiseless case and stable recovery in the noisy case with high probability. The non-asymptotic analysis sheds light on an interplay between optimization error and statistical error. The proposed procedure is shown to be rate-optimal under certain conditions. As a technical by-product, novel high-order concentration inequalities are derived for studying high-moment sub-Gaussian tensors. An interesting tensor formulation illustrates the potential application to high-order interaction pursuit in high-dimensional linear regression.


Matrix-M™ adjuvanted envelope protein vaccine protects against lethal lineage 1 and 2 West Nile virus infection in mice.
West Nile virus (WNV) is a mosquito-transmitted flavivirus and an emerging pathogen in many parts of the world. In the elderly and immunosuppressed, infection can progress rapidly to debilitating and sometimes fatal neuroinvasive disease. Currently, no WNV vaccine is approved for use in humans. As there have been several recent outbreaks in the United States and Europe, there is an increasing need for a human WNV vaccine. In this study, we formulated the ectodomain of a recombinant WNV envelope (E) protein with the particulate saponin-based adjuvant Matrix-M™ and studied the antigen-specific immune responses in mice. Animals immunized with Matrix-M™ formulated E protein developed higher serum IgG1 and IgG2a and neutralizing antibody titers at antigen doses ranging from 0.5 to 10 μg compared to those immunized with 3 or 10 μg of E alone, E adjuvanted with 1% Alum, or with the inactivated virion veterinary vaccine, Duvaxyn(®) WNV. This phenotype was accompanied by strong cellular recall responses as splenocytes from mice immunized with Matrix-M™ formulated vaccine produced high levels of Th1 and Th2 cytokines. Addition of Matrix-M™ prolonged the duration of the immune response, as elevated humoral and cellular responses were maintained for more than 200 days. Importantly, mice vaccinated with Matrix-M™ formulated E protein were protected from lethal challenge with both lineage 1 and 2 WNV strains. In summary, Matrix-M™ adjuvanted E protein elicited potent and durable immune responses that prevented lethal WNV infection, and thus is a promising vaccine candidate for humans.


Substrate-binding clusters of the K+-transporting Kdp ATPase of Escherichia coli investigated by amber suppression scanning mutagenesis.
The Kdp-ATPase of Escherichia coli is a four-subunit P-type ATPase that accumulates K(+) with high affinity and specificity. Residues clustered in four regions of the KdpA subunit of Kdp were implicated as critical for K(+) binding from the analysis of mutants with reduced affinity for K(+) (Buurman, E., Kim, K.-T., and Epstein, W. (1995) J. Biol. Chem. 270, 6678-6685). K(+) binding by this pump has been analyzed in detail by site-directed mutagenesis. We have examined 83 of the 557 residues in KdpA, from 11 to 34 residues in each of four binding clusters known to affect K(+) binding. Amber mutations were constructed in a plasmid carrying the kdpFABC structural genes. Transferring these plasmids to 12 suppressor strains, each inserting a different amino acid at amber codons, created 12 different substitutions at the mutated sites. This study delineates the four clusters and confirms that they are important for K(+) affinity but have little effect on the rate of transport. At only 21 of the residues studied did at least three substitutions alter affinity for K(+), an indication that a residue is in or very near a K(+) binding site. At many residues lysine was the only substitution that altered its affinity. The effect of lysine is most likely a repulsive effect of this cationic residue on K(+) and thus reflects the effective distance between a residue and the site of binding or passage of K(+) in KdpA. Once a crystallographic structure of Kdp is available, this measure of effective distance will help identify the path of K(+) as it moves through the KdpA subunit to cross the membrane.


Resistance to DNA damage and enhanced DNA repair capacity in the hypoxia-tolerant blind mole rat Spalax carmeli.
Blind mole rats of the genus Spalax are the only mammalian species to date for which spontaneous cancer has never been reported and resistance to carcinogen-induced cancers has been demonstrated. However, the underlying mechanisms are still poorly understood. The fact that Spalax spp. are also hypoxia-tolerant and long-lived species implies the presence of molecular adaptations to prevent genomic instability, which underlies both cancer and aging. We previously demonstrated the upregulation of transcripts related to DNA replication and repair pathways in Spalax Yet, to date, no direct experimental evidence for improved genomic maintenance has been demonstrated for this genus. Here, we show that compared with skin fibroblasts of the above-ground rat, Spalax carmeli skin fibroblasts in culture resist several types of genotoxic insult, accumulate fewer genotoxic lesions and exhibit an enhanced DNA repair capacity. Our results strongly support that this species has evolved efficient mechanisms to maintain DNA integrity as an adaptation to the stressful conditions in the subterranean habitat.


Symmetry, sexual dimorphism in facial proportions and male facial attractiveness.
Facial symmetry has been proposed as a marker of developmental stability that may be important in human mate choice. Several studies have demonstrated positive relationships between facial symmetry and attractiveness. It was recently proposed that symmetry is not a primary cue to facial attractiveness, as symmetrical faces remain attractive even when presented as half faces (with no cues to symmetry). Facial sexual dimorphisms ('masculinity') have been suggested as a possible cue that may covary with symmetry in men following data on trait size/symmetry relationships in other species. Here, we use real and computer graphic male faces in order to demonstrate that (i) symmetric faces are more attractive, but not reliably more masculine than less symmetric faces and (ii) that symmetric faces possess characteristics that are attractive independent of symmetry, but that these characteristics remain at present undefined.


A binding site for multiple transcriptional activators in the fushi tarazu proximal enhancer is essential for gene expression in vivo.
The Drosophila homeobox gene fushi tarazu (ftz) is expressed in a highly dynamic striped pattern in early embryos. A key regulatory element that controls the ftz pattern is the ftz proximal enhancer, which mediates positive autoregulation via multiple binding sites for the Ftz protein. In addition, the enhancer is necessary for stripe establishment prior to the onset of autoregulation. We previously identified nine binding sites for multiple Drosophila nuclear proteins in a core 323-bp region of the enhancer. Three of these nine sites interact with the same cohort of nuclear proteins in vitro. We showed previously that the nuclear receptor Ftz-F1 interacts with this repeated module. Here we purified additional proteins interacting with this module from Drosophila nuclear extracts. Peptide sequences of the zinc finger protein Ttk and the transcription factor Adf-1 were obtained. While Ttk is thought to be a repressor of ftz stripes, we have shown that both Adf-1 and Ftz-F1 activate transcription in a binding site-dependent fashion. These two proteins are expressed ubiquitously at the time ftz is expressed in stripes, suggesting that either may activate striped expression alone or in combination with the Ftz protein. The roles of the nine nuclear factor binding sites were tested in vivo, by site-directed mutagenesis of individual and multiple sites. The three Ftz-F1-Adf-1-Ttk binding sites were found to be functionally redundant and essential for stripe expression in transgenic embryos. Thus, a biochemical analysis identified cis-acting regulatory modules that are required for gene expression in vivo. The finding of repeated binding sites for multiple nuclear proteins underscores the high degree of redundancy built into embryonic gene regulatory networks.


Facile Method for the Investigation of Temperature-Dependent C60 Diffusion in Conjugated Polymers.
We developed a novel all-optical method for monitoring the diffusion of a small quencher molecule through a polymer layer in a bilayer architecture. Experimentally, we injected C60 molecules from a C60 layer into the adjacent donor layer by stepwise heating, and we measured how the photoluminescence (PL) of the donor layer becomes gradually quenched by the incoming C60 molecules. By analyzing the temporal evolution of the PL, the diffusion coefficient of C60 can be extracted, as well as its activation energy and an approximate concentration profile in the film. We applied this technique to three carbazole-based low-bandgap polymers with different glass temperatures with a view to study the impact of structural changes of the polymer matrix on the diffusion process. We find that C60 diffusion is thermally activated and not driven by WFL-type collective motion above Tg but rather by local motions mediated by the sidechains. The results are useful as guidance for material design and device engineering, and the approach can be adapted to a wide range of donor and acceptor materials.


Congenital adrenal hyperplasia: Treatment and outcomes.
Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders where there is impairment of cortisol biosynthesis. CAH due to 21-hydroxylase deficiency accounts for 95% of cases and shows a wide range of clinical severity. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment of CAH. The optimal treatment for adults with CAH continues to be a challenge. Important long-term health issues for adults with CAH affect both men and women. These issues may either be due to the disease or to steroid treatment and may affect final height, fertility, cardiometabolic risk, bone metabolism, neuro-cognitive development and the quality-of-life. Patients with CAH should be regularly followed-up from childhood to adulthood by multidisciplinary teams who have knowledge of CAH. Optimal replacement therapy, close clinical and laboratory monitoring, early life-style interventions, early and regular fertility assessment and continuous psychological management are needed to improve outcome.


Practical applications of averages and differences of Friedel opposites.
The practical use of the average and difference intensities of Friedel opposites at different stages of structure analysis has been investigated. It is shown how these values may be properly and practically used at the stage of space-group determination. At the stage of least-squares refinement, it is shown that increasing the weight of the difference intensities does not improve their fit to the model. The correct form of the coefficients for a difference electron-density calculation is given. In the process of structure validation, it is further shown that plots of the observed and model difference intensities provide an objective method to evaluate the fit of the data to the model and to reveal insufficiencies in the intensity measurements. As a further tool for the validation of structure determinations, the use of the Patterson functions of the average and difference intensities has been investigated and their clear advantage demonstrated.


The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer.
MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets, derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study, the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2D(b) peptides, Trh4 takes a noncanonical peptide-binding pattern with extensive sulfur-π interactions that contribute to the overall complex stability. Importantly, the noncanonical methionine at peptide position 5 acts as a main anchor, altering only the conformation of the H-2D(b) residues Y156 and H155 and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. Substitution of peptide residues p2C and p5M to the conservative α-aminobutyric acid and norleucine, respectively, significantly reduced complex stability, without altering peptide conformation or T cell recognition. In contrast, substitution of p5M to a conventional asparagine abolished recognition by the H-2D(b)/Trh4-specific T cell clone LnB5. We anticipate that the H-2D(b)/Trh4 complex represents the first example, to our knowledge, of a broader repertoire of alternative MHC class I binders.


Mechanism of the rejection of major histocompatibility complex class I-disparate murine skin grafts: rejection can be mediated by CD4+ cells activated by allo-class I + II antigen in CD8+ cell-depleted hosts.
In the preceding article, we analyzed the immunohistochemical rejection mechanism of major histocompatibility complex (MHC) class I (H-2K)-disparate murine skin grafts, and showed that only CD8+ cells infiltrated at the site of the epithelial tissue of MHC class I-disparate graft. We also showed that perfect survival of MHC class I-disparate grafts were attained in thymectomized recipients treated with anti-Lyt-2 monoclonal antibody. In this report, we showed that these long-surviving allo-class I grafts were rejected in the absence of CD8+ cells by stimulation with allo-MHC class I + II-disparate graft as the second stimulation. Furthermore, it was immunohistochemically revealed that under that condition, a large number of CD4+ cells infiltrated into the epithelial tissue of these long-surviving class I grafts, which were going to be rejected 2-5 d after the transplantation of a second graft with MHC class I + II difference. This result directly shows that CD4+ cells are able to became effectors for the rejection of allo-MHC class I (H-2K) skin graft.


Intranasal corticosteroids compared with oral antihistamines in allergic rhinitis: A systematic review and meta-analysis.
Intranasal corticosteroids (INS) (corticosteroid nasal sprays) and oral antihistamines (OA) are two of the most common treatments for patients with allergic rhinitis (AR). To our knowledge, there are no systematic reviews on this topic including trials published after 2007. To compare INS with nonsedating OAs as treatments for AR. The systematic review and meta-analysis were based on the Grades of Recommendation, Assessment, Development, and Evaluation principles and the Patient, Intervention, Comparison, and Outcome approach. Primary literature was searched up to January 22, 2015. Criteria for eligibility were randomized controlled trials that compared the efficacy and/or adverse effects of INS and OA in patients with AR. Continuous outcome data were analyzed by using standardized mean differences (SMD) for multiple outcome measures, and mean differences in the case of a single study or outcome. Pooled estimates of effects, 95% confidence interval (CI), were calculated by using random-effects models. The meta-analysis included five randomized controlled trials with a total of 990 patients. INS were superior to OAs in improving total nasal symptoms score (SMD -0.70 [95% CI, -0.93 to -0.47]) and in relieving the following: nasal obstruction (SMD -0.56 [95% CI, -0.82 to -0.29]), rhinorrhea (SMD -0.47 [95% CI, -1.00 to 0.05]), nasal itching (SMD -0.42 [95% CI, -0.65 to -0.18]), sneezing (SMD -0.52 [95% CI, -0.73 to -0.32]), and quality of life mean difference -0.90 [95% CI, -1.18 to -0.62]). There was no difference in relief of ocular symptoms (SMD -0.08 [95% CI, -0.23 to 0.08]). In addition, four randomized controlled trials were included in a narrative analysis. The results in the narrative analysis were comparable with those found in the meta-analysis. INS were superior to OAs in improving nasal symptoms and quality of life in patients with AR.


Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism.
Thrombospondin (TSP) forms specific complexes with transforming growth factor-beta (TGF-beta) in the alpha granule releasate of platelets and these TSP-TGF-beta complexes inhibit the growth of bovine aortic endothelial cells (BAE). In these studies, we report that TSP stripped of associated TGF-beta (sTSP) retained growth inhibitory activity which was partially reversed by a neutralizing antibody specific for TGF-beta. Since BAE cells secrete latent TGF-beta, we determined whether sTSP activates the latent TGF-beta secreted by BAE cells. Cells were cultured with or without sTSP and then the conditioned medium was tested for the ability to support TGF-beta-dependent normal rat kidney (NRK) colony formation in soft agar. Medium conditioned with sTSP showed a dose- and time-dependent ability to stimulate BAE-secreted TGF-beta activity, reaching maximal activation by 1-2 h with 0.4 micrograms/ml (0.9 nM) sTSP. The sTSP-mediated stimulation of TGF-beta activity is not dependent on serum factors and is not a general property of extracellular matrix molecules. The sTSP-mediated stimulation of TGF-beta activity was blocked by a mAb specific for sTSP and by neutralizing antibodies to TGF-beta. Activation of BAE cell secreted latent TGF-beta by sTSP can occur in the absence of cells and apparently does not require interactions with cell surface molecules, since in conditioned medium removed from cells and then incubated with sTSP, activation occurs with kinetics and at levels similar to what is seen when sTSP is incubated in the presence of cells. Serine proteases such as plasmin are not involved in sTSP-mediated activation of TGF-beta. Factors that regulate the conversion of latent to active TGF-beta are keys to controlling TGF-beta activity. These data suggest that TSP is a potent physiologic regulator of TGF-beta activation.


Mineral Properties and Dietary Value of Raw and Processed Stinging Nettle (Urtica dioica L.).
Stinging nettle (Urtica dioica L.) has a long history of usage and is currently receiving attention as a source of fiber and alternative medicine. In many cultures, nettle is also eaten as a leafy vegetable. In this study, we focused on nettle yield (edible portion) and processing effects on nutritive and dietary properties. Actively growing shoots were harvested from field plots and leaves separated from stems. Leaf portions (200 g) were washed and processed by blanching (1 min at 96-98°C) or cooking (7 min at 98-99°C) with or without salt (5 g·L(-1)). Samples were cooled immediately after cooking and kept in frozen storage before analysis. Proximate composition, mineral, amino acid, and vitamin contents were determined, and nutritive value was estimated based on 100 g serving portions in a 2000 calorie diet. Results show that processed nettle can supply 90%-100% of vitamin A (including vitamin A as β-carotene) and is a good source of dietary calcium, iron, and protein. We recommend fresh or processed nettle as a high-protein, low-calorie source of essential nutrients, minerals, and vitamins particularly in vegetarian, diabetic, or other specialized diets.


Characterization of Laminar Zones in the Mid-Gestation Primate Brain with Magnetic Resonance Imaging and Histological Methods.
Distinct populations of progenitor and postmitotic neural and glial cells are stratified in the fetal primate brain across developmentally transient tissue zones between the ventricular and pial surfaces. These zones were originally identified by light microscopy. However, it has subsequently been shown that various forms of magnetic resonance image (MRI) contrast can be used to distinguish layers of developing neural tissue in ex vivo, as well as in vivo (including in utero) conditions. Here we compare mid-gestation rhesus macaque tissue zones identified using histological techniques to ex vivo as well as in utero MRI performed on the same brains. These data are compared to mid-gestation fetal human brain MRI results, obtained in utero. We observe strong similarity between MRI contrast in vivo and post mortem, which facilitates interpretation of in utero images based on the histological characterization performed here. Additionally, we observe differential correspondence between the various forms of ex vivo MRI contrast and microscopy data, with maps of the water apparent diffusion coefficient providing the closest match to histologically-identified lamina of the nonhuman primate brain. Examination of histology and post mortem MRI helps to provide a better understanding of cytoarchitectrual characteristics that give rise to in utero MRI contrast.


Comparing CISNET Breast Cancer Models Using the Maximum Clinical Incidence Reduction Methodology.
Collaborative modeling has been used to estimate the impact of potential cancer screening strategies worldwide. A necessary step in the interpretation of collaborative cancer screening model results is to understand how model structure and model assumptions influence cancer incidence and mortality predictions. In this study, we examined the relative contributions of the pre-clinical duration of breast cancer, the sensitivity of screening, and the improvement in prognosis associated with treatment of screen-detected cases to the breast cancer incidence and mortality predictions of 5 Cancer Intervention and Surveillance Modeling Network (CISNET) models. To tease out the impact of model structure and assumptions on model predictions, the Maximum Clinical Incidence Reduction (MCLIR) method compares changes in the number of breast cancers diagnosed due to clinical symptoms and cancer mortality between 4 simplified scenarios: 1) no-screening; 2) one-time perfect screening exam, which detects all existing cancers and perfect treatment (i.e., cure) of all screen-detected cancers; 3) one-time digital mammogram and perfect treatment of all screen-detected cancers; and 4) one-time digital mammogram and current guideline-concordant treatment of all screen-detected cancers. The 5 models predicted a large range in maximum clinical incidence (19% to 71%) and in breast cancer mortality reduction (33% to 67%) from a one-time perfect screening test and perfect treatment. In this perfect scenario, the models with assumptions of tumor inception before it is first detectable by mammography predicted substantially higher incidence and mortality reductions than models with assumptions of tumor onset at the start of a cancer's screen-detectable phase. The range across models in breast cancer clinical incidence (11% to 24%) and mortality reduction (8% to 18%) from a one-time digital mammogram at age 62 y with observed sensitivity and current guideline-concordant treatment was considerably smaller than achievable under perfect conditions. The timing of tumor inception and its effect on the length of the pre-clinical phase of breast cancer had a substantial impact on the grouping of models based on their predictions for clinical incidence and breast cancer mortality reduction. This key finding about the timing of tumor inception will be included in future CISNET breast analyses to enhance model transparency. The MCLIR approach should aid in the interpretation of variations in model results and could be adopted in other disease screening settings to enhance model transparency.


Isolation of recombinant antibodies against EspA and intimin of Escherichia coli O157:H7.
Intimin, Tir, and EspA proteins are expressed by attaching-effacing Escherichia coli, which include enteropathogenic and enterohemorrhagic E. coli pathotypes. EspA proteins are part of the type three secretion system needle complex that delivers Tir to the host epithelial cell, while surface arrayed intimin docks the bacterium to the translocated Tir. This intimate attachment leads to attaching and effacing lesions. Recombinant forms of these effector proteins from enterohemorrhagic E. coli O157:H7 were produced by using E. coli expression vectors. Binding of intimin and Tir fragments in enzyme-linked immunosorbent assay (ELISAs) demonstrated the interaction of intimin fragments containing the C-terminal 282 or 188 amino acids to a Tir fragment containing amino acid residues 258 to 361. Recombinant intimin and EspA proteins were used to elicit immune responses in rabbits and immune phage-display antibody libraries were produced. Screening of these immune libraries by conventional phage-antibody panning and colony filter screening produced a panel of antibodies with specificity for EspA or intimin. Antibodies recognizing different C-terminal epitopes on intimin bound specifically to the gamma intimin of O157:H7 and not to other classes of intimin. Antibodies recognizing EspA from E. coli O157 also recognized the protein from the eae-deficient O157 mutant DM3 and from E. coli O111. Anti-intimin antibodies were also produced as fusion proteins coupled to the reporter molecule alkaline phosphatase, allowing the one-step detection of gamma intimin. The isolated recombinant monoclonal antibodies were functional in a range of assay formats, including ELISA, Western blotting, and dot blots, thus demonstrating their diagnostic potential.


TRAPID: an efficient online tool for the functional and comparative analysis of de novo RNA-Seq transcriptomes.
Transcriptome analysis through next-generation sequencing technologies allows the generation of detailed gene catalogs for non-model species, at the cost of new challenges with regards to computational requirements and bioinformatics expertise. Here, we present TRAPID, an online tool for the fast and efficient processing of assembled RNA-Seq transcriptome data, developed to mitigate these challenges. TRAPID offers high-throughput open reading frame detection, frameshift correction and includes a functional, comparative and phylogenetic toolbox, making use of 175 reference proteomes. Benchmarking and comparison against state-of-the-art transcript analysis tools reveals the efficiency and unique features of the TRAPID system. TRAPID is freely available at http://bioinformatics.psb.ugent.be/webtools/trapid/.


Cardiac rehabilitation adapted to transient ischaemic attack and stroke (CRAFTS): a randomised controlled trial.
Coronary Heart Disease and Cerebrovascular Disease share many predisposing, modifiable risk factors (hypertension, abnormal blood lipids and lipoproteins, cigarette smoking, physical inactivity, obesity and diabetes mellitus). Lifestyle interventions and pharmacological therapy are recognised as the cornerstones of secondary prevention. Cochrane review has proven the benefits of programmes incorporating exercise and lifestyle counselling in the cardiac disease population. A Cochrane review highlighted as priority, the need to establish feasibility and efficacy of exercise based interventions for Cerebrovascular Disease. A single blind randomised controlled trial is proposed to examine a primary care cardiac rehabilitation programme for adults post transient ischemic attack (TIA) and stroke in effecting a positive change in the primary outcome measures of cardiac risk scores derived from Blood Pressure, lipid profile, smoking and diabetic status and lifestyle factors of habitual smoking, exercise and healthy eating participation. Secondary outcomes of interest include health related quality of life as measured by the Hospital Anxiety and Depression Scale, the Stroke Specific Quality of Life scale and WONCA COOP Functional Health Status charts and cardiovascular fitness as measured by a sub-maximal fitness test.A total of 144 patients, over 18 years of age with confirmed diagnosis of ischaemic stroke or TIA, will be recruited from Dublin community stroke services and two tertiary T.I.A clinics. Exclusion criteria will include oxygen dependence, unstable cardiac conditions, uncontrolled diabetes, major medical conditions, claudication, febrile illness, pregnancy or cognitive impairment. Participants will be block-statified, randomly allocated to one of two groups using a pre-prepared computer generated randomisation schedule. Both groups will receive a two hour education class on risk reduction post stroke. The intervention group will receive a 10 week programme of supervised aerobic exercises (twice weekly) and individually tailored brief intervention lifestyle counselling. Both groups will be tested on week one and week ten of the programme. Follow-up at 1 year will assess longer term benefits. Analysis will test for significant changes in the key variables indicated. Application of the Cardiac Rehabilitation paradigm to patients with ischaemic stroke or TIA has not been explored despite the obvious overlap in aetiology. It is hoped the anticipated improvement in vascular risk factors and fitness resulting from such a programme will enhance health and social gain in this population. Current Controlled Trials ISCTRN90272638.


International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs.
This article outlines the consensus proposal on diagnosis of epilepsy in dogs by the International Veterinary Epilepsy Task Force. The aim of this consensus proposal is to improve consistency in the diagnosis of epilepsy in the clinical and research settings. The diagnostic approach to the patient presenting with a history of suspected epileptic seizures incorporates two fundamental steps: to establish if the events the animal is demonstrating truly represent epileptic seizures and if so, to identify their underlying cause. Differentiation of epileptic seizures from other non-epileptic episodic paroxysmal events can be challenging. Criteria that can be used to make this differentiation are presented in detail and discussed. Criteria for the diagnosis of idiopathic epilepsy (IE) are described in a three-tier system. Tier I confidence level for the diagnosis of IE is based on a history of two or more unprovoked epileptic seizures occurring at least 24 h apart, age at epileptic seizure onset of between six months and six years, unremarkable inter-ictal physical and neurological examination, and no significant abnormalities on minimum data base blood tests and urinalysis. Tier II confidence level for the diagnosis of IE is based on the factors listed in tier I and unremarkable fasting and post-prandial bile acids, magnetic resonance imaging (MRI) of the brain (based on an epilepsy-specific brain MRI protocol) and cerebrospinal fluid (CSF) analysis. Tier III confidence level for the diagnosis of IE is based on the factors listed in tier I and II and identification of electroencephalographic abnormalities characteristic for seizure disorders. The authors recommend performing MRI of the brain and routine CSF analysis, after exclusion of reactive seizures, in dogs with age at epileptic seizure onset <6 months or >6 years, inter-ictal neurological abnormalities consistent with intracranial neurolocalisation, status epilepticus or cluster seizure at epileptic seizure onset, or a previous presumptive diagnosis of IE and drug-resistance with a single antiepileptic drug titrated to the highest tolerable dose.This consensus article represents the basis for a more standardised diagnostic approach to the seizure patient. These recommendations will evolve over time with advances in neuroimaging, electroencephalography, and molecular genetics of canine epilepsy.


MiR-30a Regulates S100A12-induced Retinal Microglial Activation and Inflammation by Targeting NLRP3.
Purpose: Our previous study has identified that plasma levels of S100A12 are closely associated with presence and severity of diabetic retinopathy (DR). In this work, we explored whether S100A12 can contribute to retinal microglial activation and inflammatory changes of DR via a microRNA-dependent mechanism.Material and Methods: Streptozotocin (STZ)-induced DR model was developed. Retinal microglia of rats were activated through intravitreal injection of S100A12. Differential expression of miRNAs on retinal microglia treated with S100A12 or DMEM/F-12 alone was determined using microarray analysis. Luciferase reporter assays were performed, which explored the regulation of a putative target of miR-30a.Results: S100A12 was increased approximately fivefold in the retina of 16-week diabetic rats compared with nondiabetic retinas. Furthermore, the levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly increased in the retina of rats treated with intravitreal injection of S100A12. Moreover, S100A12 induced an increased expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in a dose- and time-dependent manner in retinal microglia. S100A12 was a proinflammatory trigger in diabetes-induced retinal microglial activation by activating NLRP3 in vivo and in vitro. In addition, S100A12 induced retinal microglial activation via a miR-30a-dependent mechanism. Mechanistically, S100A12 inhibited miR-30a expression, which was controlled by HDAC, and miR-30a downregulated NLRP3 expression by directly targeting its 3'-UTR.Conclusions: S100A12 plays an important role in the pathogenesis of DR by activating retinal microglia via a miR-30a-dependent mechanism.


Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA.
Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells. The effect of THC on HT1080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting. Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis. Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins.


Eliminating Medicaid adult dental coverage in California led to increased dental emergency visits and associated costs.
Dental coverage for adults is an elective benefit under Medicaid. As a result of budget constraints, California Medicaid eliminated its comprehensive adult dental coverage in July 2009. We examined the impact of this policy change on emergency department (ED) visits by Medicaid-enrolled adults for dental problems in the period 2006-11. We found that the policy change led to a significant and immediate increase in dental ED use, amounting to more than 1,800 additional dental ED visits per year. Young adults, members of racial/ethnic minority groups, and urban residents were disproportionately affected by the policy change. Average yearly costs associated with dental ED visits increased by 68 percent. The California experience provides evidence that eliminating Medicaid adult dental benefits shifts dental care to costly EDs that do not provide definitive dental care. The population affected by the Medicaid adult dental coverage policy is increasing as many states expand their Medicaid programs under the ACA. Hence, such evidence is critical to inform decisions regarding adult dental coverage for existing Medicaid enrollees and expansion populations.


International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder.
Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. Within the framework of the International Society for Bipolar Disorders Task Force on Suicide, a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and 'suicide attempts' or 'suicide', was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which ≥ 3 studies with usable data were available were meta-analyzed using fixed or random-effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first-degree family history of suicide. Suicide deaths were significantly associated with male gender and first-degree family history of suicide. This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis-specific data in the development of models of understanding suicide in bipolar disorder.


NMR landscapes for chemical shift prediction.
The ability to reliably predict NMR chemical shifts plays an important role in elucidating the structure of organic molecules. Additionally, an intriguing question is how the multitude of variable factors (structural, electronic, and environmental) correlate with the actual electromagnetic shielding effect that determines the chemical shift value. This work presents NMRscape as a new tool for understanding these correlations by constructing the landscape that describes the relationship between the chemical shift value and the moieties bonded to a molecular scaffold. The scaffold may be as small as a single atom probed by NMR or a larger molecular framework containing the probed atom. NMRscape operates with only a list of the chemical moieties bonded to the scaffold, without utilizing any potentially biasing chemometric descriptors. The corresponding chemical shift landscape is constructed based on fundamental physical principles, which makes NMRscape a credible chemical shift prediction and analysis tool. As an illustration, we demonstrate that NMRscape can predict (13)C chemical shifts with an accuracy exceeding the substituent chemical shift (SCS) increment, hierarchical organization of spherical environments (HOSE), and neural networks (NN), methods for three distinct families of molecules sharing a common scaffold structure with moieties placed at two variable sites. The constructed NMR landscapes confirmed known empirical rules relating chemical shift values to the variation of chemical moieties on a scaffold, as well as uncovered hitherto hidden relationships. The practical importance of NMRscape is discussed.


Iridium anomaly approximately synchronous with terminal eocene extinctions.
An iridium anomaly has been found in coincidence with the known microtektite level in cores from Deep Sea Drilling Project site 149 in the Caribbean Sea. The iridium was probably not in the microtektites but deposited simultaneously with them; this could occur if the iridium was deposited from a dust cloud resulting from a bolide impact, as suggested for the anomaly associated with the Cretaceous-Tertiary boundary. Other workers have deduced that the microtektites are part of the North American strewn tektite field, which is dated at about 34 million years before present, and that the microtektite horizon in deep-sea cores is synchronous with the extinction of five radiolarian species. Mass extinctions also occur in terrestrial mammals within 4 million years of this time. The iridium anomaly and the tektites and microtektites are supportive of a major bolide impact about 34 million years ago.


Detection of Cryptosporidium parvum infection in childhood using various techniques.
The protozoan parasite Cryptosporidium parvum, which causes acute gastroenteritis in both humans and animals, has become an important pathogen all over the world. C. parvum may cause asymptomatic or symptomatic acute infections of the digestive system in immunocompetent subjects, but life-threatening disease in immunocompromised hosts. The aim of this study was to determine the usefulness of conventional microscopic staining techniques in the detection of C. parvum. For this purpose, 50 unselected immunocompetent asymptomatic children were evaluated for C. parvum during routine upper endoscopy. Duodenal aspirates and duodenal biopsy samples from 37 girls and 13 boys, between the ages of 2 and 18 years, obtained by gastrointestinal upper endoscopy and concomitant stool samples were examined with different staining techniques. Two stool samples and one duodenal aspirate were positive for C. parvum, but we could not demonstrate C. parvum in any duodenal biopsy samples. Dyspepsia was the primary indication for upper endoscopy in the patient with positive duodenal aspirate sample. These findings indicate that there is a low asymptomatic carrier rate in immunocompetent subjects with no involvement of intestinal villius attachment in the duodenum. We also conclude that C. parvum is an infrequent parasite in asymptomatic subjects, most probably due to a very low prevalence of HIV positivity in Turkey.


Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.
Epidemiologic studies have suggested that folate intake decreases risk of cardiovascular diseases. However, the results of randomized controlled trials on dietary supplementation with folic acid to date have been inconsistent. To evaluate the effects of folic acid supplementation on risk of cardiovascular diseases and all-cause mortality in randomized controlled trials among persons with preexisting cardiovascular or renal disease. Studies were retrieved by searching MEDLINE (January 1966-July 2006) using the Medical Subject Headings cardiovascular disease, coronary disease, coronary thrombosis, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular accident, randomized controlled trial, clinical trials, homofolic acid, and folic acid, and the text words folic acid and folate. Bibliographies of all retrieved articles were also searched, and experts in the field were contacted. From 165 relevant retrieved reports, 12 randomized controlled trials compared folic acid supplementation with either placebo or usual care for a minimum duration of 6 months and with clinical cardiovascular disease events reported as an end point. Data on study design, characteristics of participants, changes in homocysteine levels, and cardiovascular disease outcomes were independently abstracted by 2 investigators using a standardized protocol. Studies including data from 16 958 participants with preexisting vascular disease were analyzed using a random-effects model. The overall relative risks (95% confidence intervals) of outcomes for patients treated with folic acid supplementation compared with controls were 0.95 (0.88-1.03) for cardiovascular diseases, 1.04 (0.92-1.17) for coronary heart disease, 0.86 (0.71-1.04) for stroke, and 0.96 (0.88-1.04) for all-cause mortality. The relative risk was consistent among participants with preexisting cardiovascular or renal disease. Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. Several ongoing trials with large sample sizes might provide a definitive answer to this important clinical and public health question.


Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations.
Recently, we developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserve the natural extracellular matrix structure, mechanical anisotropy, and vasculature templates and also show good cell recellularization and differentiation potential. In this study, a multistimulation bioreactor was built to provide coordinated mechanical and electrical stimulation for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (10(6) cells/mL) by needle injection and subjected to 5-azacytidine treatment (3 μmol/L, 24 h) and various bioreactor conditioning protocols. We found that after 2 days of culturing with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed a cardiomyocyte-like phenotype by expressing sarcomeric α-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2 days of bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2 day and 4 day tissue constructs were comparable to those of the tissue constructs produced by stirring reseeding followed by 2 weeks of static culturing, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development but also for patients by reducing the waiting time in future clinical scenarios.


Numerical and experimental study of disordered multilayers for broadband x-ray reflection.
The effect of layer thickness disorder in periodic multilayers on x-ray reflectivity is investigated numerically and experimentally. We present ensemble calculations, taking into account absorption and interfacial roughness. It is demonstrated that layer thickness disorder yields band broadening and increased integrated reflectivity For applications we concentrate on extrema of the ensembles, giving the highest integrated reflectivity We develop global optimization methods that can also be used to generate specified reflection band structures. In a few examples, applications of the optimization methods are discussed. To illustrate the practical applicability of the methods, we compare experimental realizations to the calculation. In one case we achieve a 42% increase in integrated reflectivity in the 130 Å < λ < 190 Å spectral range with respect to a periodic multilayer with its first-order Bragg peak in the center of that range. Accurate control of layer thicknesses is our main experimental obstacle.


All-soft, battery-free, and wireless chemical sensing platform based on liquid metal for liquid- and gas-phase VOC detection.
Lightweight, flexible, stretchable, and wireless sensing platforms have gained significant attention for personal healthcare and environmental monitoring applications. This paper introduces an all-soft (flexible and stretchable), battery-free, and wireless chemical microsystem using gallium-based liquid metal (eutectic gallium-indium alloy, EGaIn) and poly(dimethylsiloxane) (PDMS), fabricated using an advanced liquid metal thin-line patterning technique based on soft lithography. Considering its flexible, stretchable, and lightweight characteristics, the proposed sensing platform is well suited for wearable sensing applications either on the skin or on clothing. Using the microfluidic sensing platform, detection of liquid-phase and gas-phase volatile organic compounds (VOC) is demonstrated using the same design, which gives an opportunity to have the sensor operate under different working conditions and environments. In the case of liquid-phase chemical sensing, the wireless sensing performance and microfluidic capacitance tunability for different dielectric liquids are evaluated using analytical, numerical, and experimental approaches. In the case of gas-phase chemical sensing, PDMS is used both as a substrate and a sensing material. The gas sensing performance is evaluated and compared to a silicon-based, solid-state gas sensor with a PDMS sensing film.


Peg-Interferon Lambda Treatment Induces Robust Innate and Adaptive Immunity in Chronic Hepatitis B Patients.
IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4+ T cells producing IFN-γ with maintenance of HBV-specific CD8+ T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8+ T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment. ClinicalTrials.gov NCT01204762.


Areas of vulnerability to HIV/TB co-infection in Southeastern Brazil.
To identify areas of vulnerability to new cases of HIV/tuberculosis (TB) co-infection. An ecological descriptive study was conducted by georeferencing new HIV/TB cases reported in the city of Ribeirão Preto, Southeastern Brazil, in 2006. Data were obtained from the São Paulo state information system for TB notification (TB-WEB) database. New cases of HIV/TB co-infection were analyzed according to sociodemographic and clinical characteristics and, subsequently, georeferenced in the city's cartographic basis, based on home addresses. City sectors were categorized into three socioeconomic levels: lower, average and upper levels, based on the analysis of the main components of the 2000 Demographic Census variables (income, level of education and percentage of households with five or more residents). The incidence of HIV/TB co-infection was calculated for each socioeconomic level. HIV/TB co-infection affected a higher number of economically active adult males and the pulmonary form of TB was the most frequent. Spatial distribution showed that the incidences in areas with average and lower socioeconomic levels (8.3 and 11.5 cases per 100,000 inhabitants, respectively) were higher than that with a higher socioeconomic level (4.8 cases per 100,000 inhabitants). The incidence rate of HIV/TB co-infection, analyzed according to socioeconomic levels, showed a non-homogeneous spatial pattern of distribution and higher values in more socially vulnerable areas. The present study identified priority geographical areas to control co-infection and revealed that the geographical information system technology can be used by city managers to plan health actions.


Genome-wide gene expression profiling of SCID mice with T-cell-mediated Colitis.
Inflammatory bowel disease (IBD) is a multifactorial disorder with an unknown aetiology. The aim of this study is to employ a murine model of IBD to identify pathways and genes, which may play a key role in the pathogenesis of IBD and could be important for discovery of new disease markers in human disease. Here, we have investigated severe combined immunodeficient (SCID) mice, which upon adoptive transfer with concanavalin A-activated CD4(+) T cells develop inflammation of the colon with predominance in rectum. Mice with increasing level of inflammation was studied. RNA from rectum of transplanted and non-transplanted SCID mice was investigated by a genome-wide gene expression analysis using the Affymetrix mouse expression array 430A (MOE430A) including 22,626 probe sets. A significant change in gene expression (P = 0.00001) is observed in 152 of the genes between the non-transplanted control mice and colitis mice, and among these genes there is an overrepresentation of genes involved in inflammatory processes. Some of the most significant genes showing higher expression encode S100A proteins and chemokines involved in trafficking of leucocytes in inflammatory areas. Classification by gene clustering based on the genes with the significantly altered gene expression corresponds to two different levels of inflammation as established by the histological scoring of the inflamed rectum. These data demonstrate that this SCID T-cell transfer model is a useful animal model for human IBD and can be used for suggesting candidate genes involved in the pathogenesis and for identifying new molecular markers of chronic inflammation in human IBD.


Switching Selective Serotonin Reuptake Inhibitors in Adolescents with Selective Serotonin Reuptake Inhibitor-Resistant Major Depressive Disorder: Balancing Tolerability and Efficacy.
Objective: To guide clinicians in selecting the "next line" selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine (p = 0.247) or for fluoxetine compared with paroxetine (p = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p = 0.055). For efficacy-tolerability models, citalopram and fluoxetine were superior to paroxetine (p = 0.029 and p = 0.022, respectively) but did not differ between each other (p = 0.146). Conclusions: Joint efficacy-tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.


App Use in Psychiatric Education: A Medical Student Survey.
The objective of the study is to understand and appraise app use by medical students during their clerkships. Following Creighton University IRB approval, a voluntary and anonymous paper-based, 15-question survey was distributed to third-year medical students. Data were analyzed using Microsoft Excel. Of 112 medical students available, 76.7% (86) participated in the survey. All participants owned a smartphone or tablet with 84.9% using Apple iOS, followed by 12.8% using Android platform. Students reported using the fewest number of apps during surgery, psychiatry, and obstetrics and gynecology clerkships. The largest number of apps were used during the internal medicine rotation (70.3%). The three most popular apps were Epocrates, UpToDate, and UWorld. The most common uses for these apps were as references during the clerkship, followed by improving knowledge, and test taking. Perceived major benefits included accessibility (96% of student respondents) and interactivity (39.5%). Common apps used during the psychiatry clerkship included UpToDate (71%), Epocrates (51%), and Medscape (43%). Despite less frequent app use during their psychiatry clerkship, 90% felt there was a utility for educational apps in psychiatric education. Consistent with the previous literature on medical students preferring educational apps, students suggest developers focus on question bank-type apps, followed by clinical support-focused and self-directed case-based learning apps for psychiatry clerkship learning. Educators should factor these modes of educational delivery into future educational app development. This survey shows a high degree of smartphone and tablet use among medical students, and they attest to mobile phone app utility in psychiatric education.


How do obese individuals perceive and respond to the different types of obesity stigma that they encounter in their daily lives? A qualitative study.
Obesity stigma exists within many institutions and cultural settings. Most studies suggest that stigmatising experiences have a negative impact on individuals' health and social behaviours and outcomes. However, some studies indicate that obesity stigma can motivate individuals to lose weight. Limited research has examined weight-based stigma from the perspective of obese individuals, including their perceptions of, and responses to, the different types of weight-based stigma they face in their daily lives. This study advances knowledge about weight-based stigma by documenting how obese adults (mostly female) described the different types of obesity stigma that they faced, how they responded to this stigma, and how different types of stigma impact on health and social wellbeing. Semi-structured, qualitative interviews were conducted between April 2008 and March 2009 with a diverse sample of 141 obese Australian adults. Guided by Link and Phelan's (2006) categorisation of different types of discrimination, participants' experiences could be grouped into three distinct types of stigma: 1) Direct (e.g. being abused when using public transport); 2) Environmental (e.g. not being able to fit into seats on planes); and 3) Indirect (e.g. people staring at the contents of their supermarket trolley). Participants described that more subtle forms of stigma had the most impact on their health and social wellbeing. However, it was the interaction between direct, environmental and indirect stigma that created a barrier to participation in health-promoting activities. Participants rarely challenged stigma and often blamed themselves for stigmatising experiences. They also avoided situations where they perceived they would be stigmatised and constantly thought about how they could find a solution to their obesity.


A UK wide cohort study describing management and outcomes for infants with surgical Necrotising Enterocolitis.
The Royal College of Surgeons have proposed using outcomes from necrotising enterocolitis (NEC) surgery for revalidation of neonatal surgeons. The aim of this study was therefore to calculate the number of infants in the UK/Ireland with surgical NEC and describe outcomes that could be used for national benchmarking and counselling of parents. A prospective nationwide cohort study of every infant requiring surgical intervention for NEC in the UK was conducted between 01/03/13 and 28/02/14. Primary outcome was mortality at 28-days. Secondary outcomes included discharge, post-operative complication, and TPN requirement. 236 infants were included, 43(18%) of whom died, and eight(3%) of whom were discharged prior to 28-days post decision to intervene surgically. Sixty infants who underwent laparotomy (27%) experienced a complication, and 67(35%) of those who were alive at 28 days were parenteral nutrition free. Following multi-variable modelling, presence of a non-cardiac congenital anomaly (aOR 5.17, 95% CI 1.9-14.1), abdominal wall erythema or discolouration at presentation (aOR 2.51, 95% CI 1.23-5.1), diagnosis of single intestinal perforation at laparotomy (aOR 3.1 95% CI 1.05-9.3), and necessity to perform a clip and drop procedure (aOR 30, 95% CI 3.9-237) were associated with increased 28-day mortality. These results can be used for national benchmarking and counselling of parents.


Age at onset as stratifier in idiopathic Parkinson's disease - effect of ageing and polygenic risk score on clinical phenotypes.
Several phenotypic differences observed in Parkinson's disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients.


Microextraction by packed sorbent liquid chromatography with time-of-flight mass spectrometry of triazines employing a molecularly imprinted polymer.
Molecularly imprinted polymers for the determination of triazines were synthesized by precipitation using atrazine as template, methacrylic acid as functional monomer, ethylene glycol dimethacrylate as crosslinker, and 2,2'-azobisisobutrynitrile as initiator. The polymers were characterized by infrared spectroscopy and scanning electron microscopy and packed in a device for microextraction by packed sorbent aiming for the preconcentration/cleanup of herbicides, such as atrazine, simazine, simetryn, ametryn, and terbutryn in corn samples. Liquid chromatography coupled with time-of-flight mass spectrometry was used for the separation and determination of the herbicides. The selectivity coefficient of molecularly imprinted polymers was compared with that of nonimprinted polymer for the binary mixtures of atrazine/propanil and atrazine/picloram, and the values obtained were 15.6 and 2.96, respectively. The analytical curve ranged from 10 to 80 μg/kg (r = 0.989) and the limits of detection and quantification in the corn matrices were 3.3 and 10 μg/kg, respectively. Intra- and interday precisions were < 14.8% and accuracy was better than 90.9% for all herbicides. Polymer synthesis was successfully applied to the cleanup and preconcentration of triazines from fortified corn samples with 91.1-109.1% of recovery.


Augmenting sensorimotor control using "goal-aware" vibrotactile stimulation during reaching and manipulation behaviors.
We describe two sets of experiments that examine the ability of vibrotactile encoding of simple position error and combined object states (calculated from an optimal controller) to enhance performance of reaching and manipulation tasks in healthy human adults. The goal of the first experiment (tracking) was to follow a moving target with a cursor on a computer screen. Visual and/or vibrotactile cues were provided in this experiment, and vibrotactile feedback was redundant with visual feedback in that it did not encode any information above and beyond what was already available via vision. After only 10 minutes of practice using vibrotactile feedback to guide performance, subjects tracked the moving target with response latency and movement accuracy values approaching those observed under visually guided reaching. Unlike previous reports on multisensory enhancement, combining vibrotactile and visual feedback of performance errors conferred neither positive nor negative effects on task performance. In the second experiment (balancing), vibrotactile feedback encoded a corrective motor command as a linear combination of object states (derived from a linear-quadratic regulator implementing a trade-off between kinematic and energetic performance) to teach subjects how to balance a simulated inverted pendulum. Here, the tactile feedback signal differed from visual feedback in that it provided information that was not readily available from visual feedback alone. Immediately after applying this novel "goal-aware" vibrotactile feedback, time to failure was improved by a factor of three. Additionally, the effect of vibrotactile training persisted after the feedback was removed. These results suggest that vibrotactile encoding of appropriate combinations of state information may be an effective form of augmented sensory feedback that can be applied, among other purposes, to compensate for lost or compromised proprioception as commonly observed, for example, in stroke survivors.


Analysis of serial ovarian volume measurements and incidence of ovarian cancer: implications for pathogenesis.
Accumulating evidence suggests that many ovarian cancers represent metastases from occult fallopian tube carcinomas or tumors arising within ovarian endometriosis. We hypothesized that small ovarian volumes, as reflected in nonvisualization by transvaginal ultrasound (TVU), would be a marker of lower ovarian cancer risk, whereas enlargement on serial examinations would indicate higher risk. To address these hypotheses, we analyzed serial ovarian volume measurements determined by TVU for 29321 women (102787 scans) performed in the ovarian cancer screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. Cox models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of association between TVU results and ovarian cancer. We assessed whether increasing ovarian volume preceded diagnosis of ovarian cancer in a nested case-control analysis comparing case patients and control patients matched on age, center, and screening year (1:4 ratio). All statistical tests were two-sided. Visualization of normal-appearing ovaries at the last TVU scan was associated with marginally higher ovarian cancer risk compared with nonvisualization of the ovaries (HR = 1.42, 95% CI = 1.00 to 2.01). Ovarian volume increased statistically significantly in ovarian cancer case patients one to two years before diagnosis (P < .001), but not in matched control patients. Our analysis of TVU data suggests that increasing ovarian volume is associated with greater ovarian cancer risk, but it is only detectable one to two years before diagnosis.


Validation of a novel traditional chinese medicine pulse diagnostic model using an artificial neural network.
In view of lacking a quantifiable traditional Chinese medicine (TCM) pulse diagnostic model, a novel TCM pulse diagnostic model was introduced to quantify the pulse diagnosis. Content validation was performed with a panel of TCM doctors. Criterion validation was tested with essential hypertension. The gold standard was brachial blood pressure measured by a sphygmomanometer. Two hundred and sixty subjects were recruited (139 in the normotensive group and 121 in the hypertensive group). A TCM doctor palpated pulses at left and right cun, guan, and chi points, and quantified pulse qualities according to eight elements (depth, rate, regularity, width, length, smoothness, stiffness, and strength) on a visual analog scale. An artificial neural network was used to develop a pulse diagnostic model differentiating essential hypertension from normotension. Accuracy, specificity, and sensitivity were compared among various diagnostic models. About 80% accuracy was attained among all models. Their specificity and sensitivity varied, ranging from 70% to nearly 90%. It suggested that the novel TCM pulse diagnostic model was valid in terms of its content and diagnostic ability.


Modulating the physical properties of solid forms of urea using co-crystallization technology.
The solid-form landscape of urea was explored using full interaction maps (FIMs) and data from the CSD to develop optimum protocols for synthesizing co-crystals of urea. As a result, 49 of the 60 attempted reactions produced new co-crystals, and the crystal structures of four of these are presented. Moreover, the goal of reducing the solubility and lowering the hygroscopicity of the parent compound was achieved, which in turn offers new opportunities for application as a slow-release fertilizer with limited hygroscopicity, thereby reducing many current problems of transport, handling, and storage of urea.


Two Auxin Response Elements Fine-Tune PINOID Expression During Gynoecium Development in Arabidopsis thaliana.
The plant hormone auxin controls almost all aspects of plant development through the gene regulatory properties of auxin response factors (ARFs) which bind so-called auxin responsive elements (AuxREs) in regulatory regions of their target genes. It has been proposed that ARFs interact and cooperate with other transcription factors (TFs) to bind to complex DNA-binding sites harboring cis-elements for several TFs. Complex DNA-binding sites have not been studied systematically for ARF target genes. ETTIN (ETT; ARF3) is a key regulator of gynoecium development. Cooperatively with its interacting partner INDEHISCENT (IND), ETT regulates PINOID (PID), a gene involved in the regulation gynoecium apical development (style development). Here, we mutated two ETT-bound AuxREs within the PID promoter and observed increased style length in gynoecia of plants carrying mutated promoter variants. Furthermore, mutating the AuxREs led to ectopic repression of PID in one developmental context while leading to ectopically upregulated PID expression in another stage. Our data also show that IND associates with the PID promoter in an auxin-sensitive manner. In summary, we demonstrate that targeted mutations of cis-regulatory elements can be used to dissect the importance of single cis-regulatory elements within complex regulatory regions supporting the importance of the ETT-IND interaction for PID regulation. At the same time, our work also highlights the challenges of such studies, as gene regulation is highly robust, and mutations within gene regulatory regions may only display subtle phenotypes.


SU-E-T-142: Evaluation of the Energy Dependence of Gafchromic EBT3 Film for Electron Beams.
To evaluate the energy dependence of Gafchromic EBT3 film for establishing a quality assurance method of bolus electron conformal radiotherapy. We irradiated electron beam to EBT3 films, which were set in the water tank. The linear accelerator used was Varian Clinac 21EX. The energy of electron beams were 9 and 12 MeV. The irradiated field size was 10×10 cm2 and the source to surface distance was 100 cm. The depths of measurement were 22 (depth of dose maximum; dmax), 31, and 37 mm for 9 MeV and 28 (dmax), 43, and 50 mm for 12 MeV. The irradiated doses were 25, 50, 75, 100, 150, 200, and 300 cGy. EBT3 films were readout with a flat-bed scanner 48 hours after irradiation, and the optical density (OD) curve was obtained for each beam energy and depth. The OD curves were approximated by a third-order polynomial. The doses were evaluated at netOD 0.1 and 0.3 from the approximated curves. The differences of the evaluated doses from those for 9 MeV at 22 mm depth were from 2 to 14 % for netOD=0.1, and from 1 to 13 % for netOD=0.3, respectively. The netOD curves of dmax for both energies showed good agreement, while large discrepancy was found in the deeper depths. The dependence of dose response of EBT3 film on electron beam energy was small at dmax, while it increased at deeper depth in the present study. It can be considered that the discrepancy was caused by setup error because dose gradient was steeper at the deeper region. In future work, we will perform more precise measurement with a solid phantom to evaluate the energy dependence of EBT3 film.


The yeast genome may harbor hypoxia response elements (HRE).
The hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated when cells are submitted to hypoxia. The heterodimer is composed of two subunits, HIF-1alpha and the constitutively expressed HIF-1beta. During normoxia, HIF-1alpha is degraded by the 26S proteasome, but hypoxia causes HIF-1alpha to be stabilized, enter the nucleus and bind to HIF-1beta, thus forming the active complex. The complex then binds to the regulatory sequences of various genes involved in physiological and pathological processes. The specific regulatory sequence recognized by HIF-1 is the hypoxia response element (HRE) that has the consensus sequence 5'BRCGTGVBBB3'. Although the basic transcriptional regulation machinery is conserved between yeast and mammals, Saccharomyces cerevisiae does not express HIF-1 subunits. However, we hypothesized that baker's yeast has a protein analogous to HIF-1 which participates in the response to changes in oxygen levels by binding to HRE sequences. In this study we screened the yeast genome for HREs using probabilistic motif search tools. We described 24 yeast genes containing motifs with high probability of being HREs (p-value<0.1) and classified them according to biological function. Our results show that S. cerevisiae may harbor HREs and indicate that a transcription factor analogous to HIF-1 may exist in this organism.


Determination of accurate electron chiral asymmetries in fenchone and camphor in the VUV range: sensitivity to isomerism and enantiomeric purity.
Photoelectron circular dichroism (PECD) manifests itself as an intense forward/backward asymmetry in the angular distribution of photoelectrons produced from randomly-oriented enantiomers by photoionization with circularly-polarized light (CPL). As a sensitive probe of both photoionization dynamics and of the chiral molecular potential, PECD attracts much interest especially with the recent performance of related experiments with visible and VUV laser sources. Here we report, by use of quasi-perfect CPL VUV synchrotron radiation and using a double imaging photoelectron/photoion coincidence (i(2)PEPICO) spectrometer, new and very accurate values of the corresponding asymmetries on showcase chiral isomers: camphor and fenchone. These data have additionally been normalized to the absolute enantiopurity of the sample as measured by a chromatographic technique. They can therefore be used as benchmarking data for new PECD experiments, as well as for theoretical models. In particular we found, especially for the outermost orbital of both molecules, a good agreement with CMS-Xα PECD modeling over the whole VUV range. We also report a spectacular sensitivity of PECD to isomerism for slow electrons, showing large and opposite asymmetries when comparing R-camphor to R-fenchone (respectively -10% and +16% around 10 eV). In the course of this study, we could also assess the analytical potential of PECD. Indeed, the accuracy of the data we provide are such that limited departure from perfect enantiopurity in the sample we purchased could be detected and estimated in excellent agreement with the analysis performed in parallel via a chromatographic technique, establishing a new standard of accuracy, in the ±1% range, for enantiomeric excess measurement via PECD. The i(2)PEPICO technique allows correlating PECD measurements to specific parent ion masses, which would allow its application to analysis of complex mixtures.


A Mediterranean diet supplemented with dairy foods improves mood and processing speed in an Australian sample: results from the MedDairy randomized controlled trial.
Background The Mediterranean diet has been linked to improved cognitive function and reduced risk of dementia. However, a traditional Mediterranean diet may not meet calcium requirements for older non-Mediterranean populations, which could limit long-term sustainability in Western countries. The current study therefore aimed to determine the cognitive and psychological effects of a Mediterranean diet with adequate calcium for an ageing Australian population. Method: A randomized controlled cross-over design trial compared a Mediterranean diet with 3-4 daily serves of dairy food (MedDairy) with a low-fat (LF) control diet. Forty-one participants aged ≥45 years with systolic blood pressure ≥120 mm Hg and at least two other risk factors for cardiovascular disease completed each dietary intervention for 8 weeks, with an 8-week washout period separating interventions. Attention, processing speed, memory and planning were assessed at the start and end of each intervention using the Cambridge Automated Neuropsychological Test Battery. Mood and health-related quality of life were evaluated using the Profile of Mood States (POMS) and Short-Form Health Survey (SF-36). Dementia risk was also measured using the Framingham Vascular Risk and CAIDE scores. Results Significant improvements were observed for processing speed (P = .04), Total Mood Disturbance (P = .01), Tension (P = .03), Depression (P = .03), Anger (P = .02), and Confusion (P = .004) following the MedDairy intervention. No significant effects were found for attention, memory and planning, or measures of dementia risk. Conclusion Our study provides evidence that a Mediterranean diet supplemented with dairy foods may benefit cognitive function and psychological well-being in an ageing population at risk of dementia.


Viscosupplementation for knee osteoarthritis: a systematic review.
Due to the rising number of patients affected by osteoarthritis (OA), appropriate management decisions for minimizing pain and improving physical function for patients with OA are important. Hyaluronic acid (HA) knee injections have become a common tool for the management of OA of the knee, and the number of randomized controlled trials on the efficacy and safety of this treatment is growing. We performed a systematic review of the five published meta-analyses, which include single- or double-blinded randomized trials performed at one center or multiple centers (Level I evidence). Within each meta-analysis, a quality assessment tool for each trial was used based on outcome measures of OA-related pain, disease severity, trial period, and mean efficacy. We analyzed and compared the data collection and qualitative analysis methods, outcomes, and conclusions presented for each meta-analysis. Although they used different strategies, each used scientifically sound methods for analysis of many of the same trials; however, each used a different measure of trial quality and heterogeneity. Despite these differences, all come to a similar conclusion that when the strictest quality tools and interpretation of heterogeneity are used, Level I evidence demonstrates that the use of HA in patients with OA results in modest improvement in validated outcomes.


Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism.
Germline loss-of-function mutations of TSH receptor (TSHR) gene have been described in families with partial or complete TSH resistance. Large TSH elevations were generally found in the patients with homozygous or compound heterozygous mutations. In this study, we sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations. Thyroid volume was normal in all patients, except two with a modest hypoplasia. Autoimmune thyroid disease was excluded in all patients on the basis of clinical and biochemical parameters. Eight patients had at least one first-degree relative bearing the same biochemical picture. TSHR mutations were detected in 4 of 10 cases by analyzing DNA from peripheral leukocytes. A compound heterozygosity (P162A on maternal allele, and the novel mutation C600R on the paternal one) was found in the patient with the highest TSH levels. Only one TSHR allele was mutated in the remaining three cases, and no alterations in TSHR gene promoter were detected in all of these probands. A novel mutation (L467P) was detected on the maternal allele in one patient and in her monozygotic twin. Previously described inactive mutants, T655Delta and C41S, were detected in the other two cases. When tested on several occasions, circulating TSH values fluctuating above the upper limit of the normal range could be shown in heterozygous subjects of these families. A dominant mode of inheritance of the biochemical alterations was detected in these cases. Mutant TSHRs were studied during transient expression in COS7 and HEK293T cells. Their TSH-independent cAMP accumulation activities were very low or similar to mock-transfected cells, and no increases were seen after maximal hormone stimulation. Flow cytometry experiments showed a poor level of expression of all mutant TSHRs at the cell membrane. In conclusion, we found several loss-of-function mutations of TSHR, including two novel ones, in a series of unrelated patients with slightly elevated TSH levels. Therefore, partial resistance to TSH action is a frequent finding among patients with slight hyperthyrotropinemia of nonautoimmune origin. Germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state.


Gastrocnemius Medialis Muscle Geometry and Extensibility in Typically Developing Children and Children With Spastic Paresis Aged 6-13 Years.
Gait of children with spastic paresis (SP) is frequently characterized by a reduced ankle range of motion, presumably due to reduced extensibility of the triceps surae (TS) muscle. Little is known about how morphological muscle characteristics in SP children are affected. The aim of this study was to compare gastrocnemius medialis (GM) muscle geometry and extensibility in children with SP with those of typically developing (TD) children and assess how GM morphology is related to its extensibility. Thirteen children with SP, of which 10 with a diagnosis of spastic cerebral palsy and three with SP of unknown etiology (mean age 9.7 ± 2.1 years; GMFCS: I-III), and 14 TD children (mean age 9.3 ± 1.7 years) took part in this study. GM geometry was assessed using 3D ultrasound imaging at 0 and 4 Nm externally imposed dorsal flexion ankle moments. GM extensibility was defined as its absolute length change between the externally applied 0 and 4 Nm moments. Anthropometric variables and GM extensibility did not differ between the SP and TD groups. While in both groups, GM muscle volume correlated with body mass, the slope of the regression line in TD was substantially higher than that in SP (TD = 3.3 ml/kg; SP = 1.3 ml/kg, p < 0.01). In TD, GM fascicle length increased with age, lower leg length and body mass, whereas in SP children, fascicle length did not correlate with any of these variables. However, the increase in GM physiological cross-sectional area as a function of body mass did not differ between SP and TD children. Increases in lengths of tendinous structures in children with SP exceeded those observed in TD children (TD = 0.85 cm/cm; SP = 1.16 cm/cm, p < 0.01) and even exceeded lower-leg length increases. In addition, only for children with SP, body mass (r = -0.61), height (r = -0.66), muscle volume (r = - 0.66), physiological cross-sectional area (r = - 0.59), and tendon length (r = -0.68) showed a negative association with GM extensibility. Such negative associations were not found for TD children. In conclusion, physiological cross-sectional area and length of the tendinous structures are positively associated with age and negatively associated with extensibility in children with SP.


Continuous daily use of cilostazol prevents in-stent restenosis following carotid artery stenting: serial angiographic investigation of 229 lesions.
Several studies have reported that cilostazol (CLS) may reduce in-stent restenosis (ISR) after carotid artery stenting (CAS). However, it is not known for how long CLS must be continued to prevent ISR. We retrospectively reviewed a prospectively collected database of patients who underwent elective CAS and follow-up angiography at 3 months and 1 year after the procedure. ISR was defined as stenosis of 50% or greater on digital subtraction angiography. The cumulative incidence rates of angiographic ISR were compared between the three groups, divided according to duration of CLS use : (1) patients who were maintained on CLS for 12 months or more after CAS (12M CLS group, n=70), (2) patients who were treated with CLS for the first 3 months after CAS (3M CLS group, n=23), and (3) patients who did not receive CLS (no CLS group, n=136). A total of 229 lesions in 199 patients were included in our analysis. During a median follow-up of 365 days, ISR was detected in 15 lesions. The cumulative ISR rates overall and in the 12M CLS, 3M CLS, and no CLS groups were 5.6%, 0%, 5.0%, and 8.4%, respectively, at 1 year, and the log rank test showed that there was a significant difference between the three groups (p<0.05). Cox regression analysis demonstrated that the 12M CLS group had a significantly lower risk of ISR than the 3M CLS group (adjusted relative risk (aRR) 3.06e-10, 95% CI 0 to 0.51, p<0.05) and the no CLS group (aRR 1.41e-10, 95% CI 0 to 0.15, p<0.001), whereas no difference was found between the 3M CLS group and the no CLS group. An overall cumulative ISR rate of 5.6% was documented angiographically at 1 year after CAS. Continuous daily use of CLS (for at least 1 year) may have a beneficial effect on long term prevention of ISR.