Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the Acute Respiratory Distress Syndrome (ARDS). In animal models of ARDS, Keratinocyte Growth Factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.

Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.

Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50μg lipopolysaccharide. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.

Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of Surfactant Protein D (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.

Conclusions: KGF treatment increases BAL SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).

Physical coronary arteriogenesis: a human "model" of collateral growth promotion

In patients with coronary artery disease, the size of myocardial infarction mainly determines the subsequent clinical outcome. Accordingly, it is the primary strategy to decrease cardiovascular mortality by minimizing infarct size. Promotion of collateral artery growth (arteriogenesis) is an appealing option of reducing infarct size. It has been demonstrated in experimental models that tangential fluid shear stress is the major trigger of arterial remodeling and, thus, of collateral growth. Lower-leg, high-pressure external counterpulsation triggered to occur during diastole induces a flow velocity signal and thus tangential endothelial shear stress in addition to the flow signal caused by cardiac stroke volume. We here present two cases of cardiac transplant recipients as human "models" of physical coronary arteriogenesis, providing an example of progressing and regressing clinical arteriogenesis, and review available evidence from clinical studies on other feasible forms of physical arteriogenesis.

A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with ≈50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50–70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.

Proteomic analysis of a noninvasive human model of acute inflammation and its resolution:the twenty-one day gingivitis model

The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC-MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins.

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.

Soft tissue human thigh and buttock finite element model to simulate vehicle seat cushion indentation

Accurate modelling of automotive occupant posture 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 thigh-buttock surface shell model was based on 95th percentile male subject scan data and made of two layers, covering thin to moderate thigh and buttock proportions. To replicate the effects of skin and fat, the neoprene rubber layer was modelled as a hyperelastic material with viscoelastic behaviour. The analytical seat model is based on a Ford production seat. The result of the finite-element indentation simulation is compared to a previous simulation of an indentation with a hard shell human model of equal geometry, and to the physical indentation result. We conclude that SAE composite buttock form and human-seat indentation of a suspended seat cushion can be validly simulated.

Chimpanzee: A predictive model for the human cytochrome P450 3A subfamily

The human cytochrome P450 3A (CYP3A) subfamily is responsible for most of the metabolism of therapeutic drugs; however, an adequate in vivo model has yet to be discovered. This study begins with an investigation of a controversial topic surrounding the human CYP3As--estrogen regulation. A novel approach to this topic was used by defining expression in the estrogen-responsive endometrium. This study shows that estrogen down-regulates CYP3A4 expression in the endometrium. On the other hand, analogous studies showed an increase in CYP3A expression as age increases in liver tissue. Following the discussion of estrogen regulation, is an investigation of the cross-species relationships among all of the CYP3As was completed. The study compares isoforms from piscines, avians, rodents, canines, ovines, bovines, and primates. Using the traditional phylogenetic analyses and employing a novel approach using exon and intron lengths, the results show that only another primate could be the best animal model for analysis of the regulation of the expression of the human CYP3As. This analysis also demonstrated that the chimpanzee seems to be the best available human model. Moreover, the study showed the presence and similarities of one additional isoform in the chimpanzee genome that is absent in humans. Based on these results, initial characterization of the chimpanzee CYP3A subfamily was begun. While the human genome contains four isoforms--CYP3A4, CYP3A5, CYP3A7, and CYP3A43--the chimpanzee genome has five, the four previously mentioned and CYP3A67. Both species express CYP3A4, CYP3A5, and CYP3A43, but humans express CYP3A7 while chimpanzees express CYP3A67. In humans, CYP3A4 is expressed at higher levels than the other isoforms, but some chimpanzee individuals express CYP3A67 at higher levels than CYP3A4. Such a difference is expected to alter significantly the total CYP3A metabolism. On the other hand, any study considering individual isoforms would still constitute a valid method of study for the human CYP3A4, CYP3A5, and CYP3A43 isoforms. ^

Decomposition of human behavior using model of competencies: application to robotic control system

For many years, humans and machines have shared the same physical space. To facilitate their interaction with humans, their social integration and for more rational behavior has been sought that the robots demonstrate human-like behavior. For this it is necessary to understand how human behavior is generated, discuss what tasks are performed and how relate to themselves, for subsequent implementation in robots. In this paper, we propose a model of competencies based on human neuroregulator system for analysis and decomposition of behavior into functional modules. Using this model allow separate and locate the tasks to be implemented in a robot that displays human-like behavior. As an example, we show the application of model to the autonomous movement behavior on unfamiliar environments and its implementation in various simulated and real robots with different physical configurations and physical devices of different nature. The main result of this work has been to build a model of competencies that is being used to build robotic systems capable of displaying behaviors similar to humans and consider the specific characteristics of robots.

Model of Competencies for Decomposition of Human Behavior: Application to Control System of Robots

Humans and machines have shared the same physical space for many years. To share the same space, we want the robots to behave like human beings. This will facilitate their social integration, their interaction with humans and create an intelligent behavior. To achieve this goal, we need to understand how human behavior is generated, analyze tasks running our nerves and how they relate to them. Then and only then can we implement these mechanisms in robotic beings. In this study, we propose a model of competencies based on human neuroregulator system for analysis and decomposition of behavior into functional modules. Using this model allow separate and locate the tasks to be implemented in a robot that displays human-like behavior. As an example, we show the application of model to the autonomous movement behavior on unfamiliar environments and its implementation in various simulated and real robots with different physical configurations and physical devices of different nature. The main result of this study has been to build a model of competencies that is being used to build robotic systems capable of displaying behaviors similar to humans and consider the specific characteristics of robots.

Interfacing Jack and anybody : towards anthropometric musculoskeletal digital human modeling

Virtual prototyping emerges as a new technology to replace existing physical prototypes for product evaluation, which are costly and time consuming to manufacture. Virtualization technology allows engineers and ergonomists to perform virtual builds and different ergonomic analyses on a product. Digital Human Modelling (DHM) software packages such as Siemens Jack, often integrate with CAD systems to provide a virtual environment which allows investigation of operator and product compatibility. Although the integration between DHM and CAD systems allows for the ergonomic analysis of anthropometric design, human musculoskeletal, multi-body modelling software packages such as the AnyBody Modelling System (AMS) are required to support physiologic design. They provide muscular force analysis, estimate human musculoskeletal strain and help address human comfort assessment. However, the independent characteristics of the modelling systems Jack and AMS constrain engineers and ergonomists in conducting a complete ergonomic analysis. AMS is a stand alone programming system without a capability to integrate into CAD environments. Jack is providing CAD integrated human-in-the-loop capability, but without considering musculoskeletal activity. Consequently, engineers and ergonomists need to perform many redundant tasks during product and process design. Besides, the existing biomechanical model in AMS uses a simplified estimation of body proportions, based on a segment mass ratio derived scaling approach. This is insufficient to represent user populations anthropometrically correct in AMS. In addition, sub-models are derived from different sources of morphologic data and are therefore anthropometrically inconsistent. Therefore, an interface between the biomechanical AMS and the virtual human model Jack was developed to integrate a musculoskeletal simulation with Jack posture modeling. This interface provides direct data exchange between the two man-models, based on a consistent data structure and common body model. The study assesses kinematic and biomechanical model characteristics of Jack and AMS, and defines an appropriate biomechanical model. The information content for interfacing the two systems is defined and a protocol is identified. The interface program is developed and implemented through Tcl and Jack-script(Python), and interacts with the AMS console application to operate AMS procedures.

The contribution of seat components to seat hardness and the interface between human occupant and a driver seat

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 comprises: a study investigating the component mechanical behaviour of a spring-suspended, production level seat when indented by SAE J826 type, human thigh-buttock representing hard shell; a model of seated human buttock shape for improved indenter design using a multivariate representation of Australian population thigh-buttock anthropometry; and a finite-element study simulating the deflection of human buttock and thigh soft tissue when seated, based on seated MRI. The results of the three studies provide a description of the mechanical properties of the driver-seat interface, and allow validation of future dynamic simulations, involving multi-body and finite-element (FE) DHM in virtual ergonomic studies.

Standardisation of digital human models

Digital human models (DHM) have evolved as useful tools for ergonomic workplace design and product development, and found in various industries and education. DHM systems which dominate the market were developed for specific purposes and differ significantly, which is not only reflected in non-compatible results of DHM simulations, but also provoking misunderstanding of how DHM simulations relate to real world problems. While DHM developers are restricted by uncertainty about the user need and lack of model data related standards, users are confined to one specific product and cannot exchange results, or upgrade to another DHM system, as their previous results would be rendered worthless. Furthermore, origin and validity of anthropometric and biomechanical data is not transparent to the user. The lack of standardisation in DHM systems has become a major roadblock in further system development, affecting all stakeholders in the DHM industry. Evidently, a framework for standardising digital human models is necessary to overcome current obstructions.

A spatio-temporal 2D-models framework for human pose recovery in monocular sequences

This paper addresses the pose recovery problem of a particular articulated object: the human body. In this model-based approach, the 2D-shape is associated to the corresponding stick figure allowing the joint segmentation and pose recovery of the subject observed in the scene. The main disadvantage of 2D-models is their restriction to the viewpoint. To cope with this limitation, local spatio-temporal 2D-models corresponding to many views of the same sequences are trained, concatenated and sorted in a global framework. Temporal and spatial constraints are then considered to build the probabilistic transition matrix (PTM) that gives a frame to frame estimation of the most probable local models to use during the fitting procedure, thus limiting the feature space. This approach takes advantage of 3D information avoiding the use of a complex 3D human model. The experiments carried out on both indoor and outdoor sequences have demonstrated the ability of this approach to adequately segment pedestrians and estimate their poses independently of the direction of motion during the sequence. (c) 2008 Elsevier Ltd. All rights reserved.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Model based experimental investigation on Powered Gait Orthosis (PGO)

Research on rehabilitation showed that appropriate and repetitive mechanical movements can help spinal cord injured individuals to restore their functional standing and walking. The objective of this paper was to achieve appropriate and repetitive joint movements and approximately normal gait through the PGO by replicating normal walking, and to minimize the energy consumption for both patients and the device. A model based experimental investigative approach is presented in this dissertation. First, a human model was created in Ideas and human walking was simulated in Adams. The main feature of this model was the foot ground contact model, which had distributed contact points along the foot and varied viscoelasticity. The model was validated by comparison of simulated results of normal walking and measured ones from the literature. It was used to simulate current PGO walking to investigate the real causes of poor function of the current PGO, even though it had joint movements close to normal walking. The direct cause was one leg moving at a time, which resulted in short step length and no clearance after toe off. It can not be solved by simply adding power on both hip joints. In order to find a better answer, a PGO mechanism model was used to investigate different walking mechanisms by locking or releasing some joints. A trade-off between energy consumption, control complexity and standing position was found. Finally a foot release PGO virtual model was created and simulated and only foot release mechanism was developed into a prototype. Both the release mechanism and the design of foot release were validated through the experiment by adding the foot release on the current PGO. This demonstrated an advancement in improving functional aspects of the current PGO even without a whole physical model of foot release PGO for comparison.