The metal accumulating ability of plants has previously been used to capture metal contaminants from the environment; however, the full potential of this process is yet to be realized. Herein, the first use of living plants to recover palladium and produce catalytically active palladium nanoparticles is reported. This process eliminates the necessity for nanoparticle extraction from the plant and reduces the number of production steps compared to traditional catalyst palladium on carbon. These heterogeneous plant catalysts have demonstrated high catalytic activity in Suzuki coupling reactions between phenylboronic acid and a range of aryl halides containing iodo-, bromo- and chloro- moieties.
Hearing loss is a prevalent consequence of aging and also poses special challenges for older adults. Particularly when superimposed on other age-related conditions, presbycusis (age-related hearing loss) places the older adult at risk for social isolation and associated psychological and general health sequelae. The increasing cognitive demand of verbal communication, as well as the diminished sense of social and physical connectedness, can furthermore contribute to a feeling of vulnerability and poor health that worsens with advancing presbycusis. This cascade of downstream effects of hearing loss has implications for the self-assessment of health related quality of life (HRQL) and resulting estimates of associated costs. There is accumulating evidence of a potential role for cochlear implants (CI) in older adults with poor word understanding despite conventional hearing aid (HA) usage. In our review of the literature we identify strong evidence for the restoration of communication capacity in the deaf and hard of hearing geriatric population, little published work on communication performance in the real world and HRQL, and significant gaps of knowledge regarding how CI rehabilitation interacts with changing psychosocial and functional status. We therefore propose a broader conceptual framework than is currently available for the role of CI rehabilitation in the management of severe-to-profound hearing loss in older adults. We posit that the use of such a model in future investigations is needed to guide multidisciplinary investigations into the unique challenges of hearing loss in older adults as well as open new opportunities for innovation.
presbycusis; hearing loss; aging; older adults; cochlear implant; communication; conceptual framework; cascade
The study of the effect of large-scale drivers (e.g., climate) of human diseases typically relies on aggregate disease data collected by the government surveillance network. The usual approach to analyze these data, however, often ignores a) changes in the total number of individuals examined, b) the bias towards symptomatic individuals in routine government surveillance, and; c) the influence that observations can have on disease dynamics. Here, we highlight the consequences of ignoring the problems listed above and develop a novel modeling framework to circumvent them, which is illustrated using simulations and real malaria data. Our simulations reveal that trends in the number of disease cases do not necessarily imply similar trends in infection prevalence or incidence, due to the strong influence of concurrent changes in sampling effort. We also show that ignoring decreases in the pool of infected individuals due to the treatment of part of these individuals can hamper reliable inference on infection incidence. We propose a model that avoids these problems, being a compromise between phenomenological statistical models and mechanistic disease dynamics models; in particular, a cross-validation exercise reveals that it has better out-of-sample predictive performance than both of these alternative models. Our case study in the Brazilian Amazon reveals that infection prevalence was high in 2004–2008 (prevalence of 4% with 95% CI of 3–5%), with outbreaks (prevalence up to 18%) occurring during the dry season of the year. After this period, infection prevalence decreased substantially (0.9% with 95% CI of 0.8–1.1%), which is due to a large reduction in infection incidence (i.e., incidence in 2008–2010 was approximately one fifth of the incidence in 2004–2008).We believe that our approach to modeling government surveillance disease data will be useful to advance current understanding of large-scale drivers of several diseases.
Disease data collected by the government surveillance system are frequently used to understand the influence of large-scale phenomena (e.g., climate) on human health because these data often have a large temporal and/or geographical span. The down side is that a) these data are often biased towards individuals that come to the health facilities (i.e., symptomatic individuals); and b) the number of individuals examined can vary substantially regardless of concurrent changes in prevalence or incidence (e.g., due to shortage of personnel or supplies in health facilities), directly impacting the number of disease cases detected. Current modeling approaches typically ignore these peculiarities of the government data. Furthermore, current approaches do not take into account that observations directly influence disease dynamics since individuals with a positive diagnosis are often subsequently treated for the disease. In this article, we develop a novel model to circumvent these shortcomings and apply it to simulated data, highlighting how inference on infection incidence and prevalence might be misleading when some of the issues mentioned above are ignored. Finally, we illustrate this model using malaria data from the Brazilian Amazon, revealing the strong role of precipitation on infection prevalence seasonality and striking patterns in infection incidence.
Population dynamics with regard to evolution of traits has typically been studied using matrix projection models (MPMs). Recently, to work with continuous traits, integral projection models (IPMs) have been proposed. Imitating the path with MPMs, IPMs are handled first with a fitting stage, then with a projection stage. Fitting these models has so far been done only with individual-level transition data. These data are used to estimate the demographic functions (survival, growth, fecundity) that comprise the kernel of the IPM specification. Then, the estimated kernel is iterated from an initial trait distribution to project steady state population behavior under this kernel. When trait distributions are observed over time, such an approach does not align projected distributions with these observed temporal benchmarks.
The contribution here, focusing on size distributions, is to address this issue. Our concern is that the above approach introduces an inherent mismatch in scales. The redistribution kernel in the IPM proposes a mechanistic description of population level redistribution. A kernel of the same functional form, fitted to data at the individual level, would provide a mechanistic model for individual-level processes. Resulting parameter estimates and the associated estimated kernel are at the wrong scale and do not allow population-level interpretation.
Our approach views the observed size distribution at a given time as a point pattern over a bounded interval. We build a three-stage hierarchical model to infer about the dynamic intensities used to explain the observed point patterns. This model is driven by a latent deterministic IPM and we introduce uncertainty by having the operating IPM vary around this deterministic specification. Further uncertainty arises in the realization of the point pattern given the operating IPM. Fitted within a Bayesian framework, such modeling enables full inference about all features of the model. Such dynamic modeling, optimized by fitting data observed over time, is better suited to projection.
Exact Bayesian model fitting is very computationally challenging; we offer approximate strategies to facilitate computation. We illustrate with simulated data examples as well as well as a set of annual tree growth data from Duke Forest in North Carolina. A further example shows the benefit of our approach, in terms of projection, compared with the foregoing individual level fitting.
density dependence; Fourier transform; hierarchical model; integro-difference equation; Laplace approximation; nonhomogeneous Poisson process; spectral domain
The downstream consequences of inflammation in the adult mammalian heart are formation of a non-functional scar, pathological remodelling and heart failure. In zebrafish, hydrogen peroxide (H2O2) released from a wound is the initial instructive chemotactic cue for the infiltration of inflammatory cells, however, the identity of a subsequent resolution signal(s), to attenuate chronic inflammation, remains unknown. Here we reveal that Thymosin β4-Sulfoxide inhibits interferon-γ, and increases monocyte dispersal and cell death, lies downstream of H2O2 in the wounded fish and triggers depletion of inflammatory macrophages at the injury site. This function is conserved in the mouse and observed after cardiac injury, where it promotes wound healing and reduced scarring. In human T cell/CD14+ monocyte co-cultures, Tβ4-SO inhibits IFN-γ and increases monocyte dispersal and cell death, likely by stimulating superoxide production. Thus, Tβ4-SO is a putative target for therapeutic modulation of the immune response, resolution of fibrosis and cardiac repair.
To assess children’s health-related quality of life (HRQL) and development after cochlear implant (CI) surgery, and compare improvements between different age of implantation categories.
Prospective, longitudinal study comparing outcomes of deaf children post-CI with hearing controls.
Six US CI centers.
Deaf children who received CI (n=188) and hearing children of comparable ages (n=97).
CI before 5 years of age.
MAIN OUTCOME MEASURE
Parental ratings of global HRQL and development, as assessed over the first 4 years of follow-up using visual analog scales. Development scores assess parental views of children’s growth and development, motor skills, ability to express themselves and communicate with others, and learning abilities. Associations of baseline child and family characteristics with post-CI HRQL and development were investigated using multivariable analysis, controlling for factors that influence post-CI language learning.
Baseline deficits of CI candidates relative to hearing controls were larger in development than HRQL. Development scores improved significantly by four years after CI, particularly in the youngest CI recipients. Developmental deficits of older CI recipients with early, extended hearing aid use were only partially remediated by CI. Overall, no significant health deficits were observed in CI children after four years. Cognition and speech recognition were positively associated with both HRQL and development.
Parental perspectives on quality of their child’s life and development provide practical insight into the optimal timing of interventions for early onset deafness. Validity of parental global assessments is supported by clinical measures of speech perception and language learning and comparison with a well-validated health status instrument.
Body condition is an indicator of health, and it plays a key role in many vital processes for mammalian species. While evidence of individual body condition can be obtained, these observations provide just brief glimpses into the health state of the animal. An analytical framework is needed for understanding how health of animals changes over space and time.Through knowledge of individual health we can better understand the status of populations. This is particularly important in endangered species, where the consequences of disruption of critical biological functions can push groups of animals rapidly toward extinction. Here we built a state-space model that provides estimates of movement, health, and survival. We assimilated 30+ years of photographic evidence of body condition and three additional visual health parameters in individual North Atlantic right whales, together with survey data, to infer the true health status as it changes over space and time. We also included the effect of reproductive status and entanglement status on health. At the population level, we estimated differential movement patterns in males and females. At the individual level, we estimated the likely animal locations each month. We estimated the relationship between observed and latent health status. Observations of body condition, skin condition, cyamid infestation on the blowholes, and rake marks all provided measures of the true underlying health. The resulting time series of individual health highlight both normal variations in health status and how anthropogenic stressors can affect the health and, ultimately, the survival of individuals. This modeling approach provides information for monitoring of health in right whales, as well as a framework for integrating observational data at the level of individuals up through the health status of the population. This framework can be broadly applied to a variety of systems – terrestrial and marine – where sporadic observations of individuals exist.
Divers are taught some basic physiology during their training. There is therefore some underlying knowledge and understandable concern in the diving community about the presence of a patent foramen ovale (PFO) as a cause of decompression illness (DCI). There is an agreement that PFO screening should not be done routinely on all divers; however, when to screen selected divers is not clear. We present the basic physiology and current existing guidelines for doctors, advice on the management and identify which groups of divers should be referred for consideration of PFO screening. Venous bubbles after diving and right to left shunts are common, but DCI is rare. Why this is the case is not clear, but the divers look to doctors for guidance on PFO screening and closure; both of which are not without risks. Ideally, we should advise and apply guidelines that are consistent and based on best available evidence. We hope this guideline and flow chart helps address these issues with regard to PFOs and diving.
Patent foramen ovale; Decompression illness; Arterial gas embolism; Screening
Exposure of mice to hyperoxia produces pulmonary toxicity similar to acute lung injury/acute respiratory distress syndrome, but little is known about the interactions within the cardiopulmonary system. This study was designed to characterize the cardiopulmonary response to hyperoxia, and to identify candidate susceptibility genes in mice. Electrocardiogram and ventilatory data were recorded continuously from 4 inbred and 29 recombinant inbred strains during 96 hours of hyperoxia (100% oxygen). Genome-wide linkage analysis was performed in 27 recombinant inbred strains against response time indices (TIs) calculated from each cardiac phenotype. Reductions in minute ventilation, heart rate (HR), low-frequency (LF) HR variability (HRV), high-frequency HRV, and total power HRV were found in all mice during hyperoxia exposure, but the lag time before these changes began was strain dependent. Significant (chromosome 9) or suggestive (chromosomes 3 and 5) quantitative trait loci were identified for the HRTI and LFTI. Functional polymorphisms in several candidate susceptibility genes were identified within the quantitative trait loci and were associated with hyperoxia susceptibility. This is the first study to report highly significant interstrain variation in hyperoxia-induced changes in minute ventilation, HR, and HRV, and to identify polymorphisms in candidate susceptibility genes that associate with cardiac responses. Results indicate that changes in HR and LF HRV could be important predictors of subsequent adverse outcome during hyperoxia exposure, specifically the pathogenesis of acute lung injury. Understanding the genetic mechanisms of these responses may have significant diagnostic clinical value.
heart rate; hyperoxia; genome-wide mapping
Large-scale forest conservation projects are underway in the Brazilian Amazon but little is known regarding their public health impact. Current literature emphasizes how land clearing increases malaria incidence, leading to the conclusion that forest conservation decreases malaria burden. Yet, there is also evidence that proximity to forest fringes increases malaria incidence, which implies the opposite relationship between forest conservation and malaria. We compare the effect of these environmental factors on malaria and explore its implications.
Methods and Findings
Using a large malaria dataset (∼1,300,000 positive malaria tests collected over ∼4.5 million km2), satellite imagery, permutation tests, and hierarchical Bayesian regressions, we show that greater forest cover (as a proxy for proximity to forest fringes) tends to be associated with higher malaria incidence, and that forest cover effect was 25 times greater than the land clearing effect, the often cited culprit of malaria in the region. These findings have important implications for land use/land cover (LULC) policies in the region. We find that cities close to protected areas (PA’s) tend to have higher malaria incidence than cities far from PA’s. Using future LULC scenarios, we show that avoiding 10% of deforestation through better governance might result in an average 2-fold increase in malaria incidence by 2050 in urban health posts.
Our results suggest that cost analysis of reduced carbon emissions from conservation efforts in the region should account for increased malaria morbidity, and that conservation initiatives should consider adopting malaria mitigation strategies. Coordinated actions from disparate science fields, government ministries, and global initiatives (e.g., Reduced Emissions from Deforestation and Degradation; Millenium Development Goals; Roll Back Malaria; and Global Fund to Fight AIDS, Tuberculosis and Malaria), will be required to decrease malaria toll in the region while preserving these important ecosystems.
Dasatinib 100 mg daily and nilotinib 600/800 mg daily have been compared to imatinib as first line treatments for CML in two recent randomised studies. However, no head to head evidence exists of the relative efficacy of dasatinib and nilotinib.
We conducted a systematic literature review and used the data extracted to perform an indirect comparison meta-analysis of the three interventions.
Data from eight clinical studies (3,520 individuals) were included, all of which were of good quality (low risk of bias). At six months, the odds of complete cytogenetic response (CCyR) for dasatinib and nilotinib were approximately three times those for imatinib (range 2.77 to 3.06, all values not significant). At twelve months datatinib and nilotinib were significantly better than imatinib for both CCyR and major molecular response (MMR) (CCyR odds range 2.06 to 2.41, MMR odds range 2.09 to 2.87). At eighteen months dasatinib and nilotinib were again significantly better in terms of CCyR than imatinib (response odds 1.55 to 2.01). When dasatinib and nilotinib were compared to each other, for both clinical endpoints at all time points the response odds were not significantly different.
On the basis of a systematic review of the current literature base, dasatinib 100 mg, nilotinib 600 mg and nilotinib 800 mg should be viewed as equivalent in terms of complete cytogenetic and major molecular response.
Dasatinib; CML; Chronic myeloid leukaemia; Network meta-analysis; Systematic review; Relative efficacy
Anticipating how biodiversity will respond to climate change is challenged by the fact that climate variables affect individuals in competition with others, but interest lies at the scale of species and landscapes. By omitting the individual scale, models cannot accommodate the processes that determine future biodiversity. We demonstrate how individual-scale inference can be applied to the problem of anticipating vulnerability of species to climate. The approach places climate vulnerability in the context of competition for light and soil moisture. Sensitivities to climate and competition interactions aggregated from the individual tree scale provide estimates of which species are vulnerable to which variables in different habitats. Vulnerability is explored in terms of specific demographic responses (growth, fecundity and survival) and in terms of the synthetic response (the combination of demographic rates), termed climate tracking. These indices quantify risks for individuals in the context of their competitive environments. However, by aggregating in specific ways (over individuals, years, and other input variables), we provide ways to summarize and rank species in terms of their risks from climate change.
biodiversity; climate change; forest dynamics; hierarchical models; model selection; risk analysis
Over the last half century there has been an epidemic of diminished health status induced by what seems as a concurrent rise in a population of individuals that are overfat. During the past few decades, the use of exercise has become a staple in the prevention and treatment options for the retarding the development of health issues pertaining to individuals who are overweight, overfatness or experience obesity. However, there are few studies and reviews look at the global issues surrounding the metabolic and hormone consequences of overfatness and the interaction of exercise with adiposity in humans developing the health status for the individual. This review offers an insight into our current understanding of health issues pertaining to metabolic and hormonal disruption related to overfatness and the treatment effect that exercise, especially resistance exercise, can have on impacting the health status, and overall well-being, for individuals who are overfat, regardless of body compositional changes leading toward a lessening of diseased state, and eventually a return to a normal health status for the individual.
Fatness; Fitness; Exercise; Health status
Sequential multispectral imaging is an acquisition technique that involves collecting images
of a target at different wavelengths, to compile a spectrum for each pixel. In surgical
applications it suffers from low illumination levels and motion artefacts. A three-channel
rigid endoscope system has been developed that allows simultaneous recording of stereoscopic
and multispectral images. Salient features on the tissue surface may be tracked during the
acquisition in the stereo cameras and, using multiple camera triangulation techniques, this
information used to align the multispectral images automatically even though the tissue or
camera is moving. This paper describes a detailed validation of the set-up in a controlled
experiment before presenting the first in vivo use of the device in a porcine
minimally invasive surgical procedure. Multispectral images of the large bowel were acquired
and used to extract the relative concentration of haemoglobin in the tissue despite motion due
to breathing during the acquisition. Using the stereoscopic information it was also possible to
overlay the multispectral information on the reconstructed 3D surface. This experiment
demonstrates the ability of this system for measuring blood perfusion changes in the tissue
during surgery and its potential use as a platform for other sequential imaging modalities.
(170.2150) Endoscopic imaging; (170.3010) Image reconstruction techniques; (170.6510) Spectroscopy, tissue diagnostics
PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter two genes playing prominent roles in the field effect. The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence.
An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP). The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients. Multiplexing affects copy number calculations in a consistent way per assay. Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent. In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner. The age of FFPE-samples does have a negative impact on DNA quality and quantity.
The developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation. This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability. Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.
GSTP1; APC; RASSF1; Methylation; Epigenetics; Prostate cancer; Diagnosis; Multiplex; Singleplex; MSP
Nut-bearing trees, including oaks (Quercus spp.), are considered to be highly dispersal limited, leading to concerns about their ability to colonize new sites or migrate in response to climate change. However, estimating seed dispersal is challenging in species that are secondarily dispersed by animals, and differences in disperser abundance or behavior could lead to large spatio-temporal variation in dispersal ability. Parentage and dispersal analyses combining genetic and ecological data provide accurate estimates of current dispersal, while spatial genetic structure (SGS) can shed light on past patterns of dispersal and establishment.
Methodology and Principal Findings
In this study, we estimate seed and pollen dispersal and parentage for two mixed-species red oak populations using a hierarchical Bayesian approach. We compare these results to those of a genetic ML parentage model. We also test whether observed patterns of SGS in three size cohorts are consistent with known site history and current dispersal patterns. We find that, while pollen dispersal is extensive at both sites, the scale of seed dispersal differs substantially. Parentage results differ between models due to additional data included in Bayesian model and differing genotyping error assumptions, but both indicate between-site dispersal differences. Patterns of SGS in large adults, small adults, and seedlings are consistent with known site history (farmed vs. selectively harvested), and with long-term differences in seed dispersal. This difference is consistent with predator/disperser satiation due to higher acorn production at the low-dispersal site. While this site-to-site variation results in substantial differences in asymptotic spread rates, dispersal for both sites is substantially lower than required to track latitudinal temperature shifts.
Animal-dispersed trees can exhibit considerable spatial variation in seed dispersal, although patterns may be surprisingly constant over time. However, even under favorable conditions, migration in heavy-seeded species is likely to lag contemporary climate change.
To develop preliminary “growth curves” of Functioning after Pediatric Cochlear Implantation (FAPCI) scores using a cross-sectional sample of normal hearing children and to compare these curves to trajectories of FAPCI scores in children receiving cochlear implants.
Quantile regression was used to develop growth curves from the FAPCI scores of a cross-sectional sample of 82 normal hearing children (age range 7 months – 5 years). Trajectories of FAPCI scores from a longitudinal cohort of 75 children with cochlear implants (age range 1-5 years) were compared to these growth curves.
FAPCI scores were positively associated with increasing age in normal hearing children with a rapid increase in scores observed at earlier ages followed by a plateau at age 3 years. FAPCI trajectories for cochlear-implanted children varied with age at implantation and did not reach a plateau until age 5-6 years.
Normal hearing children demonstrated increasing FAPCI scores with age, and these preliminary growth curves allow for the interpretation of a cochlear-implanted child's FAPCI scores in comparison to normal hearing children. Additional research using a larger, longitudinal cohort of normal hearing children will be needed to develop definitive normative FAPCI trajectories.
FAPCI; Pediatric; Cochlear Implantation; Communicative Performance
To review natural orifice translumenal endoscopic surgery (NOTES) applications in clinical practice and assess the evidence base for each application as reported in the literature. An electronic literature search was performed. Inclusion criteria were publications relating to NOTES applications in humans. For each type of operation the highest level of evidence available for clinical NOTES publications was evaluated. Morbidity and short-term operative outcomes were compared with gold standard published evidence where available. Finally, registered trials recruiting patients for NOTES applications were identified. Human NOTES publications with the highest level of evidence in each application are identified. There were no RCTs in the literature to date. The strongest evidence came in the form of large, multi-centre trials with 300-500 patients. The results are encouraging, comparable with gold standard techniques on morbidity and mortality. While short-term operative outcomes were also similar when compared to the gold standard techniques, other than improved cosmesis little else can definitely be concluded as a clear benefit of a NOTES procedure. The most common procedures are cholecystectomy, appendicectomy and peritoneoscopy mainly performed via transvaginal access. It is evident that morbidity appears to be higher when the transgastric route is used. The safety profile of hybrid NOTES transvaginal procedures is beginning to be confirmed as is evident from the large number of procedures presented in this review. A number of authors have presented work on pure NOTES procedures but the results are inconsistent and thus the vast majority of NOTES procedures worldwide are performed in a hybrid fashion with a variable amount of laparoscopy. This review of the clinical applications of NOTES summarises the growing evidence behind this surgical discipline and highlights NOTES procedures with an acceptable safety profile.
Natural orifice translumenal endoscopic surgery; Humans; Clinical practice
For competing species to coexist, individuals must compete more with others of the same species than with those of other species. Ecologists search for tradeoffs in how species might partition the environment. The negative correlations among competing species that would be indicative of tradeoffs are rarely observed. A recent analysis showed that evidence for partitioning the environment is available when responses are disaggregated to the individual scale, in terms of the covariance structure of responses to environmental variation. That study did not relate that variation to the variables to which individuals were responding. To understand how this pattern of variation is related to niche variables, we analyzed responses to canopy gaps, long viewed as a key variable responsible for species coexistence.
A longitudinal intervention analysis of individual responses to experimental canopy gaps with 12 yr of pre-treatment and 8 yr post-treatment responses showed that species-level responses are positively correlated – species that grow fast on average in the understory also grow fast on average in response to gap formation. In other words, there is no tradeoff. However, the joint distribution of individual responses to understory and gap showed a negative correlation – species having individuals that respond most to gaps when previously growing slowly also have individuals that respond least to gaps when previously growing rapidly (e.g., Morus rubra), and vice versa (e.g., Quercus prinus).
Because competition occurs at the individual scale, not the species scale, aggregated species-level parameters and correlations hide the species-level differences needed for coexistence. By disaggregating models to the scale at which the interaction occurs we show that individual variation provides insight for species differences.
While the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e. blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT-prolongation and cardiotoxicity.
ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (−/−) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced QTc prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype.
Here, we demonstrate that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT-prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also demonstrate that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin.
To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT-prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT-prolongation following the administration of ABCB1-substrate drugs.
Depsipeptide; FK228; polymorphisms; ABCB1; QTc
The R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding expression of these is lacking, especially with regard to autoimmune diseases.
We have investigated the mRNA expression of known PTPN22 splice forms with TaqMan real-time PCR in relation to ZNF592 as an endogenous reference in peripheral blood cells from three independent cohorts with RA patients (n = 139) and controls (n = 111) of Caucasian origin. Polymorphisms in the PTPN22 locus (25 SNPs) and phenotypic data (gender, disease activity, ACPA and RF status) were used for analysis. Additionally, we addressed possible effects of methotrexate treatment on PTPN22 expression.
We found consistent differences in the expression of the PTPN22 splice forms in unstimulated peripheral blood mononuclear cells between RA patients and normal controls. This difference was more pronounced when comparing the ratio of splice forms and was not affected by methotrexate treatment.
Our data show that RA patients and healthy controls have a shift in balance of expression of splice forms derived from the PTPN22 gene. This balance seems not to be caused by treatment and may be of importance during immune response due to great structural differences in the encoded PTPN22 proteins.
A common challenge to the study of several infectious diseases consists in combining limited cross-sectional survey data, collected with a more sensitive detection method, with a more extensive (but biased) syndromic sentinel surveillance data, collected with a less sensitive method. Our article describes a novel modeling framework that overcomes this challenge, resulting in enhanced understanding of malaria in the Western Brazilian Amazon.
A cohort of 486 individuals was monitored using four cross-sectional surveys, where all participants were sampled regardless of symptoms (aggressive-active case detection), resulting in 1,383 microscopy and 1,400 polymerase chain reaction tests. Data on the same individuals were also obtained from the local surveillance facility (i.e., passive and active case detection), totaling 1,694 microscopy tests. Our model accommodates these multiple pathogen and case detection methods. This model is shown to outperform logistic regression in terms of interpretability of its parameters, ability to recover the true parameter values, and predictive performance. We reveal that the main infection determinant was the extent of forest, particularly during the rainy season and in close proximity to water bodies, and participation on forest activities. We find that time residing in Acrelandia (as a proxy for past malaria exposure) decreases infection risk but surprisingly increases the likelihood of reporting symptoms once infected, possibly because non-naïve settlers are only susceptible to more virulent Plasmodium strains. We suggest that the search for asymptomatic carriers should focus on those at greater risk of being infected but lower risk of reporting symptoms once infected.
The modeling framework presented here combines cross-sectional survey data and syndromic sentinel surveillance data to shed light on several aspects of malaria that are critical for public health policy. This framework can be adapted to enhance inference on infectious diseases whenever asymptomatic carriers are important and multiple datasets are available.
Introduction. Appropriate prevention of infection is a key area of research in natural orifice translumenal endoscopic surgery (NOTES), as identified by the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). Methods. A review of the literature was conducted evaluating the evidence base for access orifice preparation/treatment in NOTES procedures in the context of infectious
complications. Recommendations based on the Oxford Centre for Evidence-Based Medicine guidelines were made.
Results. The most robust evidence includes several experimental randomised controlled trials assessing infectious complications in the transgastric approach to NOTES. Transvaginal procedures are long established for accessing the peritoneal cavity following disinfection with antiseptic. Only experimental case series for transcolonic and transvesical approaches are described. Conclusion. Grade C recommendation requiring no preoperative preparation can be made for the transgastric approach. Antiseptic irrigation is recommended for transvaginal (grade C) NOTES access, as is current practice. Further human trials need to be conducted to corroborate the current evidence base for transgastric closure. It is important that future trials are conducted in a methodologically robust fashion, with emphasis on clinical outcomes and standardisation of enterotomy closure and postoperative therapy.
Silver nanoparticles (AgNP) confined within porous starch have been prepared in a simple, green and efficient manner, utilising the nanoporous structure of predominantly mesoporous starch (MS) to act as nanoparticle stabiliser, support and reducing surface. MS/AgNP materials present high surface areas (SBET > 150 m2 g−1) and mesopore volumes (Vmeso > 0.45 cm3 g−1). The interaction of the AgNP precursor and forming nanoparticle nuclei with the mesoporous domains of the porous polysaccharide, direct porosity to increasingly narrower and more defined pore size distributions, indicative of a degree of cooperative assembly. Transmission electron microscopy images indicated the presence of spherical AgNP of a size reflective of the porous polysaccharide mesopore diameter (e.g., 5–25 nm), whilst XPS analysis confirmed the metallic Ag0 state. Materials were prepared at relatively low Ag loadings (<0.18 mmol g−1), demonstrating excellent antimicrobial activity in solid and liquid phase testing against Gram negative (E. coli) and positive (S. aureus) model bacteria. The resulting materials are biocompatible and present a useful solid porous carbohydrate-based polymer vehicle to control the AgNP size regime and facilitate transference to a biological environment.
antibacterial; mesoporous; nanoparticles; nanotechnology; polysaccharide; silver; starch
Phosphorylation and inactivation of glycogen synthase kinase 3 (GSK-3) is observed in the failing heart induced by chronic pharmacological stress and aortic banding. Constitutive kinase activity attenuates pathological remodelling, suggesting an obligatory role in stress signalling. However, this has been challenged by recent data whereby conditional GSK-3β deletion has been shown to protect against post-infarct remodelling. Here, we set out to determine the chronic remodelling response to infarction in hearts of GSK-3α/βAla21/9 knockin (KI) mice encoding constitutively active GSK-3 isoforms. At 4 weeks after infarction there were significant increases in normalised heart weight and left ventricular (LV) muscle volume compared to sham in both KI and wild type animals. This was associated with an increase in LV cavity dimensions and remote LV wall thickness. Hypertrophy in both genotypes resulted in marked contractile impairment on both invasive and non-invasive interrogation. Increased phosphorylation of GSK-3β, but not GSK-3α, was demonstrated at 1 week after infarction and remained elevated at 4 weeks compared to sham-treated hearts. In conclusion, GSK-3β phosphorylation and inactivation occurs with, but is not an obligatory signalling event in, chronic post-infarct remodelling in the mouse heart. This highlights the heterogeneity of pathological hypertrophy and the divergent role of GSK-3 signalling in chronic myocardial stress.
GSK-3; Myocardial infarction; Remodelling