Musculoskeletal knowledge: how do you stack up?
One of every 4 or 5 primary care visits is for a musculoskeletal problem. Yet undergraduate and graduate training for this burden of illness continues to constitute typically less than 5% of the medical curriculum. This is an area of clear concern, but also one in which sports medicine practitioners can assume leadership.


The effects of dexamethasone and 1,25-dihydroxyvitamin D3 on osteogenic differentiation of human marrow stromal cells in vitro.
Effects of dexamethasone and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] were studied in cultures of adult human marrow stromal cells. In primary culture, dexamethasone (10(-8) M) increased the number of fibroblast colonies formed but decreased their average size. The number of colonies expressing alkaline phosphatase activity was increased, consistent with the enhancement of osteogenic differentiation by this glucocorticoid. In secondary culture, osteogenic differentiation was assessed by measurement of the steady-state levels of particular mRNAs that are characteristic of cells of the osteoblast lineage. The mRNAs for alpha 1(I)-procollagen, alkaline phosphatase, osteopontin and bone sialoprotein were expressed under all culture conditions used. In contrast, osteocalcin mRNA expression was detectable only in cultures treated with 1,25(OH)2D3 (10(-8) M). Addition of 1,25(OH)2D3 to control increased the expression of the mRNAs for alkaline phosphatase and osteopontin but had no significant effect on bone sialoprotein expression. The highest levels of expression of the mRNAs for alkaline phosphatase, bone sialoprotein and osteocalcin were observed in dexamethasone-treated cultures to which 1,25(OH)2D3 had been added. These results demonstrate that, as earlier found in other species, dexamethasone and 1,25(OH)2D3 promote the osteogenic differentiation of human marrow stromal cells as measured by expression of these osteogenic markers.


Multiple-array passive acoustic source localization in shallow water.
This paper considers concurrent matched-field processing of data from multiple, spatially-separated acoustic arrays with application to towed-source data received on two bottom-moored horizontal line arrays from the SWellEx-96 shallow water experiment. Matched-field processors are derived for multiple arrays and multiple-snapshot data using maximum-likelihood estimates for unknown complex-valued source strengths and unknown error variances. Starting from a coherent processor where phase and amplitude is known between all arrays, likelihood expressions are derived for various assumptions on relative source spectral information (amplitude and phase at different frequencies) between arrays and from snapshot to snapshot. Processing the two arrays with a coherent-array processor (with inter-array amplitude and phase known) or with an incoherent-array processor (no inter-array spectral information) both yield improvements in localization over processing the arrays individually. The best results with this data set were obtained with a processor that exploits relative amplitude information but not relative phase between arrays. The localization performance improvement is retained when the multiple-array processors are applied to short arrays that individually yield poor performance.


A mid-cretaceous origin of sociality in xylocopine bees with only two origins of true worker castes indicates severe barriers to eusociality.
The origin of sterile worker castes, resulting in eusociality, represents one of the major evolutionary transitions in the history of life. Understanding how eusociality has evolved is therefore an important issue for understanding life on earth. Here we show that in the large bee subfamily Xylocopinae, a simple form of sociality was present in the ancestral lineage and there have been at least four reversions to purely solitary nesting. The ancestral form of sociality did not involve morphological worker castes and maximum colony sizes were very small. True worker castes, entailing a life-time commitment to non-reproductive roles, have evolved only twice, and only one of these resulted in discrete queen-worker morphologies. Our results indicate extremely high barriers to the evolution of eusociality. Its origins are likely to have required very unusual life-history and ecological circumstances, rather than the amount of time that selection can operate on more simple forms of sociality.


Treatment of sporadic nonmedullary thyroid carcinomas in pediatric age.
Nonmedullary thyroid carcinomas are rare malignancies in pediatric ages. The vast majority of them are papillary carcinomas with an overall survival of approximately 100%. Their outcome is independent of strong prognostic factors of adults, such as papillary carcinoma histological subtype, invasion into soft tissue of the neck, presence and site of distant metastases, relapse and type of surgery. In these ages, follicular carcinomas and poorly differentiated carcinomas are exceptional. Undifferentiated (anaplastic) carcinomas are practically absent. In most institutions, the therapy of choice for all pediatric thyroid carcinomas is the radical approach, aimed at the eradication at diagnosis of all clinical and subclinical neoplastic foci, both at thyroid, lymph node and distant level. It consists of total thyroidectomy and lymphadenectomy in children with clinically evident lymph-node metastases, followed by radioactive iodine therapy independent of histotype and stage. Recently, owing also to the high sensitivity to hormonal manipulation shown by pediatric papillary carcinomas, a conservative approach has been proposed for selected cases, consisting of the removal of only the grossly detectable disease followed by thyroid-stimulating hormone-suppressive hormonal therapy to control subclinical disease. Today, the existence of two therapeutic approaches, radical versus conservative therapy, should be considered whenever treating a child or adolescent with a nonmedullary thyroid carcinoma. Not least, permanent post-treatment complications of radical surgery and radioactive iodine therapy should be taken into account. The future tasks include the stratification of thyroid carcinomas into low- and high-risk cases, also including their molecular alterations and the possibility of a molecularly targeted therapy against tyrosine kinases involved in the pathogenesis of thyroid carcinomas.


Engineered antifouling microtopographies: the role of Reynolds number in a model that predicts attachment of zoospores of Ulva and cells of Cobetia marina.
A correlation between the attachment density of cells from two phylogenetic groups (prokaryotic Bacteria and eukaryotic Plantae), with surface roughness is reported for the first time. The results represent a paradigm shift in the understanding of cell attachment, which is a critical step in the biofouling process. The model predicts that the attachment densities of zoospores of the green alga, Ulva, and cells of the marine bacterium, Cobetia marina, scale inversely with surface roughness. The size and motility of the bacterial cells and algal spores were incorporated into the attachment model by multiplying the engineered roughness index (ERI(II)), which is a representation of surface energy, by the Reynolds number (Re) of the cells. The results showed a negative linear correlation of normalized, transformed attachment density for both organisms with ERI(II) x Re (R(2) = 0.77). These studies demonstrate for the first time that organisms respond in a uniform manner to a model, which incorporates surface energy and the Reynolds number of the organism.


MicroRNA Expression Profiling in Psoriatic Arthritis.
Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by bone erosions and new bone formation. MicroRNAs (miRNAs) are key regulators of the immune responses. Differential expression of miRNAs has been reported in several inflammatory autoimmune diseases; however, their role in PsA is not fully elucidated. We aimed to identify miRNA expression signatures associated with PsA and to investigate their potential implication in the disease pathogenesis. miRNA microarray was performed in blood cells of PsA patients and healthy controls. miRNA pathway analyses were performed and the global miRNA profiling was combined with transcriptome data in PsA. Deregulation of selected miRNAs was validated by real-time PCR. We identified specific miRNA signatures associated with PsA patients with active disease. These miRNAs target pathways relevant in PsA, such as TNF, MAPK, and WNT signaling cascades. Network analysis revealed several miRNAs regulating highly connected genes within the PsA transcriptome. miR-126-3p was the most downregulated miRNA in active patients. Noteworthy, miR-126 overexpression induced a decreased expression of genes implicated in PsA. This study sheds light on some epigenetic aspects of PsA identifying specific miRNAs, which may represent promising candidates as biomarkers and/or for the design of novel therapeutic strategies in PsA.


Effect of procedure simulation workshops on resident procedural confidence and competence.
Pediatrics residents perform a limited number of some procedures in the clinical setting and may benefit from procedure simulation workshops. To examine (1) the number and types of procedures performed by pediatrics residents in the clinical setting, (2) the relationship between the number of procedures performed and self-reported procedural confidence and competence, and (3) the effect of a procedure simulation workshop on self-reported procedural confidence and competence. Pediatrics residents at Lucile Packard Children's Hospital at Stanford attended a half-day procedure workshop, rotating between 6 procedure simulation stations: vascular access, airway management, bladder catheterization, chest tube placement, lumbar puncture, and umbilical lines. Residents completed a survey immediately before and after the workshop to self-assess procedural confidence and competence. Seventy-two residents participated in a procedure workshop. The average number of procedures performed increased significantly from intern to junior to senior year. A positive correlation was found between number of procedures performed and preworkshop confidence (P < .001, R (2) = 0.86) and competence (P < .001, R (2) = 0.88). For each procedure assessed, completion of the procedure simulation workshop resulted in a statistically significant (P < .001) increase in self-perceived confidence (14%-131%; average, 48%) and competence (12%-119%; average, 50%). Statistically significant (P < .05) increases remained when results for interns, juniors, and seniors were examined separately. Procedure simulation workshops improve resident self-reported procedural confidence and competence, particularly for procedures that are least performed.


Cemento-Osseous Dysplasias: Imaging Features Based on Cone Beam Computed Tomography Scans.
Imaging exams have important role in diagnosis of cemento-osseous dysplasia (COD). Cone beam computed tomography (CBCT) stands out for allowing three-dimensional image evaluation. This study aimed to assess the prevalence of cases diagnosed as COD on CBCT scans, as well identify the main imaging features related to these lesions. An analysis was performed in a database containing 22,400 radiological reports, in which all cases showing some type of COD were initially selected. These CBCT exams were reevaluated to confirm the radiographic diagnosis and determine the prevalence and distribution of the types of COD with regard to gender, age and preferred location, while describing its most common imaging aspects. Data were presented using descriptive analyses. There were 82 cases diagnosed as COD in the CBCT images (prevalence of 0.4%). The distribution of patients was 11 (13.4%) male and 71 (86.6%) female, with a mean age of 49.8 years (age-range 17-85 years). There were 47 (57.3%) cases of periapical COD, 23 (28%) of focal COD and 12 (14.6%) of florid COD. The mandible was more affected than the maxilla. In most cases, the lesions were mixed or hyperdense. All COD had well-defined limits and there were no cases of tooth displacement. In conclusion, periapical COD was the most common type and the most affected bone was the mandible. Imaging evaluation is critical for diagnosis and dentists should bear in mind all possible radiographic presentations of COD in order to prevent misleading diagnoses and consequently, inadequate treatments.


Tezepelumab in Adults with Uncontrolled Asthma.
In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids. In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period. The primary end point was the annualized rate of asthma exacerbations (events per patient-year) at week 52. The use of tezepelumab at a dose of 70 mg every 4 weeks (low dose; 145 patients), 210 mg every 4 weeks (medium dose; 145 patients), or 280 mg every 2 weeks (high dose; 146 patients) resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group (148 patients). Thus, exacerbation rates in the respective tezepelumab groups were lower by 61%, 71%, and 66% than the rate in the placebo group (P<0.001 for all comparisons). Similar results were observed in patients regardless of blood eosinophil counts at enrollment. The prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12 liters with the low dose [P=0.01], 0.11 liters with the medium dose [P=0.02], and 0.15 liters with the high dose [P=0.002]). A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events. Among patients treated with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .).


Analysis of interaction between the apicomplexan protozoan Toxoplasma gondii and host cells using label-free Raman spectroscopy.
Label-free imaging using Raman micro-spectroscopy (RMS) was used to characterize the spatio-temporal molecular changes of T. gondii tachyzoites and their host cell microenvironment. Raman spectral maps were recorded from isolated T. gondii tachyzoites and T. gondii-infected human retinal cells at 6 h, 24 h and 48 h post-infection. Principal component analysis (PCA) of the Raman spectra of paraformaldehyde-fixed infected cells indicated a significant increase in the amount of lipids and proteins in the T. gondii tachyzoites as the infection progresses within host cells. These results were confirmed by experiments carried out on live T. gondii-infected cells and were correlated with an increase in the concentration of proteins and lipids required for the replication of this intracellular pathogen. These findings demonstrate the potential of RMS to characterize time- and spatially-dependent molecular interactions between intracellular pathogens and the host cells. Such information may be useful for discovery of pharmacological targets or screening compounds with potential neuro-protective activity for eminent effects of changes in brain infection control practices.


Hybrid low-voltage physical unclonable function based on inkjet-printed metal-oxide transistors.
Modern society is striving for digital connectivity that demands information security. As an emerging technology, printed electronics is a key enabler for novel device types with free form factors, customizability, and the potential for large-area fabrication while being seamlessly integrated into our everyday environment. At present, information security is mainly based on software algorithms that use pseudo random numbers. In this regard, hardware-intrinsic security primitives, such as physical unclonable functions, are very promising to provide inherent security features comparable to biometrical data. Device-specific, random intrinsic variations are exploited to generate unique secure identifiers. Here, we introduce a hybrid physical unclonable function, combining silicon and printed electronics technologies, based on metal oxide thin film devices. Our system exploits the inherent randomness of printed materials due to surface roughness, film morphology and the resulting electrical characteristics. The security primitive provides high intrinsic variation, is non-volatile, scalable and exhibits nearly ideal uniqueness.


Analysis of phosphopeptide changes as spermatozoa acquire functional competence in the epididymis demonstrates changes in the post-translational modification of Izumo1.
Spermatozoa are functionally inert when they emerge from the testes. Functional competence is conferred upon these cells during a post-testicular phase of sperm maturation in the epididymis. Remarkably, this functional transformation of epididymal spermatozoa occurs in the absence of nuclear gene transcription or protein translation. To understand the cellular mechanisms underpinning epididymal maturation, we have performed a label-free, MS-based, comparative quantification of peptides from caput, corpus and caudal epididymal spermatozoa. In total, 68 phosphopeptide changes could be detected during epididymal maturation corresponding to the identification of 22 modified proteins. Included in this list are the sodium-bicarbonate cotransporter, the sperm specific serine kinase 1, AKAP4 and protein kinase A regulatory subunit. Furthermore, four phosphopeptide changes came from Izumo1, the sperm-egg fusion protein, in the cytoplasmic segment of the protein. 2D-PAGE confirmed that Izumo1 is post-translationally modified during epididymal transit. Interestingly, phosphorylation on Izumo1 was detected on residue S339 in the caput and corpus but not caudal cells. Furthermore, Izumo1 exhibited four phosphorylated residues when spermatozoa reached the cauda, which were absent from caput cells. A model is advanced suggesting that these phospho-regulations are likely to act as a scaffold for the association of adaptor proteins with Izumo1 as these cells prepare for fertilization.


High-throughput screening of dipeptide utilization mediated by the ABC transporter DppBCDF and its substrate-binding proteins DppA1-A5 in Pseudomonas aeruginosa.
In this study, we show that the dppBCDF operon of Pseudomonas aeruginosa PA14 encodes an ABC transporter responsible for the utilization of di/tripeptides. The substrate specificity of ABC transporters is determined by its associated substrate-binding proteins (SBPs). Whereas in E. coli only one protein, DppA, determines the specificity of the transporter, five orthologous SBPs, DppA1-A5 are present in P. aeruginosa. Multiple SBPs might broaden the substrate specificity by increasing the transporter capacity. We utilized the Biolog phenotype MicroArray technology to investigate utilization of di/tripeptides in mutants lacking either the transport machinery or all of the five SBPs. This high-throughput method enabled us to screen hundreds of dipeptides with various side-chains, and subsequently, to determine the substrate profile of the dipeptide permease. The substrate spectrum of the SBPs was elucidated by complementation of a penta mutant, deficient of all five SBPs, with plasmids carrying individual SBPs. It became apparent that some dipeptides were utilized with different affinity for each SBP. We found that DppA2 shows the highest flexibility on substrate recognition and that DppA2 and DppA4 have a higher tendency to utilize tripeptides. DppA5 was not able to complement the penta mutant under our screening conditions. Phaseolotoxin, a toxic tripeptide inhibiting the enzyme ornithine carbamoyltransferase, is also transported into P. aeruginosa via the DppBCDF permease. The SBP DppA1, and with much greater extend DppA3, are responsible for delivering the toxin to the permease. Our results provide a first overview of the substrate pattern of the ABC dipeptide transport machinery in P. aeruginosa.


A shady phytoplankton paradox: when phytoplankton increases under low light.
Light is a fundamental driver of ecosystem dynamics, affecting the rate of photosynthesis and primary production. In spite of its importance, less is known about its community-scale effects on aquatic ecosystems compared with those of nutrient loading. Understanding light limitation is also important for ecosystem management, as human activities have been rapidly altering light availability to aquatic ecosystems. Here we show that decreasing light can paradoxically increase phytoplankton abundance in shallow lakes. Our results, based on field manipulation experiments, field observations and models, suggest that, under competition for light and nutrients between phytoplankton and submersed macrophytes, alternative stable states are possible under high-light supply. In a macrophyte-dominated state, as light decreases phytoplankton density increases, because macrophytes (which effectively compete for nutrients released from the sediment) are more severely affected by light reduction. Our results demonstrate how species interactions with spatial heterogeneity can cause an unexpected outcome in complex ecosystems. An implication of our findings is that partial surface shading for controlling harmful algal bloom may, counterintuitively, increase phytoplankton abundance by decreasing macrophytes. Therefore, to predict how shallow lake ecosystems respond to environmental perturbations, it is essential to consider effects of light on the interactions between pelagic and benthic producers.


Anoxic ventilation improves systemic perfusion during extracorporeal circulation with uncontrolled systemic-to-pulmonary shunt.
Uncontrolled systemic-to-pulmonary shunt results in decreased systemic flow during extracorporeal life support (ECLS). Ligation of systemic-to-pulmonary shunts during ECLS is associated with poor outcome and is not always readily achieved. In ex vivo preparations, alveolar hypoxia results in pulmonary vasoconstriction despite normoxic pulmonary perfusate. We hypothesized that anoxic ventilation would result in reduced pulmonary shunting and increased systemic flow during ECLS in piglets with systemic-to-pulmonary shunt. Four piglets were placed on ECLS with right and left atrial drainage. A shunt was created between the bicarotid trunk and pulmonary artery, using 5-mm ePTFE tubing. Inspired oxygen was reduced to <1% for 10 minutes, then returned to room air; pH, hematocrit, temperature, ventilatory pressures, and total pump flow were maintained constant. Systemic arterial pressure and right atrial return volume and hemoglobin saturation were measured: All decreased significantly upon shunt unclamping. Anoxic ventilation caused increased systemic pressure (34 vs. 28 mm Hg, p < 0.05), flow (335 vs. 278 mL/min, p < 0.05), and systemic venous saturation (53% vs. 48%, p = 0.13) compared with room air ventilation. In conclusion, anoxic ventilation during normoxic ECLS in subjects with systemic-to-pulmonary shunts results in a significant and potentially clinically useful reduction in pulmonary shunting.


The search for the ideal biocatalyst.
While the use of enzymes as biocatalysts to assist in the industrial manufacture of fine chemicals and pharmaceuticals has enormous potential, application is frequently limited by evolution-led catalyst traits. The advent of designer biocatalysts, produced by informed selection and mutation through recombinant DNA technology, enables production of process-compatible enzymes. However, to fully realize the potential of designer enzymes in industrial applications, it will be necessary to tailor catalyst properties so that they are optimal not only for a given reaction but also in the context of the industrial process in which the enzyme is applied.


Molecular Diagnostics for Precision Medicine in Colorectal Cancer: Current Status and Future Perspective.
Precision medicine, a concept that has recently emerged and has been widely discussed, emphasizes tailoring medical care to individuals largely based on information acquired from molecular diagnostic testing. As a vital aspect of precision cancer medicine, targeted therapy has been proven to be efficacious and less toxic for cancer treatment. Colorectal cancer (CRC) is one of the most common cancers and among the leading causes for cancer related deaths in the United States and worldwide. By far, CRC has been one of the most successful examples in the field of precision cancer medicine, applying molecular tests to guide targeted therapy. In this review, we summarize the current guidelines for anti-EGFR therapy, revisit the roles of pathologists in an era of precision cancer medicine, demonstrate the transition from traditional "one test-one drug" assays to multiplex assays, especially by using next-generation sequencing platforms in the clinical diagnostic laboratories, and discuss the future perspectives of tumor heterogeneity associated with anti-EGFR resistance and immune checkpoint blockage therapy in CRC.


Cyclic gas-phase heterogeneous process in a metal-organic framework involving a nickel nitrosyl complex.
The cubic metal-organic framework MFU-4l ([Zn5Cl4(BTDD)3], H2-BTDD = bis(1H-1,2,3-triazolo[4,5-b],[4',5'-i])dibenzo[1,4]dioxin) featuring large pore apertures can be modified post-synthetically via partial or complete substitution of peripheral metal sites and chloride side-ligands, thus opening a route towards a large variety of functionalized MOFs. In this way, Ni-MFU-4l-nitrite (or Ni-MFU-4l-NO2) with an analytically determined chemical composition [Zn2.6Ni2.4(NO2)2.9Cl1.1(BTDD)3], containing accessible Ni-NO2 units, was prepared. Ni-MFU-4l-NO2 undergoes selective heterogeneous gas-phase reduction by carbon monoxide at 350 °C, leading to formation of Ni-NO units at the peripheral sites of the MFU-4l framework (Ni-MFU-4l-NO). The crystallinity and porosity of the MFU-4l framework are completely retained upon this transformation. The so-formed nickel nitrosyl complex, showing high thermal stability, readily reacts with nitrogen monoxide at room temperature, producing Ni-NO2 units and dinitrogen monoxide (N2O). Hence, the reaction of Ni-MFU-4l-NO2 with CO followed by NO represents a cyclic process with an overall stoichiometry 2NO + CO → N2O + CO2, in which the Ni-MFU-4l framework serves as a catalyst. It can be considered as a model process for the removal of highly toxic NO and CO gases, which are converted to non-toxic CO2 and N2O. Diffuse reflectance infrared Fourier transform spectroscopic studies show that at least 10 cycles can be repeated. The framework's reactivity drops down by ca. 50% after 10 cycles, which is most likely due to the accumulation of highly reactive NO2 and N2O4 contaminants. Therefore, further investigations on characterizing reaction intermediates should be done in order to improve the catalyst's performance. Our results confirm the potential of MFU-4l frameworks as selective single-site catalysts for heterogeneous gas-phase transformations and provide a motivation for further studies.


[Clinical profile of cluster headaches in Japan].
This study examined the clinical profile of cluster headache (CH) in Japan and the potential presence of features peculiar to Japan. Subjects comprised 110 consecutive new CH patients (83 males, 27 females; mean age, 38.1 ± 11.7 years). While 85% of patients had visited other medical institutions, only 19% had received a correct diagnosis. Mean delay in diagnosis was 8.1 years. The common clinical features of the present report and previous Japanese reports were as follows: 1) a low prevalence of chronic CH; 2) a low prevalence of sense of restlessness; 3) an uncoupling of a sense of restlessness and restless behavior; 4) approximately half of all patients experiencing CH attacks ranging in duration from 1-2 hours; 5) the location of CH most commonly reported as retro-orbital; and 6) lacrimation representing the most consistently reported autonomic feature. The common clinical features from 1) to 3) were seen in other East-Asia countries. Both frequencies of locations of CH and autonomic features differed between Caucasian and East-Asian populations. These characteristics may reflect ethnic and/or cultural differences between Eastern and Western CH patients.


A meta-composite software development approach for translational research.
Translational researchers conduct research in a highly data-intensive and continuously changing environment and need to use multiple, disparate tools to achieve their goals. These researchers would greatly benefit from meta-composite software development or the ability to continuously compose and recompose tools together in response to their ever-changing needs. However, the available tools are largely disconnected, and current software approaches are inefficient and ineffective in their support for meta-composite software development. Building on the composite services development approach, the de facto standard for developing integrated software systems, we propose a concept-map and agent-based meta-composite software development approach. A crucial step in composite services development is the modeling of users' needs as processes, which can then be specified in an executable format for system composition. We have two key innovations. First, our approach allows researchers (who understand their needs best) instead of technicians to take a leadership role in the development of process models, reducing inefficiencies and errors. A second innovation is that our approach also allows for modeling of complex user interactions as part of the process, overcoming the technical limitations of current tools. We demonstrate the feasibility of our approach using a real-world translational research use case. We also present results of usability studies evaluating our approach for future refinements.


Chiral particles in the dual-beam optical trap.
We investigate the dynamics of chiral microparticles in a dual-beam optical trap. The chiral particles have the structure of spherical chiral microresonators, with a reflectance deriving from the supramolecular helicoidal arrangement. Due to the strong asymmetric response of the particles to light with a specific helicity and wavelength, their trapping position and rotational frequency can be controlled by proper combination of the polarization state of the two light beams. Here symmetric and asymmetric polarization configurations of dual- interfering beam traps have been investigated. Based on the polarization controlled asymmetric transmission of the chiral particles, a tunable wash-board potential is created enabling the control of the trapping position along the beams axis. Asymmetric configurations display polarization controlled rotation of the trapped particles. Optical binding of rotating particles exhibits a complex dynamics.


The relationship of stress coping styles on substance use, depressive symptoms, and personality traits of nurses in higher education institution.
This study examined the collective characteristics of nurses and their stress coping style. We conducted a cluster analysis of the stress coping strategies of 841 nurses belonging to Dokkyo Medical University Hospital, as measured by the Brief COPE (Coping Orientation to Problems Experienced). We also conducted multivariate analyses of each cluster's sociodemographic characteristics, personality traits, depressive symptoms, work attitudes, sense of fairness, and turnover intention. The results of cluster analysis using the standardized z scores of the Brief COPE demonstrated that the study participants were classified into three clusters. The "emotional-response type" tended to favor the use of emotional support, venting, and self-blame. The "reality-escape type" tended to prefer alcohol and substance use, behavioral resignation, use of instrumental support, and lack of acceptance. The "problem-solving type" tended to prefer planning, positive reframing, and acceptance and to dislike "alcohol and substance use" and behavioral disengagement. A multinomial logistic regression analysis revealed that compared to the problem-solving type, the emotional-response type had a lower job title, a higher "neuroticism" score on the TIPI-J, and a higher K6 score. However, compared to the problem-solving type, the reality-escape type was younger, consumed more alcohol and substances, and had a higher K6 score. Stress coping styles were found to be associated with substance use, depressive symptoms, and personality traits among nurses in higher education institutions. Thus, the results suggest that nurses who choose maladaptive stress coping styles require mental support and early identification of depressive symptoms and alcohol problems.


Use of seating devices in infants too young to sit.
To determine how frequently seating devices are available in homes with small infants and how often they are used for infants who are too young to sit erect and unsupported. Observational study using a questionnaire administered to a cohort of parents of well infants younger than 5 months. Well-Baby Clinic, Department of Pediatrics, Tripler Army Medical Center, a tertiary care center serving the population of military dependents on the island of Oahu, Hawaii. Infant seating devices were available in the homes of all of the infants whose parents completed the questionnaire during the study. Of 187 infants, 176 (94%) spent 30 minutes or longer in seating devices each day. The mean (tSD) time spent each day in seating devices was 5.7 +/- 3.5 hours and ranged from 0 to 16 hours. Seating devices were widely available for use in the care of the infants. Car seats that double as infant carriers and infant seats likely are being used extensively outside of automobiles. Prolonged use of infant seating devices with infants who are too young to sit unsupported may have several potential adverse consequences.


Zinc oxide nanoparticle based optical fiber humidity sensor having linear response throughout a large dynamic range.
The main objective of the present work is to develop an optical fiber relative humidity (RH) sensor having a linear response throughout over the widest possible dynamic range. We report an optical fiber RH sensor based on the evanescent wave absorption spectroscopy that fulfills this objective. The fiber sensor employs a specific nanoparticle (zinc oxide) doped sol-gel nanostructured sensing film of optimum thickness, synthesized over a short length of a centrally decladded straight and uniform optical fiber. A detailed experimental investigation is carried out to analyze the sensor response/characteristics. Fiber sensor response is observed to be linear throughout the dynamic range as wide as 4% to 96% RH. The observed linear sensitivity for the fiber sensor is 0.0012 RH(-1). The average response time of the reported sensor is observed to be as short as 0.06 s during the humidification. In addition, the sensor exhibited a very good degree of reversibility and extremely high reliability as well as repeatability.


Vasospasm contributes to monosodium glutamate-induced headache.
Consumption of monosodium glutamate has long been considered to precipitate headaches in susceptible patients. In this study the direct effects of glutamate and its metabolite, glutamine, on arterial contractility were examined using rings of rabbit aorta. In a high concentration glutamate caused significant concentration-dependent contractions (EC50, 10(-1)M; maximum tension, 188.4 +/- 33.3 mg wt tension/mg tissue). Agonists and antagonists for alpha-adrenergic, histaminergic, serotonergic, cholinergic, and GABA-nergic receptors as well as inhibition of prostaglandin synthesis failed to influence glutamate contractions. At high concentrations (10(-5)M) the calcium channel blocker, verapamil, inhibited the glutamate response. Glutamate and glutamine both exhibited concentration dependent relaxation of norepinephrine (NE), phenylephrine (PE), histamine, serotonin (5-HT), and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. Kainic acid (10(-4)M), an agonist of one subpopulation of central glutamate receptor, potentiated glutamate-induced vasoconstriction; a higher concentration (10(-3)M) produced an irreversible inhibition of glutamate contractility. Only the central glutamate receptor antagonist, ketamine (10(-4)-10(-2)M), induced a reversible, concentration dependent inhibition of glutamate-induced contractions. Glutamate contractility was not dependent on extracellular calcium, an intact endothelium or neuronal function. These results demonstrate a direct effect of glutamate on peripheral arterial tone. Dietary consumption of large quantities of MSG may represent a serious health hazard to certain individuals with pre-existing vascular disease.


Occupational factors in multiple sclerosis: an analysis of occupational mortality statistics for men and married women in Great Britain.
This paper presents an exploratory study based on occupational mortality statistics for Great Britain. It examines disease concordance between marital partners for multiple sclerosis (MS). Previous studies have revealed that a married woman's life expectancy and her specific cause of death is reliably associated with the occupational mortality of her husband. This relationship exists across a wide range of occupations but is particularly marked in the case of MS. The present study examines the mortality rates for MS for a large number of occupations (taking into account possible sources of statistical bias) and considers the relationship of these findings with existing hypotheses about the aetiology of MS. It is suggested that there should be more consideration of occupational and psychological factors in multicausal explanations of the disease.


Guideline for the assessment of trauma centres for South Africa.
Trauma is a well-known leading cause of unnatural death and disability in South Africa. Internationally the trend is moving toward systematised care. To revise the Trauma Centre Criteria of the Trauma Society of South Africa and align these with the terminology and modern scope of emergency care practice, using best-care principles as a prelude to the development of trauma systems in South Africa. Revision of existing documents of the Trauma Society of South Africa, the Emergency Medicine Society of South Africa and the Critical Care Society of Southern Africa, where these are relevant to the care of trauma. The committee attempted to harmonise these criteria with the goals of the World Health Organization essential trauma care guidelines for trauma centres and trauma systems. Wide expert consultation was undertaken to refine the criteria before final compilation. Four levels of trauma care facility are outlined, with the criteria focusing on the trauma-specific requirements of the facilities and their place in the greater trauma system. Accreditation of hospitals according to the criteria will allow for appropriate transfer and designation of patient destination for trauma patients and will improve the quality of care provided. The criteria address structural, process and human resource requirements and medical aspects for the accreditation of various level of trauma centre. There is a great opportunity to apply best practice criteria to improve the care of trauma in South Africa and improve patient outcome.


Mimiviridae: clusters of orthologous genes, reconstruction of gene repertoire evolution and proposed expansion of the giant virus family.
The family Mimiviridae belongs to the large monophyletic group of Nucleo-Cytoplasmic Large DNA Viruses (NCLDV; proposed order Megavirales) and encompasses giant viruses infecting amoeba and probably other unicellular eukaryotes. The recent discovery of the Cafeteria roenbergensis virus (CroV), a distant relative of the prototype mimiviruses, led to a substantial expansion of the genetic variance within the family Mimiviridae. In the light of these findings, a reassessment of the relationships between the mimiviruses and other NCLDV and reconstruction of the evolution of giant virus genomes emerge as interesting and timely goals. Database searches for the protein sequences encoded in the genomes of several viruses originally classified as members of the family Phycodnaviridae, in particular Organic Lake phycodnaviruses and Phaeocystis globosa viruses (OLPG), revealed a greater number of highly similar homologs in members of the Mimiviridae than in phycodnaviruses. We constructed a collection of 898 Clusters of Orthologous Genes for the putative expanded family Mimiviridae (MimiCOGs) and used these clusters for a comprehensive phylogenetic analysis of the genes that are conserved in most of the NCLDV. The topologies of the phylogenetic trees for these conserved viral genes strongly support the monophyly of the OLPG and the mimiviruses. The same tree topology was obtained by analysis of the phyletic patterns of conserved viral genes. We further employed the mimiCOGs to obtain a maximum likelihood reconstruction of the history of genes losses and gains among the giant viruses. The results reveal massive gene gain in the mimivirus branch and modest gene gain in the OLPG branch. These phylogenomic results reported here suggest a substantial expansion of the family Mimiviridae. The proposed expanded family encompasses a greater diversity of viruses including a group of viruses with much smaller genomes than those of the original members of the Mimiviridae. If the OLPG group is included in an expanded family Mimiviridae, it becomes the only family of giant viruses currently shown to host virophages. The mimiCOGs are expected to become a key resource for phylogenomics of giant viruses.


Neurobehavioral disinhibition predicts initiation of substance use in children with prenatal cocaine exposure.
In previous work we (Fisher et al., 2011) examined the emergence of neurobehavioral disinhibition (ND) in adolescents with prenatal substance exposure. We computed ND factor scores at three age points (8/9, 11 and 13/14 years) and found that both prenatal substance exposure and early adversity predicted ND. The purpose of the current study was to determine the association between these ND scores and initiation of substance use between ages 8 and 16 in this cohort as early initiation of substance use has been related to later substance use disorders. Our hypothesis was that prenatal cocaine exposure predisposes the child to ND, which, in turn, is associated with initiation of substance use by age 16. We studied 386 cocaine exposed and 517 unexposed children followed since birth in a longitudinal study. Five dichotomous variables were computed based on the subject's report of substance use: alcohol only; tobacco only; marijuana only; illicit substances and any substance. Cox proportional hazard regression showed that the 8/9 year ND score was related to initiation of alcohol, tobacco, illicit and any substance use but not marijuana use. The trajectory of ND across the three age periods was related to substance use initiation in all five substance use categories. Prenatal cocaine exposure, although initially related to tobacco, marijuana and illicit substance initiation, was no longer significant with ND scores in the models. Prenatal drug exposure appears to be a risk pathway to ND, which by 8/9 years portends substance use initiation.


Is there a relationship between physical fitness and academic achievement? Positive results from public school children in the northeastern United States.
To determine relationships between physical fitness and academic achievement in diverse, urban public school children. This cross-sectional study used public school data from 2004 to 2005. Academic achievement was assessed as a passing score on Massachusetts Comprehensive Assessment System (MCAS) achievement tests in Mathematics (fourth, sixth, and eighth grade, n = 1103) and in English (fourth and seventh grade, n = 744). Fitness achievement was assessed as the number of physical fitness tests passed during physical education (PE). Multivariate logistic regression analyses were conducted to assess the probability of passing the MCAS tests, controlling for students' weight status (BMI z score), ethnicity, gender, grade, and socioeconomic status (school lunch enrollment). The odds of passing both the MCAS Mathematics test and the MCAS English test increased as the number of fitness tests passed increased (p < .0001 and p < .05, respectively). Results show statistically significant relationships between fitness and academic achievement, though the direction of causation is not known. While more research is required, promoting fitness by increasing opportunities for physical activity during PE, recess, and out of school time may support academic achievement.


Association Between Diabetes-Related Eye Complications and Symptoms of Anxiety and Depression.
This study is needed to clarify inconsistent findings regarding the association between diabetes-related eye complications and psychological well-being. To examine the association between severity of diabetic retinopathy (DR) and diabetic macular edema (DME) with symptoms of depression and anxiety in adults with diabetes. A cross-sectional study was conducted in a tertiary eye hospital in Melbourne, Australia. The study comprised 519 participants with diabetes. The median duration of diabetes was 13.0 (interquartile range, 14.0) years. The study was conducted from March 1, 2009, to December 24, 2010. Patients underwent a comprehensive eye examination in which dilated fundus photographs (disc and macula centered) were obtained and graded for the presence and severity of DR and DME. Presenting distance uniocular and binocular visual acuity were assessed using a 3-m logMAR chart. Symptoms of depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS), which comprises 7 questions specific to anxiety and 7 specific to depression with scores ranging from 0 to 21; scores higher than 8 signify possible anxiety or depression. The ordinal raw scores of the HADS questionnaire were transformed to estimates of interval measure using Rasch analysis and evaluated as continuous variables. Participants also completed standardized interview-administered questionnaires. Blood samples were assessed for hemoglobin A1c, fasting blood glucose, and serum lipids. Multiple linear regression models were used to determine the associations between the severity of DR and DME with symptoms of anxiety and depression and commonality analysis was used to quantify the unique variance explained. Of the 519 participants in the study, 170 individuals (32.8%) were female; mean (SD) age was 64.9 (11.6) years. Raw scores indicated that 80 individuals (15.4%) screened positive for depressive symptoms and 118 persons (22.7%) screened positive for symptoms of anxiety. In multivariate analysis using Rasch scores, severe nonproliferative DR (NPDR)/PDR was independently associated with greater depressive symptoms (regression coefficient [β] = 0.69; 95% CI, 0.03-1.34) after controlling for sociodemographic factors and clinical characteristics, including visual acuity. A history of depression or anxiety accounted for 60.6% (95% CI, 23.9%-83.2%) of the unique variance in depressive symptoms, and severe NPDR or PDR contributed to 19.1% (95% CI, 1.7%-44.4%) of the total explained variance of depressive symptoms. Diabetic macular edema was not associated with depressive symptoms. No association between DR and symptoms of anxiety was identified. Severe NPDR or PDR, but not DME, was independently associated with depressive symptoms. The severity of DR could be an indicator to prompt monitoring of depression in at-risk individuals with diabetes. Further work is required to replicate these findings and determine the clinical significance of the association.


High predicted strain coverage by the multicomponent meningococcal serogroup B vaccine (4CMenB) in Poland.
Neisseria meningitidis of serogroup B (MenB) is currently responsible for more than 70% of cases of invasive meningococcal disease (IMD) in Poland and Europe as a whole. The aim of this study was to estimate strain coverage of a multicomponent meningococcal serogroup B vaccine (4CMenB) in Poland; the meningococcal antigen typing system (MATS) was used to test a panel of 196 invasive MenB strains isolated in Poland in 2010 and 2011. The strains were also characterized by MLST and sequencing of porA, factor H-binding protein (fHbp), Neisserial heparin-binding antigen (nhba) and Neisserial adhesin A (nadA) genes. MATS and molecular data were analyzed independently and in combination. The MATS results predicted that 83.7% (95% CI: 78.6-91.0%) of isolates would be covered by the 4CMenB vaccine; 59.2% by one vaccine antigen, 19.9% by two and 4.6% by three antigens. Coverage by each antigen was as follows: fHbp 73.0% (95% CI: 68.9-77.5%), NHBA 28.6% (95% CI: 13.3-47.4%), NadA 1.0% (95% CI: 1.0-2.0%) and PorA 10.2%. Molecular analysis revealed that the most frequent clonal complexes (ccs) were cc32 (33.2%), cc18 (17.9%) and cc41/44 (15.8%) with estimated coverage of 98.5%, 88.6% and 93.5%, respectively. Consistent with findings for other European countries, our study predicts high coverage by the 4CMenB vaccine in Poland.


Uukuniemi Phlebovirus assembly and secretion leave a functional imprint on the virion glycome.
Uukuniemi virus (UUKV) is a model system for investigating the genus Phlebovirus of the Bunyaviridae. We report the UUKV glycome, revealing differential processing of the Gn and Gc virion glycoproteins. Both glycoproteins display poly-N-acetyllactosamines, consistent with virion assembly in the medial Golgi apparatus, whereas oligomannose-type glycans required for DC-SIGN-dependent cellular attachment are predominant on Gc. Local virion structure and the route of viral egress from the cell leave a functional imprint on the phleboviral glycome.


Disseminated Cryptococcosis in an HIV-negative patient in South Africa: the elusive differential diagnosis.
The presence of an opportunistic infection in a patient in sub-Saharan Africa is assumed to be due to underlying immunosuppression from human immunodeficiency virus (HIV) infection. The presence of disseminated cryptococcosis in a non-HIV-infected patient is interesting as it is unique in our setting because the majority of infections are found in HIV-infected individuals. The protean manifestations of the disease and its predilection for immunosuppressed patients make cryptococcosis a challenging and elusive disease to diagnose in HIV-negative patients in our setting, especially due to limited resources. We present a case of disseminated cryptococcosis in an immunocompetent patient and discuss diagnostic and therapeutic features in this subset of patients.


Adoption of cardiovascular risk reduction guidelines: a cluster-randomized trial.
Cardiovascular disease (CVD) and underlying atherosclerosis begin in childhood and are related to CVD risk factors. This study evaluates tools and strategies to enhance adoption of new CVD risk reduction guidelines for children. Thirty-two practices, recruited and supported by 2 primary care research networks, were cluster randomized to a multifaceted controlled intervention. Practices were compared with guideline-based individual and composite measures for BMI, blood pressure (BP), and tobacco. Composite measures were constructed by summing the numerators and denominators of individual measures. Preintervention and postintervention measures were assessed by medical record review of children ages 3 to 11 years. Changes in measures (pre-post and intervention versus control) were compared. The intervention group BP composite improved by 29.5%, increasing from 49.7% to 79.2%, compared with the control group (49.5% to 49.6%; P < .001). Intervention group BP interpretation improved by 61.1% (from 0.2% to 61.3%), compared with the control group (0.4% to 0.6%; P < .001). The assessment of tobacco exposure or use for 5- to 11-year-olds in the intervention group improved by 30.3% (from 3.4% to 49.1%) versus the control group (0.6% to 21.4%) (P = .042). No significant change was seen in the BMI or tobacco composites measures. The overall composite of 9 measures improved by 13.4% (from 48.2% to 69.8%) for the intervention group versus the control group (47.4% to 55.2%) (P = .01). Significant improvement was demonstrated in the overall composite measure, the composite measure of BP, and tobacco assessment and advice for children aged 5 to 11 years.


Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon.
We have used the quantitative binding of murine monoclonal antibodies to the surface of cultured human umbilical vein endothelial (HUVE) cells to study the responses of HUVE cells to three different immune mediators: interleukin 1 (IL 1), tumor necrosis factor (TNF), and immune interferon (IFN-gamma). Antibody H4/18, reactive with an endothelial cell-specific activation antigen, does not bind to unstimulated HUVE cells but shows rapidly and transiently inducible binding (peak 4 to 6 hr) to cells stimulated by IL 1 or TNF that declines to basal levels by 24 hr, even in the continued presence of mediator. Binding of H4/18 is unaffected by IFN-gamma. Antibody RR1/1, reactive with intercellular adhesion molecule 1, binds to unstimulated HUVE cells, but binding is rapidly increased (plateau 24 hr) after stimulation by IL 1 or TNF and slowly increased (over several days) by IFN-gamma. In contrast to H4/18 binding, the increase in RR1/1 binding is sustained in the continued presence of mediator. Antibody W6/32, reactive with HLA-A,B antigens, binds to unstimulated HUVE cells and shows gradually progressive increases (over several days) in binding upon treatment with IFN-gamma or TNF. These observations demonstrate that HUVE cells show distinct but overlapping patterns of antigenic modulation in response to three different lymphokines, and suggest that the "activation" of endothelial cells observed in situ may represent a complex integration of several lymphokine-mediated signals.


A multiobjective evolutionary method for the design of peptidic mimotopes.
Peptides that mimic protein epitopes are interesting drug candidates. However, the design of effective peptidic drugs is difficult for several reasons, such as the fast degradation of peptides, their high flexibility, and thus high entropy loss on binding to the target. We therefore propose an in silico method for the automated design of peptides that are optimal with respect to several objectives. We present a Pareto-based multiobjective evolutionary algorithm for in silico peptide design. Using a simple molecular model, we apply the method to the design of peptides that (a) mimic antibody epitopes of the proteins thrombin and blood coagulation factor VIII, respectively, that (b) are short, and (c) are conformationally stable.


Protective effects of hydroalcoholic extracts from an ancient apple variety 'Mela Rosa dei Monti Sibillini' against renal ischemia/reperfusion injury in rats.
The purpose of this work was to investigate the effect of hydroalcoholic extracts from the peel (APE) and pulp (APP) of a traditional apple variety of central Italy, the 'Mela Rosa dei Monti Sibillini', on the damage caused by renal ischemia/reperfusion injury (IRI) in rats. Thirty mg per kg b.w. of the extracts were administered intraperitoneally to male adult Wistar rats 3 days before the induction of IRI by pedicle clamping. A significant decrease in the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNFα), interleukin 1 beta (IL-1β) and nuclear factor-κB (NF-κB) was observed in the groups pre-treated with APE when compared with IRI rats. The chemical composition of APE was determined by HPLC-DAD-MSn highlighting a significant amount of proanthocyanidins (52.9 mg g-1), flavonols (42.27 mg g-1) and dihydrochalcones (11.75 mg g-1). These findings indicated that this ancient apple variety is a promising source of nutraceuticals and functional foods helpful to manage complications of renal disorders.


Edge-oriented and steerable hyperbolic polaritons in anisotropic van der Waals nanocavities.
Highly confined and low-loss polaritons are known to propagate isotropically over graphene and hexagonal boron nitride in the plane, leaving limited degrees of freedom in manipulating light at the nanoscale. The emerging family of biaxial van der Waals materials, such as α-MoO3 and V2O5, support exotic polariton propagation, as their auxiliary optical axis is in the plane. Here, exploiting this strong in-plane anisotropy, we report edge-tailored hyperbolic polaritons in patterned α-MoO3 nanocavities via real-space nanoimaging. We find that the angle between the edge orientation and the crystallographic direction significantly affects the optical response, and can serve as a key tuning parameter in tailoring the polaritonic patterns. By shaping α-MoO3 nanocavities with different geometries, we observe edge-oriented and steerable hyperbolic polaritons as well as forbidden zones where the polaritons detour. The lifetime and figure of merit of the hyperbolic polaritons can be regulated by the edge aspect ratio of nanocavity.


Alteration of galectin-3 in tears of patients with dry eye disease.
To investigate the expression, release, and proteolytic degradation of galectin-3 in patients with dry eye disease. Observational case series with a comparison group. Tear washes and conjunctival impression cytology specimens were collected through standard procedures from 16 patients with dry eye and 11 age-matched healthy subjects. Galectin-3 content in tears was analyzed by quantitative Western blot, using recombinant galectin-3 protein to generate a calibration curve. The relative expression of galectin-3 and matrix metalloproteinase 9 (MMP9) was evaluated by quantitative polymerase chain reaction. The cleavage of galectin-3 was studied in vitro using activated recombinant MMP9 and protease inhibitors. The concentration of galectin-3 protein in tears, but not galectin-3 expression in conjunctival epithelium, was significantly higher in tears of patients with dry eye (0.38 ng/μg total protein, range 0.04-1.36) compared to healthy subjects (0.12 ng/μg total protein, range 0.00-0.41) (P < .01). By Western blot, an intact (∼28.0 kDa) galectin-3 band was identified in tear samples from healthy subjects, whereas 50% of the dry eye samples were characterized by the additional presence of a partially degraded form (∼25.4 kDa). In our experiments, elevated expression of MMP9 in dry eye subjects correlated with the ability of active MMP9 to cleave galectin-3 from recombinant origin. Interestingly, cleavage of endogenous galectin-3 in tear samples was impaired using a broad-spectrum proteinase inhibitor cocktail, but not the pan-specific MMP inhibitor GM6001, suggesting the presence of proteases other than MMPs in promoting galectin-3 degradation in dry eye. Our results indicate that release of cellular galectin-3 into tears is associated with epithelial dysfunction in dry eye, and that galectin-3 proteolytic cleavage may contribute to impaired ocular surface barrier function.


Facial width-to-height ratio in a large sample of Commonwealth Games athletes.
Evidence that facial width-to-height ratio (FWHR) is a sexually dimorphic morphological measure is mixed. Research has also linked FWHR with aggression and other behavioral tendencies, at least in men. Again, other research has found no such relationship. Here, I tested for both possible relationships using a sample of 2,075 male and 1,406 female athletes from the Glasgow 2014 Commonwealth Games. Men showed significantly greater FWHRs than women, but this difference could be attributed to differences in body size. In addition, I found greater FWHRs in men who competed in sports involving physical contact and those stereotyped as more masculine. Again, these results could be attributed to differences in body size between categories. For women, no differences in FWHR were found regarding the amount of contact involved in a sport and how that sport was stereotyped. Finally, the FWHRs of athletes showed no relationship with the amount of aggression and related traits that were judged as required for success in those sports, although FWHRs did correlate with perceived endurance demands in women. Therefore, in a large sample of athletes, the sex difference in FWHR could be attributed to body size, and little support was found for the predicted links between this facial measure and behavior.


Plasmid replication in Xenopus eggs and egg extracts: a 2D gel electrophoretic analysis.
We have examined the replication patterns of ribosomal DNA plasmids in vivo and in vitro using Xenopus eggs. Plasmids carrying different parts of the Xenopus ribosomal DNA sequence were allowed to replicate either in vitro in an egg extract or in vivo after microinjection into unfertilized eggs. The replication intermediates were analyzed by the 2D gel electrophoretic technique of Brewer and Fangman (1), using original or modified electrophoresis conditions. With standard electrophoresis conditions, the patterns obtained for restriction fragments larger than 5 kb were unreliable because of artefactually distorted Y arcs and unrecognizable bubble arcs. Interpretable patterns could nevertheless be obtained using suitably modified electrophoresis parameters. Under these conditions, replication was found to initiate and terminate at multiple, random locations on each plasmid both in vivo and in vitro. However, only one or very few of these potential initiation sites are used during the replication of an individual plasmid molecule. We discuss the possible artefacts and misinterpretations that can result when the 2D electrophoresis parameters are not adapted to the size of the fragment examined. We also discuss the relevance of the random replication mode to the mechanisms and the control of DNA replication in eukaryotes.


Validation of clinic weights from electronic health records against standardized weight measurements in weight loss trials.
To validate clinic weights in electronic health records against researcher-measured weights for outcome assessment in weight loss trials. Clinic and researcher-measured weights from a published trial (BE WELL) were compared using Lin's concordance correlation coefficient, Bland and Altman's limits of agreement, and polynomial regression model. Changes in clinic and researcher-measured weights in BE WELL and another trial, E-LITE, were analyzed using growth curve modeling. Among BE WELL (n = 330) and E-LITE (n = 241) participants, 96% and 90% had clinic weights (mean [SD] of 5.8 [6.1] and 3.7 [3.9] records) over 12 and 15 months of follow-up, respectively. The concordance correlation coefficient was 0.99, and limits of agreement plots showed no pattern between or within treatment groups, suggesting overall good agreement between researcher-measured and nearest-in-time clinic weights up to 3 months. The 95% confidence intervals for predicted percent differences fell within ±3% for clinic weights within 3 months of the researcher-measured weights. Furthermore, the growth curve slopes for clinic and researcher-measured weights by treatment group did not differ significantly, suggesting similar inferences about treatment effects over time, in both trials. Compared with researcher-measured weights, close-in-time clinic weights showed high agreement and inference validity. Clinic weights could be a valid pragmatic outcome measure in weight loss studies.


Editorial Commentary: Indiscriminate Iliopsoas Tenotomy May Cause Complications-With Tight Indications and Transbursal Lengthening, We May Avoid Them.
Surgical management of iliopsoas pathology that fails conservative treatment is controversial. Potential complications following iliopsoas tenotomy include recurrent painful internal snapping, postoperative pain, and hip flexor weakness. Concerns are even greater in dysplastic patients, in whom the iliopsoas may play a role as an anteromedial hip stabilizer. Although data demonstrate arthroscopic iliopsoas tenotomy for painful internal snapping as safe and effective, its use has declined for the reasons stated above. On the other hand, procedures such as capsular plication with inferior shift and anatomic labral repair, augmentation, and reconstruction have made it possible to restore the primary stabilizers in many cases of hip instability. In these cases, iliopsoas fractional lengthening (IFL) with avoidance of collateral damage to the musculature or capsule can successfully treat painful internal snapping hip. We recommend iliopsoas lengthening when (1) there is painful internal snapping, (2) IFL can be performed without collateral damage, (3) the primary soft tissue stabilizers can be restored or augmented, and (4) there is no bony morphology likely to cause continued instability.


Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells.
The aim of the present study was to investigate the antimutagenic effects of chrysin (CR), a flavonoid compound contained in many fruits, vegetables and honey. Earlier investigations with bacterial indicators showed that CR is one of the most potent antimutagens among the flavonoids. In the present study, we tested the compound in the Salmonella strains TA98 and TA100 in combination with benzo(a)pyrene (B(a)P) and 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and found pronounced protective activity over a concentration range between 10 and 100 microg/ml. The compound itself was devoid of mutagenic activity at all concentrations tested. In the micronucleus (MN) assay with human-derived HepG2 cells, a different pattern of activity was seen. CR itself caused significant induction of MN at dose levels > or =15 microg/ml; in combination experiments with B(a)P and PhIP, U-shaped dose-response curves were obtained and protection was found only in a narrow dose range (5 - 10 microg/ml). Our findings indicate that the molecular mechanisms that account for the antimutagenic effects of CR in bacterial cells are different from those responsible for the effects in HepG2 cells. Earlier reports indicate that the antimutagenic effects of CR towards B(a)P and heterocyclic amines in bacterial indicators is due to inhibition of the activity of CYP1A. In contrast to this, we found a significant induction of CYP1A1 activity in HepG2 cells by CR. It can also be excluded that induction of GST, which is involved in the detoxification of polycyclic aromatic hydrocarbons accounts for the protective effects of CR against B(a)P since this enzyme was not significantly induced in the HepG2 cells. In the case of PhIP, induction of UDGPT and/or inhibition of sulfotransferase seen in human derived HepG2 cells after exposure to CR might play a role in the antimutagenic effects. In conclusion, our findings show that data from antimutagenicity studies with bacterial indicators cannot be extrapolated to HepG2 cells, and that CR causes genotoxic effects at higher dose levels in the latter cells. The implications of these observations for human chemoprevention strategies are discussed.


Vitamin and carotenoid intake and risk of head-neck cancer subtypes in the Netherlands Cohort Study.
Head and neck cancer (HNC) is the seventh most-common type of cancer worldwide. Evidence regarding the potential protective effect of vitamins and carotenoids on HNC is limited and mostly based on case-control studies. We evaluated the association of intake of dietary vitamins C and E (including supplementation) and the most-common carotenoids (α-carotene, β-carotene, lutein plus zeaxanthin, lycopene, and β-cryptoxanthin) and risk of HNC and HNC subtypes in a large prospective study. The Netherlands Cohort Study included 120,852 participants. For efficiency reasons, a case-cohort design was used. At baseline in 1986, participants completed a food-frequency questionnaire. A subcohort was randomly selected from the total cohort. After 20.3 y of follow-up, 3898 subcohort members and 415 HNC cases [131 oral cavity cancer (OCCs), 88 oro-/hypopharyngeal cancer (OHPs), and 193 laryngeal cancer cases] were available for analysis. Rate ratios and 95% CIs for highest (quartile 4) compared with lowest (quartile 1) quartiles of vitamin and carotenoid intake were estimated by using the Cox proportional hazards model. A strong inverse association was shown between vitamin C and HNC overall (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.39; 95% CI: 0.23, 0.66; P-trend < 0.001), OCC (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.35; 95% CI: 0.16, 0.77; P-trend < 0.05), and OHPC (multivariable-adjusted rate ratio for quartile 4 compared with quartile 1: 0.29; 95% CI: 0.12, 0.67; P-trend < 0.01). No statistically significant results were shown for vitamin E, α-carotene, β-carotene, lycopene, and lutein plus zeaxanthin. The association of vitamin E and HNC was modified by alcohol status (P-interaction = 0.003) with lower risks in alcohol abstainers. With this study, we show an inverse association between intake of vitamin C and the incidence of HNC and HNC-subtypes. Future research is recommended to investigate the underlying mechanisms and to confirm our results, which may be promising for the prevention of HNC.


Altered expression of tropomodulin in cardiomyocytes disrupts the sarcomeric structure of myofibrils.
Tropomodulin is a tropomyosin-binding protein that terminates "pointed-end" actin filament polymerization. To test the hypothesis that regulation of tropomodulin:actin filament stoichiometry is critical for maintenance of actin filament length, tropomodulin levels were altered in cells by infection with recombinant adenoviral expression vectors, which produce either sense or antisense tropomodulin mRNA. Neonatal rat cardiomyocytes were infected, and sarcomeric actin filament organization was examined. Confocal microscopy indicated that overexpression of tropomodulin protein shortened actin filaments and caused myofibril degeneration. In contrast, decreased tropomodulin content resulted in the formation of abnormally long actin filament bundles. Despite changes in myofibril structure caused by altered tropomodulin expression, total protein turnover of the cardiomyocytes was unaffected. Biochemical analyses of infected cardiomyocytes indicated that changes in actin distribution, rather than altered actin content, accounted for myofibril reorganization. Ultrastructural analysis showed thin-filament disarray and revealed the presence of leptomeres after tropomodulin overexpression. Tropomodulin-mediated effects constitute a novel mechanism to control actin filaments, and our findings demonstrate that regulated tropomodulin expression is necessary to maintain stabilized actin filament structures in cardiac muscle cells.


Age-dependent axonal expression of potassium channel proteins during development in mouse hippocampus.
The development of the hippocampal network requires neuronal activity, which is shaped by the differential expression and sorting of a variety of potassium channels. Parallel to their maturation, hippocampal neurons undergo a distinct development of their ion channel profile. The age-dependent dimension of ion channel occurrence is of utmost importance as it is interdependently linked to network formation. However, data regarding the exact temporal expression of potassium channels during postnatal hippocampal development are scarce. We therefore studied the expression of several voltage-gated potassium channel proteins during hippocampal development in vivo and in primary cultures, focusing on channels that were sorted to the axonal compartment. The Kv1.1, Kv1.2, Kv1.4, and Kv3.4 proteins showed a considerable temporal variation of axonal localization among neuronal subpopulations. It is possible, therefore, that hippocampal neurons possess cell type-specific mechanisms for channel compartmentalization. Thus, age-dependent axonal sorting of the potassium channel proteins offers a new approach to functionally distinguish classes of hippocampal neurons and may extend our understanding of hippocampal circuitry and memory processing.


Social networks and female reproductive choices in the developing world: a systematized review.
Continuing high global maternal mortality and morbidity rates in developing countries have resulted in an increasing push to improve reproductive health services for women. Seeking innovative ways for assessing how positive health knowledge and behaviors spread to this vulnerable population has increased the use of social network theories and analysis in health promotion research. Despite the increased research on social networks and health, no overarching review on social networks and maternal health literature in developing countries has been conducted. This paper attempts to synthesize this literature by identifying both published and unpublished studies in major databases on social networks and maternal and child health. This review examined a range of study types for inclusion, including experimental and non-experimental study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, cohort studies, case control studies, longitudinal studies, and cross-sectional observational studies. Only those that occurred in developing countries were included in the review. Eighteen eligible articles were identified; these were published between 1997 and 2012. The findings indicated that the most common social network mechanisms studied within the literature were social learning and social influence. The main outcomes studied were contraceptive use and fertility decisions. Findings suggest the need for continuing research on social networks and maternal health, particularly through the examination of the range of social mechanisms through which networks may influence health behaviors and knowledge, and the analysis of a larger variety of reproductive outcomes.


LasI/R and RhlI/R quorum sensing in a strain of Pseudomonas aeruginosa beneficial to plants.
Pseudomonas aeruginosa possesses three quorum-sensing (QS) systems which are key in the expression of a large number of genes, including many virulence factors. Most studies of QS in P. aeruginosa have been performed in clinical isolates and have therefore focused on its role in pathogenicity. P. aeruginosa, however, is regarded as a ubiquitous organism capable of colonizing many different environments and also of establishing beneficial associations with plants. In this study we examined the role of the two N-acyl homoserine lactone systems known as RhlI/R and LasI/R in the environmental rice rhizosphere isolate P. aeruginosa PUPa3. Both the Rhl and Las systems are involved in the regulation of plant growth-promoting traits. The environmental P. aeruginosa PUPa3 is pathogenic in two nonmammalian infection models, and only the double las rhl mutants are attenuated for virulence. In fact it was established that the two QS systems are not hierarchically organized and that they are both important for the colonization of the rice rhizosphere. This is an in-depth genetic and molecular study of QS in an environmental P. aeruginosa strain and highlights several differences with QS regulation in the clinical isolate PAO1.


Profile of trauma patients in the emergency department of a tertiary care hospital in South India.
Trauma is an increasing cause of morbidity and mortality in India. This study was done to improve the understanding of the mode of trauma, severity of injuries, and outcome of trauma victims in our hospital. This was a retrospective observational study of all adult trauma patients more than 18-year-old presenting to our emergency department (ED). Details of the incident, injuries, and outcome were noted. The ED attended to 16,169 patients during the 3-month study period with 10% (1624/16,169) being adult trauma incidents. The gender distribution was 73.6% males and 26.4% females. The mean age was 40.2 ± 16.7 years. The median duration from time of incident to time of arrival to the ED was 3 h (interquartile range [IQR]: 1.5-6.5) for priority one patients, 3 h (IQR: 1.5-7.7) for priority two patients, and 1.5 h (IQR: 1-7) for priority three patients. The average number of trauma incidents increased by 28% during the weekends. Road traffic accident (RTA) (65%) was the most common mode of injury, followed by fall on level ground (13.5%), fall from height (6.3%), work place injuries (6.3%), and others. Traumatic brain injury was seen in 17% of patients while 13.3% had polytrauma with two-wheeler accidents contributing to the majority. The ED team alone managed 23.4% of patients while the remaining 76.6% required evaluation and treatment by the trauma, surgical teams. The in-hospital mortality rate was 2.3%. Multivariate analysis showed low Glasgow coma score (odds ratio [OR]: 0.65, 95% confidence interval [CI]: 0.55-0.76, P < 0.001) and high respiratory rate (OR: 1.15, 95% CI: 1.07-1.24, P < 0.001) to be independent predictors of mortality among polytrauma victims. RTA and falls are the predominant causes of trauma. A simple physiological variable-based scoring system such as the revised trauma score may be used to prioritize patients with polytrauma.


HIV voluntary counselling and testing for African communities in London: learning from experiences in Kenya.
To explore the feasibility and acceptability of translating a successful voluntary counselling and testing (VCT) service model from Kenya to African communities in London. Qualitative study with focus group discussions and a structured workshop with key informants. Five focus group discussions were conducted in London with 42 participants from 14 African countries between August 2006 and January 2007. A workshop was held with 28 key informants. Transcripts from the group discussions and workshop were analysed for recurrent themes. Participants indicated that a community-based HIV VCT service would be acceptable to African communities in London, but also identified barriers to uptake: HIV-related stigma, concerns about confidentiality, and doubts about the ability of community-based services to maintain professional standards of care. Workshop participants highlighted three key requirements to ensure feasibility: (a) efficient referrals to sexual health services for the newly diagnosed; (b) a locally appropriate testing algorithm and quality assurance scheme; (c) a training programme for VCT counsellors. Offering community-based VCT with rapid HIV tests appears feasible within a UK context and acceptable to African communities in London, provided that clients' confidentiality is ensured and appropriate support is given to the newly diagnosed. However, the persistence of concerns related to HIV-related stigma among African communities suggests that routine opt-out testing in healthcare settings may also constitute an effective approach to reducing the proportion of late diagnoses in this group. HIV service models and programmes from Africa constitute a valuable knowledge base for innovative interventions in other settings, including developed countries.


Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins.
The mammalian transcription factor AP-2 is a retinoic acid inducible sequence-specific DNA-binding protein that is developmentally regulated. In this report, the functional domains necessary for AP-2 DNA binding were studied. AP-2 required a dimerization domain and an adjacent region of net basic charge to achieve a sequence-specific protein:DNA interaction. The sequences responsible for dimerization consisted of two putative amphipathic alpha helices separated by a large intervening span region. This helix-span-helix (HSH) domain was unable to bind DNA when separated from the basic region, but was still capable of dimerization. The ability of the HSH domain to function as a module that promotes DNA binding through dimerization was further demonstrated by attaching it to the heterologous basic region of the c-Jun proto-oncogene product. The resulting chimeric protein specifically recognized an AP-1 DNA-binding site in the absence of an intact c-Jun leucine repeat and in a manner that was dependent on the presence of a functional AP-2 dimerization domain.


BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.
It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4-weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease.


Second-generation percutaneous bioprosthetic valve: a short-term study in sheep.
To eliminate occasional tilting of the original bioprosthetic venous valve (BVV) a second-generation BVV has been developed. This study was performed to evaluate deployment, stability, and short-term function of the second-generation BVV in an animal model. A second-generation percutaneously placed BVV consisting of a square stent and lyophilized small intestinal submucosa attached to a second square stent (DS BVV) or Z-stent (ZS BVV) were tested. DS BVVs (n = 32) were constructed with a nitinol (n = 28) or stainless steel double stent (n = 4), and ZS BVVs (n = 16) were made of nitinol (n = 8) or stainless steel (n = 4). BVVs were implanted percutaneously through a femoral vein approach into the jugular vein in 24 female sheep with an over-the-wire 13F or 10F delivery system. All BVVs were placed across the natural valve of the proximal jugular vein. Deployment, stability, and function of BVVs were studied at immediate venography with contrast medium injections peripheral and central to the BVVs. Animals underwent follow-up venography and were sacrificed at 6 weeks (n = 24). Gross pathologic examination was performed. Jugular vein diameter ranged from 9.8 to 14.4 mm (mean, 12.1 +/- 1.2 mm) in 24 sheep. The 10-mm to 12-mm valve was deployed in 27 jugular veins, and the 12-mm to 14-mm valve was deployed in 21 jugular veins. No tilting was seen at placement of 48 BVVs into the jugular veins, and all valves exhibited good function on immediate venograms. Angiographic competency for the nitinol and stainless steel ZS BVV (100%) was similar to that for the nitinol DS BVV (92.3%; P = .488) but was significantly better than for the stainless steel DS BVV at 6 weeks (50%; P = .03). Dysfunction of 4 valves was caused by either nitinol DS BVV oversizing (n = 2) or intimal hyperplasia with the stainless steel DS BVV (n = 2). Placement without tilting appears essential for proper valve function. The second-generation BVV enables placement without tilting. Exact matching of valve size with vein diameter is necessary for good valve function. At present there are no widely accepted surgical or percutaneous treatment options for deep chronic venous insufficiency. A manufactured, percutaneously implantable, nonimmunogenic and nonthrombogenic bioprosthetic venous valve that remains patent and competent over time is an attractive alternative to direct venous valve reconstruction or transplantation. our results and the potential for effective treatment with bioprosthetic venous valves warrants clinical research in carefully selected patients and may lead to an effective, minimally invasive treatment for deep chronic venous invasive treatment for deep chronic venous insufficiency.


Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.
For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain. We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support. Between 2005 and 2008, a total of 816 participants--408 per group--were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01). Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources. (ClinicalTrials.gov number, NCT00120510.)


The value of percutaneous transhepatic treatment of biliary strictures following pediatric liver transplantation.
To evaluate the percutaneous transhepatic approach to the treatment of biliary strictures in pediatric patients undergoing liver transplantation. This was a retrospective study of data obtained from the medical records, laboratory reports, and imaging examination reports of pediatric liver transplant recipients who underwent percutaneous transhepatic cholangiography, because of clinical suspicion of biliary strictures, between 1st September 2012 and 31 May 2015. Data were collected for 12 patients, 7 of whom were found to have biliary strictures. In the 7 patients with biliary strictures, a total of 21 procedures were carried out: 2 patients (28.6%) underwent the procedure twice; 3 (42.8%) underwent the procedure three times; and 2 (28.6%) underwent the procedure four times. Therefore, the mean number of procedures per patient was 3 (range, 2-4), and the average interval between them was 2.9 months (range, 0.8-9.1 months). The drainage tube remained in place for a mean of 5.8 months (range, 3.1-12.6 months). One patient presented with a major complication, hemobilia, which was treated with endovascular embolization. Clinical success was achieved in all 7 patients, and the mean follow-up after drain removal was 15.4 months (range, 5.3-26.7 months). The percutaneous transhepatic approach to treating biliary strictures in pediatric liver transplant recipients proved safe, with high rates of technical and clinical success, as well as a low rate of complications.


The spectrum of liver diseases in HIV infected individuals at an HIV treatment clinic in Kampala, Uganda.
Liver diseases are common in patients with HIV due to viral hepatitis B and C co-infections, opportunistic infections or malignancies, antiretroviral drugs and drugs for opportunistic infections. To describe the spectrum of liver diseases in HIV-infected patients attending an HIV clinic in Kampala, Uganda. Consecutive patients presenting with jaundice, right upper quadrant pain with fever or malaise, ascites and/or tender hepatomegaly were recruited and underwent investigations to evaluate the cause of their liver disease. Seventy-seven consecutive patients were recruited over an eleven month period. Of these, 23 (30%) had increased transaminases because of nevirapine (NVP) and/or isoniazid (INH) hepatotoxicity. Although 14 (61%) patients with drug-induced liver disease presented with jaundice, all recovered with drug discontinuation. Hepatitis B surface antigen was positive in 11 (15%) patients while anti-hepatitis C antibody was reactive in only 2 (3%). Probable granulomatous hepatitis due to tuberculosis was diagnosed in 7 (9%) patients and all responded to anti-TB therapy. Other diagnoses included alcoholic liver disease, AIDS cholangiopathy, hepatocellular carcinoma, schistosomiasis, haemangioma and hepatic adenoma. Twelve (16%) patients died during follow-up of which 7 (9%) died because of liver disease. Drug history, liver enzyme studies, ultrasound, and hepatitis B and C investigations identified the probable etiology in 60 (78%) of 77 patients with HIV infection presenting with symptoms and/or signs of liver disease.


Contribution of CD40-CD154-mediated costimulation to an alloresponse in vivo.
Costimulation through CD40-CD154 plays an important role in T-cell activation. Although systemic administration of anti-CD154 antibody prevents or delays rejection of organ allografts in animal models, the molecular mechanisms responsible for this effect are not well defined. We have previously demonstrated that priming of mice (H2d) with CD40-/- but not with wildtype naive B cells (H2b) leads to alloantigen-specific T-cell hyporesponsiveness in vitro. In the present study, we investigated whether such priming modifies allograft rejection in a major histocompatibility complex-mismatched murine cardiac transplantation model. Priming of hosts with donor-specific CD40-/- B cells delayed rejection of subsequently transplanted wild-type cardiac allografts by 8.0 days (P<0.001). The lack of CD40 on the cardiac graft delayed rejection in unprimed or primed hosts by 3-5 days. Prolongation of graft survival correlated with the failure of infused CD40-/- B cells to express B7.2 and ICAM-1 in vivo. Our data suggest that CD40-CD154 costimulation contributes to T cell priming to alloantigens in vivo and to a second set rejection phase in which donor antigens are presented to primed T cells.


Comparison of numerous delivery systems for the induction of cytotoxic T lymphocytes by immunization.
A variety of vaccine delivery systems including peptides with various adjuvants, recombinant particles, live recombinant viruses and bacteria and plasmid DNA were tested for their ability to induce CD8+ cytotoxic T lymphocytes (CTL) against a well-defined epitope (amino acids 252-260) from the circumsporozoite (CS) protein of Plasmodium berghei. We compared routes of immunization that would be applicable for the administration of a malaria vaccine in humans. The majority of these vaccines did not induce high CTL responses in the spleens of immunized mice. However, both a yeast-derived Ty virus-like particle expressing the optimal nine-amino acid epitope SYIPSAEKI from the CS protein (CSP-VLP) and a lipid-tailed peptide of this same sequence induced high levels of the major histocompatibility complex (MHC) class I-restricted CTL with one and three subcutaneous immunizations, respectively. Moreover, these CTL were able to recognize naturally processed antigen expressed by a recombinant vaccinia virus. The levels of CTL induced by CSP-VLP could be augmented by co-immunization with certain cytokines. Target cells pulsed with CSP-VLP were recognized and lysed, showing that the particles were effectively processed and presented through MHC class I presentation pathway. The levels of CTL induced using CSP-VLP and lipopeptides are comparable to those observed after immunization with multiple doses of irradiated sporozoites.


Strong Improvement of Long-Term Chemical and Thermal Stability of Plasmonic Silver Nanoantennas and Films.
Silver (Ag) nanostructures and thin films are advantageous plasmonic materials as they have significantly lower losses than gold (Au). Unfortunately, Ag nanostructures suffer from poor chemical and thermal stability, which limit their applications. Here, the mechanisms leading to the deterioration of Ag nanostructures are clarified. It is first shown that oxygen alone cannot oxidize Ag nanostructures. Then, experiments using X-ray photoelectron spectroscopy reveal that the amount of sulfur in ambient air is too low for efficient tarnishing of the Ag surface. Finally, water is found to be the most critical factor for the degradation of Ag nanostructures and thin films. At high relative humidity, adsorbed water forms a thin film enabling the migration of Ag ions at the Ag/air interface, which deteriorates the Ag nanostructures. A dehydration treatment is developed which alters the morphology of the deposited silver, leading to an improved chemical and thermal stability of the Ag nanostructures and films, which then remain stable for more than 14 weeks under ambient laboratory conditions. In addition, dehydration also improves significantly the root-mean-square roughness for Ag thin films deposited on a glass substrate.


What are the basic self-monitoring components for cardiovascular risk management?
Self-monitoring is increasingly recommended as a method of managing cardiovascular disease. However, the design, implementation and reproducibility of the self-monitoring interventions appear to vary considerably. We examined the interventions included in systematic reviews of self-monitoring for four clinical problems that increase cardiovascular disease risk. We searched Medline and Cochrane databases for systematic reviews of self-monitoring for: heart failure, oral anticoagulation therapy, hypertension and type 2 diabetes. We extracted data using a pre-specified template for the identifiable components of the interventions for each disease. Data was also extracted on the theoretical basis of the education provided, the rationale given for the self-monitoring regime adopted and the compliance with the self-monitoring regime by the patients. From 52 randomized controlled trials (10,388 patients) we identified four main components in self-monitoring interventions: education, self-measurement, adjustment/adherence and contact with health professionals. Considerable variation in these components occurred across trials and conditions, and often components were poorly described. Few trials gave evidence-based rationales for the components included and self-measurement regimes adopted. The components of self-monitoring interventions are not well defined despite current guidelines for self-monitoring in cardiovascular disease management. Few trials gave evidence-based rationales for the components included and self-measurement regimes adopted. We propose a checklist of factors to be considered in the design of self-monitoring interventions which may aid in the provision of an evidence-based rationale for each component as well as increase the reproducibility of effective interventions for clinicians and researchers.