Restoring the Final Frontier: Exosomal MicroRNA and Cutaneous Wound Repair

Non-healing wounds present a major healthcare challenge associated with the ageing population, the rising incidence of diabetes and the obesity epidermic. Driven by the need to expand therapeutic options for the treatment of such wounds, a large body of evidence has emerged in recent years demonstrating that microRNAs (miRNAs) modulate various aspects of cutaneous wound healing through effects on diverse cell types, including keratinocytes, fibroblasts, endothelial cells and macrophages. However, clear translational pathways for non-invasive cutaneous delivery of miRNAs to facilitate wound repair have not yet been established. The recognition that miRNAs can be actively partitioned into extracellular vesicles (EVs)—exosomes, microvesicles and apoptotic bodies—has stimulated research into the regulation, function and translational exploitation of EV-derived miRNAs both as a novel mode of intercellular signalling and as a tool for miRNA transfer to cells for therapeutic purposes. In particular, because mesenchymal stem cells (MSCs) were found to support wound healing, there is much interest in the therapeutic potential of EVs, especially exosomes, derived from these cells. In this review, we survey some of the main mesenchymal stem cells (MSCs) for which exosomal miRNAs have been evaluated in the context of skin repair, including exosomes from adipose-derived MSCs, bone MSCs, amniotic MSCs and umbilical cord MSCs. Epithelial stem cell (EPSC)-derived exosomes are also considered, from keratinocytes and epidermal stem cells. The picture that emerges from studies on exosomes from various cell types reveal they share a limited set of exosomal miRNAs enhancing wound repair. We suggest a need for direct comparison of exosomal miRNA profiles from a range of MSCs and EPSCs. The ability of exogenous exosomal miRNAs to promote healing of chronic diabetic wounds also warrants further attention in order to more fully establish their therapeutic potential

Human plasma-like medium (HPLM) induces Cryptococcus neoformans in vivo cell morphologies

This is the final version. Available from American Society for Microbiology via the DOI in this record. The fungal pathogen Cryptococcus neoformans (C. neoformans) forms yeast cells of different sizes and morphological characteristics during infection. These features are usually not seen in standard laboratory in vitro conditions. Here, we describe in vivo cell morphologies when C. neoformans is grown in human plasma-like medium at 37°C, 5% CO2. We observed mixed-size populations of cells less than 1 µm up to 16.8 µm in cell diameter, increased capsule size, high chitin, and DNA content in larger cells. Our findings show that serum is not required for human plasma-like medium (HPLM)-induced C. neoformans cellular heterogeneity. Thus, this new method offers an opportunity to investigate factors of C. neoformans that mediate pathogenesis or host-pathogen interactions in a physiologically relevant setting. IMPORTANCE We provide a description of new in vitro culture condition using the human plasma-like medium that supports the formation of the full range of in vivo cell morphologies of C. neoformans.Academy of Medical SciencesMedical Research Council (MRC)Wellcome Trus

Toward cost-effective staffing mixes for Veterans Affairs substance use disorder treatment programs

Background: In fiscal year (FY) 2008, 133,658 patients were provided services within substance use disorders treatment programs (SUDTPs) in the U.S. Department of Veterans Affairs (VA) health care system. To improve the effectiveness and cost-effectiveness of SUDTPs, we analyze the impacts of staffing mix on the benefits and costs of specialty SUD services. This study demonstrates how cost-effective staffing mixes for each type of VA SUDTPs can be defined empirically. Methods: We used a stepwise method to derive prediction functions for benefits and costs based on patients' treatment outcomes at VA SUDTPs nationally from 2001 to 2003, and used them to formulate optimization problems to determine recommended staffing mixes that maximize net benefits per patient for four types of SUDTPs by using the solver function with the Generalized Reduced Gradient algorithm in Microsoft Excel 2010 while conforming to limits of current practice. We conducted sensitivity analyses by varying the baseline severity of addiction problems between lower (2.5 %) and higher (97.5 %) values derived from bootstrapping. Results and conclusions: Compared to the actual staffing mixes in FY01-FY03, the recommended staffing mixes would lower treatment costs while improving patients' outcomes, and improved net benefits are estimated from $1472 to$17,743 per patient. © 2015 Im et al.1

A Time to Heal: MicroRNA and Circadian Dynamics in Cutaneous Wound Repair

Many biological systems have evolved circadian rhythms based on the daily cycles of daylight and darkness on Earth. Such rhythms are synchronised or entrained to 24-hour cycles, predominantly by light, and disruption of the normal circadian rhythms has been linked to elevation of multiple health risks. The skin serves as a protective barrier to prevent microbial infection and maintain homeostasis of the underlying tissue and the whole organism. However, in chronic non-healing wounds such as diabetic foot ulcers, pressures sores, venous and arterial ulcers, a variety of factors conspire to prevent wound repair. On the other hand, keloids and hypertrophic scars arise from over-active repair mechanisms that fail to cease in a timely fashion, leading to excessive production of extracellular matrix components such as such as collagen. Recent years have seen huge increases in our understanding of the functions of microRNAs (miRNA) in wound repair. Concomitantly, there has been growing recognition of miRNA roles in circadian processes, either as regulators or targets of clock activity or direct responders to external circadian stimuli. In addition, miRNAs are now known to function as intercellular signalling mediators through extracellular vesicles. In this review, we explore the intersection of mechanisms by which circadian and miRNA responses interact with each other in relation to wound repair in the skin, using keratinocytes, macrophages and fibroblasts as exemplars. We highlight areas for further investigation to support the development of translational insights to support circadian medicine in the context of these cells

FluTE, a Publicly Available Stochastic Influenza Epidemic Simulation Model

Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development

Histopathological retrospective study of canine renal disease in Korea, 2003~2008

Renal disease includes conditions affecting the glomeruli, tubules, interstitium, pelvis, and vasculature. Diseases of the kidney include glomerular diseases, diseases of the tubules and interstitium, diseases of renal pelvis, and developmental abnormalities. Renal tissue samples (n = 70) submitted to the Department of Veterinary Pathology of Konkuk University from 2003 to 2008 were included in this study. Tissue histopathology was performed using light microscopy with hematoxylin and eosin stains. Masson's trichrome, Congo Red, and Warthin starry silver staining were applied in several individual cases. Glomerular diseases (22.9%), tubulointerstitial diseases (8.6%), neoplastic diseases (8.6%), conditions secondary to urinary obstruction (24.3%), and other diseases (35.7%) were identified. Glomerulonephritis (GN) cases were classified as acute proliferative GN (5.7%), membranous GN (4.3%), membranoproliferative GN (4.3%), focal segmental GN (2.9%), and other GN (4.2%). The proportion of canine GN cases presently identified was not as high as the proportions identified in human studies. Conversely, urinary obstruction and end-stage renal disease cases were relatively higher in dogs than in human populations

The projection score - an evaluation criterion for variable subset selection in PCA visualization

<p>Abstract</p> <p>Background</p> <p>In many scientific domains, it is becoming increasingly common to collect high-dimensional data sets, often with an exploratory aim, to generate new and relevant hypotheses. The exploratory perspective often makes statistically guided visualization methods, such as Principal Component Analysis (PCA), the methods of choice. However, the clarity of the obtained visualizations, and thereby the potential to use them to formulate relevant hypotheses, may be confounded by the presence of the many non-informative variables. For microarray data, more easily interpretable visualizations are often obtained by filtering the variable set, for example by removing the variables with the smallest variances or by only including the variables most highly related to a specific response. The resulting visualization may depend heavily on the inclusion criterion, that is, effectively the number of retained variables. To our knowledge, there exists no objective method for determining the optimal inclusion criterion in the context of visualization.</p> <p>Results</p> <p>We present the projection score, which is a straightforward, intuitively appealing measure of the informativeness of a variable subset with respect to PCA visualization. This measure can be universally applied to find suitable inclusion criteria for any type of variable filtering. We apply the presented measure to find optimal variable subsets for different filtering methods in both microarray data sets and synthetic data sets. We note also that the projection score can be applied in general contexts, to compare the informativeness of any variable subsets with respect to visualization by PCA.</p> <p>Conclusions</p> <p>We conclude that the projection score provides an easily interpretable and universally applicable measure of the informativeness of a variable subset with respect to visualization by PCA, that can be used to systematically find the most interpretable PCA visualization in practical exploratory analysis.</p

Optimizing the primary particle size distributions of pressurized metered dose inhalers by using inkjet spray drying for targeting desired regions of the lungs

Conventional suspension pressurized metered dose inhalers (pMDIs) suffer not only from delivering small amounts of a drug to the lungs, but also the inhaled dose scatters all over the lung regions. This results in much less of the desired dose being delivered to regions of the lungs. This study aimed to improve the aerosol performance of suspension pMDIs by producing primary particles with narrow size distributions. Inkjet spray drying was used to produce respirable particles of salbutamol sulfate. The Next Generation Impactor (NGI) was used to determine the aerosol particle size distribution and fine particle fraction (FPF). Furthermore, oropharyngeal models were used with the NGI to compare the aerosol performances of a pMDI with monodisperse primary particles and a conventional pMDI. Monodisperse primary particles in pMDIs showed significantly narrower aerosol particle size distributions than pMDIs containing polydisperse primary particles. Monodisperse pMDIs showed aerosol deposition on a single stage of the NGI as high as 41.75 ± 5.76%, while this was 29.37 ± 6.79% for a polydisperse pMDI. Narrow size distribution was crucial to achieve a high FPF (49.31 ± 8.16%) for primary particles greater than 2 µm. Only small polydisperse primary particles with sizes such as 0.65 ± 0.28 µm achieved a high FPF with (68.94 ± 6.22%) or without (53.95 ± 4.59%) a spacer. Oropharyngeal models also indicated a narrower aerosol particle size distribution for a pMDI containing monodisperse primary particles compared to a conventional pMDI. It is concluded that, pMDIs formulated with monodisperse primary particles show higher FPFs that may target desired regions of the lungs more effectively than polydisperse pMDIs. Read More: http://informahealthcare.com/doi/abs/10.3109/03639045.2013.85874

Internet-based monitoring of influenza-like illness (ILI) in the general population of the Netherlands during the 2003–2004 influenza season

BACKGROUND: An internet-based survey of influenza-like illness (ILI) – the Great Influenza Survey or GIS – was launched in the Netherlands in the 2003–2004 influenza season. The aim of the present study was to validate the representativeness of the GIS population and to compare the GIS data with the official ILI data obtained by Dutch GPs participating in the Dutch Sentinel Practice Network. METHOD: Direct mailings to schools and universities, and repeated interviews on television and radio, and in newspapers were used to kindle the enthusiasm of a broad section of the public for GIS. Strict symptomatic criteria for ILI were formulated with the assistance of expert institutes and only participants who responded at least five times to weekly e-mails asking them about possible ILI symptoms were included in the survey. Validation of GIS was done at different levels: 1) some key demographic (age distribution) and public health statistics (prevalence of asthma and diabetes, and influenza vaccination rates) for the Dutch population were compared with corresponding figures calculated from GIS; 2) the ILI rates in GIS were compared with the ILI consultation rates reported by GPs participating in the Dutch Sentinel Practice Network. RESULTS: 13,300 persons (53% of total responders), replied at least five times to weekly e-mails and were included in the survey. As expected, there was a marked under-representation of the age groups 0–10 years and 81->90 years in the GIS population, although the similarities were remarkable for most other age groups, albeit that the age groups between 21 and 70 years were slightly overrepresented. There were striking similarities between GIS and the Dutch population with regard to the prevalence of asthma (6.4% vs. 6.9%) and the influenza vaccination rates, and to a lesser degree for diabetes (2.4% vs. 3.5%). The vaccination rates in patients with asthma or diabetes, and persons older than 65 years were 68%, 85%, and 85% respectively in GIS, while the corresponding percentages in the Dutch population were 73%, 85% and 87%. There was also a marked similarity between the seasonal course of ILI measured by GIS and the GPs. Although the ILI rate in GIS was about 10 times higher, the curves followed an almost similar pattern, with peak incidences occurring in the same week. CONCLUSION: The current study demonstrates that recruitment of a high number of persons willing to participate in on-line health surveillance is feasible. The information gathered proved to be reliable, as it paralleled the information obtained via an undisputed route. We believe that the interactive nature of GIS and the appealing subject were keys to its success