Adherence to antiretroviral therapy for HIV/AIDS in Latin America and the Caribbean: Systematic review and meta-analysis.
Optimal adherence to antiretroviral therapy is closely related with suppression of the HIV viral load in plasma, slowing disease progression and decreasing HIV transmission rates. Despite its importance, the estimated proportion of people living with HIV in Latin America and the Caribbean with optimal adherence has not yet been reported in a meta-analysis. Moreover, little is known of the factors leading to poor adherence which may be setting-specific. We present a pooled estimate of adherence to antiretroviral therapy (ART) of people living with HIV in Latin America and Caribbean, report the methods used to measure adherence and describe the factors associated with poor adherence among the selected studies. We electronically searched published studies up to July 2016 on the PubMed, Web of Science and Virtual Health Library (Latin America and the Caribbean Regional Portal); considering the following databases: MEDLINE, LILACS, PAHO and IBECS. Two independent reviewers selected and extracted data on ART adherence and study characteristics. Pooled estimate of adherence was derived using a random-effects model. Risk of bias in individual studies was assessed independently by two investigators using the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS). The meta-analysis included 53 studies published between 2005 and 2016, which analysed 22,603 people living with HIV in 25 Latin America and Caribbean countries. Overall adherence in Latin America and Caribbean was 70% (95% CI: 63-76; I2 = 98%), similar to levels identified by studies conducted in high-income regions. Self-report was the most frequently used method to measure adherence. Subgroup analysis showed that adherence was higher for the shortest recall time frame used, as well as in countries with lower income level, Gross National Income (GNI) per capita and Human Development Index (HDI). Studies reported diverse adherence barriers, such as alcohol and substance misuse, depression, unemployment and pill burden. Our study suggests that adherence to ART in Latin America and Caribbean may be below the sufficient levels required for a successful long-term viral load suppression.


Leprosy Reactions: Experience in the Puerto Rico Hansen's Disease Population.
Hansen's disease (HD) is a chronic granulomatous infection endemic in the tropics. Its main clinical manifestations involve the cutaneous, nervous, and musculoskeletal systems. Leprosy reactions (LR) are systemic inflammatory and immune-mediated complications of HD. These include reversal reactions (RR), erythema nodosum leprosum (ENL), and Lucio phenomenon. These reactions significantly increase disease-related morbidity and disability. We aimed to determine the number and type of LR, their association to hosts' immune responses (Ridley Jopling classification), timing of development, and treatment of HD patients in Puerto Rico. A retrospective medical record review was performed on 291 HD patients containing LR status data available from the Dermatology Service at the Hispanic Alliance for Clinical & Translational Research. Our data revealed that 83 (29%) patients developed LR, of which 31% had RR and 69% had ENL. Most LR were observed in patients in the lepromatous border (97%): Borderline lepromatous leprosy (BL) and Lepromatous Leprosy (LL). Most patients with RR and ENL had a single episode (83% and 62%, respectively), and those that received multi-drug therapy (MDT) had a reaction onset occurring most frequently within the first year of MDT and after the first year of MDT, respectively. Prednisone was the first line treatment used to manage both types of LR. Most lepromatous reactions occur within the lepromatous border. ENL was the most common LR. Prompt recognition and management of these immunologic reactions is essential to prevent long term nerve function impairment.


Resveratrol is a selective human cytochrome P450 1A1 inhibitor.
Resveratrol (trans-3,4',5-trihydroxystilbene) is a phytoalexin compound found in juice and wine produced from dark-skinned grape cultivars and reported to have anti-inflammatory and anticarcinogenic activities. To investigate the mechanism of anticarcinogenic activities of resveratrol, the effects on cytochrome P450 (P450) were determined in human liver microsomes and Escherichia coli membranes coexpressing human P450 1A1 or P450 1A2 with human NADPH-P450 reductase (bicistronic expression system). Resveratrol slightly inhibited ethoxyresorufin O-deethylation (EROD) activity in human liver microsomes with an IC(50) of 1.1 mM. Interestingly, resveratrol exhibited potent inhibition of human P450 1A1 in a dose-dependent manner with IC(50) of 23 microM for EROD and IC(50) of 11 microM for methoxyresorufin O-demethylation (MROD). However, the inhibition of human P450 1A2 by resveratrol was not so strong (IC(50) 1.2 mM for EROD and 580 microM for MROD). Resveratrol showed over 50-fold selectivity for P450 1A1 over P450 1A2. The activities of human NADPH-P450 reductase were not significantly changed by resveratrol. In a human P450 1A1/reductase bicistronic expression system, resveratrol inhibited human P450 1A1 activity in a mixed-type inhibition (competitive-noncompetitive) with a K(i) values of 9 and 89 microM. These results suggest that resveratrol is a selective human P450 1A1 inhibitor, and may be considered for use as a strong cancer chemopreventive agent in humans.


Atezolizumab in a CoHort of pretreated, advanced, non-small cell lung cancer patients with rare HistologiCal SubtypEs (CHANCE trial).
Although immunotherapy with immune-checkpoint inhibitors (ICIs) has profoundly changed the therapeutic scenario in the treatment of advanced non-small cell lung cancer (NSCLC), trials of ICIs only enrolled NSCLC patients with common histology. Atezolizumab was approved by the United States Food and Drug Administration (US FDA) in October 2016 and by the European Medicines Agency (EMA) in September 2017 for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy, regardless of PD-L1 expression. We designed a single-arm, multicenter, two-stage phase II study and plan to enroll 43 patients. The primary objective of the study is to evaluate the antitumor activity of atezolizumab in advanced NSCLC patients with rare histology subtypes. Patients with prior atezolizumab or ICI treatment and with untreated, symptomatic, or progressing brain metastases will be excluded. The primary endpoint is disease control rate. Secondary objectives are toxicity and safety, overall response rate, progression-free survival, overall survival, and time to progression. Diagnosis of NSCLC with rare histology will be confirmed by central pathology revision, and will include: colloid carcinoma, fetal adenocarcinoma, non-endocrine large cell carcinoma, sarcomatoid carcinoma, salivary gland-type tumor, lymphoepithelioma-like carcinoma, and NUT-nuclear protein in testis carcinoma. Archival tumor tissue is required for correlative studies of PD-L1 expression on tumor cells and tumor infiltrating lymphocytes. Therapeutic options in NSCLC with rare histology subtypes, to be assessed in specifically designed trials, are an unmet need. This trial will help elucidate the role of atezolizumab as a viable option in this setting.


Role of amino acid sequences flanking dibasic cleavage sites in precursor proteolytic processing. The importance of the first residue C-terminal of the cleavage site.
The amino acid sequences flanking 352 dibasic moieties contained in 83 prohormones and pro-proteins listed in a database were examined. Frequency calculations on the occurrence of given residues at positions P6 to P'4 allowed us to delineate a number of features which might be in part responsible for the in vivo discrimination between cleaved and uncleaved dibasic sites. These include the following: amino acids at these positions were characterized by a large variability in composition and properties; no major contribution of a given precursor subsite to endoprotease specificity was observed; some amino acid residues appeared to occupy preferentially certain precursor subsites (for instance, Met in P6 and P3, Asp and Ala in P'1, Pro in P6, Gly in P3 and P'2 etc.) whereas some others appeared to be excluded. Most amino acid residues occupying the P'1 position in these precursor cleavage sites were tolerated. But the beta-carbon branched side chain residues (Thr, Val, Leu, Ile) and Pro, Cys, Met and Trp were either totally excluded or poorly represented, suggesting that they might be unfavourable to cleavage. The biological relevance of these observations to the efficacy of dibasic cleavage by model propeptide convertases was in vitro tested using both pro-ocytocin convertase and Kex2 protease action on a series of pro-ocytocin related synthetic substrates reproducing the Pro7-->Leu15 sequence of the precursor in which the Ala13 residue (P'1 in the LysArg-Ala motif) was replaced by various amino acid residues. A good correlation was obtained on this model system indicating that P'1 residue of precursor dibasic processing sites is an important feature and may play the role of anchoring motif to S'1 convertase subsite. We tentatively propose that the present database, and the corresponding model, may be used for further investigation of dibasic endoproteolytic processing of propeptides and pro-proteins.


Pitfalls in the external validation of FRAX.
Recent studies have evaluated the performance of FRAX® in independent cohorts. The interpretation of most is problematic for reasons summarised in this perspective. FRAX is an extensively validated assessment tool for the prediction of fracture in men and women. The aim of this study was to review the methods used since the launch of FRAX to further evaluate this instrument. This covers a critical review of studies investigating the calibration of FRAX or assessing its performance characteristics in external cohorts. Most studies used inappropriate methodologies to compare the performance characteristics of FRAX with other models. These included discordant parameters of risk (comparing incidence with probabilities), comparison with internally derived predictors and inappropriate use and interpretation of receiver operating characteristic curves. These deficits markedly impair interpretation of these studies. Cohort studies that have evaluated the performance of FRAX need to be interpreted with caution and preferably re-evaluated.


Inositol lipids and DNA replication.
Control of DNA synthesis by growth factors seems to depend upon the generation of intracellular mitogenic signals, which are responsible for initiating the sequence of events leading to the onset of DNA synthesis. Many growth factors have tyrosine kinase activity suggesting the proteins phosphorylated on tyrosine might be likely candidates as intracellular signals. Other candidates are the calcium and hydrogen ions whose concentrations change dramatically during the action of most growth factors, many of which also stimulate the hydrolysis of inositol lipids. In particular, certain growth factors stimulate the hydrolysis of phosphatidylinositol 4,5-bisphosphate to give the two second messengers diacylglycerol and inositol 1,4,5-trisphosphate (Ins1,4,5P3). The former stimulates protein kinase C, which is responsible for increasing intracellular pH by switching on an Na+-H+ exchanger. The water-soluble Ins1,4,5P3 released to the cytosol can be metabolized along two separate pathways: it can either be dephosphorylated to free inositol or it can be converted into additional inositol polyphosphates such as Ins1,3,4,5P4 and Ins1,3,4P3. These inositol phosphates seem to play a key role in regulating intracellular calcium, with Ins1,4,5P3 functioning to release internal calcium, whereas Ins1,3,4,5P4 may function to regulate the entry of external calcium. There is evidence to suggest that these internal messengers may converge on certain key processes responsible for initiating the programme of cell growth. It is argued that an increase in intracellular calcium might be an important intracellular signal for activating both the transcription of a family of early genes, typified by fos, as well as the enzyme S6 kinase, which phosphorylates the ribosomal protein S6 which may regulate protein synthesis. The increase in pH seems to play a permissive role and may create the necessary ionic milieu for S6 phosphorylation and protein synthesis to occur. The onset of RNA and protein synthesis, which occur within the first few minutes after the arrival of a growth factor, represent the initial events of the programme of cell growth which culminates in DNA synthesis and cell division.


Is one enough? The case for non-additive influences of visual features on crossmodal Stroop interference.
When different perceptual signals arising from the same physical entity are integrated, they form a more reliable sensory estimate. When such repetitive sensory signals are pitted against other competing stimuli, such as in a Stroop Task, this redundancy may lead to stronger processing that biases behavior toward reporting the redundant stimuli. This bias would therefore, be expected to evoke greater incongruency effects than if these stimuli did not contain redundant sensory features. In the present paper we report that this is not the case for a set of three crossmodal, auditory-visual Stroop tasks. In these tasks participants attended to, and reported, either the visual or the auditory stimulus (in separate blocks) while ignoring the other, unattended modality. The visual component of these stimuli could be purely semantic (words), purely perceptual (colors), or the combination of both. Based on previous work showing enhanced crossmodal integration and visual search gains for redundantly coded stimuli, we had expected that relative to the single features, redundant visual features would have induced both greater visual distracter incongruency effects for attended auditory targets, and been less influenced by auditory distracters for attended visual targets. Overall, reaction times were faster for visual targets and were dominated by behavioral facilitation for the cross-modal interactions (relative to interference), but showed surprisingly little influence of visual feature redundancy. Post-hoc analyses revealed modest and trending evidence for possible increases in behavioral interference for redundant visual distracters on auditory targets, however, these effects were substantially smaller than anticipated and were not accompanied by a redundancy effect for behavioral facilitation or for attended visual targets.


Inadvertent Radial Head Inversion During Closed Reduction of a Pediatric Radial Neck Fracture.
Management of displaced pediatric radial neck fractures can be fraught with challenges. This unique case presents an 11-year-old female with a Salter-Harris type II radial neck fracture and how her radial head overturned 180° with the articular surface facing the radial shaft rather than the capitellum during closed manipulation under anesthesia. The malreduction subsequently required open reduction and highlights the importance of a careful stepwise approach to managing markedly displaced radial neck fractures. After closed reduction, meticulous assessment of intraoperative imaging when determining proper alignment is of the utmost importance as a result of the transverse nature of Salter-Harris type I and II fractures. LEVEL OF EVIDENCE:: Level IV.


Life threatening ventricular tachycardias in late survivors of surgically corrected tetralogy of Fallot.
Electrophysiological tests were performed in three patients with surgically corrected tetralogy of Fallot (mean age at evaluation 25 years, mean age at surgical correction 4 years) who had had either a cardiac arrest or transient neurological disturbances (presyncope, syncope) associated with ventricular arrhythmias. All three patients had an excellent haemodynamic result from surgery as judged by echocardiography and cardiac catheterisation. Ambulatory electrocardiographic monitoring and stress exercise testing were normal in two patients and showed complex ventricular ectopy in one. During invasive electrophysiological evaluation all three patients had inducible ventricular tachycardia (monomorphic QRS in two patients, cycle lengths 230 and 240 ms; polymorphic QRS in one patient, mean cycle length 200 ms) with adverse haemodynamic effects in all three patients. These findings suggest that rapid ventricular tachycardia with detrimental haemodynamic consequences, similar to that induced during laboratory study, was the basis for the presenting symptoms in each patient. This possibility was confirmed in one patient who had identical QRS morphology during both spontaneous ventricular tachycardia and that induced during the laboratory study. Thus sudden death or symptoms of syncope postoperatively in patients with surgically corrected tetralogy of Fallot appear to be due to rapid ventricular tachycardia, which may occur despite an apparently excellent surgical result.


Light stimulation evokes two different calcium responses in Müller glial cells of the guinea pig retina.
Intracellular calcium responses are a characteristic of glial activation upon neuronal activity. In acutely isolated preparations of the guinea pig retina, Müller glial cells displayed cytosolic calcium rises in response to repetitive light stimulation. The calcium rises consisted of two components, a slowly developing immediate response that occurred simultaneously over the whole length of all Müller cell fibers and a delayed fast response that originated in the ganglion cell layer and spread as a wave through the bodies of some Müller cells toward the outer processes in the photoreceptor layer. The slow calcium response was evoked by photoreceptor-to-glia signaling, resulting in a glutamate transporter- and zinc-mediated alteration in the membrane potential and an influx of calcium from the extracellular space. The fast calcium response was evoked by a release of calcium from intracellular stores, probably after activation of purinergic receptors. The data suggest that light stimulation of the retina causes glial activation by alterations in both the membrane potential and receptor-mediated mechanisms. The former may be implicated in glial support of the neuronal signal transfer from photoreceptors to ganglion cells (glial forward signaling), whereas the latter may constitute a glial feedback signaling from ganglion cells to photoreceptors.


Dorsal root ganglion neurons react to semaphorin 3A application through a biphasic response that requires multiple myosin II isoforms.
Growth cone responses to guidance cues provide the basis for neuronal pathfinding. Although many cues have been identified, less is known about how signals are translated into the cytoskeletal rearrangements that steer directional changes during pathfinding. Here we show that the response of dorsal root ganglion (DRG) neurons to Semaphorin 3A gradients can be divided into two steps: growth cone collapse and retraction. Collapse is inhibited by overexpression of myosin IIA or growth on high substrate-bound laminin-1. Inhibition of collapse also prevents retractions; however collapse can occur without retraction. Inhibition of myosin II activity with blebbistatin or by using neurons from myosin IIB knockouts inhibits retraction. Collapse is associated with movement of myosin IIA from the growth cone to the neurite. Myosin IIB redistributes from a broad distribution to the rear of the growth cone and neck of the connecting neurite. High substrate-bound laminin-1 prevents or reverses these changes. This suggests a model for the Sema 3A response that involves loss of growth cone myosin IIA to facilitate actin meshwork instability and collapse, followed by myosin IIB concentration at the rear of the cone and neck region where it associates with actin bundles to drive retraction.


Gallium arsenide modulates proteolytic cathepsin activities and antigen processing by macrophages.
Gallium arsenide (GaAs) is a semiconductor utilized in the electronics industry. Chemical exposure of animals causes a local inflammatory reaction, but systemic immunosuppression. Mice were administered i.p. 200 mg/kg GaAs crystals or latex beads, or vehicle. Five days after exposure, splenic macrophages were defective, whereas thioglycolate-elicited peritoneal macrophages (PEC) were more efficient in processing the Ag, pigeon cytochrome c, than vehicle control macrophages. Various aspects of the MHC class II Ag-processing pathway were examined. Both macrophage populations normally presented a peptide fragment to the CD4+ T cells. Surface MHC class II expression on the PEC was up-regulated, but splenic cells had normal MHC class II expression. PEC had elevated levels of glutathione and cysteine, major physiologic reducing thiols. However, the cysteine content of splenic macrophages was diminished. Proteolytic activities of aspartyl cathepsin D, and thiol cathepsins B and L were decreased significantly in splenic macrophages. On the other hand, thiol cathepsin activities were increased selectively in PEC. Latex bead-exposed PEC were not more potent APC, and their thiol cathepsin activities were unchanged, indicating that phagocytosis and nonspecific irritation were not responsible. The phenotype of PEC directly exposed to GaAs mirrored cytokine-activated macrophages, in contrast to splenic macrophages from a distant site. Therefore, GaAs exposure differentially modulated cathepsin activities in splenic macrophages and PEC, which correlated with their Ag-processing efficiency. Perhaps such distinct alterations may contribute to the local inflammation and systemic immunotoxicity caused by chemical exposure.


Hepatic Arterioportal Fistula Following Liver Trauma: Case Series and Review of the Literature.
Hepatic arterioportal fistula (HAPF) is an uncommon complication of hepatic trauma, which can manifest with abdominal pain and the sequelae of portal hypertension months to years after injury. The purpose of this study is to present cases of HAPF from our busy urban trauma center and make recommendations for management. One hundred and twenty-seven patients with high-grade penetrating liver injuries (American Association for the Surgery of Trauma [AAST] - Grades IV-V) between January 2019 and October 2022 were retrospectively reviewed. Five patients were identified with an acute hepatic arterioportal fistula following abdominal trauma from our ACS-verified adult Level 1 trauma center. Institutional experience with overall surgical management is described and reviewed with the current literature. Four of our patients presented in hemorrhagic shock requiring emergent operative intervention. The first patient had postoperative angiography and coil embolization of the HAPF. Patients 2 through 4 underwent damage control laparotomy with temporary abdominal closure followed by postoperative transarterial embolization with gelatin sponge particles (Gelfoam) or combined Gelfoam/n-butyl cyanoacrylate. The final patient went directly for angiography and Gelfoam embolization after identification of the HAPF. All 5 patients had resolution of HAPF on follow-up imaging with continued post management for traumatic injuries. Hepatic arterioportal fistula can present as a complication of hepatic injury and manifest with significant hemodynamic aberrations. Although surgical intervention was required to achieve hemorrhage control in almost all cases, management of HAPF in the setting of high-grade liver injuries was achieved successfully with modern endovascular techniques. A multidisciplinary approach to such injuries is necessary to optimize care in the acute setting following traumatic injury.


[Determination of the dimensions of the heart in experimental animals using tomography based on the principle of nuclear magnetic resonance].
A new method of tomography based on the principle of nuclear magnetic resonance (NMR-tomography) was used to determine the heart size in experimental animals. The study involved 25 rabbits and NMR-tomograms of their hearts were obtained both in situ and on the isolated heart. The results obtained were compared with the morphometric findings. It was found that the values of the heart size determined by NMR-tomograms as compared with the morphometric values both in situ and on the isolated heart were very similar, showing no statistical difference. When the tomographic findings were compared with the morphometric data, the correlation coefficient for the thickness of the left ventricle wall was 0.64; for the short axis of the left ventricle 0.55; for the perimeter of the left ventricle 0.70, and for the total size of the heart it equalled 0.98. It is inferred that NMR-tomography is quite adequate for taking the necessary measurements of the heart with sufficient precision.


Ex-vivo and in-vivo antithrombotic effect of triflavin, an RGD-containing peptide.
Triflavin, an Arg-Gly-Asp-containing snake venom peptide, inhibits platelet aggregation through the blockade of fibrinogen binding to the activated platelets. It binds to fibrinogen receptors associated with the glycoprotein IIb/IIIa complex with a Kd value of 7 x 10(-8) M. In this study, we found that 125I-triflavin reached the maximal binding to human platelets within 5 min at 25 degrees C. In addition, when triflavin was intravenously administered at 1.0 mg kg-1 to rabbits, it reversibly impaired the platelet aggregation of platelet-rich plasma caused by ADP (20 microM) ex-vivo over 30 min. The platelet counts of the experimental rabbits remained unchanged. Triflavin was effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism in mice when administered intravenously at a dose of 2 micrograms g-1. Therefore, triflavin was proven to be an effective antithrombotic agent in preventing ADP-induced acute pulmonary thromboembolism in mice and impairing reversibly the platelet function of rabbits when given intravenously.


Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals.
Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and engineers. Growth of such anisotropic nanocrystals through a simple chemical method is a challenging task. In this study, we fabricate discotic nanodisks of zirconium phosphate [Zr(HPO4)2·H2O] as a model material using hydrothermal, reflux and microwave-assisted methods. Growth of crystals is controlled by duration time, temperature, and concentration of reacting species. The novelty of the adopted methods is that discotic crystals of size ranging from hundred nanometers to few micrometers can be obtained while keeping the polydispersity well within control. The layered discotic crystals are converted to monolayers by exfoliation with tetra-(n)-butyl ammonium hydroxide [(C4H9)4NOH, TBAOH]. Exfoliated disks show isotropic and nematic liquid crystal phases. Size and polydispersity of disk suspensions is highly important in deciding their phase behavior.


Antagonistic effects of gestational dietary exposure to low-dose vinclozolin and genistein on rat fetal germ cell development.
Continuous, low-dose exposure to a phytoestrogen (1 mg/kg/day genistein) and/or to an antiandrogenic food contaminant (1 mg/kg/day vinclozolin) has been recently reported to affect male reproductive tract and fertility [1] in adults. We investigated whether alterations of the testis are already present at the end of in utero exposure using the same rat model and doses following exposure from conception to delivery. After vinclozolin exposure, we observed in the neonate a slight but significant alteration of steroidogenesis and gametogenesis with a reduction of testosterone secretion and of the number of gonocytes. In contrast, genistein exposure had no effect. While the vinclozolin-genistein mixture acts in a synergistic manner to induce the most significant alterations in the adult, interestingly, genistein antagonized the deleterious effect of vinclozolin on germ cells in the neonate. This difference emphasizes the importance of studying the effects of endocrine disruptors during various developmental stages to understand their effects.


An XML-based interchange format for genotype-phenotype data.
Recent advances in high-throughput genotyping and phenotyping have accelerated the creation of pharmacogenomic data. Consequently, the community requires standard formats to exchange large amounts of diverse information. To facilitate the transfer of pharmacogenomics data between databases and analysis packages, we have created a standard XML (eXtensible Markup Language) schema that describes both genotype and phenotype data as well as associated metadata. The schema accommodates information regarding genes, drugs, diseases, experimental methods, genomic/RNA/protein sequences, subjects, subject groups, and literature. The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB; www.pharmgkb.org) has used this XML schema for more than 5 years to accept and process submissions containing more than 1,814,139 SNPs on 20,797 subjects using 8,975 assays. Although developed in the context of pharmacogenomics, the schema is of general utility for exchange of genotype and phenotype data. We have written syntactic and semantic validators to check documents using this format. The schema and code for validation is available to the community at http://www.pharmgkb.org/schema/index.html (last accessed: 8 October 2007).


The MultiOmics Explainer: explaining omics results in the context of a pathway/genome database.
High-throughput experiments can bring to light associations between genes, proteins and/or metabolites, many of which will be explainable by existing knowledge. Our aim is to speed elucidation of such explanations and, in some cases, find explanations that scientists might otherwise overlook. We describe the MultiOmics Explainer, a new tool within the Pathway Tools software suite that leverages what is known about an organism's metabolic and regulatory network to suggest explanations for the results of omics experiments. Querying a database such as EcoCyc, the MultiOmics Explainer searches the organism's network of metabolic reactions, transporters, cofactors, enzyme substrate-level activation and inhibition relationships, and transcriptional and translational regulation relationships to identify paths of influence among input genes, proteins and metabolites. Results are presented in a combined metabolic and regulatory diagram. We present several examples of explanations generated for associations found in the Escherichia coli literature. The MultiOmics Explainer is a valuable tool that helps researchers understand and interpret the results of their omics experiments in the context of what is known about an organism's metabolic and regulatory network. It showcases the rich set of computational inferences that can be drawn from a database such as EcoCyc that encodes a diverse range of biological interactions.


Children born after elective induction of labour.
A comparison was made between the performance at eight years of age of 63 children who were born after elective induction of labour, and 29 spontaneously born children. The children had been tested previously at five years of age. Tests of reading and arithmetic achievement, visuomotor coordination, aural-visual coordination, auditory discrimination, and behavioural rating scales were administered. On two of the 12 measures (reading comprehension and euroticism) the induced children performed better than the spontaneously born. On all other measures there were no significant differences. There appeared to be no evidence of specific learning disabilities or behavioural problems among the induced children.


Heritage materials and biofouling mitigation through UV-C irradiation in show caves: state-of-the-art practices and future challenges.
Biofouling, i.e., colonization of a given substrate by living organisms, has frequently been reported for heritage materials and particularly on stone surfaces such as building facades, historical monuments, and artworks. This also concerns subterranean environments such as show caves, in which the installation of artificial light for tourism has led to the proliferation of phototrophic microorganisms. In Europe nowadays, the use of chemicals in these very sensitive environments is scrutinized and regulated by the European Union. New and environmentally friendly processes must be developed as alternative methods for cave conservation. For several years, the UV irradiation currently used in medical facilities and for the treatment of drinking water has been studied as a new innovative method for the conservation of heritage materials. This paper first presents a review of the biofouling phenomena on stone materials such as building facades and historical monuments. The biological disturbances induced by tourist activity in show caves are then examined, with special attention given to the methods and means to combat them. Thirdly, a general overview is given of the effects of UV-C on living organisms, and especially on photosynthetic microorganisms, through different contexts and studies. Finally, the authors' own experiments and findings are presented concerning the study and use of UV-C irradiation to combat algal proliferation in show caves. Both laboratory and in situ results are summarized and synthesized from their previously published works. The application of UV in caves is discussed and further experiments are proposed to enhance research in this domain.


Sponge-Like Li4Ti5O12 Constructed on Graphene for High Li Electroactivities.
A sponge-like Li(4)Ti(5)O(12)/graphene composite was prepared via sequential hydrothermal process and solid-state heat treatment process for the application to high-power lithium ion batteries. The as-prepared electrode showed outstanding Li electroactivities with a rapid and reversible Li insertion/ extraction of up to 10 C-rate (1.75 A/g). It delivered a discharge capacity of 174 mAh/g at 0.5 C, near the theoretical capacity of Li(4)Ti(5)O(12), with good rate capability and cyclic stability. First-principles calculations revealed the intimate interaction of the Li(4)Ti(5)O(12) and graphene, which implies that graphene functions as an 'electron tunnel.' Electrochemical impedance spectroscopy also proved that the graphene-hybridization and the unique structure of the Li(4)Ti(5)O(12) material significantly reduce the resistive behavior of electrodes. The 3D structured Li(4)Ti(5)O(12)/graphene hybrid reported herein could be a promising candidate for a safe, low-cost, high-power anode for lithium ion batteries, and our seeding-growth-sintering method for decorating graphene with active material will offer an effective upgrade on highly insulating Li(4)Ti(5)O(12) materials.


Differential expression of angiogenesis-related genes in goat uterus and corpus luteum during pregnancy.
Vascularization and the control of luteal and endometrial development are regulated by hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) during pregnancy. In this study, the mRNA and protein expression levels of HIFs (HIF1A, HIF2A and HIF3A) and VEGF in goat uterine and ovarian tissues during various stages of pregnancy were evaluated. A total of 42 Hair goats were used and were allocated into six groups, namely embryo-positive (G1), early pregnancy (G2), mid-term pregnancy (G3), late pregnancy (G4), oocyte-positive group (G5) and diestrus group (G6). The mRNA expression of the examined genes was evaluated by RT-qPCR, and protein expression was evaluated by immunohistochemistry (IHC). In caruncles, HIF1A mRNA expression was greater in G1, G2 and G4 than in G3 (p < .05). HIF1A and HIF2A expression was greater in G1 than in G5 (p < .05). In cotyledons, HIF1A, HIF2A and HIF3A mRNA expression was greater in G2 and G3 compared to G4 (p < .05). In luteal tissue, HIF1A mRNA expression was greater in G1 and G2 than in G3 and G4 (p < .05). In the immunohistochemical examination, HIF1A, HIF2A, HIF3A and VEGF immunoreactions were detected in uterine and luteal tissues. Findings suggest that HIFs and VEGF are involved in the regulation of ovarian functions as well as the processes of implantation and placentation.


Incorporating HYPR de-noising within iterative PET reconstruction (HYPR-OSEM).
HighlY constrained back-PRojection (HYPR) is a post-processing de-noising technique originally developed for time-resolved magnetic resonance imaging. It has been recently applied to dynamic imaging for positron emission tomography and shown promising results. In this work, we have developed an iterative reconstruction algorithm (HYPR-OSEM) which improves the signal-to-noise ratio (SNR) in static imaging (i.e. single frame reconstruction) by incorporating HYPR de-noising directly within the ordered subsets expectation maximization (OSEM) algorithm. The proposed HYPR operator in this work operates on the target image(s) from each subset of OSEM and uses the sum of the preceding subset images as the composite which is updated every iteration. Three strategies were used to apply the HYPR operator in OSEM: (i) within the image space modeling component of the system matrix in forward-projection only, (ii) within the image space modeling component in both forward-projection and back-projection, and (iii) on the image estimate after the OSEM update for each subset thus generating three forms: (i) HYPR-F-OSEM, (ii) HYPR-FB-OSEM, and (iii) HYPR-AU-OSEM. Resolution and contrast phantom simulations with various sizes of hot and cold regions as well as experimental phantom and patient data were used to evaluate the performance of the three forms of HYPR-OSEM, and the results were compared to OSEM with and without a post reconstruction filter. It was observed that the convergence in contrast recovery coefficients (CRC) obtained from all forms of HYPR-OSEM was slower than that obtained from OSEM. Nevertheless, HYPR-OSEM improved SNR without degrading accuracy in terms of resolution and contrast. It achieved better accuracy in CRC at equivalent noise level and better precision than OSEM and better accuracy than filtered OSEM in general. In addition, HYPR-AU-OSEM has been determined to be the more effective form of HYPR-OSEM in terms of accuracy and precision based on the studies conducted in this work.


Log-normal censored regression model detecting prognostic factors in gastric cancer: a study of 3018 cases.
To investigate the efficiency of Cox proportional hazard model in detecting prognostic factors for gastric cancer. We used the log-normal regression model to evaluate prognostic factors in gastric cancer and compared it with the Cox model. Three thousand and eighteen gastric cancer patients who received a gastrectomy between 1980 and 2004 were retrospectively evaluated. Clinic-pathological factors were included in a log-normal model as well as Cox model. The akaike information criterion (AIC) was employed to compare the efficiency of both models. Univariate analysis indicated that age at diagnosis, past history, cancer location, distant metastasis status, surgical curative degree, combined other organ resection, Borrmann type, Lauren's classification, pT stage, total dissected nodes and pN stage were prognostic factors in both log-normal and Cox models. In the final multivariate model, age at diagnosis, past history, surgical curative degree, Borrmann type, Lauren's classification, pT stage, and pN stage were significant prognostic factors in both log-normal and Cox models. However, cancer location, distant metastasis status, and histology types were found to be significant prognostic factors in log-normal results alone. According to AIC, the log-normal model performed better than the Cox proportional hazard model (AIC value: 2534.72 vs 1693.56). It is suggested that the log-normal regression model can be a useful statistical model to evaluate prognostic factors instead of the Cox proportional hazard model.


Line of sight robot navigation toward a moving goal.
In this paper, we consider the problem of robot tracking and navigation toward a moving goal. The goal's maneuvers are not a priori known to the robot. Thus, off-line strategies are not effective. To model the robot and the goal, we use geometric rules combined with kinematics equations expressed in a polar representation. The intent of the strategy is to keep the robot between a reference point, called the observer, and the goal. We prove under certain assumptions that the robot navigating using this strategy reaches the moving goal successfully. In the presence of obstacles, the method is combined with an obstacle avoidance algorithm. The robot then moves in two modes, the navigation mode and the obstacle avoidance mode. Simulation of various scenarios highlights the efficiency of the method and provides an instructive comparison between the paths obtained for different reference points.


Medicago truncatula histidine-containing phosphotransfer protein: structural and biochemical insights into the cytokinin transduction pathway in plants.
Histidine-containing phosphotransfer proteins (HPts) take part in hormone signal transduction in higher plants. The overall pathway of this process is reminiscent of the two-component system initially identified in prokaryotes. HPts function in histidine-aspartate phosphorelays in which they mediate the signal from sensory kinases (usually membrane proteins) to RRs in the nucleus. Here, we report the crystal structure of an HPt protein from Medicago truncatula (MtHPt1) determined at 1.45 Å resolution and refined to an R-factor of 16.7% using low-temperature synchrotron-radiation X-ray diffraction data. There is one MtHPt1 molecule in the asymmetric unit of the crystal lattice with P2(1)2(1)2(1) symmetry. The protein fold consists of six α helices, four of which form a C-terminal helix bundle. The coiled-coil structure of the bundle is stabilized by a network of S-aromatic interactions involving highly conserved sulfur-containing residues. The structure reveals a solvent-exposed side chain of His79, which is the phosphorylation site, as demonstrated by autoradiography combined with site-directed mutation. It is surrounded by highly conserved residues present in all plant HPts. These residues form a putative docking interface for either the receiver domain of the sensory kinase, or for the RR. The biological activity of MtHPt1 was tested by autoradiography. It demonstrated phosphorylation by the intracellular kinase domain of the cytokinin receptor MtCRE1. Complex formation between MtHPt1 and the intracellular fragment of MtCRE1 was confirmed by thermophoresis, with a dissociation constant K(d) of 14 μM.


A Comparative Study of the Epidemiological Aspects of Legionnaires' Disease: Outbreaks in Korea and Japan, 2010 - 2014.
In the present study, we compared the epidemiological aspects of Legionnaire' disease (LD) outbreaks in Korea and Japan by analyzing the current state from 2010 to 2014. The following factors were analyzed: nationwide cumulative incidence rate (CIR) per 100,000 populations and case-fatality rate in percentage, epidemiological aspects (i.e., case related to gender), male to female morbidity ratio (MFMR), age, seasonality and habitat distribution of LD cases. In total, there were 134 cases of LD with the CIR of 0.05 per 100,000 populations in Korea from 2010 to 2014. During the same period in Japan, there were 4,840 cases of LD with a CIR of 0.76 per 100,000 populations. The CIR in Japan was significantly higher than that in Korea. However, the case-fatality rates were at similar levels (3.0% vs. 5.9%). Moreover, LD affects both sexes differently, accounting for 2.05 and 4.41 of MFMR in Korea and Japan, respectively. In both countries, the incidence mainly occurred among people aged 40 years or older, and peaked in summer (37.3% vs. 33.7% of total cases). Significant differences were observed in the incidence of LD cases between the capital city and county areas in both two countries. These differences in LD risk factors reflect the different influences of reservoir/host with natural or artificial aquatic environments. This study provides a quantitative analysis of the epidemiological aspects and risk factors of LD outbreaks in Korea and Japan. We hope this study would be helpful for providing insight on effective future strategies to reduce LD outbreaks.


Combined modulation of polycomb and trithorax genes rejuvenates β cell replication.
Inadequate functional β cell mass underlies both type 1 and type 2 diabetes. β Cell growth and regeneration also decrease with age through mechanisms that are not fully understood. Age-dependent loss of enhancer of zeste homolog 2 (EZH2) prevents adult β cell replication through derepression of the gene encoding cyclin-dependent kinase inhibitor 2a (INK4a). We investigated whether replenishing EZH2 could reverse the age-dependent increase of Ink4a transcription. We generated an inducible pancreatic β cell-specific Ezh2 transgenic mouse model and showed that transgene expression of Ezh2 was sufficient to increase β cell replication and regeneration in young adult mice. In mice older than 8 months, induction of Ezh2 was unable to repress Ink4a. Older mice had an enrichment of a trithorax group (TrxG) protein complex at the Ink4a locus. Knockdown of TrxG complex components, in conjunction with expression of Ezh2, resulted in Ink4a repression and increased replication of β cells in aged mice. These results indicate that combined modulation of polycomb group proteins, such as EZH2, along with TrxG proteins to repress Ink4a can rejuvenate the replication capacity of aged β cells. This study provides potential therapeutic targets for expansion of adult β cell mass.


Immunogenic Display of Purified Chemically Cross-Linked HIV-1 Spikes.
HIV-1 envelope glycoprotein (Env) spikes are prime vaccine candidates, at least in principle, but suffer from instability, molecular heterogeneity and a low copy number on virions. We anticipated that chemical cross-linking of HIV-1 would allow purification and molecular characterization of trimeric Env spikes, as well as high copy number immunization. Broadly neutralizing antibodies bound tightly to all major quaternary epitopes on cross-linked spikes. Covalent cross-linking of the trimer also stabilized broadly neutralizing epitopes, although surprisingly some individual epitopes were still somewhat sensitive to heat or reducing agent. Immunodepletion using non-neutralizing antibodies to gp120 and gp41 was an effective method for removing non-native-like Env. Cross-linked spikes, purified via an engineered C-terminal tag, were shown by negative stain EM to have well-ordered, trilobed structure. An immunization was performed comparing a boost with Env spikes on virions to spikes cross-linked and captured onto nanoparticles, each following a gp160 DNA prime. Although differences in neutralization did not reach statistical significance, cross-linked Env spikes elicited a more diverse and sporadically neutralizing antibody response against Tier 1b and 2 isolates when displayed on nanoparticles, despite attenuated binding titers to gp120 and V3 crown peptides. Our study demonstrates display of cross-linked trimeric Env spikes on nanoparticles, while showing a level of control over antigenicity, purity and density of virion-associated Env, which may have relevance for Env based vaccine strategies for HIV-1. The envelope spike (Env) is the target of HIV-1 neutralizing antibodies, which a successful vaccine will need to elicit. However, native Env on virions is innately labile, as well as heterogeneously and sparsely displayed. We therefore stabilized Env spikes using a chemical cross-linker and removed non-native Env by immunodepletion with non-neutralizing antibodies. Fixed native spikes were recognized by all classes of known broadly neutralizing antibodies but not by non-neutralizing antibodies and displayed on nanoparticles in high copy number. An immunization experiment in rabbits revealed that cross-linking Env reduced its overall immunogenicity; however, high-copy display on nanoparticles enabled boosting of antibodies that sporadically neutralized some relatively resistant HIV-1 isolates, albeit at a low titer. This study describes the purification of stable and antigenically correct Env spikes from virions that can be used as immunogens.


A novel variable delay Go/No-Go task to study attention, motivation and working memory in the head-fixed rodent.
In order to parse the causal elements underlying complex behaviors and decision-making processes, appropriate behavioral methods must be developed and used in concurrence with molecular, pharmacological, and electrophysiological approaches. Presented is a protocol for a novel Go/No-Go behavioral paradigm to study the brain attention and motivation/reward circuitry in awake, head-restrained rodents. This experimental setup allows: (1) Pharmacological and viral manipulation of various brain regions via targeted guide cannula; (2) Optogenetic cell-type specific activation and silencing with simultaneous electrophysiological recording and; (3) Repeated electrophysiological single and multiple unit recordings during ongoing behavior. The task consists of three components. The subject first makes an observing response by initiating a trial by lever pressing in response to distinctive Go or No-Go tones. Then, after a variable delay period, the subject is presented with a challenge period cued by white noise during which they must respond with a lever press for the Go condition or withhold from lever pressing for the duration of the cue in the No-Go condition. After correctly responding during the challenge period (Challenge) and a brief delay, a final reward tone of the same frequency as the initiation tone is presented and sucrose reward delivery is available and contingent upon lever pressing. Here, we provide a novel procedure and validating data set that allows researchers to study and manipulate components of behavior such as attention, motivation, impulsivity, and reward-related working memory during an ongoing operant behavioral task while limiting interference from non task-related behaviors.


Magnitude of [(11)C]PK11195 binding is related to severity of motor deficits in a rabbit model of cerebral palsy induced by intrauterine endotoxin exposure.
Intrauterine inflammation is known to be a risk factor for the development of periventricular leukomalacia (PVL) and cerebral palsy. In recent years, activated microglial cells have been implicated in the pathogenesis of PVL and in the development of white matter injury. Clinical studies have shown the increased presence of activated microglial cells diffusely throughout the white matter in brains of patients with PVL. In vitro studies have reported that activated microglial cells induce oligodendrocyte damage and white matter injury by release of inflammatory cytokines, reactive nitrogen and oxygen species and the production of excitotoxic metabolites. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] is a ligand that is selective for the 18-kDa translocator protein expressed on the outer mitochondrial membrane of activated microglia and macrophages. When labeled with carbon-11, [(11)C]PK11195 can effectively be used as a ligand in positron emission tomography (PET) studies for the detection of activated microglial cells in various neuroinflammatory and neurodegenerative conditions. In this study, we hypothesized that the magnitude of [(11)C]-(R)-PK11195 uptake in the newborn rabbit brain, as measured using a small-animal PET scanner, would match the severity of motor deficits resulting from intrauterine inflammation-induced perinatal brain injury. Pregnant New Zealand white rabbits were intrauterinely injected with endotoxin or saline at 28 days of gestation. Kits were born spontaneously at 31 days and underwent neurobehavioral testing and PET imaging following intravenous injection of the tracer [(11)C]-(R)-PK11195 on the day of birth. The neurobehavioral scores were compared with the change in [(11)C]PK11195 uptake over the time of scanning, for each of the kits. Upon analysis using receiver operating characteristic curves, an optimal combined sensitivity and specificity for detecting abnormal neurobehavioral scores suggestive of cerebral palsy in the neonatal rabbit was noted for a positive change in [(11)C]PK11195 uptake in the brain over time on PET imaging (sensitivity of 100% and area under the curve of >0.82 for all parameters tested). The strongest agreements were noted between a positive uptake slope - indicating increased [(11)C]PK11195 uptake over time - and worsening scores for measures of locomotion (indicated by hindlimb movement, forelimb movement, circular motion and straight- line motion; Cohen's κ >0.75 for each) and feeding (indicated by ability to suck and swallow and turn the head during feeding; Cohen's κ >0.85 for each). This was also associated with increased numbers of activated microglia (mean ratio ± SD of activated to total microglia: 0.96 ± 0.16 in the endotoxin group vs. 0.13 ± 0.08 in controls; p < 0.001) in the internal capsule and corona radiata. Our findings indicate that the magnitude of [(11)C]PK11195 binding measured in vivo by PET imaging matches the severity of motor deficits in the neonatal rabbit. Molecular imaging of ongoing neuroinflammation in the neonatal period may be helpful as a screening biomarker for detecting patients at risk of developing cerebral palsy due to a perinatal insult.


How stakeholder participation can contribute to systematic reviews of complex interventions.
Although patient and public involvement in research is a requirement for research funding in many countries, the knowledge base for how to effectively involve people-and evidence of the effectiveness of involvement-is weak. This article describes how methods used in participatory health research were used to involve patients, clients, providers and community health workers across all stages of a realist review. Sustained involvement enabled better identification of the components of the complex intervention of community-based peer support. It also challenged assumptions of how peer support is constructed, leading the review team to question whether the process of designing and implementing interventions has more influence on effectiveness than previously recognised in empirical studies. We conclude with a discussion on when sustained involvement should be used, and the challenges of incorporating it into the traditional researcher-led approach to systematic reviews.


Meal composition affects postprandial fatty acid oxidation.
The influence of macronutrient content of a meal on postprandial fatty acid oxidation was investigated in 13 Caucasian males after consumption of a high-fat (HF) breakfast (33% carbohydrate, 52% fat, 15% protein) and after an equicaloric high-carbohydrate (HC) breakfast (78% carbohydrate, 6% fat, 15% protein). The HF breakfast contained short- and medium-chain fatty acids, as well as long-chain fatty acids. Respiratory quotient (RQ) and plasma beta-hydroxybutyrate (BHB) were measured during the 3 h after the meal as indicators of whole body substrate oxidation and hepatic fatty acid oxidation, respectively. Plasma levels of free fatty acids (FFA), triglycerides, glucose, insulin, and lactate were also determined because of their relationship to nutrient utilization. RQ was significantly lower and plasma BHB was higher after the HF breakfast than after the HC breakfast, implying that more fat is burned in general and specifically in the liver after an HF meal. As expected, plasma FFA and triglycerides were higher after the HF meal, and insulin and lactate were higher after the HC meal. In sum, oxidation of ingested fat occurred in response to a single HF meal.


Fatigue's effect on eversion force sense in individuals with and without functional ankle instability.
Force sense (FS), the proprioceptive ability to detect muscle-force generation, has been shown to be impaired in individuals with functional ankle instability (FAI). Fatigue can also impair FS in healthy individuals, but it is unknown how fatigue affects FS in individuals with FAI. To assess the effect of fatigue on ankle-eversion force-sense error in individuals with and without FAI. Case control with repeated measures. Sports medicine research laboratory. 32 individuals with FAI and 32 individuals with no ankle sprains or instability in their lifetime. FAI subjects had a history of ≥1 lateral ankle sprain and giving-way ≥1 episode per month. Three eversion FS trials were captured per load (10% and 30% of maximal voluntary isometric contraction) using a load cell before and after a concentric eversion fatigue protocol. Trial error was the difference between the target and reproduction forces. Constant error (CE), absolute error (AE), and variable error (VE) were calculated from 3 trial errors. A Group × Fatigue × Load repeated-measures ANOVA was performed for each error. There were no significant 3-way interactions or 2-way interactions involving group (all P > .05). CE and AE had a significant 2-way interaction between load and fatigue (CE: F1,62 = 8.704, P = .004; AE: F1,62 = 4.024, P = .049), and VE had a significant main effect for fatigue (F1,62 = 5.130, P = .027), all of which indicated increased FS error with fatigue at 10% load. However, at 30% load only VE increased with fatigue. The FAI group had greater error as measured by AE (F1,62 = 4.571, P = .036) but not CE or VE (P > .05). Greater AE indicates that FAI individuals are less accurate in their force production. Fatigue impaired force sense in all subjects equally. These deficits provide evidence of impaired proprioception with fatigue and in individuals with FAI.


Desensitization of calcium mobilization and cell function in human neutrophils.
Neutrophils pretreated with the chemoattractant formylmethionyl-leucyl-phenylalanine become unresponsive when re-exposed to the same ligand, a process termed desensitization. We have examined whether desensitization of transduction (Ca2+ mobilization) or of other cell functions (superoxide generation, enzyme release, or aggregation) occurs synchronously. Simultaneous studies of Ca2+ mobilization and aggregation by using Fura-2-loaded cells indicate that, under conditions where the aggregation response is abolished, most of the Ca2+ mobilization is unaltered. Further studies were then carried out to ascertain whether desensitization of Ca2+ mobilization could in fact be induced. Desensitization was observed, and was dependent on the number of exposures of the cells to the ligand, the concentration of the ligand, and whether the ligand was left in the medium or was removed. The pattern of resensitization was dependent on the experimental design. Under conditions where ligand was continuously present, no recovery of the Ca2+-mobilization response was seen with subsequent challenges. In contrast, on removal of ligand, this response showed partial recovery. Whereas complete desensitization of aggregation was noted, enzyme release showed a markedly lesser degree of desensitization and required more frequent exposures to the ligand before it was observed. Little or no desensitization of superoxide generation was observed regardless of the conditions utilized. Studies using phorbol myristate acetate as the ligand showed that Ca2+ mobilization and aggregation could be simultaneously inhibited. Our results suggest that discrete mechanisms of desensitization are possible in human neutrophils, and that desensitization of one particular function (aggregation) does not imply concomitant desensitization of other functions.


A Tissue Systems Pathology Test Detects Abnormalities Associated with Prevalent High-Grade Dysplasia and Esophageal Cancer in Barrett's Esophagus.
There is a need for improved tools to detect high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus. In previous work, we demonstrated that a 3-tier classifier predicted risk of incident progression in Barrett's esophagus. Our aim was to determine whether this risk classifier could detect a field effect in nondysplastic (ND), indefinite for dysplasia (IND), or low-grade dysplasia (LGD) biopsies from Barrett's esophagus patients with prevalent HGD/EAC. We performed a multi-institutional case-control study to evaluate a previously developed risk classifier that is based upon quantitative image features derived from 9 biomarkers and morphology, and predicts risk for HGD/EAC in Barrett's esophagus patients. The risk classifier was evaluated in ND, IND, and LGD biopsies from Barrett's esophagus patients diagnosed with HGD/EAC on repeat endoscopy (prevalent cases, n = 30, median time to HGD/EAC diagnosis 140.5 days) and nonprogressors (controls, n = 145, median HGD/EAC-free surveillance time 2,015 days). The risk classifier stratified prevalent cases and non-progressor patients into low-, intermediate-, and high-risk classes [OR, 46.0; 95% confidence interval, 14.86-169 (high-risk vs. low-risk); P < 0.0001]. The classifier also provided independent prognostic information that outperformed the subspecialist and generalist diagnosis. A tissue systems pathology test better predicts prevalent HGD/EAC in Barrett's esophagus patients than pathologic variables. The results indicate that molecular and cellular changes associated with malignant transformation in Barrett's esophagus may be detectable as a field effect using the test. A tissue systems pathology test may provide an objective method to facilitate earlier identification of Barrett's esophagus patients requiring therapeutic intervention. Cancer Epidemiol Biomarkers Prev; 26(2); 240-8. ©2016 AACR.


The impact of incarceration on obesity: are prisoners with chronic diseases becoming overweight and obese during their confinement?
The association between incarceration and weight gain, along with the public health impact of former prisoners who are overweight or obese, warrants more investigation to understand the impact of prison life. Studies regarding incarceration's impact on obesity are too few to support assertions that prisons contribute to obesity and comorbid conditions. This study examined a statewide prison population over several years to determine weight gain. Objective data for weight, height, and chronic diseases, along with demographics, were extracted from an electronic health record. These data were analyzed statistically to determine changes over time and between groups. As a total population, prisoners not only gained weight, but also reflected the distribution of BMIs for the state. There were differences within the population. Male prisoners gained significantly less weight than females. The population with chronic diseases gained less weight than the population without comorbid conditions. Prisoners with diabetes lost weight while hypertension's impact was negligible. This study found that weight gain was a problem specifically to females. However, this prison system appears to be providing effective chronic disease management, particularly for prisoners with diabetes and hypertension. Additional research is needed to understand the impact incarceration has on the female population.


MPTP-induced vulnerability of dopamine neurons in A53T α-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation.
Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the α-synuclein (α-syn) gene. Mutant α-syn expression increases the vulnerability of neurons to exogenous insults. In this study, we developed a new PD model in the transgenic mice expressing mutant hemizygous (hemi) or homozygous (homo) A53T α-synuclein (α-syn Tg) and their wildtype (WT) littermates by treatment with sub-toxic (10 mg/kg, i.p., daily for 5 days) or toxic (30 mg/kg, i.p., daily for 5 days) dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase and Bcl-2 levels were reduced in the α-syn Tg but not WT mice by sub-toxic MPTP injection. In the adhesive removal test, time to remove paper was significantly increased only in the homo α-syn Tg mice. In the challenging beam test, the hemi and homo α-syn Tg mice spent significantly longer time to traverse as compared to that of WT group. In order to find out responsible proteins related with vulnerability of mutant α-syn expressed neurons, DJ-1 and ubiquitin enzyme expressions were examined. In the SN, DJ-1 and ubiquitin conjugating enzyme, UBE2N, levels were significantly decreased in the α-syn Tg mice. Moreover, A53T α-syn overexpression decreased DJ-1 expression in SH-SY5Y cells. These findings suggest that the vulnerability to oxidative injury such as MPTP of A53T α-syn mice can be explained by downregulation of DJ-1.


Harmonics propagation and interaction evaluation in small-scale wind farms and hydroelectric generating systems.
The harmonics exacerbated by the integration of distributed energy such as wind power has been extensively studied. However, the interaction and propagation mechanism between harmonic sources in the hydro-wind complementary generation system are still not clear. To tackle this challenge, the presented study establishes the hydro-wind complementary generation system model and explores the harmonics propagation and interaction in all components. Then three operation mode of complementary system (scenario 1: stand-alone Hydroelectric Generating System, scenario 2: stand-alone Wind Farm (WF) and scenario 3: complementary generation system) are selected. The results demonstrate that the integration of HGS diminishes the harmonic at DFIG side but at the grid side. In complementary generation system, the THDu rises but the corresponding THDi declines due to the regulation of power grid. Furthermore, the odd harmonics interactions analysis reveal that the doubly-fed induction generator's (DFIG) side and the stator's side are the two high-risk sources in the complementary generation process. The presented results provide a basis for power quality evaluation of hydro-wind complementary generation system.


Psychophysical optimization of lighting spectra for naturalness, preference, and chromatic diversity.
The optimal spectral profiles of lighting for naturalness, individual preference, and chromatic diversity were estimated with psychophysical experiments in which observers selected illuminants from a set of metamers of D65 to render outdoor and indoor scenes. For naturalness, the illuminant selected was more spectrally structured than daylight and had a low color rendering index. For preference, the illuminant was similar but produced colors a little more saturated. For chromatic diversity, the spectrum was much more structured, with clearly defined peaks in the blue, green, and red spectral regions. These experiments show that light sources with specific structured spectra may have important visual applications in lighting.


[Sexual orientation in the school environment: fact or eagerness?].
This qualitative research aims to analyze how sexual orientation has been incorporated into pedagogic practices through the point of view of educators from public schools of fundamental teaching. Twenty three educators from Cajazeiras, Paralba, Brazil participated in the study. The focus group was elected as technique of investigation, and the empirical data obtained were organized according to the technique of analysis of content. It was realized that there is an effort of the actors to privilege contents related to sexual orientation in the school environment though they demand that a level of informative and subjective character about the "sexuality" be encouraged providing the educators with a space for re-significations of its internality of values. The information directed to self-care must transcend the limits of prevention and hygienisation, incorporating extensive, inclusive and reflective methodologies, which recognize human and social rights and promote the ethical construction of citizenship.


Views and experiences of young people, their parents/carers and healthcare professionals of the advance care planning process: A summary of the findings from a qualitative study.
Advance care planning for young people is relatively new in the UK. There is a lack of understanding about the engagement of young people in their own planning process, optimal timing of discussions and the facilitators and barriers to the engagement of young people. To explore the views and experiences of young people, their parents/carers and HCPs of the advance care planning process. A qualitative study, using semi-structured interviews with young people, their parents/carers and healthcare professionals across four case series. Data were analysed using thematic analysis. Fifteen participants were interviewed: young people (n = 2), parents/carers (n = 5) and healthcare professionals (n = 8). Three themes were identified from the findings. Key findings related to barriers and facilitators of engaging young people in their own care planning were apparent in the following areas: misperception of terms; hierarchies of power in relationships; and a flexible and innovative organisational structure and culture. Participants expressed a variety of views and experiences of advance care planning. Advance care planning was thought to be best initiated by a consultant when the young person is in their mid-teens, their condition is stable, and before they transition to adult care. Engagement was also considered to be facilitated by appropriate communication, developing relationships prior to initiating advance care planning, and written support for everyone involved in the process. These factors were supported by training and education for healthcare professionals and a flexible and innovative structure and cultures of organisations.


Antibacterial properties of the pituitary adenylate cyclase-activating polypeptide: A new human antimicrobial peptide.
The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a polycationic, amphiphilic and helical neuropeptide, is well known for its neuroprotective actions and cell penetrating properties. In the present study, we evaluated the potent antibacterial property of PACAP38 and related analogs against various bacterial strains. Interestingly, PACAP38 and related analogs can inhibit the growth of various bacteria including Escherichia coli (JM109), Bacillus subtilis (PY79), and the pathogenic Burkholderia cenocepacia (J2315). Investigation of the mechanism of action suggested that a PACAP metabolite, identified as PACAP(9-38), might indeed be responsible for the observed PACAP38 antibacterial action. Surprisingly, PACAP(9-38), which does not induce haemolysis, exhibits an increased specificity toward Burkholderia cenocepacia J2315 compared to other tested bacteria. Finally, the predisposition of PACAP(9-38) to adopt a π-helix conformation rather than an α-helical conformation like PACAP38 could explain this gain in specificity. Overall, this study has revealed a new function for PACAP38 and related derivatives that can be added to its pleiotropic biological activities. This innovative study could therefore pave the way toward the development of new therapeutic agents against multiresistant bacteria, and more specifically the Burkholderia cenocepacia complex.


Concordance of Nurses and Physicians on Whether Critical Care Patients are Receiving Futile Treatment.
Nurses and physicians often describe critical care that is not expected to provide meaningful benefit to a patient as futile, and providing treatments perceived as futile is associated with moral distress. To explore concordance of physicians' and nurses' assessments of futile critical care. A focus group of clinicians developed a consensus definition of "futile" critical care. Daily for 3 months, critical care physicians and nurses in a health care system identified patients perceived to be receiving futile treatment. Assessments and patients' survival were compared between nurses and physicians. Nurses and physicians made 6254 shared assessments on 1086 patients. Nurses and physicians assessed approximately the same number of patients as receiving futile treatment (110 for nurses vs 113 for physicians, P = .82); however, concordance was low as to which patients were assessed as receiving futile treatment (κ = 0.46). The 110 patients categorized by nurses as receiving futile treatment had lower 6-month mortality than did the 113 patients so assessed by physicians (68% vs 85%, P = .005). Patients who were assessed as receiving futile treatment by both providers were more likely to die in the hospital than were patients assessed as receiving futile treatment by the nurse alone (76% vs 32%, P < .001) or by the physician alone (76% vs 57%, P = .04). Interprofessional concordance on provision of critical care perceived to be futile is low; however, joint predictions between physicians and nurses were most predictive of patients' outcomes, suggesting value in collaborative decision making.


Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism.
Several drugs blocking the rapidly activating potassium (K(r)) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species. Patch-clamp and quantitative-mRNA measurements of K(r) and slowly activating K (K(s)) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K(r) channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K(r)-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K(r)-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K(s) channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit. This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.


Tumor Microenvironment-Activated Nanocomposite for Self-Amplifying Chemodynamic/Starvation Therapy Enhanced IDO-Blockade Tumor Immunotherapy.
Disrupting intracellular redox homeostasis combined with immune checkpoint blockade therapy is considered as an effective way to accelerate tumor cell death. However, suppressed tumor immune microenvironment and lower cargo delivery restrict the efficiency of tumor therapy. In this study, a multifunctional tumor microenvironment (TME)-responsive nanocomposite is constructed using manganese tetroxide (Mn3 O4 )-decorated disulfide-bond-incorporated dendritic mesoporous organosilica nanoparticles (DMONs) to co-deliver indoleamine 2,3-dioxygenase (IDO) inhibitor Epacadostat (IDOi) and glucose oxidase (GOx) following modification with polyethylene glycol. Owing to the responsiveness of Mn3 O4 -decorated DMONs to the mildly acidic and glutathione (GSH) overexpressed TME, the nanocomposite can rapidly decompose and release inner contents, thus substantially improving the cargo release ability. Mn3 O4 can effectively catalyze hydrogen peroxide (H2 O2 ) decomposition to generate oxygen, enhance the ability of GOx to consume glucose to produce H2 O2 , and further promote the generation of hydroxyl radicals (•OH) by Mn2+ . Furthermore, Mn2+ -mediated GSH depletion and the production of •OH can disrupt intracellular redox homeostasis, contributing to immunogenic cell death. Simultaneously, IDOi can inhibit IDO to reverse inhibited immune response. The results show that self-amplifying chemodynamic/starvation therapy combined IDO-blockade immunotherapy synergistically inhibits tumor growth and metastasis in vivo.


Neisseria meningitidis producing the Opc adhesin binds epithelial cell proteoglycan receptors.
Neisseria meningitidis possesses a repertoire of surface adhesins that promote bacterial adherence to and entry into mammalian cells. Here, we have identified heparan sulphate proteoglycans as epithelial cell receptors for the meningococcal Opc invasin. Binding studies with radiolabelled heparin and heparin affinity chromatography demonstrated that Opc is a heparin binding protein. Subsequent binding experiments with purified 35SO4-labelled epithelial cell proteoglycan receptors and infection assays with epithelial cells that had been treated with heparitinase to remove glycosaminoglycans confirmed that Opc-expressing meningococci exploit host cell-surface proteoglycans to gain access to the epithelial cell interior. Unexpectedly, Opa28-producing meningococci lacking Opc also bound proteoglycans. These bacteria also bound CEA receptors in contrast to the Opc-expressing phenotype, suggesting that Opa28 may possess domains with specificity for different receptors. Opa/Opc-negative meningococci did not bind either proteoglycan or CEA receptors. Using a set of genetically defined mutants with different lipopolysaccharide (LPS) and capsular phenotype, we were able to demonstrate that surface sialic acids interfere with the Opc-proteoglycan receptor interaction. This effect may provide the molecular basis for the reported modulatory effect of capsule and LPS on meningococcal adherence to and entry into various cell types.


Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores.
Treatment of pain with opioids is limited by their potential abuse liability. In an effort to develop analgesics without this side effect, a series of bivalent ligands containing a mu-opioid receptor agonist pharmacophore connected to a delta-opioid receptor antagonist pharmacophore through variable-length spacers (16-21 atoms) was synthesized. Members of this series [mu-opioid receptor (M)-delta-opioid receptor (D)-agonist (A)-antagonists (N): MDANs] are antinociceptive in the tail flick assay, but antinociceptive tolerance and physical dependence do not develop to ligands having spacers with 19-21 atoms. The current studies compared the rewarding properties of three bivalent ligands (MDAN-16, -19 and -21) and a mu-opioid receptor agonist (MA-19) to those of morphine in the conditioned place preference assay in mice after i.v. administration. Place preference developed to morphine and to MA-19, but not to the MDANs. The responses to MDAN-16 were highly variable, although place preference of borderline significance appeared to develop. Reinstatement was also evaluated after extinguishing morphine conditioned place preference; morphine and MA-19, but not the MDANs, reinstated morphine conditioned place preference. Taken together, these results suggest that the bivalents are less rewarding compared to morphine in opioid-naïve mice and do not induce reinstatement in previously morphine-preferring mice. The lack of a conditioned place preference response for MDAN-19 and -21, compared to the equivocal results with MDAN-16, suggests a minimum distance requirement between mu-opioid receptor and delta-opioid receptor recognition sites. This requirement may reflect the binding of MDAN-19 and -21 to mu-opioid receptor-delta-opioid receptor heterodimeric receptors that block reward but not antinociception.


In vitro assembly of repertoires of antibody chains on the surface of phage by renaturation.
Antibodies can be made from repertoires of associated heavy and light chains displayed on the surface of bacteriophage, and are readily diversified by random point mutation or by chain shuffling. To make extensive variations around the "core" antigen binding contacts of a crystallographically solved mouse antibody NQ10/12.5 (gamma l, kappa), the NQ10 light chain was assembled in vitro with a repertoire of about 10(7) human heavy chains displayed on the surface of phage, and selected by binding to hapten. An antibody with a much improved affinity was isolated from the repertoire (K(a) = 10(9) M-1 compared with 10(8) M-1 for NQ10). The sequence of the human heavy chain (VH-IL) was highly related to NQ10. It conserved the same folds for the H1, H2 and H3 loops, six of the seven contact residues for hapten, and also a phOx binding motif (Asp-X-Gly-X-X) in the H3 loop. It appears that the new heavy chain partners for the NQ10 light chain often retain many critical antigen binding features found in the NQ10 heavy chain.


Detrusor overactivity in Becker muscular dystrophy.
A 20-year-old man with normal motor milestones as an infant but subsequent progressive difficulty in walking in childhood, was genetically confirmed to have Becker muscular dystrophy (BMD) at age 13. He was independent in ambulation and activities of daily living. He was referred to the Department of Uro-neurology for a 5-year history of urinary urgency and incontinence. He would visit the toilet 10 times in the daytime and experience urinary urgency daily, often associated with incontinence. He did not report difficulties initiating voiding, stress incontinence, pain, or hematuria. There was no history of urinary tract infections.


Desaturation and oxygenation of 1,2-dihydronaphthalene by toluene and naphthalene dioxygenase.
Bacterial strains expressing toluene and naphthalene dioxygenase were used to examine the sequence of reactions involved in the oxidation of 1,2-dihydronaphthalene. Toluene dioxygenase of Pseudomonas putida F39/D oxidizes 1,2-dihydronaphthalene to (+)-cis-(1S,2R)-dihydroxy-1,2,3,4-tetrahydronaphthalene, (+)-(1R)-hydroxy-1,2-dihydronaphthalene, and (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene. In contrast, naphthalene dioxygenase of Pseudomonas sp. strain NCIB 9816/11 oxidizes 1,2-dihydronaphthalene to the opposite enantiomer, (-)-cis-(1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene and the identical (+)-cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene. Recombinant Escherichia coli strains expressing the structural genes for toluene and naphthalene dioxygenases confirmed the involvement of these enzymes in the reactions catalyzed by strains F39/D and NCIB 9816/11. 1-Hydroxy-1,2-dihydronaphthalene was not formed by strains expressing naphthalene dioxygenase. These results coupled with time course studies and deuterium labelling experiments indicate that, in addition to direct dioxygenation of the olefin, both enzymes have the ability to desaturate (dehydrogenate) 1,2-dihydronaphthalene to naphthalene, which serves as a substrate for cis dihydroxylation.


Short- and Long-term Pulmonary Outcome of Palivizumab in Children Born Extremely Prematurely.
Palivizumab reduces the severity of respiratory syncytial virus infection in premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely. Infants born before 29 weeks' gestation in 2000 to 2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared with age-matched children who received palivizumab prophylaxis during the first respiratory syncytial virus season. Sixty-three children with a mean age 8.9 years were included: 30 had received palivizumab and 33 had not (control subjects). The groups were similar in terms of gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation. Fifty-three percent of the palivizumab group, compared with 39% of the control group, had bronchopulmonary dysplasia (P = .14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and in 70% of control subjects (P = .008); respective hospitalization rates were 33% and 70% (P = .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV1 < 1 mg/mL) were 33% and 48%, respectively (P = .38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups. Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it did not affect pulmonary outcome at school age.


Visualization of the exocytosis/endocytosis secretory cycle in cultured adrenal chromaffin cells.
Cultured bovine adrenal medullary chromaffin cells were stimulated to secrete catecholamines by addition of veratridine or nicotine. The formation of an exocytotic pit exposes a major secretory granule membrane antigen, the enzyme dopamine beta-hydroxylase, to the external medium. By including antiserum to this enzyme in the medium, we were able to visualize sites of exocytosis by decoration of bound antibody using a fluorescent second antibody. Internalization of this antibody-antigen complex was then followed in chase experiments: approximately half the surface complex was internalized in 15-30 min. In other experiments, secretion was triggered in the absence of antiserum, and surface enzyme was revealed by binding antibodies at various times after secretion had been halted by an antagonist. Surface patches of antigen remained discrete from the bulk of the plasma membrane for at least 30 min, although a substantial proportion of the antigen was internalized within this time. Cell surface concanavalin A receptors were internalized at a roughly similar rate, suggesting that mechanisms may be similar. After internalization, chromaffin granule membranes fused to larger structures, possibly lysosomes, and were transported over a few hours to the perinuclear region of the cell.


Potential protective effect of resveratrol on acoustic trauma: electron microscopy study.
To investigate the potential preventive effect of resveratrol in rats exposed to acoustic trauma (AT). In this experimental study, Wistar albino rats were divided into three groups: Group 1 (Control, n = 6), Group 2 (AT, n = 6), and Group 3 (resveratrol + AT). The rats in Group 2 were exposed to AT. The rats in Group 3 received resveratrol (300 mg/kg/day) via gavage for 7 days. On day 7, the rats were exposed to AT 10 min following resveratrol treatment. Histological sections of the cochleae were examined using light microscopy, transmission (TEM), and scanning electron microscopy (SEM). The cochlear hair cells, stereocilia, and Deiters' cells of the control group appeared normal in all microscopic evaluations. In Group 2, light microscopy revealed predominantly inner hair cell loss, although the outer hair cells were affected. TEM and SEM examination showed severe loss of stereocilia and SEM revealed stereocilia arranged in an asymmetric array. The cochlear structure in Group 3 appeared well preserved under the light microscope, and although TEM and SEM revealed stereocilia loss, the hair cells and stereocilia appeared near normal compared with those of Group 2. Resveratrol may have a protective effect against AT damage in the cochlea, most likely through its antioxidant activity. Our results may be useful for studies in humans exposed to AT and noise-induced hearing loss related to chronic exposure to occupational noise.


New-Onset Atrial Arrhythmias Are Independently Associated With In-Hospital Mortality in Veno-Venous Extracorporeal Membrane Oxygenation.
To explore if atrial arrhythmias are associated with in-hospital mortality in veno-venous extracorporeal membrane oxygenation (VV-ECMO) patients. Retrospective observational cohort study. Quaternary care academic medical center. Patients with respiratory failure requiring VV-ECMO for >24 hours between January 1, 2016, and January 1, 2019. None, observational study. Two hundred nineteen VV-ECMO patients were included. Patients were stratified by absence or presence of clinically significant atrial arrhythmias during the VV-ECMO run. Atrial arrhythmias were defined as either atrial fibrillation or atrial flutter that occurred during VV-ECMO and required pharmacologic or electrical intervention. The primary outcome was in-hospital mortality. Secondary outcomes included a composite of thrombotic events, which included ischemic stroke and on-pump arterial thrombosis. Other objectives of this analysis included characterization of atrial arrhythmia incidence, risk factors, and management. A total of 67 patients (30.5%) experienced new-onset atrial arrhythmias post-ECMO cannulation. Age, male sex, and norepinephrine use were independently associated with atrial arrhythmia development. In-hospital mortality was significantly higher in the atrial arrhythmia group (38.8% v 19.1%; p = 0.003). In the multivariate logistic regression analysis, atrial arrhythmias during VV-ECMO were independently associated with increased odds of in-hospital mortality (odds ratio, 2.21; 95% confidence interval, 1.08-4.55; p = 0.03), after controlling for Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score, acute renal failure, total norepinephrine dose, and total cannulation time. New-onset atrial arrhythmias are a frequent complication during VV-ECMO and are independently associated with excessive in-hospital mortality. Thus, their presence may serve as an important prognostic tool in this patient population.


Secondhand smoke and earaches in adolescents: the Florida Youth Cohort Study.
The association between second-hand smoke exposure and adolescent middle ear problems has not been examined. A random sample stratified by region was drawn from a list that included approximately 40% of all Florida households with children in grades 4-7. A total of 785 Florida adolescents initially enrolled in the 4th-7th grade participated in three telephone interviews conducted over a 24-month period. At the round 3 interview, 10.3% of participants reported one or more earaches within the previous 30 days. Several second-hand smoke exposure questions asked at each of the three interviews were associated with the number of reported earaches. Stepwise polytomous logistic regression indicated that parental smoking inside the home reported at the round 3 interview was associated with the number of reported earaches (OR=3.11, 95% CI=1.70-5.66). Once this variable was selected, none of the other second-hand smoke exposure variables offered additional predictive value (p>.1). None of the non-second-hand smoke exposure variables, including the participant's own history of tobacco use, had any association with the reporting of earaches (p>.05). Second-hand smoke exposure is associated with self-reported earaches in adolescents. These findings should be replicated in a study in which clinical measures of middle ear function are performed.


Fibrodysplasia ossificans progressiva: a human genetic disorder of extraskeletal bone formation, or--how does one tissue become another?
Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis—a developmental process occurring during embryonic skeletal formation—is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone-forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extraskeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extraskeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occur during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation. In addition to postnatal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly known as ALK2). This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this receptor during tissue development and homeostasis.


Hydrogen mobility in the lightest reversible metal hydride, LiBeH3.
Lithium-beryllium metal hydrides, which are structurally related to their parent compound, BeH2, offer the highest hydrogen storage capacity by weight among the metal hydrides (15.93 wt. % of hydrogen for LiBeH3). Challenging synthesis protocols have precluded conclusive determination of their crystallographic structure to date, but here we analyze directly the hydrogen hopping mechanisms in BeH2 and LiBeH3 using quasielastic neutron scattering, which is especially sensitive to single-particle dynamics of hydrogen. We find that, unlike its parent compound BeH2, lithium-beryllium hydride LiBeH3 exhibits a sharp increase in hydrogen mobility above 265 K, so dramatic that it can be viewed as melting of hydrogen sublattice. We perform comparative analysis of hydrogen jump mechanisms observed in BeH2 and LiBeH3 over a broad temperature range. As microscopic diffusivity of hydrogen is directly related to its macroscopic kinetics, a transition in LiBeH3 so close to ambient temperature may offer a straightforward and effective mechanism to influence hydrogen uptake and release in this very lightweight hydrogen storage compound.


Melanogenesis inhibition due to NADH.
The effect of NADH on melanogenesis under aerobic conditions involves three types of reaction: (a) acting as tyrosinase substrate (a competitive substrate of L-tyrosine and L-DOPA), (b) irreversible inactivation acting as a suicide substrate of tyrosinase, and (c) non-enzymatic reduction of o-dopaquinone by NADH. Under anaerobic conditions, NADH irreversibly inhibits the enzymatic forms met-tyrosinase and deoxy-tyrosinase. In this paper, we kinetically characterize this coenzyme as it acts as a tyrosinase suicide substrate and propose a kinetic mechanism to explain its oxidation by tyrosinase. In addition, the compound is characterized as an irreversible inhibitor of met-tyrosinase and deoxy-tyrosinase.


Structure and assembly of a T=1 virus-like particle in BK polyomavirus.
In polyomaviruses the pentameric capsomers are interlinked by the long C-terminal arm of the structural protein VP1. The T=7 icosahedral structure of these viruses is possible due to an intriguing adaptability of this linker arm to the different local environments in the capsid. To explore the assembly process, we have compared the structure of two virus-like particles (VLPs) formed, as we found, in a calcium-dependent manner by the VP1 protein of human polyomavirus BK. The structures were determined using electron cryomicroscopy (cryo-EM), and the three-dimensional reconstructions were interpreted by atomic modeling. In the small VP1 particle, 26.4 nm in diameter, the pentameric capsomers form an icosahedral T=1 surface lattice with meeting densities at the threefold axes that interlinked three capsomers. In the larger particle, 50.6 nm in diameter, the capsomers form a T=7 icosahedral shell with three unique contacts. A folding model of the BKV VP1 protein was obtained by alignment with the VP1 protein of simian virus 40 (SV40). The model fitted well into the cryo-EM density of the T=7 particle. However, residues 297 to 362 of the C-terminal arm had to be remodeled to accommodate the higher curvature of the T=1 particle. The loops, before and after the C-terminal short helix, were shown to provide the hinges that allowed curvature variation in the particle shell. The meeting densities seen at the threefold axes in the T=1 particle were consistent with the triple-helix interlinking contact at the local threefold axes in the T=7 structure.


Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function.
A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping. The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C). TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n=4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (>8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5-8.9 U/ml RBC). There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.