Noncompartmental models of whole-body clearance of tracers: A review

Noncompartmental models are defined as models that allow for transport of material through regions of the body that are not necessarily well-mixed or of uniform concentration. The clearance of a substance of interest, (metabolite or drug) from a noncompartmental system will not necessarily be governed by a sum of exponentials or even be describable by a set of ordinary differential equations. The model may involve diffusion or other random walk processes, leading to the solution in terms of the partial differential equation of diffusion or in terms of probability distributions. It may use the theory of linear systems to obviate the need for defining any precise anatomical structure. A number of the models reviewed deal with plasma clearance curves that are best described by power functions of time. Circulatory models are reviewed from their inception to the present. Recent studies on clearance as a fractal process are introduced.     

Imaging of 4-AP-induced, GABA(A)-dependent spontaneous synchronized activity mediated by the hippocampal interneuron network.

Under conditions of increased excitability, such as application of the K(+) channel blocker 4-aminopyridine (4-AP, 100 microM), interneurons in the hippocampal slice show an additional form of synchronized activity that is distinct from the ictal and interictal epileptiform activity induced by these manipulations. In principal neurons, i.e., pyramidal and granule cells, this synchronized interneuron activity (SIA) generates large, multi-component synaptic potentials, which have been termed long-lasting depolarizations (LLDs). These LLDs are dependent on GABA(A) receptor-mediated synaptic transmission but not on excitatory amino acid (EAA) receptors. Intracellular recordings from hilar interneurons have shown that depolarizing GABA(A) receptor-mediated synaptic potentials are also largely responsible for the synchronization of interneurons. The spatiotemporal characteristics of this interneuron activity have not been investigated previously. Using a voltage-sensitive dye and optical techniques that are capable of recording spontaneous synchronized activity, we have characterized the spatiotemporal pattern of SIA (in the presence of 4-AP + EAA receptor antagonists) and compared it with interictal epileptiform activity (in 4-AP only). Like interictal activity, SIA could be observed throughout the hippocampal slice. Unlike interictal activity, which originated in area CA2/CA3 and spread from there, SIA was most prominent in area CA1 and originated either there or in the subiculum. In CA1, interictal activity was largest in and near stratum pyramidale, while SIA was mainly located in s. lacunosum moleculare. Furthermore SIA was equally likely to propagate in either direction, and multiple patterns of propagation could be observed within a single brain slice. These studies suggest that hippocampal area CA1 has the highest propensity for SIA, that multiple locations can serve as the site of origin, and that interneurons located in s. lacunosum moleculare or interneurons that specifically project to this region may be particularly important for synchronized interneuron activity.     

Particle image velocimetry measurements of blood velocity in a continuous flow ventricular assist device

The third prototype of a continuous flow ventricular assist device (CFVAD3) is being developed and tested for implantation in humans. The blood in the pump flows through a fully shrouded four-bladed impeller (supported by magnetic bearings) and through small clearance regions on either side of the impeller. Measurements of velocities using particle image velocimetry of a fluid with the same viscosity as blood have been made in one of these clearance regions. Particle image velocimetry is a technique that measures the instantaneous velocity field within an illuminated plane of the fluid field by scattering light from particles added to the fluid. These measurements have been used to improve understanding of the fluid dynamics within these critical regions, which are possible locations of both high shear and stagnation, both of which are to be avoided in a blood pump. Computational models of the pump exist and these models are currently being used to aid in the design of future prototypes. Among other things, these models are used to predict the potential for hemolysis and thrombosis. Measurements of steady flow at two operating speeds and flow rates are presented. The measurements are compared with the computed solutions to validate and refine, where necessary, the existing computational models.     

Mucociliary clearance--a critical upper airway host defense mechanism and methods of assessment

PURPOSE OF REVIEW: Mucociliary clearance is a critical host defense mechanism of the airways. Effective mucociliary clearance requires appropriate mucus production and coordinated ciliary activity. The important role of these two components is best demonstrated in disorders such as primary ciliary dyskinesia and cystic fibrosis, both of which lead to lifelong recurrent respiratory tract infections. We review the methods used to analyze mucociliary clearance. RECENT FINDINGS: Utilization of microdialysis probes has improved temporal resolution of mucociliary clearance in murine airways, availing many genetic mouse models to critical mucociliary clearance analysis, while improved fixation technique for transmission electron microscopy has allowed for detailed resolution of the airway surface liquid. High-speed digital video analysis has improved quantification of ciliary beat frequency while advancements in air-liquid interface culturing techniques have generated in-vitro models to investigate mucociliary clearance. SUMMARY: Advancements in techniques for analysis of mucociliary clearance have improved our understanding of the interaction between the respiratory epithelium and the airway surface liquid, resulting in the ability to study pathologic processes involving mucociliary clearance in great detail.     

Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy

Huntington's disease is caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. This gain-of-function mutation is associated with huntingtin aggregation and cell death. Autophagy is an important clearance route for mutant huntingtin exon 1. While mammalian target of rapamycin (mTOR) is a key regulator of autophagy, the upstream modifiers of this process are poorly understood. Our previous expression profiling studies in HD cell models observed changes in four genes associated with glucose metabolism, including the GLUT1 glucose transporter. A role for intracellular glucose as a modulator for polyglutamine toxicity was suggested as cell death was reduced by GLUT1 overexpression. Here we show that the protective effect of GLUT1 is associated with decreased huntingtin exon 1 aggregation in cell models. Consistent with this result, we also observed reduced aggregation and enhanced clearance of mutant huntingtin when cells were cultured in raised glucose concentrations (8 g/l). These effects were mimicked by 8 g/l 2-deoxyglucose (2DOG) (transported, phosphorylated but not metabolized further), but not with 8 g/l 3-O-methyl glucose (transported but not metabolized further). Thus, this phenomenon is probably mediated by glucose-6-phosphate. Increased clearance of mutant huntingtin by raised glucose (8 g/l) and 2DOG correlated with increased autophagy and reduced phosphorylation of mTOR, S6K1 and Akt. Thus, raised intracellular glucose/glucose 6-phosphate levels reduce mutant huntingtin toxicity by increasing autophagy via mTOR and possibly Akt. As mTOR and Akt regulate a diversity of crucial cellular processes, our data also suggest a major new set of targets for intracellular glucose signalling.     

Cystic fibrosis and other respiratory diseases of impaired mucus clearance

Exposed to a diverse array of potentially noxious agents, the respiratory tract is protected by a highly developed innate defense system. Physiologically regulated epithelial ion and water transport coordinated with mucin secretion, beating cilia, and cough results in continuous flow of fluid and mucus over airway surfaces toward the larynx. This cleansing action is the initial and perhaps most quantitatively important innate defense mechanism. Repeated lung infections and eventual respiratory insufficiency characteristic of human cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) illustrate the consequences of impaired mucus clearance. Altered mucus clearance likely contributes to the initiation, progression, and chronicity of other airway diseases characterized by inflammation and mucous secretory cell hyper/metaplasia that afflict millions worldwide, including chronic obstructive pulmonary disease (COPD). This review concisely discusses the pathophysiology of human diseases characterized by genetic defects that impair mucus clearance. It then explores animal models in which components of the mucus clearance system have been disrupted. These models firmly establish the importance of mucus clearance for respiratory health, and will help elucidate disease mechanisms and therapeutic strategies in CF, PCD and COPD.     

Evaluation of aggregated IgG in mice as an Fc receptor specific probe of the hepatic mononuclear phagocyte system.

In experimental models of immune complex diseases the hepatic mononuclear phagocyte system removes circulating immune complexes (CIC) by interaction with Fc receptors, and the spleen has a relatively insignificant role in this function. We have used heat-aggregated human IgG (AHGG) to detect altered hepatic mononuclear phagocyte system activity in an acute immune complex model in mice in order to evaluate its suitability for possible use in humans. Immune complexes inhibited the clearance of AHGG, as a function of the dose and of the time after injection of complexes. The delayed clearance resulted from decreased hepatic uptake of the AHGG. Alterations in the comparatively small splenic uptake of AHGG did not correlate with changes in the clearance or the hepatic uptake that were produced by the complexes. Studies with Rose Bengal showed that the complexes caused a small but definite decrease in hepatic blood flow. Immune complexes also inhibited the clearance and hepatic uptake of aggregated mouse albumin and aggregated ovalbumin. The aggregated albumins, however, were cleared very rapidly, indicating high extraction ratios, so their clearance was more affected by the decreased blood flow than the clearance of AHGG. We conclude that a small dose of AHGG is a sensitive probe for hepatic Fc receptor function and has potential for human use.     

Eotaxin-1-regulated eosinophils have a critical role in innate immunity against experimental Brugia malayi infection

Using two models of filarial infection in which Brugia malayi microfilariae (Mf) are contained in distinct anatomical compartments, in blood or tissue sites, we have demonstrated a critical role for eotaxin-1 in parasite clearance. In the first model, implantation of adult B. malayi into the peritoneal cavity of eotaxin-1(-/-) mice resulted in increased Mf survival associated with a dramatic reduction in peritoneal cavity eosinophilic infiltration. In the second model Mf were injected intravenously into eotaxin-1(-/-) mice; Mf clearance from the blood was more rapid than in wild-type mice and was associated with a pronounced blood eosinophilia, resulting from the inability of eosinophils to migrate to tissue sites in the absence of eotaxin-1. (Eotaxin-1 + IL-5)(-/-) mice had extended Mf survival in the blood and significantly reduced blood eosinophil levels. Interestingly, rapid clearance of a secondary Mf infection following immunization was unaltered in either eotaxin-1(-/-) mice or (eotaxin-1 + IL-5)(-/-) mice. Eosinophil peroxidase levels were high during primary, but not secondary infection, suggesting that eosinophil degranulation is important during primary Mf clearance. Thus, our data show that the presence of eosinophils is critical for innate clearance of B. malayi Mf infection, whereas rapid clearance of secondary infections is independent of both eotaxin-1 and IL-5.     

Influence of clearance on the time-dependent performance of the hip following hemiarthroplasty: A finite element study with biphasic acetabular cartilage properties

Hip hemiarthroplasty is a common treatment for femoral neck fracture. However, the acetabular cartilage may degenerate after hemiarthroplasty leading to postoperative failure and the need for revision surgery. The clearance between the acetabular cartilage and head of the prosthesis is one of the potential reasons for this failure. In this study, the influence of joint clearance on the biomechanical function of a generic hip model in hemiarthroplasty was investigated using biphasic numerical simulation. Both a prolonged loading period of 4000 s and dynamic gait load of 10 cycles were considered. It was found that a larger clearance led to a higher stress level, a faster reduction in load supported by the fluid and a faster cartilage consolidation process. Additionally, the mechanical performance of the acetabular cartilage in the natural model was similar to that in the hemiarthroplasty model with no clearance but different from the hemiarthroplasty models with clearances of 0.5 mm and larger. The results demonstrated that a larger clearance in hip hemiarthroplasty is more harmful to the acetabular cartilage and prosthesis heads with more available dimensions (i.e. smaller increments in diameter) could be manufactured for surgeons to achieve a lower clearance, and reduced contact stress in hemiarthroplasty surgeries.     

Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models

Cerebral amyloid angiopathy of the beta-amyloid type (Abeta-CAA) is a risk factor for hemorrhagic stroke and independently is believed to contribute to dementia. Naturally occurring animal models of Abeta-CAA are scarce and not well suited for the laboratory. To this end, a variety of transgenic mouse models have been developed that, similar to cerebral Abeta-amyloidosis in humans, develop either Abeta-CAA only or both Abeta-CAA and parenchymal amyloid, or primarily parenchymal amyloid with only scarce Abeta-CAA. The lessons learned from these mouse models are: i) Abeta-CAA alone is sufficient to induce cerebral hemorrhage and associate pathologies including neuroinflammation, ii) the origin of vascular amyloid is mainly neuronal, iii) Abeta-CAA results largely from impaired Abeta clearance, iv) a high ratio Abeta40:42 favors vascular over parenchymal amyloidosis, and v) genetic risk factors such as ApoE modulate Abeta-CAA and CAA-induced hemorrhages. Therapeutic strategies to inhibit Abeta-CAA are poor at the present time. Once Abeta-CAA is present current Abeta immunotherapy strategies have failed to clear vascular amyloid and even run the risk of serious side effects. Despite this progress in deciphering the pathomechanism of Abeta-CAA, with these first generation mouse models of Abeta-CAA, refining these models is needed and will help to understand the emerging importance of Abeta-CAA for dementia and to develop biomarkers and therapeutic strategies.     

Mathematical modelling for the new millenium: medicine by numbers

Physicists, engineers and mathematicians are accustomed to the combination of elegance, rigour and utility that characterise mathematical models. They are familiar with the need to dip into their mathematical toolbox to select the technique of choice. However, medicine and biology have not been characterised, in general, by a mathematical formalism.The relative paucity of mathematical models in biology and medicine reflects in part the difficulty in making accurate and appropriate experimental measurements in the field. Signal noise, the lack of appropriate sensors, and uncertainty as to what constitutes the significant measurements are largely to blame for this.The purpose of this paper is to characterise a 'good' model, encourage the development and application of such models to new areas, and outline future developments in the field. It is proposed that a good model will be accurate, predictive, economical, unique and elegant. These principles will be illustrated with reference to four models: radiosensitisation of tumours, modelling solute clearance in haemodialysis, the myogenic response in reactive hyperaemia and cardiac electrical activity.It is suggested that, in the immediate future, the mathematical model will become a useful adjunct to laboratory experiment (and possibly clinical trial), and the provision of 'in silico' models will become routine.     

Immunological and anti-chaperone therapeutic approaches for Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity.     

Adaptive immunity-dependent intestinal hypermotility contributes to host defense against Giardia spp

Humans infected with Giardia exhibit intestinal hypermotility, but the underlying mechanisms and functional significance are uncertain. Here we show in murine models of giardiasis that small-intestinal hypermotility occurs in a delayed fashion relative to peak parasite burden, is dependent on adaptive immune defenses, and contributes to giardial clearance.     

Targeting granulocyte apoptosis: mechanisms,models, and therapies

Summary: The inflammatory process is a complex series of tightly controlled cellular and biochemical events initiated by the immune system, which has evolved to eliminate or contain infectious agents and to repair damaged tissue. Apoptosis is essential for the clearance of potentially injurious inflammatory cells, such as neutrophils, eosinophils, and basophils, and the subsequent efficient resolution of inflammation. In this review, we aim to cover key features of the granulocyte life-cycle ranging from their differentiation within the bone marrow to their maturation and ultimate clearance, with a focus on granulocyte apoptosis and macrophage efferocytosis. We further aim to discuss current and emerging models of inflammation and suggest novel ways of terminating or resolving deleterious inflammatory responses with a specific view to the translation of these strategies into fully realized, pro-resolution therapies.     

Viscoelastic gel formulations enhance airway epithelial gene transfer with viral vectors

Advances in gene transfer to the conducting airways for the treatment of pulmonary diseases such as cystic fibrosis have identified several vector classes that transduce airway epithelia in vitro and in animal models. One barrier to epithelial gene transfer is the rapid removal of materials from the airway surface via mucociliary clearance. This host defense mechanism limits gene transfer efficiency to airway epithelial cells. Here we show that formulation of gene transfer vectors with viscoelastic gels provides longer epithelial residence time and increases vector-mediated gene transfer efficiency. Gene transfer with adenoviral, adeno-associated, and lentiviral vectors all significantly improved after formulation with viscoelastic gels designed to slow mucociliary clearance. Importantly, viscoelastic gel formulations enhanced vector transduction to the conducting airways, the desired treatment target for diseases such as cystic fibrosis.     

Particle deposition and clearance in the bronchial tree

Mucociliary transport is responsible for the cleansing of inhaled particles from the conducting airways of the lung. The characteristics of human tracheobronchial mucociliary transport have been investigated using radiotagged aerosols. These methods are critically reviewed together with alternative techniques. The role of predictive mathematical models of tracheobronchial clearance is discussed. Major findings regarding mucociliary clearance in health and the effects of drugs, inhaled pollutants, and disease are summarized. Throughout, areas requiring problem-solving are delineated. This research was supported in part by the Medical Research Service of the Veterans Administration, the National Institutes of Health, HL-13824 and HL-19431, and the Oak Ridge National Laboratory Basic Agreement 7762-X02.     

A multiwire hydrogen electrode for in vivo use

A multiwire surface electrode is described for measuring the partial pressure of hydrogen gas within extremely small volumes. The purpose was to record hydrogen clearance curves in vivo in order to analyse capillary blood flow. A method for improving the sensitivity and stability of the Clark-type polarographic sensor is presented. The in vitro and in vivo properties were investigated and are critically compared with the characteristics predicted from various models for the polarographic measurements of gases. The high stability and low drift of the electrode together with its small catchment volume (a hemisphere of radius 32 microns) meant that it could be reliably used for accurate, reproducible local measurements of hydrogen clearance curves in vivo. The experiments also demonstrated that the electrode could be used most successfully for the measurement of capillary blood flow even in the heart and contracting skeletal muscle.     

Impact of convective transport on dialyzer clearance

 The results of predictions of three mathematical models used to describe the impact of convective flow on dialyzer clearance are presented. These models are based on the ordinary differential equations, which describe changes of solute concentration and solute and fluid flows along the module length. One of the models takes into consideration the existence of the boundary layers on both sides of the membrane wall, by including in the equations two parameters k _B and k _D , which describe mass transport coefficients in blood and dialysate, respectively. In the second model, the boundary layers are included in one lumped membrane permeability parameter. The diffusive membrane permeability was calculated from pure diffusive clearance, which was taken from experimental results. In the third model, a linear dependence of transmittance coefficient and ultrafiltration flow was proposed. The theoretical results were compared with data obtained in experiments carried out in vitro with four types of high-flux hollow-fiber dialyzers. The comparisons demonstrate that the first two models are of similar accuracy and the third model is not suitable for small solutes. Received: June 17, 2002 / Accepted: October 16, 2002 Acknowledgments This study was supported by Fresenius Medical Care Deutschland GmbH. The authors thank Dr. Cecile Legallais, University of Compiegne, France, for help with the references. Correspondence to:M. Galach     

Cellular immunity and lung injury in respiratory virus infection

Respiratory virus infection may result in considerable lung injury, and host immune responses may be an important contributor to this. Important factors that determine the magnitude of immunopathologic tissue damage include the degree of distal distribution of infection into alveolar cells, the overall viral load, the magnitude of the T-cell responses, the effector mechanisms employed by the T cells, and regulatory mechanisms which may come into play. CD8+ T cells are important contributors to viral clearance, utilizing contact-dependent effector functions (perforin and CD95L) as well as IFN-gamma and TNF-alpha. IFN-gamma and TNF-alpha are primary perpetrators of T-cell-mediated lung injury, with TNF as the major contributor. It is not entirely clear at present the degree to which injury is a necessary consequence of host defense to respiratory virus infection, though there are tantalizing bits of evidence to the contrary. In murine models, TNF plays only a minor role in antiviral activity and clearance of laboratory strains of RSV and influenza. In the event of a pandemic with a highly virulent virus, intervention directed at TNF-alpha should be given consideration, as this may be most likely to provide protection against severe lung injury at the lowest cost to viral clearance.     

Role for Gr-1+ Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attractive target for development as a live vaccine vector delivering transgenic antigens from HIV and other pathogens. Most studies aimed at defining the clearance of BCG have been performed at doses between 10² and 10⁴ CFU. Interestingly, however, recombinant BCG (rBCG) administered at doses of >10⁶ CFU effectively generates antigen-specific T-cell responses and primes for heterologous boost responses. Thus, defining clearance at high doses might aid in the optimization of rBCG as a vector. In this study, we used bioluminescence imaging to examine the kinetics of rBCG transgene expression and clearance in mice immunized with 5 × 10⁷ CFU rBCG expressing luciferase. Similar to studies using low-dose rBCG, our results demonstrate that the adaptive immune response is necessary for long-term control of rBCG beginning 9 days after immunizing mice. However, in contrast to these reports, we observed that the majority of mycobacterial antigen was eliminated prior to day 9. By examining knockout and antibody-mediated depletion mouse models, we demonstrate that the rapid clearance of rBCG occurs in the first 24 h and is mediated by Gr-1⁺ cells. As Gr-1⁺ granulocytes have been described as having no impact on BCG clearance at low doses, our results reveal an unappreciated role for Gr-1⁺ neutrophils and inflammatory monocytes in the clearance of high-dose rBCG. This work demonstrates the potential of applying bioluminescence imaging to rBCG in order to gain an understanding of the immune response and increase the efficacy of rBCG as a vaccine vector.