Stiffening of the extracellular matrix is a sufficient condition for airway hyperreactivity.

The current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force to prevent the recurrence of symptoms. However, even when inflammation is brought under control, airways in an asthmatic can still hyperconstrict when exposed to a low dose of agonist. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction even in the absence of inflammation. To test this hypothesis, we increased the stiffness of the airway extracellular matrix by photo-crosslinking collagen fibers within the airway wall of freshly dissected bovine rings using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a twofold increase in the stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, and at a faster rate when they were exposed to 10-5 M acetylcholine for 5 min. Our results show that stiffening of the extracellular matrix is sufficient to drive excessive airway constriction even in the absence of inflammatory signals.NEW & NOTEWORTHY Targeting inflammation is the central dogma on which current asthma therapy is based. Here, we show that a healthy airway can be made to constrict excessively and at a faster rate in response to the same stimulus by increasing the stiffness of the extracellular matrix, without the use of inflammatory agents. Our results provide an independent mechanism by which airway remodeling in asthma can sustain airway hyperreactivity even in the absence of inflammatory signals.

Increased operational costs of electricity generation in the Delaware River and Estuary from salinity increases due to sea-level rise and a deepened channel.

Like many estuaries in the world, salinity levels in the Delaware River and Estuary are expected to increase due to a deepened navigational channel and sea-level rise. This study estimated operational cost increases resulting from increased ambient salinity likely to be incurred at PSEG-Hope Creek, an evaporatively cooled electricity generating station. To estimate cost increases, a linked physical-economic model was developed to generate daily forecasts of salinity and the resulting changes in facility's cooling water treatment and pumping requirements. Salinity increases under potential future bathymetric configurations were simulated using a hydrodynamic model. On an equivalent annual basis (discounted at 5%), average cost increases were $0.4M per year, or approximately 0.1% of estimated total annual operating costs for the facility. Methods developed here could be employed at other facilities anticipating future salinity increases. Results inform cost-benefit analyses for dredging projects and contribute to estimates of the indirect costs to society from carbon emissions through sea-level rise. Future research refinements can focus on modeling changes in suspended sediment concentrations and estimating their impacts on operational costs.

A mobile pool of contaminated sediment in the Penobscot Estuary, Maine, USA.

The natural recovery of estuaries from contamination is largely determined by the timescale over which contaminated sediment is exported or buried and replaced by cleaner sediment that enters from the watershed or the ocean. That timescale depends on the size of the "pool" of contaminated sediment that resides in the estuary. The larger the pool, the longer the recovery timescale for a given rate of sediment input. A field study was undertaken as part of a study of mercury contamination in the Penobscot estuary to assess the mechanisms affecting the transport and fate of contaminated sediment. Based on measurements of water properties, currents and sediment transport and seabed samples analyzed for sediment properties and contaminant concentrations, a "mobile pool" of contaminated sediment with relatively uniform geochemical characteristics along a 20-km reach of the estuary was identified. This pool of sediment is mobilized seasonally by resuspension and trapping processes associated with salinity fronts that vary in location with discharge conditions. Sediment is transported down-estuary during high discharge and up-estuary during low discharge, with seasonal, bi-directional transport of sediment in the estuary significantly exceeding the annual input of new sediment from the watershed. This continual, bi-directional transport leads to homogenization of the chemical properties of the mobile sediment, including contaminant concentrations. The large mass of mobile sediment relative to the input of sediment from the watershed helps explain the long recovery timescale of contaminants in the Penobscot estuary.

The use of allodermis prepared from Euro skin bank to prepare autologous tissue engineered skin for clinical use.

Over the past two decades a range of 3D models for human skin have been described. Some include native collagen and intrinsic basement membrane proteins and fibroblasts, others are based on xenogeneic collagen or synthetic supports often without fibroblasts. The aim of this study was to look at the influence of media calcium, basement membrane and fibroblasts on the quality of 3D tissue engineered skin produced using human de-epidermized acellular dermis. In this study we deliberately used Euro skin as the source of the donor dermis to examine to what extent this could provide an effective dermal substrate for producing 3D skin for clinical use. Keratinocytes were cultured in the presence and absence of fibroblasts and both with and without basement membrane on decellularized dermis at calcium concentrations ranging from 250µM to 1.6mM over a period of 14 days. Results showed the formation of a well attached epithelium with many of the features of normal skin in the presence of a basement membrane. This was largely independent of the presence of fibroblasts and not greatly influenced by the concentration of calcium in the media. However there was a clear requirement for physiological levels of calcium in the formation of a stratified epithelium in the absence of a basement membrane.

When should psychiatrists seek criminal prosecution of assaultive psychiatric inpatients?

This Open Forum commentary reviews the ethical considerations relevant to the question of prosecuting assaultive psychiatric patients, with particular attention to the significance that should be attached to the arguments generated by those considerations. A comprehensive literature search was conducted incorporating the terms "assaultive patients," "ethics," "psychiatric inpatients," and "law." The literature of professional medical ethics was applied to identify relevant domains of ethical argument. Five domains were identified: fiduciary obligations of physicians to assaultive and other patients; obligations to staff members; professional virtues of compassion, self-sacrifice, and self-effacement; retributive justice; and the patient's right to confidentiality. The content of each domain is explained, and guidance is provided on how to assess the relative strengths of ethical argument within each domain. All five domains must be explicitly addressed in order to make ethically disciplined judgments about whether to seek prosecution. A distinctive feature of this ethical analysis is the central importance of the professional virtues.

Disability, humanity, and personhood: a survey of moral concepts.

Three of the articles included in this issue of the Journal of Medicine and Philosophy - Ron Amundson and Shari Tresky's "On a Bioethical Challenge to Disability Rights"; Rachel Cooper's "Can It Be a Good Thing to Be Deaf?"; and Mark T. Brown's "The Potential of the Human Embryo" - interact (in various ways) with the concepts of disability, humanity, and personhood and their normative dimensions. As one peruses these articles, it becomes apparent that terms like "disability," "human being," and "person" carry with them great normative significance. There is, however, much disagreement concerning both the definition and the extension of such terms. This is significant because different terms and definitions are associated with different sets of normative requirements. In what follows we reconstruct the argument of each of the articles, and then offer some brief critical analysis intended to stimulate further thought about and discussion of the issues that each raises.

Cooking and oxygen. An explosive recipe.

BACKGROUND: Home oxygen therapy is commonly prescribed for the treatment of chronic obstructive pulmonary disease (COPD). The risks of smoking while using this therapy have been well described. OBJECTIVE: To discuss the Royal Brisbane Hospital Burns Unit's experience and present case studies which illustrate the danger of alternative ignition sources while using home oxygen. DISCUSSION: The dangers of home oxygen therapy can be minimised by careful patient selection, education and ongoing monitoring.

Baseline quality indicator rates from the National Heart Failure Project: a HCFA initiative to improve the care of medicare beneficiaries with heart failure.

This column is the third in a series reporting on Health Care Financing Administration (HCFA) initiatives to improve care for Medicare beneficiaries with heart failure. The first paper outlined the history of HCFA quality improvement projects and current initiatives to improve care in six priority areas: heart failure, acute myocardial infarction, stroke, pneumonia, diabetes, and breast cancer. The second reported in more detail the structure of the national inpatient fee-for-service heart failure initiative, known as the National Heart Failure project. It described the development of the quality indicators, the sampling strategy for selecting charts to be reviewed, and the types of local efforts spurred by the project through the activities of each state's HCFA contractor peer review organization. This article discusses baseline quality indicator rates from the National Heart Failure project. (c)2001 by CHF, Inc.

Lessons learned from the national heart failure project: a center for medicare and medicaid services initiative to improve the care of medicare beneficiaries with heart failure.

This column is the seventh in a series reporting on the efforts of the Center for Medicare and Medicaid Services (CMS), formerly known as the Health Care Financing Administration, to improve care for Medicare beneficiaries with heart failure. In previous columns we have described the overall structure of Medicare quality improvement efforts, detailed the structure of the national inpatient fee-for-service program known as the National Heart Failure project, and discussed the baseline quality indicator rates for the project, which are focused on rates of ejection fraction documentation and angiotensin-converting enzyme inhibitor prescription. In more recent columns, we reported on quality improvement projects from several participating hospitals, and on a pilot project exploring quality improvement efforts for heart failure based in physicians' offices. This column will focus on ways in which systematic examination of data, such as those from the National Heart Failure project, might shape future quality improvement and research efforts. The National Heart Failure project's quality indicator data are collected primarily to guide and evaluate the efforts of the CMS contractor peer-review organizations to facilitate quality improvement efforts in hospitals throughout the United States. (c)2001 CHF, Inc.

Influencing care in acute myocardial infarction: a randomized trial comparing 2 types of intervention.

The purpose of this study was to evaluate performance feedback delivered by on-site presentations compared to mailed feedback on improving acute myocardial infarction (AMI) care. We used a randomized trial including 18 hospitals nested within the Cooperative Cardiovascular Project. Patients comprised AMI Medicare patients admitted before (n = 929, 1994 and 1995) and after intervention (n = 438, 1996). Control hospitals received written feedback by mail. The experimental intervention group received a presentation led by a cardiologist and a quality improvement specialist. We assessed the proportion of patients receiving appropriate AMI care before and after the intervention. Both univariate and multivariate analyses demonstrated no effect of the intervention in increasing the proportion of patients who received reperfusion, aspirin, beta-blockers, or angiotensin-converting enzyme inhibitors. On-site feedback presentations were not associated with a larger improvement in AMI care compared to the mailed feedback. Other interventions, such as opinion leaders and patient-directed interventions, may be necessary in order to improve the care of AMI patients.

The requirement for basement membrane antigens in the production of human epidermal/dermal composites in vitro.

The importance of a dermal element when providing permanent wound cover for skin loss has become evident as the shortcomings of pure epidermal grafts are recognized. We are developing a skin composite formed from sterilized human de-epidermized acellular dermis, keratinocytes and fibroblasts with the ultimate aim of using this composite to cover full-thickness excised burn wounds. These composites can be prepared with or without basement membrane (BM) antigens initially present on the dermis. This study investigates the importance of retaining BM antigens on the dermis to the production and appearance of these composites in vitro. Skin composites prepared from dermis with BM antigens either present or absent initially were studied throughout 3 weeks. Composites with BM antigens present initially were significantly better than those initially lacking BM antigens in: (i) the degree of epithelial cell attachment to the underlying dermis (hemidesmosomes were seen only in the former); (ii) the morphology of the epithelial layer; (iii) the consistent presence of collagen IV and laminin and the increasing expression of tenascin; and (iv) the amount of soluble collagen IV and fibronectin detected in the conditioned media. We conclude that an initial BM antigen template is vital in this skin composite model for the attachment and differentiation of the epithelial layer and for the subsequent remodelling of the BM in vitro.

Increasing influenza and pneumococcal vaccination and tuberculosis screening among residents of Colorado long-term care facilities.

Persons residing in long-term care facilities are especially vulnerable to potentially preventable morbidity and mortality caused by influenza, S. pneumoniae, and tuberculosis. This project's objective was to increase the rates of pneumococcal vaccination, tuberculosis screening, and annual influenza vaccination. Intervention consisted of staff training videos, sample policies, and educational materials for residents and their families. At baseline during the 1995-1996 flu season, 84% of Colorado long-term care residents were vaccinated for influenza; 16% of residents had ever received pneumococcal vaccination; and 59% had been screened for tuberculosis. At remeasurement during 1997 to 1998, influenza vaccination rates were up to 89%, p = 0.006. The percentage of residents who had ever received pneumococcal vaccination increased to 48% at remeasurement, p < 0.001. Tuberculosis screening rates increased to 83%, p < 0.001. Following an educational intervention targeting both residents and staff, residents were significantly more likely to receive all three preventive services.

Skin banking in the UK: the need for proper organization.

Skin banking was set up in Sheffield in 1991 to provide a readily available source of allograft material to be used both for research purposes and also as a means of providing immediate wound cover for major burns patients. Once skin was available, however, clinical demand for it both within and outside Sheffield, outstripped the resources to run the bank. Logistical difficulties were encountered in the day to day running of the bank. These revolved around shortage of staff available for harvesting, the relative lack of public awareness of skin donation, shortage of banked skin as the bank became more widely known and lack of space and finance to expand. The decision was made to transfer the now established skin bank to the National Blood Service where it now operates with staff and resources dedicated specifically to this purpose. Experience leads to the suggestion that there is a clinical need for allograft skin in the UK which is not being met at the present time. There is a need for dedicated properly resourced skin banks and for the Department of Health to introduce regulation, monitoring and inspection of skin bank facilities in order to safeguard standards.

Alpha 1-antitrypsin and protease complexation is induced by lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha in monocytes.

Local regulation of alpha1-antitrypsin (alpha1-AT) may have importance in maintenance of the protease-antiprotease balance in the microenvironment of inflammatory cells. We therefore studied whether lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNFalpha) affect the pericellular concentration of alpha1-AT in human peripheral blood mononuclear cells (PBMC). PBMC taken from normal healthy volunteers were treated with LPS, IL-1beta, and TNFalpha, and the concentration of human alpha1-AT in conditioned supernatants was measured. When compared with unstimulated control supernatants (147 +/- 19 ng/ml), LPS (439 +/- 66 ng/ml; p < or = 0.001), IL-1beta (263 +/- 37 ng/ml; p < or = 0.01), and TNFalpha (316 +/- 59 ng/ml; p < or = 0.05) induced a 2- to 3-fold increase of alpha1-AT. Up-regulation of alpha1-AT protein correlated with an increase in alpha1-AT mRNA, suggesting a simultaneous increase in alpha1-AT synthesis. Despite the increase in alpha1-AT concentration, functional antiprotease activity could not be detected. Furthermore, protease activity was present in all samples, with the amount of activity being inversely related to the amount of alpha1-AT measured in supernatants. These findings suggest that local inflammatory conditions up-regulate alpha1-AT production by monocytes which complex with a protease derived from the PBMC population.

Effectiveness of telemedicine in the outpatient pulmonary clinic.

BACKGROUND: Over the past several years, there has been a resurgence of interest in telemedicine. Despite this renewed interest, some health care providers remain skeptical regarding the effectiveness of telemedicine for the delivery of health care. OBJECTIVE: The objective of this prospective, crossover study was to determine if there was any difference between care delivered using video conferencing-based telemedicine technology and that given by a traditional face-to-face encounter in a pulmonary medicine clinic. METHODS: Two pulmonologists sequentially examined 40 individuals via video conferencing-based telemedicine technology and by the traditional face-to-face method. Two additional pulmonologists, in a blinded fashion, compared the results for consistency in the history, examination with focus on auscultation of the lungs, diagnostic impression, and evaluation and treatment plans. RESULTS: Evaluation of patients by telemedicine was as effective as the traditional mode. The telemedicine physician and the physician examining the patient in the traditional manner were able to elicit the same key complaints and hear the same adventitious sounds on auscultation of the lungs. CONCLUSION: Telemedicine can enable the provision of high-quality care in a pulmonary clinic setting.

Keratinocytes contract human dermal extracellular matrix and reduce soluble fibronectin production by fibroblasts in a skin composite model.

Composites of human de-epidermised acellular dermis and normal adult human keratinocytes and fibroblasts were examined for the ability of cells to contract these composites. Image analysis of the outline of the composites showed that, in this model, keratinocytes alone or in the presence of fibroblasts caused highly significant contraction (of the order of 25% by day 12). There was no significant contraction of the dermis with fibroblasts alone or in the absence of cells. The presence or absence of basement membrane antigens did not influence the effect of keratinocytes on dermal contraction. Analysis of the conditioned media from these composites showed that the greatest fibronectin production was seen with fibroblasts alone in the presence of basement membrane. Keratinocytes alone produced little fibronectin irrespective of the presence of the basement membrane. If keratinocytes were present with fibroblasts, however, then fibronectin production was significantly reduced both in the presence and absence of the basement membrane, indicating that keratinocytes modify dermal fibroblast extracellular matrix production. This study shows that while keratinocytes and fibroblasts are clearly influencing each other's activity in this human skin composite model, under the circumstances we describe it is the keratinocyte and not the fibroblast which causes contraction of the human de-epidermised acellular dermis.

Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors.

Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) that accompany the neutrophilic vasculitis seen in Wegener's granulomatosis (WG), are directed against proteinase-3 (PR-3), a serine proteinase which is located in azurophilic granules of neutrophils and monocytes. PR-3, when expressed on the surface of TNFalpha-primed neutrophils, can directly activate neutrophils by complexing cANCA and promoting concomitant Fcgamma receptor (FcgammaR) cross-linking. Although the neutrophil's pathogenic role in WG has been studied, the role of the monocyte has not been explored. The monocyte, with its ability to release cytokines and regulate neutrophil influx, also expresses PR-3. Therefore, the monocyte may play a significant role in WG via the interaction of surface PR-3 with cANCA, inducing cytokine release by the monocyte. To test this hypothesis, monocytes were studied for PR-3 expression and for IL-8 release in response to cANCA IgG. PBMC obtained from healthy donors displayed dramatic surface PR-3 expression as detected by immunohistochemistry and flow cytometry in response to 0. 5-h pulse with TNFalpha (2 ng/ml). Purified monoclonal anti-PR-3 IgG added to TNFalpha-primed PBMC induced 45-fold more IL-8 release than an isotype control antibody. Furthermore, alpha 1-antitrypsin (alpha1-AT), the primary PR-3 antiprotease, inhibited the anti-PR-3 induced IL-8 release by 80%. Importantly, Fab and F(ab')2 fragments of anti-PR-3 IgG, which do not result in Fcgamma receptor cross-linking, do not induce IL-8 release. As a correlate, IgG isolated from cANCA positive patients with WG induced six times as much PBMC IL-8 release as compared to IgG isolated from normal healthy volunteers. Consistent with PR-3 associated IL-8 induction, alpha1-AT significantly inhibited this effect. These observations suggest that cANCA may recruit and target neutrophils through promoting monocyte IL-8 release. This induction is mediated via Fcgamma receptor cross-linking and is regulated in part by alpha1-AT.