Influence of stromal cells on lymphocyte adhesion and migration on endothelial cells.
Methods are described for analysing adhesion and migration of isolated lymphocytes on endothelial cell monolayers which have been co-cultured with different stromal cells, with or without additional cytokine treatment. The different cells types are grown on opposite sides of 3.0- or 0.4-mum pore filters depending on whether migration through the whole construct is to be analysed or adhesion to the endothelial cells alone. Assays may be "static" or filters can be incorporated into flow chambers so that cell behaviour can be directly observed under conditions simulating those in vivo. In general, by choice of method, one can evaluate efficiency of attachment and ability of cells to migrate across the endothelial monolayer, through the filter and through the stromal cell layer. Fluorescence microscopic examination of fixed filters can be used, e.g. to ascertain whether lymphocytes are retained by stromal cells. In general, static assays have the higher throughput and greatest ease of use, while the flow-based assays are more physiologically relevant and allow detailed recording of cell behaviour in real time.


Neonatal facial coding system scores and spectral characteristics of infant crying during newborn circumcision.
To determine the relations between Neonatal Facial Coding System (NFCS) scores and measures of infant crying during newborn circumcision. Video and audio recordings were made of infant facial activity and cry sounds, respectively, during the lysis phase of circumcisions of 44 healthy term males (<3 d of age). All infants received topical analgesia before circumcision. NFCS scores were determined by blinded assistant from video recordings of facial activity. Measures of infant crying were determined via spectrum analysis of audio recordings by a blinded, independent researcher. Pearson product-moment correlations were used to examine relationship between NFCS scores and measures of crying. Principal component factor analysis detected dimensions underlying related measures of crying. Factor scores from a factor analysis were used in stepwise linear regression to predict NFCS scores. Higher NFCS scores correlated with lower peak fundamental frequency of crying (P<0.01) and with higher amplitudes of crying at peak fundamental frequency and dominant frequency and in overall cry sample (P<0.01). The factor analysis showed 3 significant orthogonal dimensions underlying measures of crying: Power and Velocity (amplitude and rapidity), Pitch of Crying (frequency characteristics), and Infant Arousal (turbulence and intensity) accounting for 42.3%, 17.8%, and 14.6% of variance, respectively. A regression analysis showed all 3 factor scores accounted for significant and separate portions of variance (P<0.001). The best predictor of NFCS score was Power and Velocity (P<0.002), followed by Infant Arousal (P<0.002), and Pitch of Crying (P<0.007). These data provide some of the first known evidence linking specific measures of infant crying with an independent, validated measure of pain.


Lifetime learning as a factor in life history education.
An artificial life approach is taken to explore the effect that lifetime learning can have on the evolution of certain life history traits, in particular the periods of protection that parents offer young, and the age at first reproduction of those young. The study begins by simulating the evolution of simple artificial neural network systems that must learn quickly to perform well on simple classification tasks, and determining if and when extended periods of parental protection emerge. It is concluded that longer periods of parental protection of children do offer clear learning advantages and better adult performance, but only if procreation is not allowed during the protection period. In this case, a compromise protection period evolves that balances the improved learning performance against reduced procreation period. The crucial properties of the neural learning processes are then abstracted out to explore the possibility of studying the effect of learning more generally and with better computational efficiency. Throughout, the implications of these stimulations for more realistic scenarios are discussed.


Metabolic Control Analysis of glycolysis in tuber tissue of potato (Solanum tuberosum): explanation for the low control coefficient of phosphofructokinase over respiratory flux.
We have applied Metabolic Control Analysis (MCA) in an attempt to determine the distribution of glycolytic flux control between the steps of glycolysis in aged disks of potato tuber under aerobic conditions, using concentrations of glycolytic metabolites in tuber tissue from a range of transgenic potato plants and published enzyme kinetic data. We modelled the substrate and effector kinetics of potato tuber phosphofructokinase (PFK) by reanalysing published results. Despite the scarcity of reliable kinetic data, our results are in agreement with experimental findings namely that, under the conditions described, PFK has little control over glycolytic flux. Furthermore our analysis predicts that under these conditions far more control lies in the dephosphorylation of phosphoenolpyruvate and/or in the steps beyond. We have validated the results of our analysis in two ways. First, predictions based on calculated concentration control coefficients from the analysis show generally good agreement with observed metabolite deviation indices discussed in the preceding paper [Thomas, Mooney, Burrell, and Fell (1997) Biochem. J. 322, 111-117]. Second, sensitivity analysis of our results shows that the calculated control coefficients are robust to errors in the elasticities used in the analysis, of which relatively few need to be known accurately. Experimental and control analysis results agree with previous predictions of MCA that strong co-operative feedback inhibition of enzymes serves to move flux control downstream of the inhibiting metabolite. We conclude that MCA can successfully model the outcome of experiments in the genetic manipulation of enzyme amounts.


Emission Enhancement and Intermittency in Polycrystalline Organolead Halide Perovskite Films.
Inorganic-organic halide organometal perovskites have demonstrated very promising performance for opto-electronic applications, such as solar cells, light-emitting diodes, lasers, single-photon sources, etc. However, the little knowledge on the underlying photophysics, especially on a microscopic scale, hampers the further improvement of devices based on this material. In this communication, correlated conventional photoluminescence (PL) characterization and wide-field PL imaging as a function of time are employed to investigate the spatially- and temporally-resolved PL in CH₃NH₃PbI3-xClx perovskite films. Along with a continuous increase of the PL intensity during light soaking, we also observe PL blinking or PL intermittency behavior in individual grains of these films. Combined with significant suppression of PL blinking in perovskite films coated with a phenyl-C61-butyric acid methyl ester (PCBM) layer, it suggests that this PL intermittency is attributed to Auger recombination induced by photoionized defects/traps or mobile ions within grains. These defects/traps are detrimental for light conversion and can be effectively passivated by the PCBM layer. This finding paves the way to provide a guideline on the further improvement of perovskite opto-electronic devices.


Nationwide assessment of insecticide susceptibility in Anopheles gambiae populations from Zimbabwe.
The scale-up of malaria interventions in sub-Saharan Africa has been accompanied by a dramatic increase in insecticide resistance in Anopheles spp. In Zimbabwe resistance to pyrethroid insecticides was reported in Gokwe District in 2008. This study reports results of the first nation-wide assessment of insecticide susceptibility in wild populations of Anopheles gambiae sensu lato (s.l.) in Zimbabwe, and provides a comprehensive review of the insecticide resistance status of An. gambiae s.l. in southern African countries. World Health Organization (WHO) insecticide susceptibility tests were performed on 2,568 field collected mosquitoes originating from 13 sentinel sites covering all endemic regions in Zimbabwe in 2011-2012. At each site, 24-hour mortality and knock-down values for 50% and 90% of exposed mosquitoes (KD50 and KD90, respectively) were calculated for pools of 20-84 (mean, 54) mosquitoes exposed to 4% DDT, 0.1% bendiocarb, 0.05% λ-cyhalothrin or 5% malathion. Susceptibility results from Zimbabwe were compiled with results published during 2002-2012 for all southern African countries to investigate the resistance status of An. gambiae s.l. in the region. Using WHO criteria, insecticide resistance was not detected at any site sampled and for any of the insecticide formulations tested during the malaria transmission season in 2012. Knock-down within 1 hr post-insecticide exposure ranged from 95% to 100%; mortality 24 hours post-insecticide exposure ranged from 98% to 100%. Despite the lack of insecticide resistance, high variability was found across sites in KD50 and KD90 values. A total of 24 out of 64 (37.5%) sites in southern Africa with reported data had evidence of phenotypic insecticide resistance in An. gambiae s.l. to at least one insecticide. Despite a long history of indoor residual spraying of households with insecticide, up to 2012 there was no evidence of phenotypic resistance to any of the four insecticide classes in An. gambiae s.l. collected across different eco-epidemiological areas in Zimbabwe. Results reinforce the need for careful monitoring over time in sentinel sites in order to detect the potential emergence and propagation of insecticide resistance as insecticidal vector control interventions in Zimbabwe continue to be implemented.


Targeted vaccination in healthy school children - Can primary school vaccination alone control influenza?
The UK commenced an extension to the seasonal influenza vaccination policy in autumn 2014 that will eventually see all healthy children between the ages of 2-16 years offered annual influenza vaccination. Models suggest that the new policy will be both highly effective at reducing the burden of influenza as well as cost-effective. We explore whether targeting vaccination at either primary or secondary schools would be more effective and/or cost-effective than the current strategy. An age-structured deterministic transmission dynamic SEIR-type mathematical model was used to simulate a national influenza outbreak in England. Costs including GP consultations, hospitalisations due to influenza and vaccinations were compared to potential gains in quality-adjusted life years achieved through vaccinating healthy children. Costs and benefits of the new JCVI vaccination policy were estimated over a single season, and compared to the hypothesised new policies of targeted and heterogeneous vaccination. All potential vaccination policies were highly cost-effective. Influenza transmission can be eliminated for a particular season by vaccinating both primary and secondary school children, but not by vaccinating only one group. The most cost-effective policy overall is heterogeneous vaccination coverage with 48% uptake in primary schools and 34% in secondary schools. The Joint Committee on Vaccination and Immunisation can consider a modification to their policy of offering seasonal influenza vaccinations to all healthy children of ages 2-16 years.


Multi-wavelength laser from dye-doped cholesteric polymer films.
A multi-wavelength laser is demonstrated using a dye-doped cholesteric polymer film whose reflection bandwidth is broadened with several oscillations. Due to the abrupt change of the density of state between oscillation peak and valley, each oscillation functions as a photonic band gap for generating a laser wavelength under the excitation of a pumping laser. As a result, a multiple wavelength laser is generated. Results indicate that the dye-doped cholesteric liquid crystal polymer film is a good candidate for fabricating broadband lasers such as white light lasers. Potential applications include experimental testing of laser materials, identification markers, information displays, and inertial confinement laser fusion.


Effective DNA/RNA co-extraction for analysis of microRNAs, mRNAs, and genomic DNA from formalin-fixed paraffin-embedded specimens.
Retrospective studies of archived human specimens, with known clinical follow-up, are used to identify predictive and prognostic molecular markers of disease. Due to biochemical differences, however, formalin-fixed paraffin-embedded (FFPE) DNA and RNA have generally been extracted separately from either different tissue sections or from the same section by dividing the digested tissue. The former limits accurate correlation whilst the latter is impractical when utilizing rare or limited archived specimens. For effective recovery of genomic DNA and total RNA from a single FFPE specimen, without splitting the proteinase-K digested tissue solution, we optimized a co-extraction method by using TRIzol and purifying DNA from the lower aqueous and RNA from the upper organic phases. Using a series of seven different archived specimens, we evaluated the total amounts of genomic DNA and total RNA recovered by our TRIzol-based co-extraction method and compared our results with those from two commercial kits, the Qiagen AllPrep DNA/RNA FFPE kit, for co-extraction, and the Ambion RecoverAll™ Total Nucleic Acid Isolation kit, for separate extraction of FFPE-DNA and -RNA. Then, to accurately assess the quality of DNA and RNA co-extracted from a single FFPE specimen, we used qRT-PCR, gene expression profiling and methylation assays to analyze microRNAs, mRNAs, and genomic DNA recovered from matched fresh and FFPE MCF10A cells. These experiments show that the TRIzol-based co-extraction method provides larger amounts of FFPE-DNA and -RNA than the two other methods, and particularly provides higher quality microRNAs and genomic DNA for subsequent molecular analyses. We determined that co-extraction of genomic DNA and total RNA from a single FFPE specimen is an effective recovery approach to obtain high-quality material for parallel molecular and high-throughput analyses. Our optimized approach provides the option of collecting DNA, which would otherwise be discarded or degraded, for additional or subsequent studies.


C. elegans chromosomes connect to centrosomes by anchoring into the spindle network.
The mitotic spindle ensures the faithful segregation of chromosomes. Here we combine the first large-scale serial electron tomography of whole mitotic spindles in early C. elegans embryos with live-cell imaging to reconstruct all microtubules in 3D and identify their plus- and minus-ends. We classify them as kinetochore (KMTs), spindle (SMTs) or astral microtubules (AMTs) according to their positions, and quantify distinct properties of each class. While our light microscopy and mutant studies show that microtubules are nucleated from the centrosomes, we find only a few KMTs directly connected to the centrosomes. Indeed, by quantitatively analysing several models of microtubule growth, we conclude that minus-ends of KMTs have selectively detached and depolymerized from the centrosome. In toto, our results show that the connection between centrosomes and chromosomes is mediated by an anchoring into the entire spindle network and that any direct connections through KMTs are few and likely very transient.


Improving communication between physicians and patients who speak a foreign language.
Communication between physicians and patients is particularly challenging when patients do not speak the local language (in Switzerland, they are known as allophones). To assess the effectiveness of an intervention to improve communication skills of physicians who deal with allophone patients. 'Before-and-after' intervention study, in which both patients (allophone and francophone) and physicians completed visit-specific questionnaires assessing the quality of communication. Two consecutive samples of patients attending the medical outpatient clinic of a teaching hospital in French-speaking Switzerland. The intervention consisted of training physicians in communicating with allophone patients and working with interpreters. French-speaking patients served as the control group. The outcomes measured were: patient satisfaction with care received and with communication during consultation; and provider (primary care physician) satisfaction with care provided and communication during consultation. At baseline, mean scores of patients' assessments of communication were lower for allophone than for francophone patients. At follow-up, five out of six of the scores of allophone patients showed small increases (P < 0.05) when compared with French-speaking patients: explanations given by physician; respectfulness of physician; communication; overall process of the consultation; and information about future care. In contrast, physicians' assessments did not change significantly. Finally, after the intervention, the proportion of consultations with allophone patients in which professional interpreters were present increased significantly from 46% to 67%. The quality of communication as perceived by allophone patients can be improved with specific training aimed at primary care physicians.


Order to Disorder Transition in a Coarsening Two-Dimensional Foam.
We quantify the spatiotemporal transformation of a monodisperse and well-ordered monolayer of bubbles, as they undergo Ostwald ripening, by tracking the size polydispersity of the bubbles and local ordering of the foam. After nuclei of disorder appear at random locations, the transition takes place through two successive phases: first, the disordered regions grow while the value of polydispersity increases slowly, then the polydispersity grows rapidly once the disordered zones begin to merge together. The transition is captured by a modified logistic model.


How patients view probiotics: findings from a multicenter study of patients with inflammatory bowel disease and irritable bowel syndrome.
Patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) have access to a growing number of probiotic products marketed to improve digestive health. It is unclear how patients make decisions about probiotics and what role they expect their gastroenterologists to play as they consider using probiotics. Understanding patients' knowledge, attitudes and expectations of probiotics may help gastroenterologists engage patients in collaborative discussions about probiotics. Focus groups were conducted with patients with IBD and IBS at the Cleveland Clinic, Mayo Clinic, and Johns Hopkins University. Inductive analytic methods were used to identify common themes and draw interpretations from focus group narratives. One hundred thirty-six patients participated in 22 focus groups between March and August 2009. Patients viewed probiotics as an appealing alternative to pharmaceutical drugs and understood probiotics as a more "natural," low-risk therapeutic option. Many patients were hesitant to use them without consulting their gastroenterologists. Patients would weigh the risks and benefits of probiotics, their disease severity and satisfaction with current treatments when considering probiotic use. Patients are interested in probiotics but have many unanswered questions about their use. Our findings suggest that patients with IBD and IBS will look to gastroenterologists and other clinicians as trustworthy advisors regarding the utility of probiotics as an alternative or supplement to pharmaceutical drugs. Gastroenterologists and other clinicians who care for patients with these diseases should be prepared to discuss the potential benefits and risks of probiotics and assist patients in making informed decisions about their use.


Development of a general analysis and unfolding scheme and its application to measure the energy spectrum of atmospheric neutrinos with IceCube: IceCube Collaboration.
We present the development and application of a generic analysis scheme for the measurement of neutrino spectra with the IceCube detector. This scheme is based on regularized unfolding, preceded by an event selection which uses a Minimum Redundancy Maximum Relevance algorithm to select the relevant variables and a random forest for the classification of events. The analysis has been developed using IceCube data from the 59-string configuration of the detector. 27,771 neutrino candidates were detected in 346 days of livetime. A rejection of 99.9999 % of the atmospheric muon background is achieved. The energy spectrum of the atmospheric neutrino flux is obtained using the TRUEE unfolding program. The unfolded spectrum of atmospheric muon neutrinos covers an energy range from 100 GeV to 1 PeV. Compared to the previous measurement using the detector in the 40-string configuration, the analysis presented here, extends the upper end of the atmospheric neutrino spectrum by more than a factor of two, reaching an energy region that has not been previously accessed by spectral measurements.


Noncoding RNAs Set the Stage for RNA Polymerase II Transcription.
Effective synthesis of mammalian messenger (m)RNAs depends on many factors that together direct RNA polymerase II (pol II) through the different stages of the transcription cycle and ensure efficient cotranscriptional processing of mRNAs. In addition to the many proteins involved in transcription initiation, elongation, and termination, several noncoding (nc)RNAs also function as global transcriptional regulators. Understanding the mode of action of these non-protein regulators has been an intense area of research in recent years. Here, we describe how these ncRNAs influence key regulatory steps of the transcription process, to affect large numbers of genes. Through direct association with pol II or by modulating the activity of transcription or RNA processing factors, these regulatory RNAs perform critical roles in gene expression.


Metabolic cost, mechanical work, and efficiency during walking in young and older men.
To investigate mechanical work, efficiency, and antagonist muscle co-activation with a view to better understand the cause of the elevated metabolic cost of walking (C(W)) in older adults. Metabolic, mechanical and electromyographic measurements were made as healthy young (YOU; n = 12, age = 27 +/- 3 years) and older (OLD; n = 20, age = 74 +/- 3 years) men of equivalent body mass and leg length walked on a treadmill at four speeds (ranging from 0.83 to 1.67 m s(-1)). Net (above resting) C(W), determined by indirect calorimetry was 31% higher (average across speeds) in OLD (P < 0.05). The integrity of the passive pendulum like interchange of mechanical energies of the centre of mass (COM(B)), an energy-saving mechanism, was maintained in OLD. Furthermore, total mechanical work, determined from fluctuations in mechanical energy of COM(B) and of body segments relative to COM(B), was not significantly elevated in OLD. This resulted in a lower efficiency in OLD (-17%, P < 0.05). Co-activation, temporally quantified from electromyography recordings, was 31% higher in OLD for antagonist muscles of the thigh (P < 0.05). Thigh co-activation was moderately correlated with C(W) at three speeds (r = 0.38-0.52, P < 0.05). Healthy septuagenarians with no gait impairment have an elevated C(W) which is not explained by an elevation in whole body mechanical work. Increased antagonist muscle co-activation (possibly an adaptation to ensure adequate joint stability) may offer partial explanation of the elevated C(W).


Trisomy 22. Two new cases and delineation of the phenotype.
Two unrelated children, not affected with Down's syndrome, with strikingly similar phenotypes and an extra G-like chromosome are presented. Quinacrine and trypsin-Giemsa banding identified the extra chromosome as No. 22. The phenotype of these patients and the review of 15 additional similar cases from the literature permit a definition of the cardinal features of trisomy 22; mental and growth retardation, microcephaly and craniofacial asymmetry, strabismus, beaked and prominent nose, long philtrum, cleft palate, micrognathia, large low set ears with preauricular tags and/or pits, long slender fingers, congenital heart disease, inguinal hernia, and hip dislocation.


Predicting tissue specific transcription factor binding sites.
Studies of gene regulation often utilize genome-wide predictions of transcription factor (TF) binding sites. Most existing prediction methods are based on sequence information alone, ignoring biological contexts such as developmental stages and tissue types. Experimental methods to study in vivo binding, including ChIP-chip and ChIP-seq, can only study one transcription factor in a single cell type and under a specific condition in each experiment, and therefore cannot scale to determine the full set of regulatory interactions in mammalian transcriptional regulatory networks. We developed a new computational approach, PIPES, for predicting tissue-specific TF binding. PIPES integrates in vitro protein binding microarrays (PBMs), sequence conservation and tissue-specific epigenetic (DNase I hypersensitivity) information. We demonstrate that PIPES improves over existing methods on distinguishing between in vivo bound and unbound sequences using ChIP-seq data for 11 mouse TFs. In addition, our predictions are in good agreement with current knowledge of tissue-specific TF regulation. We provide a systematic map of computationally predicted tissue-specific binding targets for 284 mouse TFs across 55 tissue/cell types. Such comprehensive resource is useful for researchers studying gene regulation.


Extended-release naltrexone for alcohol dependence: persistence and healthcare costs and utilization.
Evaluate persistence with treatment, healthcare costs, and utilization in stably enrolled Aetna Behavioral Health members receiving extended-release naltrexone (XR-NTX) for alcohol use dependence compared with oral medications and psychosocial therapy only. Historical cohort study. Aetna beneficiaries with stable enrollment (at least 6 months before and after index treatment) who initiated pharmacotherapy with XR-NTX (n = 211), disulfiram (n = 1043), oral naltrexone (n = 1408), acamprosate (n = 2479), or psychosocial therapy only (n = 6374) for alcohol use disorders between January 1, 2007, and December 31, 2008, were extracted and deidentified from Aetna's nationwide claims and utilization database. Survival analysis compared persistence with XR-NTX versus oral pharmacotherapies. Difference-in-differences analysis compared healthcare costs and utilization among patients receiving XR-NTX versus oral pharmacotherapies and psychosocial therapy only. Multivariate analyses controlled for demographics. Patients taking acamprosate and disulfiram were more likely to discontinue treatment than patients taking naltrexone, and patients given oral naltrexone were more likely to discontinue treatment than those given XR-NTX. Outpatient behavioral health treatment visits increased in all study groups. Nonpharmacy healthcare costs and utilization of inpatient and emergency services decreased in the XR-NTX group relative to other study groups. Patients receiving XR-NTX persisted with treatment longer than patients receiving oral alcohol use-disorder medications or psychosocial therapy only, and had decreased inpatient and emergency healthcare costs and utilization compared with those receiving other medications.


Engineering Unique Ball-In-Ball Structured (Ni0.33Co0.67)9S8@C Nanospheres for Advanced Sodium Storage.
Constructing hollow architectures based on metal sulfides is of great interest for high-performance electrode materials for sodium-ion batteries because of their intriguing properties and various applications. However, the relatively low volumetric density and high fragile structure are the obstacles blocking the development of hollow-structured electrode materials. In this work, ball-in-ball structured (Ni0.33Co0.67)9S8@C nanospheres have been synthesized by using NiCo-glycerate as the precursor via solvothermal reaction, which was followed by a carbon coating treatment. In this structural design, hollow cavities are generated between the inner and outer balls to effectively accommodate the volume changes of the metal sulfides in the processes of charging/discharging, whereas the uniform carbon coating can increase the electrical conductivity and maintain the structural stability during repeated cycling. The Rietveld refinement, in situ X-ray diffraction, and ex situ X-ray photoelectron spectroscopy analyses provide evidence for an enlarged lattice parameter, weaker Co-S and Ni-S bondings, and a synergistic effect in (Ni0.33Co0.67)9S8@C toward boosting the conversion reaction and reversible formation of sulfur in the fully charged state, with sulfur trapped within the composite to additionally account for the superior cycling stability of this material. Capacitive behavior has been verified to dominate the electrochemical reaction, enabling fast charge-transport kinetics. Impressively, the double structural protection combined with the free hollow space and complete carbon layer endows the (Ni0.33Co0.67)9S8@C nanospheres with good electrochemical performance, featuring high cyclability and good rate capability.


Conformational changes in the metallo-beta-lactamase ImiS during the catalytic reaction: an EPR spectrokinetic study of Co(II)-spin label interactions.
Metallo-beta-lactamases are responsible for conferring antibiotic resistance on certain pathogenic bacteria. In consequence, the search for inhibitors that may be useful in combating antibiotic resistance has fueled much study of the active sites of these enzymes. There exists circumstantial evidence that the binding of substrates and inhibitors to metallo-beta-lactamases may involve binding to the organic part of the molecule, in addition to or prior to binding to one or more active site metal ions. It has also been postulated that a conformational change may accompany this putative binding. In the present study, electron paramagnetic resonance spectrokinetic study of a spin-labeled variant of the class B2 metallo-beta-lactamase ImiS identified movement of a component residue on a conserved alpha-helix in a catalytically competent time upon formation of a transient reaction intermediate with the substrate imipenem. In a significant subpopulation of ImiS, this conformational change was not associated with substrate binding to the active site metal ion but, rather, represents a distinct step in the reaction with ImiS. This observation has implications regarding the determinants of substrate specificity in metallo-beta-lactamases and the design of potentially clinically useful inhibitors.


Migration and Health in the Construction Industry: Culturally Centering Voices of Bangladeshi Workers in Singapore.
Construction workers globally face disproportionate threats to health and wellbeing, constituted by the nature of the work they perform. The workplace fatalities and lost-time injuries experienced by construction workers are significantly greater than in other forms of work. This paper draws on the culture-centered approach (CCA) to dialogically articulate meanings of workplace risks and injuries, voiced by Bangladeshi migrant construction workers in Singapore. The narratives voiced by the participants suggest an ecological approach to workplace injuries in the construction industries, attending to food insecurity, lack of sleep, transportation, etc. as contextual features of work that shape the risks experienced at work. Moreover, participant voices point to the barriers in communication, lack of understanding, and experiences of incivility as features of work that constitute the ways in which they experience injury risks. The overarching discourses of productivity and efficiency constitute a broader climate of threats to worker safety and health.


The sensitive capillary electrophoretic-LIF method for simultaneous determination of curcuminoids in turmeric by enhancing fluorescence intensities of molecules upon inclusion into (2-hydroxypropyl)-β-cyclodextrin.
Curcuminoids have received great attention in the past decades due to their health benefit properties. The aim of this study is to develop a very simple, rapid, and sensitive capillary zone electrophoresis technique coupled with a laser induced fluorescence detector (LIF) for the simultaneous determination of three major curcuminoids of turmeric, namely, curcumin, demethoxy curcumin (DMC), and bisdemethoxy curcumin (BDMC). Background electrolyte was selected as borate at pH 9.6 and (2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD) was added to prevent rapid alkali degradation of curcuminoids in buffer and to increase fluorescence intensities of molecules. With the addition of 2-HP-β-CD to the separation electrolyte, the fluorescence signal intensities of curcuminoids were enhanced considerably by 30, 40, and 54 fold for curcumin, DMC, and BDMC, respectively. The three curcuminoids of turmeric were fully separated and quantified in less than 4.5 min. The repeatability of the peak areas of curcuminoids for intra-day and inter-day experiments was in the satisfactory range of 2.26 and 2.55%, respectively. The LOD and LOQ values for the developed method were equal to or less than 0.081 and 0.270 μg/mL, respectively, for all curcuminoids. The developed method was successfully applied to find curcuminoids amount in turmeric samples and herbal supplements.


Pathogenicity and other genomic islands in plant pathogenic bacteria.
SUMMARY Pathogenicity islands (PAIs) were first described in uropathogenic E. coli. They are now defined as regions of DNA that contain virulence genes and are present in the genome of pathogenic strains, but absent from or only rarely present in non-pathogenic variants of the same or related strains. Other features include a variable G+C content, distinct boundaries from the rest of the genome and the presence of genes related to mobile elements such as insertion sequences, integrases and transposases. Although PAIs have now been described in a wide range of both plant and animal pathogens it has become evident that the general features of PAIs are displayed by a number of regions of DNA with functions other than pathogenicity, such as symbiosis and antibiotic resistance, and the general term genomic islands has been adopted. This review will describe a range of genomic islands in plant pathogenic bacteria including those that carry effector genes, phytotoxins and the type III protein secretion cluster. The review will also consider some medically important bacteria in order to discuss the range, acquisition and stabilization of genomic islands.


Local delivery of mesenchymal stem cells with poly-lactic-co-glycolic acid nano-fiber scaffold suppress arthritis in rats.
Mesenchymal stem cells (MSC) have been used recently for the treatment of autoimmune diseases in murine animal models due to the immunoregulatory capacity. Current utilization of MSC requires cells in certain quantity with multiple courses of administration, leading to limitation in clinical usage. Here we efficiently treated collagen-induced arthritis rats with a single local implantation with reduced number of MSC (2∼20% of previous studies) with nano-fiber poly-lactic-co-glycolic acid (nano-fiber) scaffold. MSC seeded on nano-fiber scaffold suppressed arthritis and bone destruction due to inhibition of systemic inflammatory reaction and immune response by suppressing T cell proliferation and reducing anti- type II collagen antibody production. In vivo tracing of MSC demonstrated that these cells remained within the scaffold without migrating to other organs. Meanwhile, in vitro culture of MSC with nano-fiber scaffold significantly increased TGF-β1 production. These results indicate an efficient utilization of MSC with the scaffold for destructive joints in rheumatoid arthritis by a single and local inoculation. Thus, our data may serve as a new strategy for MSC-based therapy in inflammatory diseases and an alternative delivery method for bone destruction treatment.


Psychosocial and Behavioral Characteristics of High-Risk Men Who Have Sex with Men (MSM) of Unknown HIV Positive Serostatus in Bangkok, Thailand.
HIV prevalence remains high in men who have sex with men (MSM) in Bangkok. Even though resources for HIV testing and treatment are available for all, a large proportion of MSM still do not get HIV tested. We studied high risk MSM who are unaware of their HIV status to help maximize effectiveness of our resources. Convenience sampling was conducted among MSM who came for HIV testing at the Thai Red Cross Anonymous Clinic and two popular drop-in centers in Bangkok. Inclusion criteria were MSM aged >18 years, have not been tested positive for HIV, who reported ≥1 of the following in the previous 6 months: condomless sex with a male, being a sex worker, or having a sexual transmitted infection diagnosis. Audio-Computer-Assisted Self-Interview was used to assess psychosocial profile, sexual risks, and HIV testing patterns prior to being informed of their HIV positive status. Among 499 high-risk MSM enrolled, the median age was 24.8 years and 112 (22 %) tested HIV-positive. Among the HIV-positive participants, 92 % self-identified as gay (versus bisexual), 39 % attained a bachelors degree or higher, 65 % had monthly income 10,000-29,999 baht ($280-830 USD), 10 % had vaginal or anal sex with a woman in the past 12 months, 39 % had condomless receptive sex with men and 21 % went to Lat Phrao to find a sexual partner. Compared to HIV negative MSM, HIV-positive MSM had less HIV testing: 31 % had ever been tested for HIV, 12 % had been tested in the past 6 months; but were more likely to guess correctly their positive status (31 %). Regarding psychosocial variables among HIV-positive MSM, 7 % had regular methamphetamine use in the past 3 months, 10 % had >2 sources of discrimination, and 8 % had >2 sources of discrimination due to being MSM. In multivariable model, age<30 year old, self-identified as gay, had monthly income <50,000 baht ($1400 USD), had anal sex with men in past 12 months, had >2 sources of discrimination because of being MSM, did not get HIV test in past 6 months, and guess of positive HIV were significantly associated with HIV positive status. Young MSM with lower socioeconomic status (SES) should be prioritized for innovative approaches to promoting awareness and uptake of HIV testing. Societal stigmatization of MSM should be addressed as a potential barrier to uptake of voluntary HIV testing. Resilience factors among these marginalized MSM who still test frequently and remain HIV-negative despite residing in a context with community viral loads and discrimination should also be studied in order to curb the HIV epidemic in Bangkok.


Exploring Multi-Use potentials in the Euro-Mediterranean sea space.
European seas are experiencing rapid development. The anthropogenic demand for marine resources and space exerts the need for novel concepts for sustainable resource exploitation and smart space allocation. Multi-Use (MU) is an emerging concept to overcome spatial claims and support Blue Growth, however its actual potentials and current status of implementation in different sea basins is to a large extent unexplored. An analytical framework using a mixed method approach is proposed for the identification and analysis of MU potentialities in eight EU countries of the Euro-Mediterranean sea basin. The paper addresses opportunities and challenges of ten existing and potential MU combinations driven by three maritime sectors: tourism, renewable energy and Oil & Gas industry. Opportunities and challenges for MU development were presented in terms of drivers, added values, barriers and impacts. Results show that highest potential for MU development are related to tourism-driven MU combinations (e.g. pescatourism), but also emerging MU potentials exist related to Floating Offshore Wind energy and aquaculture (Gulf of Lion) and the re-use of Oil & Gas decommissioned platforms (Northern-Central Adriatic Sea). Findings were discussed for their geospatial distribution and their policy, socio-economic, technical and environmental boundary conditions. Recommendations on actions to foster MU development in the Euro-Mediterranean sea space are provided.


Meta- and pooled analysis of GSTP1 polymorphism and lung cancer: a HuGE-GSEC review.
Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.


Cognition in Huntington's disease in manifest, premanifest and converting gene carriers over ten years.
Cognitive decline in Huntington's disease (HD) remains an area of inconsistencies, especially far from disease onset. To clarify the course of cognition in premanifest HD. Twenty-six premanifest HD, 19 manifest HD, and 87 control subjects were followed for ten years, using an extensive cognitive battery. Differences in baseline levels and change over time, on four factors (motor speed, global cognition, executive functioning (EF), and memory) were examined, using multilevel regression analyses. Converters were additionally analysed as a separate group. Also, the influence of motor speed and predicted years to disease onset on the cognitive factors was studied. Manifest HD subjects showed lower baseline scores compared to controls on the motor speed (p=0.002), memory (p<0.001) and EF (p<0.001). They additionally deteriorated over the ten-year follow-up on memory (p=0.01). Converters deteriorated on EF (p=0.04). Further analyses of premanifest subjects 'far from and close to predicted onset' revealed lower baseline scores for the 'close' group on EF, as compared to controls (p=0.001). They also deteriorated on memory (p=0.01). Motor speed substantially mediated the results of the three cognitive factors; when added as covariate to the model several baseline and slope differences for the cognitive factors ceased to be significant. Memory and EF are highly sensitive for ascertaining deterioration in premanifest HD gene carriers, especially in subjects close to onset. Lack of deterioration for the subjects further away from onset suggests that both domains are largely unaffected in those far from onset. Also, motor influence on cognition is substantial and should be taken into account in cognitive HD research.


Biological therapy in hereditary angioedema: transformation of a rare disease.
Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder.Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated.Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.


Progress in physical activity over the Olympic quadrennium.
On the eve of the 2012 summer Olympic Games, the first Lancet Series on physical activity established that physical inactivity was a global pandemic, and global public health action was urgently needed. The present paper summarises progress on the topics covered in the first Series. In the past 4 years, more countries have been monitoring the prevalence of physical inactivity, although evidence of any improvements in prevalence is still scarce. According to emerging evidence on brain health, physical inactivity accounts for about 3·8% of cases of dementia worldwide. An increase in research on the correlates of physical activity in low-income and middle-income countries (LMICs) is providing a better evidence base for development of context-relevant interventions. A finding specific to LMICs was that physical inactivity was higher in urban (vs rural) residents, which is a cause for concern because of the global trends toward urbanisation. A small but increasing number of intervention studies from LMICs provide initial evidence that community-based interventions can be effective. Although about 80% of countries reported having national physical activity policies or plans, such policies were operational in only about 56% of countries. There are important barriers to policy implementation that must be overcome before progress in increasing physical activity can be expected. Despite signs of progress, efforts to improve physical activity surveillance, research, capacity for intervention, and policy implementation are needed, especially among LMICs.


myExperiment: a repository and social network for the sharing of bioinformatics workflows.
myExperiment (http://www.myexperiment.org) is an online research environment that supports the social sharing of bioinformatics workflows. These workflows are procedures consisting of a series of computational tasks using web services, which may be performed on data from its retrieval, integration and analysis, to the visualization of the results. As a public repository of workflows, myExperiment allows anybody to discover those that are relevant to their research, which can then be reused and repurposed to their specific requirements. Conversely, developers can submit their workflows to myExperiment and enable them to be shared in a secure manner. Since its release in 2007, myExperiment currently has over 3500 registered users and contains more than 1000 workflows. The social aspect to the sharing of these workflows is facilitated by registered users forming virtual communities bound together by a common interest or research project. Contributors of workflows can build their reputation within these communities by receiving feedback and credit from individuals who reuse their work. Further documentation about myExperiment including its REST web service is available from http://wiki.myexperiment.org. Feedback and requests for support can be sent to firstname.lastname@example.com.


PhyloPythiaS+: a self-training method for the rapid reconstruction of low-ranking taxonomic bins from metagenomes.
Background. Metagenomics is an approach for characterizing environmental microbial communities in situ, it allows their functional and taxonomic characterization and to recover sequences from uncultured taxa. This is often achieved by a combination of sequence assembly and binning, where sequences are grouped into 'bins' representing taxa of the underlying microbial community. Assignment to low-ranking taxonomic bins is an important challenge for binning methods as is scalability to Gb-sized datasets generated with deep sequencing techniques. One of the best available methods for species bins recovery from deep-branching phyla is the expert-trained PhyloPythiaS package, where a human expert decides on the taxa to incorporate in the model and identifies 'training' sequences based on marker genes directly from the sample. Due to the manual effort involved, this approach does not scale to multiple metagenome samples and requires substantial expertise, which researchers who are new to the area do not have. Results. We have developed PhyloPythiaS+, a successor to our PhyloPythia(S) software. The new (+) component performs the work previously done by the human expert. PhyloPythiaS+ also includes a new k-mer counting algorithm, which accelerated the simultaneous counting of 4-6-mers used for taxonomic binning 100-fold and reduced the overall execution time of the software by a factor of three. Our software allows to analyze Gb-sized metagenomes with inexpensive hardware, and to recover species or genera-level bins with low error rates in a fully automated fashion. PhyloPythiaS+ was compared to MEGAN, taxator-tk, Kraken and the generic PhyloPythiaS model. The results showed that PhyloPythiaS+ performs especially well for samples originating from novel environments in comparison to the other methods. Availability. PhyloPythiaS+ in a virtual machine is available for installation under Windows, Unix systems or OS X on: https://github.com/algbioi/ppsp/wiki.


Sensory exploitation and cultural transmission: the late emergence of iconic representations in human evolution.
Iconic representations (i.e., figurative imagery and realistic art) only started to appear consistently some 45,000 years ago, although humans have been anatomically modern since 200,000-160,000 years ago. What explains this? Some authors have suggested a neurocognitive change took place, leading to a creative explosion, although this has been contested. Here, we examine the hypothesis that demographic changes caused cultural "cumulative adaptive evolution" and as such the emergence of modern symbolic behavior. This approach usefully explains the evolution of utilitarian skills and tools, and the creation of symbols to identify groups. However, it does not equally effectively explain the evolution of behaviors that may not be directly adaptive, such as the production of iconic representations like figurines and rock art. In order to shed light on their emergence, we propose to combine the above-mentioned cultural hypothesis with the concept of sensory exploitation. The concept essentially states that behavioral traits (in this case iconic art production) which exploit pre-existing sensory sensitivities will evolve if not hindered by costs (i.e., natural selection). In this view, iconic art traditions are evolved by piggy-backing on cumulative adaptive evolution. Since it is to date uncertain whether art has served any adaptive function in human evolution, parsimony demands paying more attention to the primary and a functional mechanism of sensory exploitation as opposed to mechanisms of models based exclusively on secondary benefits (such as Miller's, for instance, in which art is proposed to evolve as a sexual display of fitness).


An update on androgen deprivation therapy for prostate cancer.
Androgen deprivation therapy (ADT) with gonadal testosterone depletion is the frontline treatment for advanced prostate cancer. Other hormonal interventions have a role in the treatment of prostate cancer. We sought to examine systematically the evidence for hormonal interventions in prostate cancer, risks of ADT, and interventions that mitigate these risks. Search results for therapeutic studies were focused primarily on randomized controlled clinical trials, and the Jadad scale criteria were used to evaluate the quality of these studies. Four trials of the efficacy of intermittent ADT versus continuous ADT were included. One randomized study analysis and six postrandomization analyses were included on the effects of ADT on cardiovascular mortality. Seven randomized controlled trials of pharmacologic interventions were included for the treatment of metabolic effects due to ADT. One randomized trial of GnRH antagonist versus GnRH agonist was included. Six phase I/II clinical trials of secondary hormonal therapies with novel mechanisms of action were included. Randomized studies completed to date indicate that intermittent ADT might be equivalent to continuous ADT. Although adverse effects of ADT include risk factors for cardiovascular disease, effects on cardiovascular mortality are uncertain. Bone loss and increased risk of fracture may be effectively treated with pharmacologic interventions. Benefits of ADT must be balanced with a consideration of the risks.


Hepatocellular Carcinoma: Causes, Mechanism of Progression and Biomarkers.
Hepatocellular Carcinoma (HCC) is one of the most common malignant tumours in the world. It is a heterogeneous group of a tumour that vary in risk factor and genetic and epigenetic alteration event. Mortality due to HCC in last fifteen years has increased. Multiple factors including viruses, chemicals, and inborn and acquired metabolic diseases are responsible for its development. HCC is closely associated with hepatitis B virus, and at least in some regions of the world with hepatitis C virus. Liver injury caused by viral factor affects many cellular processes such as cell signalling, apoptosis, transcription, DNA repair which in turn induce important effects on cell survival, growth, transformation and maintenance. Molecular mechanisms of hepatocellular carcinogenesis may vary depending on different factors and this is probably why a large set of mechanisms have been associated with these tumours. Various biomarkers including α-fetoprotein, des-γ-carboxyprothrombin, glypican-3, golgi protein-73, squamous cell carcinoma antigen, circulating miRNAs and altered DNA methylation pattern have shown diagnostic significance. This review article covers up key molecular pathway alterations, biomarkers for diagnosis of HCC, anti-HCC drugs and relevance of key molecule/pathway/receptor as a drug target.


Health-based payment and computerized patient record systems.
Health care information technology is changing rapidly and dramatically. A small but growing number of clinicians, especially those in staff and group model HMOs and hospital-affiliated practices, are automating their patient medical records in response to pressure to improve quality and reduce costs. Computerized patient record systems in HMOs track risks, diagnoses, patterns of care, and outcomes across large populations. These systems provide access to large amounts of clinical information; as a result, they are very useful for risk-adjusted or health-based payment. The next stage of evolution in health-based payment is to switch from fee-for-service (claims) to HMO technology in calculating risk coefficients. This will occur when HMOs accumulate data sets containing records on provider-defined disease episodes, with every service linked to its appropriate disease episode for millions of patients. Computerized patient record systems support clinically meaningful risk-assessment models and protect patients and medical groups from the effects of adverse selection. They also offer significant potential for improving quality of care.


The role of fluoride and casein phosphopeptide/amorphous calcium phosphate in the prevention of erosive/abrasive wear in an in vitro model using hydrochloric acid.
To investigate the effect of various fluoride compounds and casein phosphopeptide/amorphous calcium phosphate (CPP-ACP) on the reduction of erosive/abrasive tooth wear. Forty enamel samples were prepared from bovine lower incisors, stratified and allocated to 4 groups (1-4). Samples in group 1 remained untreated and served as negative controls. The test samples were treated for 2 min/day as follows: group 2 amine/sodium fluoride gel (pH 4.8; 12,500 ppm), group 3 sodium fluoride gel (pH 7.1; 12,500 ppm) and group 4 CPP-ACP-containing mousse. De- and remineralization cycling was performed for 20 days with 6 erosive attacks for 20 s with HCl (pH 3.0) per day. Samples were stored in artificial saliva between cycles and overnight. Toothbrushing (15 s; 60 strokes/min; load 2.5 N) with a toothpaste slurry was performed each day before the first and 1 h after the last erosive exposure. Tooth wear was measured by comparing baseline surface profiles with the corresponding posttreatment profiles. Tooth wear was significantly reduced in groups 2 and 3 compared with group 1, while the enamel loss of group 4 was not significantly lower compared to the negative control group 1. Between the fluoride groups 2 and 3, no significant difference in tooth wear was recorded. Erosive/abrasive tooth wear under the conditions used could be reduced significantly by the daily application of fluoride gels, irrespective of the fluoride compound, while the application of CPP-ACP-containing mousse was less effective.


Chiropractic management of cow's milk protein intolerance in infants with sleep dysfunction syndrome: a therapeutic trial.
In addition to the more usual cutaneous, gastrointestinal, and respiratory problems, infants with cow's milk intolerance (CMI) may present with a disturbed sleep pattern. Frustrated mothers may turn to their doctor of chiropractic for assistance. This pilot study shows how a therapeutic trial may offer a realistic, noninvasive approach to the chiropractic management of infants with this clinical problem. A pilot study to describe the presentation and treatment of infants presenting with disturbed sleep patterns to a chiropractic clinic was undertaken. Infants fulfilling a clinical screening protocol for CMI were selected for a therapeutic trial. The sleep behavior of subjects was monitored over a 4-week period during which they were managed by dietary change and a high-impulse, low-amplitude whole-of-body chiropractic management protocol. Fifty-nine infants presented with disturbed sleep. Of these, 19 met the clinical criteria used to establish the diagnosis CMI. The mothers of breast-fed infants were counseled on how to implement a dairy-free diet, and those infants who were artificially fed were changed from cow's milk-based formulae to either a partially or wholly hydrolyzed formula. Fourteen achieved a stable sleep pattern within the study period. In 5 instances, the sleep pattern remained problematic, but other clinical evidence of hypersensitivity reactions attributable to CMI disappeared. By the end of the study, no subject had demonstrable evidence of either biomechanical derangement or functional neurologic imbalance. CMI should be considered as a possibility in infants with disturbed sleep patterns who present for chiropractic care. This study describes how a therapeutic trial involving dietary modification, parental counseling, and comprehensive chiropractic care may offer a noninvasive approach to excluding and/or managing this condition. Further research is required before definitive recommendations can be made.


Hardware accelerated optical alignment of lasers using beam-specific matched filters.
Accurate automated alignment of laser beams in the National Ignition Facility (NIF) is essential for achieving extreme temperature and pressure required for inertial confinement fusion. The alignment achieved by the integrated control systems relies on algorithms processing video images to determine the position of the laser beam images in real time. Alignment images that exhibit wide variations in beam quality require a matched-filter algorithm for position detection. One challenge in designing a matched-filter-based algorithm is to construct a filter template that is resilient to variations in imaging conditions while guaranteeing accurate position determination. A second challenge is to process images for thousands of templates in under a second, as may be required in future high-energy laser systems. This paper describes the development of a new analytical template that captures key recurring features present in the beam image to accurately estimate the beam position under good image quality conditions. Depending on the features present in a particular beam, the analytical template allows us to create a highly tailored template containing only those selected features. The second objective is achieved by exploiting the parallelism inherent in the algorithm to accelerate processing using parallel hardware that provides significant performance improvement over conventional processors. In particular, a Xilinx Virtex II Pro field programmable gate array (FPGA) hardware implementation processing 32 templates provided a speed increase of about 253 times over an optimized software implementation running on a 2.2 GHz AMD Opteron core.


Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery: a randomized pilot feasibility trial.
Glutamine (GLN) has been shown to protect against in vitro and in vivo myocardial injury. In humans, perioperative ischemia/reperfusion (I/R) injury during cardiac surgery is associated with higher morbidity and mortality. The objective of this safety and feasibility pilot trial was to determine if pharmacologically dosed, preoperative oral GLN attenuates myocardial injury in cardiac surgery patients. Patients undergoing elective cardiac surgery, requiring cardiopulmonary bypass, were enrolled in a randomized, double-blind pilot trial to receive 25 g twice of oral alanyl-glutamine (GLN; n = 7) or maltodextrin (CONT; n = 7) daily for 3 days preoperatively. Serum troponin (TROP I), creatine kinase (CK-MB), and myoglobin (MG) were measured at multiple perioperative time points. Clinical outcomes were also recorded and assessed. GLN therapy significantly decreased TROP I levels at 24, 48, and 72 hours postoperatively (all P < .05) vs CONT. GLN also reduced CK-MB at 24 and 48 hours (P < .05, P < .001) vs CONT. MG was reduced at 24 hours vs control (P = .0397). GLN also significantly reduced pooled clinical complications vs CONT (P = .03). This pilot study showed that pharmacologically dosed oral GLN therapy prior to cardiac surgery was safe, well tolerated, and feasible. GLN therapy reduced myocardial injury and clinical complications in this small randomized, blinded feasibility trial. These data indicate that a larger trial of preoperative GLN therapy in patients undergoing cardiac surgery is needed to confirm clinical benefit.


Student evaluation of an OSCE in paediatrics at the University of the West Indies, Jamaica.
The Faculty of Medical Sciences, University of the West Indies first implemented the Objective Structured Clinical Examination (OSCE) in the final MB Examination in Medicine and Therapeutics during the 2000-2001 academic year. Simultaneously, the Child Health Department initiated faculty and student training, and instituted the OSCE as an assessment instrument during the Child Health (Paediatric) clerkship in year 5. The study set out to explore student acceptance of the OSCE as part of an evaluation of the Child Health clerkship. A self-administered questionnaire was completed by successive groups of students immediately after the OSCE at the end of each clerkship rotation. Main outcome measures were student perception of examination attributes, which included the quality of instructions and organisation, the quality of performance, authenticity and transparency of the process, and usefulness of the OSCE as an assessment instrument compared to other formats. There was overwhelming acceptance of the OSCE in Child Health with respect to the comprehensiveness (90%), transparency (87%), fairness (70%) and authenticity of the required tasks (58-78%). However, students felt that it was a strong anxiety-producing experience. And concerns were expressed regarding the ambiguity of some questions and inadequacy of time for expected tasks. Student feedback was invaluable in influencing faculty teaching, curriculum direction and appreciation of student opinion. Further psychometric evaluation will strengthen the development of the OSCE.


Long Waiting Times for Elective Hospital Care - Breaking the Vicious Circle by Abandoning Prioritisation.
Policies assigning low-priority patients treatment delays for care, in order to make room for patients of higher priority arriving later, are common in secondary healthcare services today. Alternatively, each new patient could be granted the first available appointment. We aimed to investigate whether prioritisation can be part of the reason why waiting times for care are often long, and to describe how departments can improve their waiting situation by changing away from prioritisation. We used patient flow data from 2015 at the Department of Otorhinolaryngology, Haukeland University Hospital, Norway. In Dynaplan Smia, Dynaplan AS, dynamic simulations were used to compare how waiting time, size and shape of the waiting list, and capacity utilisation developed with and without prioritisation. Simulations were started from the actual waiting list at the beginning of 2015, and from an empty waiting list (simulating a new department with no initial patient backlog). From an empty waiting list and with capacity equal to demand, waiting times were built 7 times longer when prioritising than when not. Prioritisation also led to poor resource utilisation and short-lived effects of extra capacity. Departments where prioritisation is causing long waits can improve their situation by temporarily bringing capacity above demand and introducing "first come, first served" instead of prioritisation. A poor appointment allocation policy can build long waiting times, even when capacity is sufficient to meet demand. By bringing waiting times down and going away from prioritisation, the waiting list size and average waiting times at the studied department could be maintained almost 90% below the current level - without requiring permanent change in the capacity/demand ratio.


NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity.
Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-kappaB is regulated by the inducible phosphorylation of NF-kappaB inhibitor IkappaB by IkappaB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-kappaB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-kappaB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IkappaBalphaM pancreatic tumor cells and wild-type, IKK1-/-, and IKK2-/- murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-kappaB downstream target genes. Inhibition of NF-kappaB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-kappaB in participating in the regulation of elk-1, c-fos, and VEGF expression.


Enhancement in thermoelectric performance of SiGe nanoalloys dispersed with SiC nanoparticles.
SiGe is one of the most widely used thermoelectric materials for radioisotope thermoelectric generator applications for harnessing waste-heat at high temperatures. In the present study, we report a simple experimental strategy for enhancing the thermoelectric and mechanical properties of n-type SiGe nanoalloys by dispersing SiC nanoparticles in a SiGe nanoalloy matrix. This strategy yielded a high value of figure-of-merit (ZT) of ∼1.7 at 900 °C in the SiGe/SiC nanocomposite, which is nearly twice that reported for its pristine bulk counterpart and ∼15% higher than that of pristine SiGe nanoalloys. This significant enhancement in the ZT primarily originates from a reduction in the lattice thermal conductivity, owing to a high density of nano-scale interfaces, lattice-scale modulations and mass fluctuations, which lead to extensive scattering of heat-carrying phonons. The dispersion of SiC nanoparticles also significantly enhances the mechanical properties of the resulting SiGe/SiC nanocomposite, including fracture toughness and hardness. The enhancement in the thermoelectric and mechanical properties of the SiGe/SiC nanocomposites has been correlated with their microstructural features, elucidated employing X-ray diffraction, and scanning and transmission electron microscopy.


Influence of culture and age on control beliefs: the missing link of interdependence.
A number of studies have found that primary control declines in old age and is lower in Asian countries, while secondary control increases in old age and is higher in Asian countries. We examined whether these patterns may be due to the mediating influence of interdependence. In a sample of 557 young and old adults in Japan and the United States, primary and secondary control, age, and interdependence were measured. We found that interdependence mediates the influence of: (1) culture on secondary control; and (2) age on both primary and secondary control. Findings suggest that interdependence is an important factor that should be considered in trying to understand the determinants of control cross-culturally and developmentally.


Simulated juvenile salmon growth and phenology respond to altered thermal regimes and stream network shape.
It is generally accepted that climate change will stress coldwater species like Pacific salmon. However, it is unclear what aspect of altered thermal regimes (e.g., warmer winters, springs, summers, or increased variability) will have the greatest effect, and what role the spatial properties of river networks play. Thermally diverse habitats may afford protection from climate change by providing opportunities for aquatic organisms to find and use habitats with optimal conditions for growth. We hypothesized that climate-altered thermal regimes will change growth and timing of life history events such as emergence or migration but that changes will be moderated in topologically complex stream networks where opportunities to thermoregulate are more readily available to mobile animals. Because climate change effects on populations are spatially variable and contingent upon physiological optima, assessments of risk must take a spatially explicit approach. We developed a spatially-structured individual based model for Chinook Salmon (Oncorhynchus tshawytscha) in which movement decisions and growth were governed by water temperature and conspecific density. We evaluated growth and phenology (timing of egg emergence and smolting) under a variety of thermal regimes (each having a different minimum, rate of warming, maximum, and variability) and in three network shapes of increasing spatial complexity. Across networks, fish generally grew faster and were capable of smolting earlier in warmer scenarios where water temperatures experienced by fish were closer to optimal; however, growth decreased for some fish. We found that salmon size and smolt date responded more strongly to warmer springs and summers than to warmer winters or increased variability. Fish in the least complex network grew faster and were ready to smolt earlier than fish in the more spatially complex network shapes in the contemporary thermal regime; patterns were similar but less clear in warmer thermal regimes. Our results demonstrate that network topology may influence how fish respond to thermal landscapes, and this information will be useful for incorporating a spatiotemporal context into conservation decisions that promote long-term viability of salmon in a changing climate.


A forensic investigation into the etiology of bat mortality at a wind farm: barotrauma or traumatic injury?
Migrating bats have increased mortality near moving turbine blades at wind farms. The authors evaluated competing hypotheses of barotrauma and traumatic injury to determine the cause. They first examined the utility of lungs from salvaged bat carcasses for histopathologic diagnosis of barotrauma and studied laboratory mice as a model system. Postmortem time, environmental temperature, and freezing of carcasses all affected the development of vascular congestion, hemorrhage, and edema. These common tissue artifacts mimicked the diagnostic criteria of pulmonary barotrauma; therefore, lung tissues from salvaged bats should not be used for barotrauma diagnosis. The authors next compared wind farm (WF) bats to building collision (BC) bats collected near downtown Chicago buildings. WF bats had an increased incidence in fracture cases and specific bone fractures and had more external lacerations than BC bats. WF bats had additional features of traumatic injury, including diaphragmatic hernia, subcutaneous hemorrhage, and bone marrow emboli. In summary, 73% (190 of 262) of WF bats had lesions consistent with traumatic injury. The authors then examined for ruptured tympana, a sensitive marker of barotrauma in humans. BC bats had only 1 case (2%, 1 of 42), but this was attributed to concurrent cranial fractures, whereas WF bats had a 20% (16 of 81) incidence. When cases with concurrent traumatic injury were excluded, this yielded a small fraction (6%, 5 of 81) of WF bats with lesions possibly consistent with barotrauma etiology. Forensic pathology examination of the data strongly suggests that traumatic injury is the major cause of bat mortality at wind farms and, at best, barotrauma is a minor etiology.


Vardenafil improves patient satisfaction with erection hardness, orgasmic function, and overall sexual experience, while improving quality of life in men with erectile dysfunction.
The North American Pivotal Trial was designed to investigate the efficacy and safety of vardenafil in males with erectile dysfunction (ED). In this randomized, double-blind, placebo-controlled, multicenter, fixed-dose, parallel group, 6-month study, vardenafil at three doses (5 mg, 10 mg, and 20 mg) was compared to placebo with the primary efficacy variables being the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score and per patient diary response success rates for penetration and maintenance of erection through completion of intercourse. Additional efficacy variables included IIEF domain scores measuring intercourse satisfaction, orgasmic function, sexual desire, and overall satisfaction. Diary entries for overall per patient satisfaction rates for hardness and sexual experience were also measured. Improvements in quality of sexual life were assessed using the Fugl-Meyer quality of life (QoL) questionnaire. Compared to placebo, patients taking 10 mg and 20 mg doses of vardenafil showed statistically significantly greater improvement in IIEF domain scores measuring intercourse satisfaction (10.3 and 10.3 vs. 7.7), orgasmic function (7.1 and 6.9 vs. 5.3), overall satisfaction. (7.1 and 7.1 vs. 5.2) for vardenafil 10 mg and 20 mg vs. placebo, respectively, at last observation carried forward (LOCF). Vardenafil 5 mg was statistically significantly better than placebo for the secondary IIEF domain variables of intercourse satisfaction (8.9 vs. 7.7) and overall satisfaction (6.3 vs. 5.2) for vardenafil vs. placebo, respectively, at LOCF. Per patient satisfaction rates for the secondary diary variables measuring erection hardness (38%, 52%, 58% and 18%) and overall satisfaction (45%, 58%, 62% and 23%) were dose dependent and statistically significantly superior for vardenafil at 5 mg, 10 mg and 20 mg compared with placebo, respectively. Patients' answers to the Fugl-Meyer QoL questionnaire assessing improvement in sexual life also indicated statistically significant superiority for all doses of vardenafil vs. placebo treatment. The most frequent adverse events (AE) in the 5 mg, 10 mg, and 20 mg of vardenafil and placebo groups, respectively, were: headache (10%, 22%, 21% and 4%), flushing (5%, 10%, 13% and 0%), dyspepsia (1%, 4%, 6% and < 1%), and rhinitis (9%, 14%, 17% and 5%). Most AEs were mild or moderate in severity and transient in nature. Vardenafil was superior to placebo for IIEF domain scores, per patient success rates for diary questions, and assessment of quality of sexual life, in a broad range of patients with ED irrespective of etiology or severity. Vardenafil was generally well tolerated, with most AEs being mild or moderate in severity and transient in nature.


Protocol for serum exosomal miRNAs analysis in prostate cancer patients treated with radiotherapy.
Circulating exosomes from prostate cancer (PCa) patients undergoing radiotherapy are attractive candidate biomarkers for monitoring treatment response. Multiple workflows for isolation and content characterization of exosomes in biofluids have been attempted. We report a protocol to isolate and characterize exosomal miRNAs content and assess radiation-induced changes. In this pilot study, we performed targeted exosomal miRNA profiling of 25 serum samples obtained from PCa patients with intermediate- and high-risk disease treated with curative radiotherapy (RT), and controls. Post-treatment blood samples were collected at least 28 days after radiation therapy as a paired follow-up sample. The complete workflow consisted of two phases: I) filtration and polyethylene glycol salt precipitation phase which enriched particles below 200 nm in size followed by characterization using electron microscopy, and II) flow cytometry. Finally, miRNA expression analysis between untreated and treated patient samples was performed using RNA extraction kit, and qRT-PCR. In our preliminary data, 1 ml of serum from PCa patients showed higher exosomal concentration (3.68E+10) compared to controls (6.07E+08). The overall expression of exosomes after RT was found to be higher compared to untreated samples; the median value changed from 3.68E+10 to 5.40E+10; p = 0.52. Using electron microscopy, we were able to visualize cup-shaped vesicles with morphology and size compatible with exosomes. The bead-based flow cytometry showed positivity for exosomal tetraspanins surface markers CD63 and CD9. All five miRNAs (hsa-let-7a-5p, hsa-miR-141-3p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-99b-5p) have been identified in exosomes. Despite overall changes in hsa-let-7a-5p expression after radiation, the difference was significant only in the high-risk group (p = 0.037). In addition, the radiation response to hsa-miR-21-5p was elevated in the high-risk group compared to the intermediate group (p = 0.036). Herewith, we demonstrated a protocol for isolation of serum exosomes and exosomal miRNA amplification. The recovery of exosomal miRNAs and their differential expression after radiation treatment suggests promising biomarker potential that requires further investigation in larger patient cohorts.


Propylene glycol is essential in the LCModel basis set for pediatric 1H-MRS.
Propylene glycol (PG) is an organic solvent used in a variety of parenterally injected pharmaceutical preparations. In this current study, we analyzed neonatal brains following routine MRS evaluation at 1.5 T, using the LCModel software, with and without the addition of PG to the analysis basis-set. We suggest including PG in the LCModel basis-set for neonatal brain H-MRS to improve the discrimination and quantification of lactate and inositol.


Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes.
Cardiac myosin binding protein-C (cMyBP-C) is a structural and regulatory component of cardiac thick filaments. It is observed in electron micrographs as seven to nine transverse stripes in the central portion of each half of the A band. Its C-terminus binds tightly to the myosin rod and contributes to thick filament structure, while the N-terminus can bind both myosin S2 and actin, influencing their structure and function. Mutations in the MYBPC3 gene (encoding cMyBP-C) are commonly associated with hypertrophic cardiomyopathy (HCM). In cardiac cells there exists a population of myosin heads in the super-relaxed (SRX) state, which are bound to the thick filament core with a highly inhibited ATPase activity. This report examines the role cMyBP-C plays in regulating the population of the SRX state of cardiac myosin by using an assay that measures single ATP turnover of myosin. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. A smaller, non-significant decrease is observed when thoracic aortic constriction is used to induce cardiac hypertrophy in mutation negative mice. These results support the proposal that cMyBP-C stabilises the thick filament and that the loss of cMyBP-C results in an untethering of myosin heads. This results in an increased myosin ATP turnover, further consolidating the relationship between thick filament structure and the myosin ATPase.


Piracetam in the treatment of different types of myoclonus.
Forty patients with different clinical and electrophysiological types of myoclonus were treated with piracetam (18-24 g per day, p.o.) alone, or with other drugs (clonazepam, sodium valproate, and primidone) in different combinations. Piracetam in monotherapy improved the electrophysiological abnormalities in patients with cortical reflex myoclonus, but had no useful clinical effect. Sixteen patients obtained benefit from piracetam when given in combination with other antimyoclonic drugs; improvement was dramatic in two patients, moderate in seven and mild in seven. All patients showing some response to piracetam had myoclonus of cortical origin; however, five other patients with similar cortical myoclonus failed to improve when piracetam was added. Tolerance was excellent and side effects were minimal and transient. It is concluded that piracetam probably has an antimyoclonic action, but its potential value as a therapeutic tool for disabling myoclonus requires further study.


Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate.
We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.


Integrating the Built and Social Environment into Health Assessments for Maternal and Child Health: Creating a Planning-Friendly Index.
Environmental and community context earliest in the life course have a profound effect on life-long health outcomes. Yet, standard needs assessments for maternal and child health (MCH) programs often overlook the full range of influences affecting health in-utero and early childhood. To address this, we developed a methodology for assessing community risk in MCH based on six domains integrating 66 indicators across community, environment, socioeconomic indicators, and MCH outcomes. We pilot this methodology in Pennsylvania, and share examples of how local governments, planners, and public health officials across the geographic spectrum can integrate this data into community planning for improved maternal and child health.


High Rates of Vertical Crustal Movement near Ventura, California.
Fission track, radiometric, and paleomagnetic age determinations in marine sedimentary rocks of the Ventura Basin make it possible to estimate the vertical components of displacement rates for the last 2 million years. The basin subsided at rates up to 9.5 +/- 2.5 millimeters per year until about 0.6 million years ago, when subsidence virtually ceased. Since then, the northern margin of the basin has been rising at an average rate of 10 +/- 2 millimeters per year, about the same rate as that based on the geodetic record north and west of Ventura since 1960 but considerably lower than the rate along the San Andreas fault at Palmdale since 1960.


The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling.
The NOVH protein belongs to the emerging CCN [Connective tissue growth factor (CTGF), Cyr61/Cef10, nephroblastoma overexpressed gene] family of growth regulators sharing a strikingly conserved multimodular organization but exhibiting distinctive functional features. Two members of the family (CYR61 and CTGF) are positive regulators of cell proliferation, whereas NOVH and two other members (ELM1 and RCOP-1) exhibit features of negative regulators of growth. The multimodular structure of these proteins suggests that their biological role(s) may depend on interactions with several factors as well as proteins constitutive of the extracellular matrix. To gain insight into the functionality of these domains, we have used a two-hybrid system to identify proteins interacting with NOVH. We report here that the C-terminal domain confers on the full-length NOVH protein the capacity to bind fibulin 1C, a protein of the extracellular matrix that interacts with several other regulators of cell adhesion. Furthermore, we show that a natural N-truncated isoform of NOVH produced by cells expressing the full-length NOVH protein also binds fibulin 1C with a high affinity, and we hypothesize that the production of truncated isoforms of NOVH (and probably of other CCN proteins) may be a critical aspect in the modulation of their biological activity. These results set the stage for a study of NOVH-fibulin 1C interactions and their potential significance in cell-adhesion signaling in normal and pathological conditions.


Simultaneous formation of Bi2O2(OH)(NO3)/BiOBr ultrathin hierarchical microspheres for effectively promoting visible-light-driven photocatalytic activity in environmental remediation.
As a two-dimensional nanomaterial, bismuth oxybromide (BiOBr) have attracted tremendous interest in the area of visible-light photocatalysis since it can provide the internal electric field (IEF) through z-axis through its unique electronic band structure. However, the insufficient active sites and rapid recombination rate of charged carriers hamper the efficiency of the photocatalysis. To address these two major obstacles, an enticing strategy of constructing heterojunction was established by introducing Bi2O2(OH)(NO3) (BiON) in BiOBr with the same precursor. Through a facile one-pot hydrothermal synthesis, two Sillén-type layered photocatalysts, with intimately constructed ultrathin heterostructure, was synthesized by the co-precipitation method. In this work, the formation of Bismuth-based heterojunction for charge separation is established by the excessive bismuth nitrate, which subsequently participates with the in situ growth of ultrathin hierarchical microspheres. By attenuating the thickness of BiOBr from 20 nm to 8 nm with the aid of BiON, the photogenerated charges could migrate to the active sites through shorter charge diffusion pathway. Also, the BiOBr and BiON act as an active bridge to promote the separation of electron-hole pairs, which also brings out more active sites due to its increased specific surface area. BiON/BiOBr ultrathin hierarchical microspheres exhibited enhanced visible-light photocatalytic activity for decontaminating several types of pollutants. Besides, the activity of as-prepared BiON/BiOBr was further evaluated by inhibiting the growth of kanamycin-resistant bacteria strains. This study presents a novel strategy to incorporate the crystalline bismuth hydrate nitrate into BiOBr to form ultrathin hierarchical microspheres with high surface area for environmental remediation.


TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry.
Dysfunction of basal forebrain cholinergic neurons (BFCNs) is an early pathological hallmark of Alzheimer's disease (AD). Numerous studies have indicated that nerve growth factor (NGF) supports survival and phenotypic differentiation of BFCNs. Consistent with a potential link to AD pathogenesis, TrkA, a NGF receptor, is expressed in cholinergic forebrain neuronal populations including those in BF and striatum, and is markedly reduced in individuals with mild cognitive impairment (MCI) without dementia and early-stage AD. To investigate the role of TrkA in the development, connectivity, and function of the BF cholinergic system and its contribution to AD pathology, we have generated a forebrain-specific conditional TrkA knock-out mouse line. Our findings show a key role for TrkA signaling in establishing the BF cholinergic circuitry through the ERK pathway, and demonstrate that the normal developmental increase of choline acetyltransferase expression becomes critically dependent on TrkA signaling before neuronal connections are established. Moreover, the anatomical and physiological deficits caused by lack of TrkA signaling in BFCNs have selective impact on cognitive activity. These data demonstrate that TrkA loss results in cholinergic BF dysfunction and cognitive decline that is reminiscent of MCI and early AD.


Fifty years later: the disk goes to the prom.
Although age-related macular degeneration is the most prevalent macular disease in the world, numerous discoveries regarding the molecular bases of vision have been made through genetic association studies of rare inherited maculopathies. In this issue of the JCI, Yang et al. present a functional genetics study that identifies a role for prominin 1 (PROM1), best known as a stem cell and/or progenitor cell marker, in the biogenesis of retinal photoreceptor disk arrays (see the related article beginning on page 2908). This study supports an established model in which disk morphogenesis occurs through membrane evagination and extends other recent studies assigning PROM1 important functions outside of the stem cell niche.


Salvage therapy with abacavir in HIV-1-infected patients with previously documented M184V mutation: a possibility of NRTI recycling.
We evaluated in an open-label, randomized, controlled, pilot trial if the re-emergence of previously selected resistant strains, harbouring M184V mutation, could be modulated by the use of different drug associations as components of the new antiretroviral regimens. In addition, we assessed the clinical relevance of this mutation on the management of heavily pretreated HIV-infected patients. The primary end-point of the study was the reselection of M184V mutation. Secondary end-points were the variation over time of HIV RNA plasma levels and CD4 cell counts and the progression of HIV disease. The primary population for efficacy analysis was the intention-to-treat exposed population. After a run-in phase consisting in a new treatment regimen excluding either lamivudine (3TC) or abacavir (ABC) so as to clear the previously documented M184V mutation, 18 patients with an HIV RNA plasma level greater than 10000 copies/ml were randomized to receive an antiretroviral drug regimen (at least three drugs) including either ABC or the association of ABC+3TC. All patients were naive to ABC. The M184V mutation reappeared in 1/9 patients in the ABC group and in 8/9 patients in the ABC+3TC group (P<0.003, 95% CI: 0.5-1). In the ABC group we observed a rapid decrement of viral load that was maintained throughout all the study period (P<0.05). On the contrary, in the ABC+3TC group, after a transient decrement at 2 months, a progressive increment towards baseline values was observed. The proportion of patients with a viral load reduction of at least 0.5 logs at 12 months was significantly higher in the ABC group: 8/9 patients vs 3/9 (P=0.05, 95% CI: 0.2-0.92). Similarly, from an immunological point-of-view, the increase at all time points (since randomization) in CD4 cell count was statistically significant in the ABC group (P<0.01), while no difference was observed in the ABC+3TC group. The possibility of a successful use of ABC in salvage regimens opens alternative therapeutic options for heavily pretreated patients with previously documented M184V mutation. Further studies should clarify whether this is true for other drugs of the nucleoside analogues class.


Increasing comorbidity is associated with worsening physical function and pain after primary total knee arthroplasty.
Previous studies suggested that pre-operative comorbidity was a risk factor for worse outcomes after TKA. To our knowledge, studies have not examined whether postoperative changes in comorbidity impact pain and function outcomes longitudinally. Our objective was to examine if increasing comorbidity postoperatively is associated with worsening physical function and pain after primary total knee arthroplasty (TKA). We performed a retrospective chart review of veterans who had completed Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form-36 (SF36) surveys at regular intervals after primary TKA. Comorbidity was assessed using a variety of scales: validated Charlson comorbidity index score, and a novel Arthroplasty Comorbidity Severity Index score (Including medical index, local musculoskeletal index [including lower extremity and spine] and TKA-related index subscales; higher scores are worse ), at multiple time-points post-TKA. We used mixed model linear regression to examine the association of worsening comorbidity post-TKA with change in WOMAC and SF-36 scores in the subsequent follow-up periods, controlling for age, length of follow-up, and repeated observations. The study cohort consisted of 124 patients with a mean age of 71.7 years (range 58.6-89.2, standard deviation (SD) 6.9) followed for a mean of 4.9 years post-operatively (range 1.3-11.4; SD 2.8). We found that post-operative worsening of the Charlson Index score was significantly associated with worsening SF-36 Physical Function (PF) (beta coefficient (ß) = -0.07; p < 0.0001), SF-36 Bodily Pain (BP) (ß = -0.06; p = 0.002), and WOMAC PF subscale (ß = 0.08; p < 0.001; higher scores are worse) scores, in the subsequent periods. Worsening novel medical index subscale scores were significantly associated with worsening SF-36 PF scores (ß = -0.03; p = 0.002), SF-36 BP (ß = -0.04; p < 0.001) and showed a non-significant trend for worse WOMAC PF scores (ß = 0.02; p = 0.11) subsequently. Local musculoskeletal index subscale scores were significantly associated with worsening SF-36 PF (ß = -0.05; p = 0.001), SF-36 BP (ß = -0.04; p = 0.03) and WOMAC PF (ß = 0.06; p = 0.01) subsequently. None of the novel index subscale scores were significantly associated with WOMAC pain scores. TKA complications, as assessed by TKA-related index subscale, were not significantly associated with SF-36 or WOMAC domain scores. Increasing Charlson index as well as novel medical and local musculoskeletal index subscale scores (from novel Arthroplasty Comorbidity Severity Index) post-TKA correlated with subsequent worsening of physical function and pain outcomes post-TKA. Further studies should examine which comorbidity management could have the greatest impact on these outcomes.


Safety and immune responses in children after concurrent or sequential 2009 H1N1 and 2009-2010 seasonal trivalent influenza vaccinations.
Administering 2 separate vaccines for seasonal and pandemic influenza was necessary in 2009. Therefore, we conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in previously vaccinated children. Children randomized to 4 study groups and stratified by age received 1 dose of seasonal TIV and 2 doses of 2009 H1N1 vaccine in 1 of 4 combinations. Injections were given at 21-day intervals and serum samples for hemagglutination inhibition antibody responses were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. All combinations of vaccines were safe in the 531 children enrolled. Generally, 1 dose of 2009 H1N1 vaccine and 1 dose of TIV, regardless of sequence or concurrency of administration, was immunogenic in children ≥ 10 years of age; children <10 years of age required 2 doses of 2009 H1N1 vaccine. Vaccines were generally well tolerated. The immune responses to 2009 H1N1 vaccine were adequate regardless of the sequence of vaccination in all age groups but the sequence affected titers to TIV antigens. Two doses of 2009 H1N1 vaccine were required to achieve a protective immune response in children <10 years of age. NCT00943202.