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PubMed1997

A mathematical analysis of the bioenergetics of hurdling.

A mathematical model of the bioenergetics of running has been extended to apply to hurdling. This has been achieved by two principal modifications. First, a new term has been added to the energy equation to account for the potential energy required to negotiate each hurdle. Secondly, the term describing the degradation of mechanical energy to thermal energy has been modified to account for the adjustments in stride pattern necessary to negotiate the hurdles. A comparison of predicted and actual running times of elite athletes was made and good levels of agreement were achieved.

Anthropometry↗
PubMed2006

Parameters favouring successful adult pig islet isolations for xenotransplantation in pig-to-primate models.

BACKGROUND: In the near future, adult porcine islets of Langerhans appear as an unlimited source of insulin-producing cells which could play a major role for treating diabetes mellitus. There is, however, an obvious lack of pre-clinical results and data in the pig-to-primate model. One of the main hurdles of this model is certainly related to the difficulty of reproducing regularly successful porcine islet isolation. This experimental work was designed to provide guidelines applicable in pig pancreas procurement and islet isolation for successful islet xenotransplantation into primates. METHODS: Pancreases were harvested from adult Belgium Landrace pigs (n = 79) in a single centre. The impact on islet yield of (1) pancreas procurement (blood exsanguination and warm ischaemia time (WIT)), (2) cold storage solutions (classic UW and modified UW (without hydroxyethyl starch and inverse K+/Na+ concentration)), (3) a dynamic or static method of pancreas digestion, and (4) the endotoxin content and enzymatic activity from five different batches of Liberase PI was studied. In addition, pancreatic biopsies (n = 18), performed before isolation, were retrospectively analyzed to study the impact of histomorphometry on porcine islet yield. Finally, two diabetic cynomolgus monkeys were transplanted without immunosuppression with 15,000 pig islet equivalents/kg body weight of recipient to assess in vivo the function of freshly isolated islets. Univariate and multivariate analyses were performed. RESULTS: By multiple linear regression, the most significant variables that significantly improved islet yield were, firstly, the presence of <30 EU (endotoxin units) of endotoxin in Liberase batches, followed by a WIT under 10 min and the use of blood exsanguination before pancreas harvesting (P < 0.005). In contrast, isolation method (dynamic vs. static) and the solution used for storage (short-term) (UW vs. modified UW) did not significantly influence islet yield. The correlation of retrospective histomorphometry analysis of native pancreas and extemporaneous biopsy before isolation clearly determined a positive relationship between isolated islet number and the number of islets/cm2 (r = 0.708, P < 0.01) or with the percentage of large islets (r = 0.680, P < 0.01) found in pancreas biopsies. Pig pancreases containing more than 82 islets/cm2 and more than 42% of large islets (>100 microm) thus enabled more than 120,000 islet equivalents to be obtained in 90% of the cases, which is an ideal amount of islets to transplant into a primate of 4 to 5 kg. In vivo, a reduction of blood glucose (<200 mg/dl), associated with porcine C-peptide production, was observed in two primates after transplantation with adult pig islets. At day 7 post-transplantation, however, loss of islet function was associated with graft destruction and immune reaction. CONCLUSIONS: Morphological screening of the pig pancreas before isolation, optimal blood exsanguination, WIT <10 min, and an endotoxin content <30 EU/mg in Liberase PI batches determine successful pig islet isolation for xenotransplantation in primates.

Adenosine↗
PubMedDate not supplied

'Fourth hurdle reviews', NICE, and database applications.

The 'fourth hurdle' is commonly described as what has to be done to gain market access and reimbursement for a pharmaceutical, medical technology, or biotech product. Demonstrating to regulatory agencies just a product's safety, efficacy, and quality (the first three hurdles) is no longer sufficient. Manufacturers must often now demonstrate both clinical effectiveness (Is the new product better than currently available alternatives, including no treatment?) as well as cost-effectiveness (Is the product good value for money?) in order to assure success in the marketplace. In the last few years there have been a number of governmental and non-governmental agencies constituted for fourth hurdle reviews and recommendations to governments and other funding and reimbursement agencies. The National Institute for Clinical Effectiveness (NICE) in the UK, although not the first such group, is arguably the most visible and influential. This paper describes the NICE review process in detail, as well as the expected substantial impact of fourth hurdle reviews on drug development and clinical trials. Potential uses of databases and modelling in fourth hurdle reviews are also explored.

Cost-Benefit Analysis↗
PubMed2001

Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation.

Elucidation of the molecular and cellular mechanisms responsible for the pathogenesis of psoriasis had been significantly handicapped due to lack of an ideal animal model. To overcome this hurdle several investigators have developed a number of animal models for psoriasis. Recent establishment of the SCID-human skin chimeras with transplanted psoriasis plaques has opened new vistas to study the molecular complexities involved in psoriasis. This model also offers a unique opportunity to investigate various key biological events such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. The SCID mouse model will be of immense help to target the cellular and molecular events associated with these pathogenic processes and develop novel drugs for psoriasis and other inflammatory diseases. In this article we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.

Animals↗
PubMed2005

Adeno-associated virus vectors: potential applications for cancer gene therapy.

Augmenting cancer treatment by protein and gene delivery continues to gain momentum based on success in animal models. The primary hurdle of fully exploiting the arsenal of molecular targets and therapeutic transgenes continues to be efficient delivery. Vectors based on adeno-associated virus (AAV) are of particular interest as they are capable of inducing transgene expression in a broad range of tissues for a relatively long time without stimulation of a cell-mediated immune response. Perhaps the most important attribute of AAV vectors is their safety profile in phase I clinical trials ranging from CF to Parkinson's disease. The utility of AAV vectors as a gene delivery agent in cancer therapy is showing promise in preclinical studies. In this review, we will focus on the basic biology of AAV as well as recent progress in the use of this vector in cancer gene therapy.

Animals↗
PubMed1998

[Gene therapy of restenosis].

Although angioplasty has undergone considerable development, restenosis remains an unsolved problem. No drugs have been proved effective in the prevention of restenosis. Prophylactic stenting is the only treatment with some efficacy. The pathophysiology of restenosis involves both intimal hyperplasia with a major proliferative component at the dilated site and geometric constrictive remodeling of the artery. Stenting seems to prevent the remodeling but does not prevent and may even worsen the intimal hyperplasia. Gene therapy may be effective in preventing the proliferative component of the intimal hyperplasia: therapeutic genes can be delivered locally to the arterial wall cells at the dilated site during or immediately after angioplasty, using viral (e.g., adenoviruses) or nonviral vectors. The main candidate genes stimulate a variety of endogenous mechanisms whose effects consist in inhibition of smooth muscle cell proliferation (Rb gene); sensitization of proliferating cells to the effects of cytotoxic substances, thus allowing selective chemotherapy (HSV-tk gene); or stimulation of reendothelization (VEGF gene). Other genes have also yielded promising results (ecNOs, p21, Coxl, etc.). Clinical application of these techniques cannot be envisioned until studies are available proving that the delivery methods (transfer vectors or local delivery systems) are completely safe, and that the candidate genes are effective in "realistic" models. If these hurdles are cleared successfully, preventive gene therapy for gene restenosis may well become a clinical reality.

Angioplasty, Balloon, Coronary↗
PubMed2006

Improved technique of mouse heterotopic heart graft retransplantation.

Research on chronic graft failure requires a graft retransplantation model to elucidate the affects of early transplant episodes on long-term graft survival. Prolonged ischemic time is the major hurdle for this retransplant model. Here we describe a novel technique of mouse heart retransplantation, with a shortened retransplant ischemic time and higher success rate. The primary heart transplant employed an allogeneic abdominal heart-transplant technique (Balb/C to C57BL/6 mice). Thirty to 60 days later, the graft was reharvested and retransplanted into the second syngeneic recipient (Balb/C mice) by using cervical heterotopic heart transplantation with a cuff technique. The total ischemic time of retransplant was reduced to within 35 min with the cuff technique, and a greater retransplant success rate (90.6%) was achieved. This heart retransplantation technique is a novel, useful tool in transplantation research.

Animals↗
PubMed1996

Expressiveness and query complexity in an electronic health record data model.

OBJECTIVE: Describe a high-level conceptual electronic health record (EHR) data model, explain how the model is expressive, present an algorithm for querying the model and determine the complexity of this algorithm. DESIGN: Entity-Relationship diagramming is used to represent the model, which relies on variably nested relations to enable expressiveness. The algorithm complexity is described using "big-oh" or "O()" notation. RESULTS: The data model appears to be highly expressive. A tractable recursive query processing algorithm is presented which is polynomial in time and space complexity. CONCLUSION: Several hurdles remain before the model and algorithm described can be fully tested in a live setting, including the development of techniques to populate the model. However, the study does show the ability to formally analyze an EHR model to understand its particular expressiveness and query complexity.

Algorithms↗
PubMed2006

Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF.

Targeted oncolytic viruses and immunostimulatory therapeutics are being developed as novel cancer treatment platforms. These approaches can be combined through the expression of immunostimulatory cytokines from targeted viruses, including adenoviruses and herpesviruses. Although intratumoral injection of such viruses has been associated with tumor growth inhibition, eradication of distant metastases was not reported. The major limitations for this approach to date have been (1) inefficient intravenous virus delivery to tumors and (2) the lack of predictive, immunocompetent preclinical models. To overcome these hurdles, we developed JX-594, a targeted, thymidine kinase(-) vaccinia virus expressing human GM-CSF (hGM-CSF), for intravenous (i.v.) delivery. We evaluated two immunocompetent liver tumor models: a rabbit model with reproducible, time-dependent metastases to the lungs and a carcinogen-induced rat liver cancer model. Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated. JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic. These two tumor models hold promise for the optimization of this approach.

Animals↗
PubMed2006

Rediscovering the species in community-wide predictive modeling.

Broadening the scope of conservation efforts to protect entire communities provides several advantages over the current species-specific focus, yet ecologists have been hampered by the fact that predictive modeling of multiple species is not directly amenable to traditional statistical approaches. Perhaps the greatest hurdle in community-wide modeling is that communities are composed of both co-occurring groups of species and species arranged independently along environmental gradients. Therefore, commonly used "short-cut" methods such as the modeling of so-called "assemblage types" are problematic. Our study demonstrates the utility of a multiresponse artificial neural network (MANN) to model entire community membership in an integrative yet species-specific manner. We compare MANN to two traditional approaches used to predict community composition: (1) a species-by-species approach using logistic regression analysis (LOG) and (2) a "classification-then-modeling" approach in which sites are classified into assemblage "types" (here we used two-way indicator species analysis and multiple discriminant analysis [MDA]). For freshwater fish assemblages of the North Island, New Zealand, we found that the MANN outperformed all other methods for predicting community composition based on multiscaled descriptors of the environment. The simple-matching coefficient comparing predicted and actual species composition was, on average, greatest for the MANN (91%), followed by MDA (85%), and LOG (83%). Mean Jaccard's similarity (emphasizing model performance for predicting species' presence) for the MANN (66%) exceeded both LOG (47%) and MDA (46%). The MANN also correctly predicted community composition (i.e., a significant proportion of the species membership based on a randomization procedure) for 82% of the study sites compared to 54% (MDA) and 49% (LOG), resulting in the MANN correctly predicting community composition in a total of 311 sites and an additional 117 sites (n = 379), on average, compared to LOG and MDA. The MANN also provided valuable explanatory power by simultaneously quantifying the nature of the relationships between the environment and both individual species and the entire community (composition and richness), which is not readily available from traditional approaches. We discuss how the MANN approach provides a powerful quantitative tool for conservation planning and highlight its potential for biomonitoring programs that currently depend on modeling discrete assemblage types to assess aquatic ecosystem health.

Animals↗
PubMed2001

Alternative approaches to obtain optimal bid values in contingent valuation studies and to model protest zeros. Estimating the determinants of individuals' willingness to pay for home care services in day case surgery.

The use of day case surgery has increased rapidly as an alternative to inpatient surgery. Little is known, however, about the value of day case surgery to patients. The aim of this paper was to develop a contingent valuation survey to investigate how individuals value the costs of shifting from inpatient to day case surgery based on home care services. Using the willingness to pay (WTP) approach, two kinds of sequential experiments are compared: the maximum likelihood recursion (MLR) method and the C-optimal sequential procedure. The goal of sequential experimentation is to find bid values that provide the maximum possible information about the parameters of the WTP distribution, especially when the sample size is small. The C-optimal sequential procedure is shown to be an improvement, in terms of the statistical precision in small samples, over the MLR method. In addition, the paper presents a double hurdle (DH) approach for modelling the determinants of individuals' WTP. Using data from a contingent valuation survey conducted in 1996 on patients selected from the Day Case Surgery Unit in a hospital in the region of Catalonia, we argue that participation in the market offered and the level of consumption, that is, people's WTP, should be treated as individual choices. The results show that income and sex are related to WTP. Also, in this study, a clear presence of starting-point bias, introduced by the bid offered, was found. It is concluded that the WTP technique is potentially useful in evaluating health care programmes, although it is important to note that the criteria used to find an optimal design (in our model to minimize the asymptotic variance of the estimator used) may be restrictive from an economic point of view.

Ambulatory Surgical Procedures↗
PubMed1997

Clinical xenotransplantation of solid organs.

A possible solution to the chronic shortage of allografts is xenotransplantation, the use of tissue from an animal donor. Most experts believe that the pig will provide the most suitable solid organs for use in human beings. Although porcine organs are rapidly rejected by a process called hyperacute rejection (HAR), there is hope that several novel therapeutic strategies, already tested in animal models, will overcome this hurdle in patients. Successful clinical trials of these strategies, expected within the next few years, may herald the era of clinical xenotransplantation. However, there is increasing evidence that other barriers, both immune and non-immune, might exist to limit the survival of xenografts beyond the HAR phase. New strategies to overcome these barriers will be needed if long-term xenograft survival equivalent to, or better than, that of allografts is ever to be achieved.

Animal Rights↗
PubMed2002

Prospects for stem cell therapeutics: myths and medicines.

With common scientific themes and experimental strategies, stem cell biology is evolving into a recognizable discipline. Its clinical arm, regenerative medicine, is also gaining momentum-invigorated by the potential of stem cells to provide treatments for a host of medical conditions that are poorly served by drug therapy. But are the expectations for stem cell therapies realistic or overstated? In the past year, neurons, insulin-producing cells, and hematopoietic stem cells have been generated from embryonic stem cells or cultivated from somatic tissues of the adult. These cells have yielded modest and preliminary hints of functional reconstitution in animal models. Although encouraging, significant hurdles remain before the promise of stem cells will be realized in the clinic.

Animals↗
PubMed2005

Lattice Boltzmann simulation of rarefied gas flows in microchannels.

For gas flows in microchannels, slip motion at the solid surface can occur even if the Mach number is negligibly small. Since the Knudsen number of the gas flow in a long microchannel can vary widely and the Navier-Stokes equations are not valid for Knudsen numbers beyond 0.1, an alternative method that can be applicable to continuum, slip and transition flow regimes is highly desirable. The lattice Boltzmann equation (LBE) approach has recently been expected to have such potential. However, some hurdles need to be overcome before it can be applied to simulate rarefied gas flows. The first major hurdle is to accurately model the gas molecule and wall surface interactions. In addition, the Knudsen number needs to be clearly defined in terms of LBE properties to ensure that the LBE simulation results can be checked against experimental measurements and other simulation results. In this paper, the Maxwellian scattering kernel is adopted to address the gas molecule and surface interactions with an accommodation coefficient (in addition to the Knudsen number) controlling the amount of slip motion. The Knudsen number is derived consistently with the macroscopic property based definition. The simulation results of the present LBE model are in quantitative agreement with the established theory in the slip flow regime. In the transition flow regime, the model captures the Knudsen minimum phenomenon qualitatively. Therefore, the LBE can be a competitive method for simulation of rarefied gas flows in microdevices.

Journal Article↗
PubMed1981

Are there gay genes? Sociobiology and homosexuality.

This paper considers recent hypotheses prepared by sociobiologists purportedly giving Darwinian evolutionary explanations of human homosexuality. Four models are considered: balanced superior heterozygote fitness, kin selection, parental manipulation, and homosexuality as a maladaptive side effect of intensive natural selection for superior male heterosexual behavior. The evidence for the models is reviewed, and their philosophical adequacy is considered in some depth. It is argued that although the models pass obvious methodological hurdles and meet other criteria, as yet, the evidence for their applicability is indecisive.

Female↗
PubMed2004

Overcoming the hurdles to providing urban health care in the 21st century.

The delivery of health care services to urban populations in the United States is a system of rapidly increasing complexity. With the emergence of superspecialized physicians, a scientific approach to disease management has received great emphasis. Those providing health care at the population level may also apply this evidence-based approach. Analysis of the process of health care delivery in its entirety is complicated, confusing, and may be fraught with bias. In this article, a powerful instrument for providing a scientific approach to urban health care health policy development is introduced. This tool allows for analysis and assessment of hurdles to health care delivery to urban populations by dividing the process into elements of "administration," "provision," and "utilization" (APU). This APU triangle model, while intuitive, also allows a more definitive analysis by parts than would be possible to make of the whole. Using this model, the authors explore some of the hurdles faced by each element as well as some potential solutions. Although this model is presented in the context of urban hurdles to health care, it is equally applicable to rural environments or other service-delivery systems. In conclusion, this article discusses the emergence of the role of the public health department as the facilitator and manager between sectors of the community not traditionally connected in a collaborative health care model. Thus, the urban public health department coordinates efforts to surmount the hurdles and provides the venue for analysis, development, and employment of successful strategies.

Cities↗
PubMed2000

Modelling covariance structure in the analysis of repeated measures data.

The term 'repeated measures' refers to data with multiple observations on the same sampling unit. In most cases, the multiple observations are taken over time, but they could be over space. It is usually plausible to assume that observations on the same unit are correlated. Hence, statistical analysis of repeated measures data must address the issue of covariation between measures on the same unit. Until recently, analysis techniques available in computer software only offered the user limited and inadequate choices. One choice was to ignore covariance structure and make invalid assumptions. Another was to avoid the covariance structure issue by analysing transformed data or making adjustments to otherwise inadequate analyses. Ignoring covariance structure may result in erroneous inference, and avoiding it may result in inefficient inference. Recently available mixed model methodology permits the covariance structure to be incorporated into the statistical model. The MIXED procedure of the SAS((R)) System provides a rich selection of covariance structures through the RANDOM and REPEATED statements. Modelling the covariance structure is a major hurdle in the use of PROC MIXED. However, once the covariance structure is modelled, inference about fixed effects proceeds essentially as when using PROC GLM. An example from the pharmaceutical industry is used to illustrate how to choose a covariance structure. The example also illustrates the effects of choice of covariance structure on tests and estimates of fixed effects. In many situations, estimates of linear combinations are invariant with respect to covariance structure, yet standard errors of the estimates may still depend on the covariance structure.

Analysis of Variance↗
PubMed2003

Dynamic modeling and jaw biomechanics.

Bioengineered simulations of dynamic events in the human masticatory system are relatively new. A primary advantage is their ability to integrate structure and function in cause-and-effect scenarios. By permitting detailed analyses of these interactions, and the prototyping of prosthetic additions, the models generate working hypotheses. Significant issues in their use include the importation and measurement of structural geometry, the choice of parameters affecting dynamics (e.g. inertial properties and viscoelasticities) and the nature of the modeling process (e.g. whether models are kinetically driven by muscle contraction, or kinematically defined by movement channels). Presently, there are few accepted standards or conventions for managing these computational data in the human jaws, and the data used are often derived from multiple and disparate sources. This review focuses on the approaches, assumptions, and key applications of dynamic modeling in the human masticatory system. It considers the role of imaging, the restrictions imposed by assumptions of unknown or unverifiable data, and how modeling can be a useful research technique despite these hurdles. The review concludes with a comment on creating virtual models for educational purposes.

Biomechanical Phenomena↗