Early inflammation precedes cardiac fibrosis and heart failure in desmoglein 2 murine model of arrhythmogenic cardiomyopathy.

The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in Dsg2-null (Dsg2-/-) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were also upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression.

Voluntary sustainability standards could significantly reduce detrimental impacts of global agriculture.

Voluntary sustainability standards (VSS) are stakeholder-derived principles with measurable and enforceable criteria to promote sustainable production outcomes. While institutional commitments to use VSS to meet sustainable procurement policies have grown rapidly over the past decade, we still have relatively little understanding of the (i) direct environmental benefits of large-scale VSS adoption; (ii) potential perverse indirect impacts of adoption; and (iii) implementation pathways. Here, we illustrate and address these knowledge gaps using an ecosystem service modeling and scenario analysis of Bonsucro, the leading VSS for sugarcane. We find that global compliance with the Bonsucro environmental standards would reduce current sugarcane production area (-24%), net tonnage (-11%), irrigation water use (-65%), nutrient loading (-34%), and greenhouse gas emissions from cultivation (-51%). Under a scenario of doubled global sugarcane production, Bonsucro adoption would further limit water use and greenhouse gas emissions by preventing sugarcane expansion into water-stressed and high-carbon stock ecosystems. This outcome was achieved via expansion largely on existing agricultural lands. However, displacement of other crops could drive detrimental impacts from indirect land use. We find that over half of the potential direct environmental benefits of Bonsucro standards under the doubling scenario could be achieved by targeting adoption in just 10% of global sugarcane production areas. However, designing policy that generates the most environmentally beneficial Bonsucro adoption pathway requires a better understanding of the economic and social costs of VSS adoption. Finally, we suggest research directions to advance sustainable consumption and production.

Brain-derived neurotrophic factor genotype is associated with brain gray and white matter tissue volumes recovery in abstinent alcohol-dependent individuals.

Neuroimaging studies have linked the methionine (Met) allele of the brain-derived neurotrophic factor (BDNF) gene to abnormal regional brain volumes in several psychiatric and neurodegenerative diseases. However, no neuroimaging studies assessed the effects of this allele on brain morphology in alcohol use disorders and its demonstrated change during abstinence from alcohol. Here we assessed the effects of the BDNF Val66Met (rs6265) polymorphism on regional brain tissue volumes and their recovery during short-term abstinence in treatment-seeking alcohol-dependent individuals. 3D T1 weighted magnetic resonance images from 62 individuals were acquired at 1.5 T at one week of abstinence from alcohol; 41 of the participants were rescanned at 5 weeks of abstinence. The images were segmented into gray matter (GM), white matter (WM) and cerebrospinal fluid and parcellated into regional volumes. The BDNF genotype was determined from blood samples using the TaqMan technique. Alcohol-dependent Val (Valine)/Met heterozygotes and Val homozygotes had similar regional brain volumes at either time point. However, Val homozygotes had significant GM volume increases, while Val/Met heterozygotes increased predominantly in WM volumes over the scan interval. Longitudinal increases in GM but not WM volumes were related to improvements in neurocognitive measures during abstinence. The findings suggest that functionally significant brain tissue volume recovery during abstinence from alcohol is influenced by BDNF genotype.

The use of a measure of acute irritation to predict the outcome of repeated usage of hand soap products.

BACKGROUND: Healthcare-associated infection is an important worldwide problem that could be reduced by better hand hygiene practice. However, an increasing number of healthcare workers are experiencing irritant contact dermatitis of the hands as a result of repeated hand washing. This may lead to a reduced level of compliance with regard to hand hygiene. OBJECTIVES: To assess whether a measure of acute irritation by hand soaps could predict the effects of repeated usage over a 2-week period. METHODS: In a double-blind, randomized comparison study, the comparative irritation potential of four different hand soaps was assessed over a 24-h treatment period. The effect of repeated hand washing with the hand soap products over a 2-week period in healthy adult volunteers on skin barrier function was then determined by assessment of transepidermal water loss (TEWL), epidermal hydration and a visual assessment using the Hand Eczema Severity Index (HECSI) at days 0, 7 and 14. RESULTS: A total of 121 subjects from the 123 recruited completed phase 1 of the study. All four products were seen to be significantly different from each other in terms of the irritant reaction observed and all products resulted in a significantly higher irritation compared with the no-treatment control. Seventy-nine of the initial 121 subjects were then enrolled into the repeated usage study. A statistically significant worsening of the clinical condition of the skin as measured by HECSI was seen from baseline to day 14 in those subjects repeatedly washing their hands with two of the four soap products (products C and D) with P-values of 0·02 and 0·01, respectively. Subclinical assessment of the skin barrier function by measuring epidermal hydration was significantly increased from baseline to day 7 after repeated hand washing with products A, B and D but overall no significant change was seen in all four products tested by day 14. A statistically significant increase in TEWL at day 14 was seen for product A (P = 0·02) indicating a worsening of skin barrier function. This effect was also seen initially for product D at day 7 although this was then lost at day 14. Further regression analysis was then performed to see if the acute irritant test data for each product correlated with the skin barrier data from the repeated usage component of the study. This showed that the results of acute irritant testing of the individual products did not predict the results of chronic use of hand soaps. CONCLUSIONS: The results from phase 2 of our study confirm the work of previous studies that show that regular exposure to irritants in daily life leads to stratum corneum damage and impairment of the skin barrier. Although significant differences were seen between the products in phase 1 of the study, regression analysis showed that the results of patch testing of the individual products did not predict the results of chronic use of hand soaps. When designing a study to assess the effects of cumulative use of a product on the skin, the study should mirror the use conditions of the product as closely as possible.

A double-blind, randomized study to assess the effectiveness of different moisturizers in preventing dermatitis induced by hand washing to simulate healthcare use.

BACKGROUND: Healthcare-associated infection is an important worldwide problem that could be reduced by better hand hygiene practice. However, irritant contact dermatitis of the hands as a result of repeated hand washing is a potential complication that may be preventable by the regular use of an emollient. OBJECTIVES: To assess the effect of moisturizer application after repeated hand washing (15 times daily) vs. soap alone. METHODS: In a double-blind, randomized study, the effect of five different moisturizers on skin barrier function was determined by assessment after repeated hand washing over a 2-week period in healthy adult volunteers. Assessments of transepidermal water loss (TEWL), epidermal hydration and a visual assessment using the Hand Eczema Severity Index (HECSI) were made at days 0, 7 and 14. RESULTS: In total, 132 patients were enrolled into the study. A statistically significant worsening of the clinical condition of the skin as measured by HECSI was seen from baseline to day 14 (P = 0.003) in those subjects repeatedly washing their hands with soap without subsequent application of moisturizer. No change was seen in the groups using moisturizer. Subclinical assessment of epidermal hydration as a measure of skin barrier function showed significant increases from baseline to day 14 after the use of three of the five moisturizing products (P = 0.041, 0.001 and 0.009). Three of the five moisturizers tested led to a statistically significant decrease in TEWL at day 7 of repeated hand washing. This effect was sustained for one moisturizing product at day 14 of hand washing (P = 0.044). CONCLUSIONS: These results support the view that the regular application of moisturizers to normal skin offers a protective effect against repeated exposure to irritants, with no evidence of a reduction in barrier efficiency allowing the easier permeation of irritant substances into the skin as has been suggested by other studies. Regular use of emollient in the healthcare environment may prevent the development of dermatitis.

Flap-in-flap method for enhancing the advancement of a V-Y flap.

The V-Y principal is used in a number of flap reconstruction techniques. V-Y flaps suffer from design problems of the advancing edge, which is usually concave, trying to match another concave edge on the opposite side of the defect. The flap-in-flap technique uses a second V-Y flap at the advancing edge of the main flap to overcome this mismatch, and also improves the amount of advancement possible. The technique has been used in three patients, demonstrating reliability and a further advantage, which is the ability of the second flap to rotate at an angle to the main flap to aid in reconstructing a complex defect such as the alar base of the nose. Further experience with this technique should widen its applications.

Comparison of angioplasty and surgery for neonatal aortic coarctation.

BACKGROUND: The efficacy of balloon dilatation as primary treatment for neonatal aortic coarctation remains controversial. METHODS: A retrospective comparison between balloon angioplasty and surgery for the treatment of neonatal aortic coarctation was undertaken on 57 neonates younger than 40 days of age (angioplasty, 23 patients; surgery, 34 patients) treated between 1994 and 2004. RESULTS: Cohorts were similar with respect to the preinterventional variables of age, weight, upper extremity systolic blood pressure, coarctation gradient, degree of aortic arch hypoplasia, associated conditions, and mean follow-up (angioplasty, 36 months; surgery, 38 months). Among the angioplasty group, 13 patients (57%) required surgery, and 8 required a second balloon dilatation, of whom 3 patients had an aortic aneurysm. Among the surgery cohort, 6 patients experienced recurrence (18%) after either SFA (3) or XETE anastomosis repair (3). All were successfully treated with balloon angioplasty. Actuarial freedom from any intervention was significantly greater in the surgery cohort as was the degree of aortic arch growth. At latest follow-up, antihypertensive medication was required in 3 of 9 angioplasty patients (33%) and 2 of 27 surgery patients (7%). No repeat intervention was required in the 13 patients who underwent angioplasty followed by surgery. CONCLUSIONS: Primary angioplasty is palliative treatment for neonatal aortic coarctation, but it is the treatment of choice for recurrence after surgery. Surgery for neonatal aortic coarctation is associated with fewer reinterventions, improved aortic arch growth, no aortic aneurysm formation, and decreased need for antihypertensive medication when compared with neonates treated primarily with balloon angioplasty.

Cyclic exchanges and level of coupling between environmental media: intermedia feedback in multimedia fate models.

The importance of cyclic transport of chemicals between media in the environment can be expressed in terms of the Feedback correction factor--a multiplier that accounts for the fraction of an emission that returns to the medium of release after transfer to other media. This factor is calculated analytically by explicitly solving the appropriate system of mass balance equations or using matrix techniques. It generalizes the concept of stickiness, the ratio between the net and the overall deposition rate constants, to multipathway feedback, while providing a clearer view of the level of coupling between media and analyzing the importance of coupling. This paper first shows the usefulness of the total removal rate coefficient in each media (sum of degradation rate and all intermedia transfer rates) as a baseline to determine the chemical mass in different media, the characteristic travel distance and to understand the cyclic behavior, rather than starting from the degradation lifetimes or the overall persistence in the environment. Starting from this baseline, the importance of feedback is limited for most organic chemicals. The predicted media concentrations are influenced by less than 10% due to the cyclic nature of the intermedia transport for more than 90% of the 317 tested chemicals in a 4-compartment, steady-state, closed-system multimedia model. The Feedback correction factor is always less than a factor of 5 with the greatest values when transfer fractions are important in both directions for adjacent media. This corresponds to a restricted range in the K(AW) and K(OA) space with long chemical lifetimes in both adjacent media. This analysis of the importance of the Feedback correction factor, in conjunction with resultant criteria for when cyclic exchanges between media are likely to be significant, facilitates a more transparent understanding of how substance masses are distributed in the modeled system. It is one of the important criteria to determine to what extent media can be independently modeled.

Life cycle assessment part 1: framework, goal and scope definition, inventory analysis, and applications.

Sustainable development requires methods and tools to measure and compare the environmental impacts of human activities for the provision of goods and services (both of which are summarized under the term "products"). Environmental impacts include those from emissions into the environment and through the consumption of resources, as well as other interventions (e.g., land use) associated with providing products that occur when extracting resources, producing materials, manufacturing the products, during consumption/use, and at the products' end-of-life (collection/sorting, reuse, recycling, waste disposal). These emissions and consumptions contribute to a wide range of impacts, such as climate change, stratospheric ozone depletion, tropospheric ozone (smog) creation, eutrophication, acidification, toxicological stress on human health and ecosystems, the depletion of resources, water use, land use, and noise-among others. A clear need, therefore, exists to be proactive and to provide complimentary insights, apart from current regulatory practices, to help reduce such impacts. Practitioners and researchers from many domains come together in life cycle assessment (LCA) to calculate indicators of the aforementioned potential environmental impacts that are linked to products-supporting the identification of opportunities for pollution prevention and reductions in resource consumption while taking the entire product life cycle into consideration. This paper, part 1 in a series of two, introduces the LCA framework and procedure, outlines how to define and model a product's life cycle, and provides an overview of available methods and tools for tabulating and compiling associated emissions and resource consumption data in a life cycle inventory (LCI). It also discusses the application of LCA in industry and policy making. The second paper, by Pennington et al. (Environ. Int. 2003, in press), highlights the key features, summarises available approaches, and outlines the key challenges of assessing the aforementioned inventory data in terms of contributions to environmental impacts (life cycle impact assessment, LCIA).

Life cycle assessment part 2: current impact assessment practice.

Providing our society with goods and services contributes to a wide range of environmental impacts. Waste generation, emissions and the consumption of resources occur at many stages in a product's life cycle-from raw material extraction, energy acquisition, production and manufacturing, use, reuse, recycling, through to ultimate disposal. These all contribute to impacts such as climate change, stratospheric ozone depletion, photooxidant formation (smog), eutrophication, acidification, toxicological stress on human health and ecosystems, the depletion of resources and noise-among others. The need exists to address these product-related contributions more holistically and in an integrated manner, providing complimentary insights to those of regulatory/process-oriented methodologies. A previous article (Part 1, Rebitzer et al., 2004) outlined how to define and model a product's life cycle in current practice, as well as the methods and tools that are available for compiling the associated waste, emissions and resource consumption data into a life cycle inventory. This article highlights how practitioners and researchers from many domains have come together to provide indicators for the different impacts attributable to products in the life cycle impact assessment (LCIA) phase of life cycle assessment (LCA).

Evaluating multimedia/multipathway model intake fraction estimates using POP emission and monitoring data.

This paper presents a structured evaluation of a novel multimedia chemical fate and multi-pathway human exposure model for Western Europe, IMPACT 2002, using data for PCDD/F congeners. PCDD/F congeners provide an illustration of the potential use of POPs (Persistent Organic Pollutant) data for the evaluation of such models. Based on available emission estimates, model predictions with and without spatial resolution are evaluated at three different stages against monitored data: at environmental contamination levels, food exposure concentration, and in terms of human intake fractions (iF): the fraction of an emission that is taken in by the population. The iF is approximately 3.5.10(-3) for emissions of dioxin in Western Europe. This iF compares well to the traditional non-spatial multi-media/-pathway model predictions of 3.9.10(-3) for the same region and to 2.10(-3) for the USA. Approximately 95% of the intake from Western European emissions occurs within the same region, 5% being transferred out of the region in terms of food contaminants and atmospheric advective transport.

An anatomical and clinical study of the dorsal intercostal cutaneous perforators, and application to free microvascular augmented subdermal vascular network (ma-SVN) flaps.

We report a two-part anatomical and clinical study whose aim was to map the dominant dorsal intercostal cutaneous perforators (DICPs), which are useful for microvascular augmentation of flaps raised from the skin of the back called subdermal vascular network (SVN) flaps, and to test their reliability in the clinical setting. In the anatomical arm of the study, using preserved cadavers, we macroscopically confirmed the location of DICPs, and performed micro-angiography of the dorsal skin to find each dominant DICP. In the clinical arm of the study, we confirmed the location of the dominant DICP during microvascular augmented SVN flap transfer. Postoperatively, posteroanterior radiographs of the chest were taken to locate vessel clips used to ligate the DICPs. The combined study results showed that the dominant DICP is the sixth or seventh in most instances, but there are some anatomical variations. If no dominant DICP is found in the sixth or seventh spaces, at least one DICP that is of sufficient calibre for microvascular augmentation can usually be found in the general vicinity, such as the fifth, eighth or ninth spaces. The clinical application of microvascular augmented SVN flaps, both pedicled and free, is presented.

The microvascular augmented subdermal vascular network (ma-SVN) flap: its variations and recent development in using intercostal perforators.

In 1994 we reported the use of the microvascular augmented occipito-cervico-dorsal 'super-thin' flap for reconstruction of the cervical region in three cases. Since this preliminary report, we have performed a further 17 flaps, and the usefulness of the flap in the treatment of anterior cervical scar contractures in extensively burned patients has become apparent. Moreover, we have devised flaps with not only a narrow skin pedicle but also myocutaneous or island vascular pedicles. Various augmentation vessels, including myocutaneous perforators of the intercostal spaces in the back and chest, have also been used successfully. Here, we describe the microvascular augmented subdermal vascular network flaps that we have devised.

Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts.

OBJECTIVE: As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGF beta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts. METHODS: We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGF beta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects. RESULTS: Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGF beta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGF beta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGF beta-mediated induction of connective tissue growth factor promoter activity. CONCLUSION: SSc is characterized by overproduction of matrix; that is, genes that are targets of TGF beta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGF beta.

Experimental measurements of deep directional columnar heating by laser-generated relativistic electrons at near-solid density.

In our experiments, we irradiated solid CH targets with a 400 J, 5 ps, 3 x 10(19) W/cm(2) laser, and we used x-ray imaging and spectroscopic diagnostics to monitor the keV x-ray emission from thin Al or Au tracer layers buried within the targets. The experiments were designed to quantify the spatial distribution of the thermal electron temperature and density as a function of buried layer depth; these data provide insights into the behavior of relativistic electron currents which flow within the solid target and are directly and indirectly responsible for the heating. We measured approximately 200-350 eV temperatures and near-solid densities at depths ranging from 5 to 100 microm beneath the target surface. Time-resolved x-ray spectra from Al tracers indicate that the tracers emit thermal x rays and cool slowly compared to the time scale of the laser pulse. Most intriguingly, we consistently observe annular x-ray images in all buried tracer-layer experiments, and these data show that the temperature distribution is columnar, with enhanced heating along the edges of the column. The ring diameters are much greater than the laser focal spot diameter and do not vary significantly with the depth of the tracer layer for depths greater than 30 microm. The local temperatures are 200-350 eV for all tracer depths. We discuss recent simulations of the evolution of electron currents deep within solid targets irradiated by ultra-high-intensity lasers, and we discuss how modeling and analytical results suggest that the annular patterns we observe may be related to locally strong growth of the Weibel instability. We also suggest avenues for future research in order to further illuminate the complex physics of relativistic electron transport and energy deposition inside ultra-high-intensity laser-irradiated solid targets.

Management of postpneumonectomy bronchopleural-cutaneous fistula with a single free flap.

A variety of local flaps have been described for chest wall and bronchopleural fistula reconstruction. When local options cannot be used because of previous surgery, trauma, radiation, or body habitus, free flaps become an acceptable option. The authors report a case of persistent bronchopleural-cutaneous fistula treated with a free latissimus dorsi musculocutaneous flap that obliterated the right chest cavity, closed the site of empyema drainage, and aided healing of a bronchopleural fistula. Surgical technique including anastomosis to the innominate vein is described.

Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection.

To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.