A new alternative method for testing skin irritation using a human skin model: a pilot study.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo. To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test). Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization). We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were <0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI). This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Enhancement of a telemanipulator design with a human arm model

In this chapter we described how the inclusion of a model of a human arm, combined with the measurement of its neural input and a predictor, can provide to a previously proposed teleoperator design robustness under time delay. Our trials gave clear indications of the superiority of the NPT scheme over traditional as well as the modified Yokokohji and Yoshikawa architectures. Its fundamental advantages are: the time-lead of the slave, the more efficient, and providing a more natural feeling manipulation, and the fact that incorporating an operator arm model leads to more credible stability results. Finally, its simplicity allows less likely to fail local control techniques to be employed. However, a significant advantage for the enhanced Yokokohji and Yoshikawa architecture results from the very fact that it’s a conservative modification of current designs. Under large prediction errors, it can provide robustness through directing the master and slave states to their means and, since it relies on the passivity of the mechanical part of the system, it would not confuse the operator. An experimental implementation of the techniques will provide further evidence for the performance of the proposed architectures. The employment of neural networks and fuzzy logic, which will provide an adaptive model of the human arm and robustifying control terms, is scheduled for the near future.

Robotic Outcome Assessment in a Non-Human Primate Model of Middle Cerebral Artery Stroke

Stroke is a prevalent disorder with immense socioeconomic impact. A variety of chronic neurological deficits result from stroke. In particular, sensorimotor deficits are a significant barrier to achieving post-stroke independence. Unfortunately, the majority of pre-clinical studies that show improved outcomes in animal stroke models have failed in clinical trials. Pre-clinical studies using non-human primate (NHP) stroke models prior to initiating human trials are a potential step to improving translation from animal studies to clinical trials. Robotic assessment tools represent a quantitative, reliable, and reproducible means to assess reaching behaviour following stroke in both humans and NHPs. We investigated the use of robotic technology to assess sensorimotor impairments in NHPs following middle cerebral artery occlusion (MCAO). Two cynomolgus macaques underwent transient MCAO for 90 minutes. Approximately 1.5 years following the procedure these NHPs and two non-stroke control monkeys were trained in a reaching task with both arms in the KINARM exoskeleton. This robot permits elbow and shoulder movements in the horizontal plane. The task required NHPs to make reaching movements from a centrally positioned start target to 1 of 8 peripheral targets uniformly distributed around the first target. We analyzed four movement parameters: reaction time, movement time (MT), initial direction error (IDE), and number of speed maxima to characterize sensorimotor deficiencies. We hypothesized reduced performance in these attributes during a neurobehavioural task with the paretic limb of NHPs following MCAO compared to controls. Reaching movements in the non-affected limbs of control and experimental NHPs showed bell-shaped velocity profiles. In contrast, the reaching movements with the affected limbs were highly variable. We found distinctive patterns in MT, IDE, and number of speed peaks between control and experimental monkeys and between limbs of NHPs with MCAO. NHPs with MCAO demonstrated more speed peaks, longer MTs, and greater IDE in their paretic limb compared to controls. These initial results qualitatively match human stroke subjects’ performance, suggesting that robotic neurobehavioural assessment in NHPs with stroke is feasible and could have translational relevance in subsequent human studies. Further studies will be necessary to replicate and expand on these preliminary findings.

Using an in vitro human airway model to study the toxic effects of components of e-cigarettes

Cigarette smoke is a complex mixture of more than 4000 hazardous chemicals including the carcinogenic benzopyrenes. Nicotine, the most potent component of tobacco, is responsible for the addictive nature of cigarettes and is a major component of e-cigarette cartridges. Our study aims to investigate the toxicity of nicotine with special emphasis on the replacement of animals. Furthermore, we intend to study the effect of nicotine, cigarette smoke and e-cigarette vapours on human airways. In our current work, the BEAS 2B human bronchial epithelial cell line was used to analyse the effect of nicotine in isolation, on cell viability. Concentrations of nicotine from 1.1µM to 75µM were added to 5x105 cells per well in a 96 well plate and incubated for 24 hours. Cell titre blue results showed that all the nicotine treated cells were more metabolically active than the control wells (cells alone). These data indicate that, under these conditions, nicotine does not affect cell viability and in fact, suggests that there is a stimulatory effect of nicotine on metabolism. We are now furthering this finding by investigating the pro-inflammatory response of these cells to nicotine by measuring cytokine secretion via ELISA. Further work includes analysing nicotine exposure at different time points and on other epithelial cells lines like Calu-3.

Robotic Outcome Assessment in a Non-Human Primate Model of Middle Cerebral Artery Stroke

Stroke is a prevalent disorder with immense socioeconomic impact. A variety of chronic neurological deficits result from stroke. In particular, sensorimotor deficits are a significant barrier to achieving post-stroke independence. Unfortunately, the majority of pre-clinical studies that show improved outcomes in animal stroke models have failed in clinical trials. Pre-clinical studies using non-human primate (NHP) stroke models prior to initiating human trials are a potential step to improving translation from animal studies to clinical trials. Robotic assessment tools represent a quantitative, reliable, and reproducible means to assess reaching behaviour following stroke in both humans and NHPs. We investigated the use of robotic technology to assess sensorimotor impairments in NHPs following middle cerebral artery occlusion (MCAO). Two cynomolgus macaques underwent transient MCAO for 90 minutes. Approximately 1.5 years following the procedure these NHPs and two non-stroke control monkeys were trained in a reaching task with both arms in the KINARM exoskeleton. This robot permits elbow and shoulder movements in the horizontal plane. The task required NHPs to make reaching movements from a centrally positioned start target to 1 of 8 peripheral targets uniformly distributed around the first target. We analyzed four movement parameters: reaction time, movement time (MT), initial direction error (IDE), and number of speed maxima to characterize sensorimotor deficiencies. We hypothesized reduced performance in these attributes during a neurobehavioural task with the paretic limb of NHPs following MCAO compared to controls. Reaching movements in the non-affected limbs of control and experimental NHPs showed bell-shaped velocity profiles. In contrast, the reaching movements with the affected limbs were highly variable. We found distinctive patterns in MT, IDE, and number of speed peaks between control and experimental monkeys and between limbs of NHPs with MCAO. NHPs with MCAO demonstrated more speed peaks, longer MTs, and greater IDE in their paretic limb compared to controls. These initial results qualitatively match human stroke subjects’ performance, suggesting that robotic neurobehavioural assessment in NHPs with stroke is feasible and could have translational relevance in subsequent human studies. Further studies will be necessary to replicate and expand on these preliminary findings.

A finite element model of seat cushion indentation with a soft tissue human occupant model

Effective digital human model (DHM) simulation of automotive driver packaging ergonomics, safety and comfort depends on accurate modelling of occupant posture, which is strongly related to the mechanical interaction between human body soft tissue and flexible seat components. This paper presents a finite-element study simulating the deflection of seat cushion foam and supportive seat structures, as well as human buttock and thigh soft tissue when seated. The three-dimensional data used for modelling thigh and buttock geometry were taken on one 95th percentile male subject, representing the bivariate percentiles of the combined hip breadth (seated) and buttock-to-knee length distributions of a selected Australian and US population. A thigh-buttock surface shell based on this data was generated for the analytic model. A 6mm neoprene layer was offset from the shell to account for the compression of body tissue expected through sitting in a seat. The thigh-buttock model is therefore made of two layers, covering thin to moderate thigh and buttock proportions, but not more fleshy sizes. To replicate the effects of skin and fat, the neoprene rubber layer was modelled as a hyperelastic material with viscoelastic behaviour in a Neo-Hookean material model. Finite element (FE) analysis was performed in ANSYS V13 WB (Canonsburg, USA). It is hypothesized that the presented FE simulation delivers a valid result, compared to a standard SAE physical test and the real phenomenon of human-seat indentation. The analytical model is based on the CAD assembly of a Ford Territory seat. The optimized seat frame, suspension and foam pad CAD data were transformed and meshed into FE models and indented by the two layer, soft surface human FE model. Converging results with the least computational effort were achieved for a bonded connection between cushion and seat base as well as cushion and suspension, no separation between neoprene and indenter shell and a frictional connection between cushion pad and neoprene. The result is compared to a previous simulation of an indentation with a hard shell human finite-element model of equal geometry, and to the physical indentation result, which is approached with very high fidelity. We conclude that (a) SAE composite buttock form indentation of a suspended seat cushion can be validly simulated in a FE model of merely similar geometry, but using a two-layer hard/soft structure. (b) Human-seat indentation of a suspended seat cushion can be validly simulated with a simplified human buttock-thigh model for a selected anthropomorphism.

Numerical solution of an optimal control model of dendritic cell treatment of a growing tumour

A new optimal control model of the interactions between a growing tumour and the host immune system along with an immunotherapy treatment strategy is presented. The model is based on an ordinary differential equation model of interactions between the growing tu- mour and the natural killer, cytotoxic T lymphocyte and dendritic cells of the host immune system, extended through the addition of a control function representing the application of a dendritic cell treat- ment to the system. The numerical solution of this model, obtained from a multi species Runge–Kutta forward-backward sweep scheme, is described. We investigate the effects of varying the maximum al- lowed amount of dendritic cell vaccine administered to the system and find that control of the tumour cell population is best effected via a high initial vaccine level, followed by reduced treatment and finally cessation of treatment. We also found that increasing the strength of the dendritic cell vaccine causes an increase in the number of natural killer cells and lymphocytes, which in turn reduces the growth of the tumour.

Sport across cultures: Applications of the human capital model in refugee communities

When working with the world’s most vulnerable populations there are questions surrounding the salience of physical activity promotion programs given the multitude of basic needs that must first be met. Indeed, physical activity may be a low priority for individuals seeking safety, reunification with loved ones, and food for their families, as a subsistence lifestyle makes excess weight gain, diabetes, and cardiovascular disease irrelevant. Yet, when working with people from a refugee background for whom these challenges all too frequently apply, opportunities for sport and activity have repeatedly surfaced as desirable and needed, yet are utterly deficient. If we conceptualize physical activity purely as a chronic disease prevention tool, its significance within under-resourced communities is most assuredly lost; however, if we harness the power of physical activity to serve as an agent of positive social change, then it instantly becomes more meaningful and necessary.

An instantaneous control model for flow control in an ATM network

This paper is concerned with the optimal flow control of an ATM switching element in a broadband-integrated services digital network. We model the switching element as a stochastic fluid flow system with a finite buffer, a constant output rate server, and a Gaussian process to characterize the input, which is a heterogeneous set of traffic sources. The fluid level should be maintained between two levels namely b1 and b2 with b1control on the ATM network is considered

An economic air pollution control model-application : photochemical smog in Los Angeles County in 1975

An economic air pollution control model, which determines the least cost of reaching various air quality levels, is formulated. The model takes the form of a general, nonlinear, mathematical programming problem. Primary contaminant emission levels are the independent variables. The objective function is the cost of attaining various emission levels and is to be minimized subject to constraints that given air quality levels be attained.

The model is applied to a simplified statement of the photochemical smog problem in Los Angeles County in 1975 with emissions specified by a two-dimensional vector, total reactive hydrocarbon, (RHC), and nitrogen oxide, (NO_x), emissions. Air quality, also two-dimensional, is measured by the expected number of days per year that nitrogen dioxide, (NO₂), and mid-day ozone, (O₃), exceed standards in Central Los Angeles.

The minimum cost of reaching various emission levels is found by a linear programming model. The base or "uncontrolled" emission levels are those that will exist in 1975 with the present new car control program and with the degree of stationary source control existing in 1971. Controls, basically "add-on devices", are considered here for used cars, aircraft, and existing stationary sources. It is found that with these added controls, Los Angeles County emission levels [(1300 tons/day RHC, 1000 tons /day NO_x) in 1969] and [(670 tons/day RHC, 790 tons/day NO_x) at the base 1975 level], can be reduced to 260 tons/day RHC (minimum RHC program) and 460 tons/day NO_x (minimum NO_x program).

"Phenomenological" or statistical air quality models provide the relationship between air quality and emissions. These models estimate the relationship by using atmospheric monitoring data taken at one (yearly) emission level and by using certain simple physical assumptions, (e. g., that emissions are reduced proportionately at all points in space and time). For NO₂, (concentrations assumed proportional to NO_x emissions), it is found that standard violations in Central Los Angeles, (55 in 1969), can be reduced to 25, 5, and 0 days per year by controlling emissions to 800, 550, and 300 tons /day, respectively. A probabilistic model reveals that RHC control is much more effective than NO_x control in reducing Central Los Angeles ozone. The 150 days per year ozone violations in 1969 can be reduced to 75, 30, 10, and 0 days per year by abating RHC emissions to 700, 450, 300, and 150 tons/day, respectively, (at the 1969 NO_x emission level).

The control cost-emission level and air quality-emission level relationships are combined in a graphical solution of the complete model to find the cost of various air quality levels. Best possible air quality levels with the controls considered here are 8 O₃ and 10 NO₂ violations per year (minimum ozone program) or 25 O₃ and 3 NO₂ violations per year (minimum NO₂ program) with an annualized cost of $230,000,000 (above the estimated $150,000,000 per year for the new car control program for Los Angeles County motor vehicles in 1975).

a state-adaptive access control model for web-based idrs system

Huazhong Univ Sci & Technol, Natl Tech Univ Ukraine, Huazhong Normal Univ, Harbin Inst Technol, IEEE Ukraine Sect, I& M/CI Joint Chapter

Friendly Virtual Machine: Leveraging a Feedback-Control Model for Application Adaptation

With the increased use of "Virtual Machines" (VMs) as vehicles that isolate applications running on the same host, it is necessary to devise techniques that enable multiple VMs to share underlying resources both fairly and efficiently. To that end, one common approach is to deploy complex resource management techniques in the hosting infrastructure. Alternately, in this paper, we advocate the use of self-adaptation in the VMs themselves based on feedback about resource usage and availability. Consequently, we define a "Friendly" VM (FVM) to be a virtual machine that adjusts its demand for system resources, so that they are both efficiently and fairly allocated to competing FVMs. Such properties are ensured using one of many provably convergent control rules, such as AIMD. By adopting this distributed application-based approach to resource management, it is not necessary to make assumptions about the underlying resources nor about the requirements of FVMs competing for these resources. To demonstrate the elegance and simplicity of our approach, we present a prototype implementation of our FVM framework in User-Mode Linux (UML)-an implementation that consists of less than 500 lines of code changes to UML. We present an analytic, control-theoretic model of FVM adaptation, which establishes convergence and fairness properties. These properties are also backed up with experimental results using our prototype FVM implementation.

Development of an ex vivo human skin model for intradermal vaccination : tissue viability and Langerhans cell behaviour

The presence of resident Langerhans cells (LCs) in the epidermis makes the skin an attractive target for DNA vaccination. However, reliable animal models for cutaneous vaccination studies are limited. We demonstrate an ex vivo human skin model for cutaneous DNA vaccination which can potentially bridge the gap between pre-clinical in vivo animal models and clinical studies. Cutaneous transgene expression was utilised to demonstrate epidermal tissue viability in culture. LC response to the culture environment was monitored by immunohistochemistry. Full-thickness and split-thickness skin remained genetically viable in culture for at least 72 h in both phosphate-buffered saline (PBS) and full organ culture medium (OCM). The epidermis of explants cultured in OCM remained morphologically intact throughout the culture duration. LCs in full-thickness skin exhibited a delayed response (reduction in cell number and increase in cell size) to the culture conditions compared with split-thickness skin, whose response was immediate. In conclusion, excised human skin can be cultured for a minimum of 72 h for analysis of gene expression and immune cell activation. However, the use of split-thickness skin for vaccine formulation studies may not be appropriate because of the nature of the activation. Full-thickness skin explants are a more suitable model to assess cutaneous vaccination ex vivo.