Local delivery of tacrolimus using electrospun poly-ϵ-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts.

Objective.Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair.Approach.A coaxial electrospinning approach was used to produce poly-ϵ-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then testedin vivothrough implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue.Main results.Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at 3 weeks post-transplantation.Significance.These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting.

In silico framework to inform the design of repair constructs for peripheral nerve injury repair.

Peripheral nerve injuries affect millions of people per year and cause loss of sensation and muscle control alongside chronic pain. The most severe injuries are treated through a nerve autograft; however, donor site morbidity and poor outcomes mean alternatives are required. One option is to engineer nerve replacement tissues to provide a supportive microenvironment to encourage nerve regeneration as an alternative to nerve grafts. Currently, progress is hampered due to a lack of consensus on how to arrange materials and cells in space to maximize rate of regeneration. This is compounded by a reliance on experimental testing, which precludes extensive investigations of multiple parameters due to time and cost limitations. Here, a computational framework is proposed to simulate the growth of repairing neurites, captured using a random walk approach and parameterized against literature data. The framework is applied to a specific scenario where the engineered tissue comprises a collagen hydrogel with embedded biomaterial fibres. The size and number of fibres are optimized to maximize neurite regrowth, and the robustness of model predictions is tested through sensitivity analyses. The approach provides an in silico tool to inform the design of engineered replacement tissues, with the opportunity for further development to multi-cue environments.

Combining in silico and in vitro models to inform cell seeding strategies in tissue engineering.

The seeding density of therapeutic cells in engineered tissue impacts both cell survival and vascularization. Excessively high seeded cell densities can result in increased death and thus waste of valuable cells, whereas lower seeded cell densities may not provide sufficient support for the tissue in vivo, reducing efficacy. Additionally, the production of growth factors by therapeutic cells in low oxygen environments offers a way of generating growth factor gradients, which are important for vascularization, but hypoxia can also induce unwanted levels of cell death. This is a complex problem that lends itself to a combination of computational modelling and experimentation. Here, we present a spatio-temporal mathematical model parametrized using in vitro data capable of simulating the interactions between a therapeutic cell population, oxygen concentrations and vascular endothelial growth factor (VEGF) concentrations in engineered tissues. Simulations of collagen nerve repair constructs suggest that specific seeded cell densities and non-uniform spatial distributions of seeded cells could enhance cell survival and the generation of VEGF gradients. These predictions can now be tested using targeted experiments.

Anti-Factor Xa measurements in acute care surgery patients to examine enoxaparin dose.

BACKGROUND: The purpose of this study was to determine if fixed dose enoxaparin prophylaxis provided effective anticoagulation for acute care surgery patients and to examine whether a real-time enoxaparin dose adjustment algorithm optimized anticoagulation. METHODS: Acute care surgical patients placed on enoxaparin prophylaxis 30 mg twice daily were recruited prospectively. Peak steady state aFXa levels were drawn with a goal peak aFXa range of 0.2-0.4 IU/ml. A real time dose adjustment algorithm was implemented for patients with out-of-range levels. RESULTS: Fifty five patients were included. 56.4% of patients had low aFXa levels (<0.2 IU/mL). Real-time enoxaparin dose adjustment significantly increased the proportion of patients who achieved in-range peak aFXa levels, compared to standard dosing (74.5% vs 41.8%, p < 0.001). Patients with initial inadequate peak aFXa levels had a higher rate of 90-day post-operative VTE, although not statistically significant (16.1% vs. 8.3%, p = 0.50). CONCLUSION: The majority of acute care surgery patients receive inadequate VTE prophylaxis with fixed enoxaparin dosing.

Malaria in British military personnel deployed to Sierra Leone: a case series.

From December 2014 to April 2015, seven cases of malaria were seen in 1530 military personnel deployed to Sierra Leone on Operation GRITROCK in response to the West African Ebola outbreak, despite predeployment briefings, prescription of chemoprophylactic agents and bite prevention measures. The cases have prompted discussion regarding the efficacy of current measures and how to prevent future cases in deployed military personnel or more widely, those working in malaria-risk environments. All of the cases have made a full recovery and returned to work. We discuss what can be learnt concerning the choice of chemoprophylactic agent and whether anything further be added to standard operating procedures regarding bite prevention and treatment of cases.

A strategy to determine operating parameters in tissue engineering hollow fiber bioreactors.

The development of tissue engineering hollow fiber bioreactors (HFB) requires the optimal design of the geometry and operation parameters of the system. This article provides a strategy for specifying operating conditions for the system based on mathematical models of oxygen delivery to the cell population. Analytical and numerical solutions of these models are developed based on Michaelis-Menten kinetics. Depending on the minimum oxygen concentration required to culture a functional cell population, together with the oxygen uptake kinetics, the strategy dictates the model needed to describe mass transport so that the operating conditions can be defined. If c(min) ≫ K(m) we capture oxygen uptake using zero-order kinetics and proceed analytically. This enables operating equations to be developed that allow the user to choose the medium flow rate, lumen length, and ECS depth to provide a prescribed value of c(min) . When c(min) />>K(m), we use numerical techniques to solve full Michaelis-Menten kinetics and present operating data for the bioreactor. The strategy presented utilizes both analytical and numerical approaches and can be applied to any cell type with known oxygen transport properties and uptake kinetics.

Definition and validation of operating equations for poly(vinyl alcohol)-poly(lactide-co-glycolide) microfiltration membrane-scaffold bioreactors.

The aim of this work is to provide operating data for biodegradable hollow fiber membrane bioreactors. The physicochemical cell culture environment can be controlled with the permeate flowrate, so this aim necessitates the provision of operating equations that enable end-users to set the pressures and feed flowrates to obtain their desired culture environment. In this paper, theoretical expressions for the pure water retentate and permeate flowrates, derived using lubrication theory, are compared against experimental data for a single fiber poly(vinyl alcohol)-poly(lactide-co-glycolide) crossflow module to give values for the membrane permeability and slip. Analysis of the width of the boundary layer region where slip effects are important, together with the sensitivity of the retentate and permeate equations to the slip parameter, show that slip is insignificant for these membranes, which have a mean pore diameter of 1.1 microm. The experimental data is used to determine a membrane permeability, of k = 1.86 x 10(-16) m(2), and to validate the model. It was concluded that the operating equation that relates the permeate to feed ratio, c, lumen inlet flowrate, Q (l,in), lumen outlet pressure, P (1), and ECS outlet pressure, P (0), is P(1) - P(0) = Q(l),in (Ac + B) where A and B are constants that depend on the membrane permeability and geometry (and are given explicitly). Finally, two worked examples are presented to demonstrate how a tissue engineer can use Equation (1) to specify operating conditions for their bioreactor.

Design criteria for a printed tissue engineering construct: a mathematical homogenization approach.

Cartilage tissue repair procedures currently under development aim to create a construct in which patient-derived cells are seeded and expanded ex vivo before implantation back into the body. The key challenge is producing physiologically realistic constructs that mimic real tissue structure and function. One option with vast potential is to print strands of material in a 3D structure called a scaffold that imitates the real tissue structure; the strands are composed of gel seeded with cells and so provide a template for cartilaginous tissue growth. The scaffold is placed in the construct and pumped with nutrient-rich culture medium to supply nutrients to the cells and remove waste products, thus promoting tissue growth. In this paper we use asymptotic homogenization to determine the effective flow and transport properties of such a printed scaffold system. These properties are used to predict the distribution of nutrient/waste products through the construct, and to specify design criteria for the scaffold that will optimize the growth of functional tissue.

An equine protozoal myeloencephalitis challenge model testing a second transport after inoculation with Sarcocystis neurona sporocysts.

Previous challenge studies performed at Ohio State University involved a transport-stress model where the study animals were dosed with Sarcocystis neurona sporocysts on the day of arrival. This study was to test a second transportation of horses after oral inoculation with S. neurona sporocysts. Horses were assigned randomly to groups: group 1, transported 4 days after inoculation (DAI); group 2, at 11 DAI; group 3, at 18 DAI; and group 4, horses were not transported a second time (controls). An overall neurologic score was determined on the basis of a standard numbering system used by veterinarians. All scores are out of 5, which is the most severely affected animal. The mean score for the group 1 horses was 2.42; group 2 horses was 2.5; group 3 horses was 2.75; and group 4 horses was 3.25. Because the group 4 horses did not have a second transport, they were compared with all other groups. Statistically different scores were present between group 4 and groups 1 and 2. There was no difference in the time of seroconversion between groups. There was a difference between the time of onset of first clinical signs between groups 1 and 4. This difference was likely because of the different examination days. Differences in housing and handling were likely the reason for the differences in severity of clinical signs. This model results in consistent, significant clinical signs in all horses at approximately the same time period after inoculation but was most severe in horses that did not experience a second transport.

An automated injection system (with patient selection) for SPECT imaging in seizure localization.

PURPOSE: Ictal single-photon-emission computed tomography (SPECT) provides lateralization but has technical limitations: (a) a "truly ictal" injection must be shortly after seizure onset; (b) therefore, a seizure of brief duration may be missed; (c) more than one patient may need testing at any given time; (d) a trained health professional must stay next to each patient to inject; and (e) because the radionuclide is placed in the syringe in advance of the injection, decay of the radioactive element could result in less than optimal uptake, if the same volume of material were to be used regardless of the time after ligand preparation. METHODS: We developed an automated method of ligand injection that shortens time and increases efficiency of ictal SPECT ligand injection. By using an experimental setup, we compared manual injection times with times using an automated injection system. We determined relative costs and efficiency in work hours for the manual and automated methods. RESULTS: Injection times were 8-14 s with automated versus 19-26 s with manual injection. Readjusting volume for "ligand" decay was simple and accurate with the automated system. Injection times for clinical SPECT studies in three patients were 13, 13, and 12 s, respectively. The price of one pump equals 120 work hours of a nurse or 24 ictal injection attempts. Much of the nurse's time is "wasted" because no seizure occurs. CONCLUSIONS: The method can be more efficient of staff, shorten injection time, and facilitate obtaining "truly ictal" injections. It allows more cost-effective use of personnel.

Refractory ceramic fiber exposure and pleural plaques.

Refractory ceramic fibers (RCF) are manmade vitreous fibers (MMVF) manufactured for high-temperature applications. Between 1987 and 1992, a retrospective cohort and nested case-control study evaluated chest radiographs from 652 workers involved in the manufacture of these fibers for plausibility of a causal relationship between exposure to RCF and chest-radiographic changes. The exposure-response relationship was modeled with three variables: years since first fiber production job, years in fiber production, and cumulative fiber exposure to date of study X-ray. The case-control study used a comprehensive characterization of possible asbestos exposure to investigate asbestos as the potential causative agent of chest-radiographic changes. Chest radiographs of 20 workers (3.1%) demonstrated 19 pleural plaques and one diffuse pleural thickening. Nine of 72 workers (12.5%) with more than 20 yr since their first fiber-production job had plaques (odds ratio [OR] = 9.5; 95% confidence interval [CI] = 1.9 to 48.2). Five of 19 workers with more than 20 yr in fiber-production work (26.3%) had plaques (OR = 22.3; 95% CI = 3.6 to 137.0). Similarly, adjusted ORs demonstrated a progressive relationship between cumulative fiber-months per milliliter (fiber-mo/ml) exposure and plaques. The case-control study confirmed that asbestos exposure did not account for the observed association between fiber exposure and plaques. A validity review of historical films demonstrated biologic plausibility for the association, since sufficient latency existed from the time of first RCF exposure to the development of plaques. There was no significant increase in parenchymal changes consistent with interstitial fibrosis.

Promoting worksite smoking control policies and actions: the Community Intervention Trial for Smoking Cessation (COMMIT) experience. The COMMIT Research Group.

BACKGROUND: As an important aspect of the COMMIT trial, worksite smoking-control consultations and supports were provided to employers in 11 diverse, moderate-sized communities. After a 4-year intervention period (1989-1992), impacts on worksite policies, support resources for smokers, and employee perceptions were assessed in these communities and in 11 matched Comparison communities. METHODS: Data from two surveys are reported here. In each of the 22 COMMIT communities, a sample of worksites within each of four size strata were surveyed to determine worksite policies, activities, and resources regarding smoking. Data from employees were obtained from independent community-wide surveys of community residents. RESULTS: Overall, 44% of the worksites surveyed reported having smoke-free policies, with no differences between Intervention and Comparison communities. Thirty-seven percent of Intervention community work-sites reported offering smoking cessation resources or assistance for employees during the period of the study, compared to 31% of Comparison community worksites (P = 0.04). Employees in Intervention communities, relative to those in Comparison communities, reported greater awareness of stop-smoking resources, but equivalent increases in worksite smoking bans. CONCLUSION: Although the level of worksite smoking-cessation activities was higher in Intervention than in Comparison communities, there remains a substantial need to increase the level of such activities and to integrate such activities with restrictive smoking policies.

Smoking withdrawal symptoms in response to a trauma-related stressor among Vietnam combat veterans with posttraumatic stress disorder.

This study investigated the relationship between a trauma-related stressor and smoking withdrawal symptoms in 25 male Vietnam combat veterans with posttraumatic stress disorder (PTSD) using a within-subjects design. All subjects were smokers. The stressor involved a modified Stroop task, in which the veterans color-named either anxiety-related or neutral control words. Anxiety-related words produced more withdrawal symptoms than neutral control words, including increased craving, negative affect symptoms, somatic symptoms, and lack of alertness.

Smoking in Vietnam combat veterans with post-traumatic stress disorder.

The present study investigated smoking prevalence, smoking motives, demographic variables and psychological symptoms in 124 help-seeking, male Vietnam combat veterans with post-traumatic stress disorder (PTSD). A high percentage of these veterans smoked (60%). Vietnam veterans with PTSD who smoked were more likely than those who did not smoke to report higher levels of PTSD symptoms, depression and trait anxiety. Increased depression was associated with increased automatic smoking. Smokers reported a high frequency of smoking in response to military memories. Implications for smoking interventions, cessation, and relapse prevention efforts are discussed.

Community stop-smoking contests in the COMMIT trial: relationship of participation to costs. Community Intervention trials.

BACKGROUND: This study quantifies resources used to conduct 26 community-wide quit-smoking contests, the percentage of smokers that participated in these contests, and the statistical associations between resource inputs and participation percentages. METHODS: Data collected from the 11 COMMIT intervention communities (adult population range 47,490-185,913) included number of contest participants, contest procedures, and resource inputs. Stepwise regression was used to find the most meaningful association(s) of independent variables with contest participation percentage. RESULTS: Contest participation percentages ranged from 0.27 to 3.11% of smokers (mean = 1.26%). Total cost (COMMIT and community-contributed resources and dollar expenditures) to conduct a contest averaged $24,857 (range $5,751-$74,556), or $78.57 per contest participant. Expenditures in various specific resource categories varied greatly. Total expenditures per smoker in the community (excluding expenditures for prizes) was the independent variable most highly correlated with contest participation percentage, accounting for 63% of the total variability in participation percentages. CONCLUSIONS: The percentage of smoker participation in community-wide stop-smoking contests appears primarily to be a function of total resource expenditures, regardless of the specific types of resources funded. Stop-smoking contests are judged to be quite cost effective. Study strengths and weaknesses are discussed.

Clinical trials using ascorbic acid aerosol to aid smoking cessation.

Sensory aspects of cigarette smoke are important for providing smoking satisfaction. In previous studies, we have found that substitution of the sensory cues of smoking with a citric acid aerosol significantly reduces craving for cigarettes and enhances smoking reduction and cessation with people trying to quit smoking cigarettes. In the current study, we conducted two clinical smoking cessation trials using an ascorbic acid aerosol as a sensory substitute. The cigarette substitute consisted of a cigarette-sized tube which delivered a fine aerosol of ascorbic acid (approx. 1 mg/puff, up to a maximum of 300 mg/day). Study 1 examined the overall effectiveness of the ascorbic acid smoking substitute device. One group of subjects which used the device and received clinical counseling was compared with another group which received only clinical counseling. The group using the device showed significantly greater abstinence rates at 3 weeks post-cessation. After the subjects stopped using the device, no difference in abstinence was detected. Study 2 was conducted to focus specifically on the role of tracheobronchial sensations in relieving craving for cigarettes. Two closely matched ascorbic acid delivery systems were compared. One device delivered fine particles of ascorbic acid that were targeted to reach the trachea, while the other delivered coarser particles of ascorbic acid that were not expected to reach the trachea or lower airways. An initial enhancement in smoking reduction was found for subjects using the fine particle device relative to those using the coarse particle device. However, by the end of treatment (5 weeks) both groups showed similar degrees of smoking reduction. For those who were abstinent from smoking at the end of treatment, craving for cigarettes and negative mood were both significantly lower for those using the fine particle device. Also, hunger for food was significantly lower in the fine particle device group. These results suggest that ascorbic acid delivered from a cigarette substitute may be effective in reducing smoking and promoting smoking abstinence.

Fibrosing mediastinitis causing nonvisualization of one lung on pulmonary scintigraphy.

An interesting case of fibrosing mediastinitis, which is a rare cause of total nonvisualization of one lung on pulmonary scintigraphy, is presented. Scintigraphy with Tc-99m MAA showed a severe deficit of perfusion in the right lung, with normal perfusion of the left lung. Ventilation images were normal. CT and MRI each demonstrated the mediastinal nodal enlargement and MRI demonstrated the "flow void" signal phenomenon in the right pulmonary artery indicating its patency. Confirmation of actual patency without pulmonary artery emboli and with poor venous opacification was documented with angiography. Multiple complementary imaging modalities were helpful in correctly diagnosing fibrosing mediastinitis from an extensive list of differential possibilities for unilateral non-visualization of the lung on perfusion scanning.

Increased Pneumocystis carinii recovery from the upper lobes in Pneumocystis pneumonia. The effect of aerosol pentamidine prophylaxis.

STUDY OBJECTIVE: To determine the relative distribution of Pneumocystis carinii in the lungs of patients with P carinii pneumonia and to see the effect of aerosol pentamidine prophylaxis on this distribution. DESIGN: A prospective study of all human immunodeficiency virus-infected patients with pulmonary symptoms over a nine-month period. Patients were followed up for at least six weeks after bronchoscopy. SETTING: Inpatient and outpatient service at one referral center. PATIENTS: Human immunodeficiency virus-infected patients with pulmonary symptoms were referred for evaluation. Those patients subsequently found to have P carinii pneumonia were studied. INTERVENTION: Bronchoalveolar lavage was performed in the middle lobe (or lingula) and the apical segment of the same lung. MEASUREMENTS AND RESULTS: The aspirated fluids were kept separate and modified Wright-Giemsa-stained cytocentrifuge-prepared slides were made from each area, and the number of P carinii clusters per 500 nucleated cells was counted. Fifty patients were studied: 27 receiving pentamidine prophylaxis and 23 receiving no aerosol therapy. There was no significant difference in the amount of fluid retrieved by lavage from the middle or upper lobe for either group. Both groups had significantly lower numbers of P carinii clusters per 500 cells in the middle lobe (receiving pentamidine: 10 +/- 15.8 [SD]; not receiving pentamidine: 15 +/- 12.3) than in the upper lobe (receiving pentamidine: 22 +/- 19.8; not receiving pentamidine: 24 +/- 21.5; p < 0.02). In six patients, there were no P carinii organisms seen in the middle lobe lavage specimen. CONCLUSION: Pneumocystis carinii has a preference for the upper lobes which may be apparent even in patients not receiving aerosol pentamidine. In addition, yield for P carinii may be increased by performing lavage in the apical segment.

The 1980 ILO classification of radiographs of the pneumoconioses.

The 1980 ILO classification of radiographs of the pneumoconioses has undergone revision and improvement in response to increases in knowledge and international concerns. Its goal is to standardize the reading and reporting of radiographic manifestations of the inhalation of dust so that international epidemiologic comparisons are possible. It remains an imperfect instrument, but "... although total elimination of variation is impossible, some measure of control can be achieved."