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PubMed1998

A graph-theoretic algorithm for comparative modeling of protein structure.

The interconnected nature of interactions in protein structures appears to be the major hurdle in preventing the construction of accurate comparative models. We present an algorithm that uses graph theory to handle this problem. Each possible conformation of a residue in an amino acid sequence is represented using the notion of a node in a graph. Each node is given a weight based on the degree of the interaction between its side-chain atoms and the local main-chain atoms. Edges are then drawn between pairs of residue conformations/nodes that are consistent with each other (i.e. clash-free and satisfying geometrical constraints). The edges are weighted based on the interactions between the atoms of the two nodes. Once the entire graph is constructed, all the maximal sets of completely connected nodes (cliques) are found using a clique-finding algorithm. The cliques with the best weights represent the optimal combinations of the various main-chain and side-chain possibilities, taking the respective environments into account. The algorithm is used in a comparative modeling scenario to build side-chains, regions of main chain, and mix and match between different homologs in a context-sensitive manner. The predictive power of this method is assessed by applying it to cases where the experimental structure is not known in advance.

Algorithms↗
PubMed1999

Gene therapy in the cardiovascular system: an update.

This update reviews the remarkable progression in several cardiovascular gene transfer domains. The first chemical gene therapy protocols to stimulate angiogenesis in ischemic myocardium are discussed and both the great expectations as well as remaining hurdle are highlighted. In experimental models of restenosis and heart failure gene therapy shows promising results. Important question regarding vector-related limitations and suboptimal in vivo delivery systems will require expeditious attention for gene therapy to become a more widely applicable option in cardiovascular diseases.

Animals↗
PubMed2003

Gene therapy for asthma.

The accessibility of the airway epithelium and the limitations of current treatments for asthma make the disease a logical target for gene therapy. Study of the immunopathology of chronic airway inflammation has recently identified several pathways that lead to the maladaptive, antigen-induced polarization of CD4+ T cells to a type-2 phenotype. This polarization is thought to lead to IgE production and eosinophil recruitment and activation that is associated with epithelial cell injury and airway hyper-reactivity. Gene transfer to the bronchial epithelium has been used in experimental models to redirect these pathways toward a less injurious, type-1 phenotype. This mini-review highlights recent mechanism-based immunomodulatory and supportive gene transfer approaches to treat animal models of asthma. Although substantial hurdles to airway gene transfer remain, gene transfer offers the possibility of interrupting the pathophysiology of airway inflammation. Doing so can be expected to yield long-lasting protection from bronchospastic challenge and reduced dependence on inhaled and oral medications.

Animals↗
PubMed1988

United they thrive: merger of two healthcare systems.

On March 15, 1987, the Sisters of St. Francis of Perpetual Adoration of Colorado Springs and the Sisters of Charity of Cincinnati agreed to consolidate. It marked the culmination of years of building mutual trust and months of intense negotiations. The Sisters of St. Francis realized in 1983 that some major decisions had to be made regarding the future direction of its healthcare ministry because of rapid changes within the healthcare industry and declining numbers of Franciscan sisters working in healthcare. In January 1986 leaders of the two institutes and their healthcare systems sat down for the first time to discuss issues surrounding the collaborative effort and to recommend a list of objectives, including joint ventures in various areas. Other recommendations included the formation of a joint steering council to direct the collaborative effort and the formation of a Colorado Springs Task Force to end the rivalry existing between two local hospitals--one Franciscan-sponsored, the other Charity-sponsored. Additional hurdles included finding an affiliation model that all parties would accept (the one endorsed allows the Sisters of St. Francis to continue to exercise substantial control over the future of its healthcare institutions but gives the Sisters of Charity Health Care System much of the operational control); due diligence reviews of legal and financial documents; canonical review; detailed financial analysis; review of all state and federal regulatory requirements, including antitrust; and educating and preparing members of the Franciscan Healthcare Corporation.

Catholicism↗
PubMed2001

How many patients with a sexually transmitted infection are cured by health services? A study from Mwanza region, Tanzania.

OBJECTIVES: To estimate the proportion of symptomatic patients with a bacterial sexually transmitted infection (STI) cured by primary health care services in Mwanza Region, Tanzania, and to compare the cure rate achieved by health centres before and after the introduction of improved STI treatment services. METHODS: A model was used that describes the different hurdles patients with an STI take before they can be considered cured by the health services. The values for the input parameters for the model were taken from different studies. Data from an intervention trial as well as from a population-based study on male urethritis were used to estimate the proportion of symptomatic patients with an STI who seek care from a health centre. An observational study in four health centres where improved STI treatment services had been introduced provided estimates of the proportions of patients with an STI correctly diagnosed and treated. Patients who returned to the health centres after 1 week were interviewed about compliance. An estimate of the efficacy of treatments prescribed for STIs in health centres before the introduction of improved STI services was obtained from a study on prescription patterns for genital discharge syndrome (GDS) and genital ulcer disease (GUD). RESULTS: It was estimated that in the catchment area of health centres offering improved STI services, 51-72% of patients with STI symptoms sought care from those health centres. About 76-85% of cases were correctly diagnosed, and of these 69-80% received efficacious treatment. Compliance with full treatment was estimated at 84%. The estimated overall cure rate achieved by the health centres offering improved STI services ranged between 23 and 41%. The proportion of symptomatic STI patients who attended a health centre before improved STI services were introduced was estimated at 39%. The estimated efficacy of the treatments prescribed was 28%. The overall cure rate achieved by these health centres was less than 10%. CONCLUSIONS: When assessing the performance of STI case detection and management all steps have to be taken into account that are taken by patients with an STI before they can be considered cured by the health services. The intervention to improve STI services in Mwanza Region has resulted in an improvement of the cure rate of STIs achieved by primary health care centres.

Adolescent↗
PubMed2001

The use of nonhuman primate models to improve gene transfer into haematopoietic stem cells.

Primitive haematopoietic progenitor and stem cells (HSC) have been pursued as highly desirable targets for genetic therapy as technology allowing safe and controllable transfer of exogenous genes into eukaryotic cells was developed a decade ago. Retroviral vectors have been used for the majority of preclinical and clinical studies directed at these cells, because these vectors have a number of the necessary properties, including chromosomal integration, helper-free production systems, and lack of toxicity. Until recently, however, results with these vectors in clinical trials and large animal models indicated efficiency of gene transfer as a major hurdle to be overcome. We have focused on using the rhesus macaque autologous transplantation model to optimize gene transfer to primitive haematopoietic cells, and investigate questions regarding in vivo stem cell behaviour, in a system with proven predictive value for human haematopoiesis. By optimization of transduction conditions using standard vectors, gene transfer efficiency to primitive repopulating cells has reached the clinically relevant range of 5-20% long-term. Alternative vector systems, have also yielded promising results. We have also found that relatively simple manipulation of cell cycle status prior to reinfusion of marked cells results in significantly improved engraftment of transduced cells: this finding may have an impact particularly in the nonablative setting. The high level marking has permitted insertion site analysis and clonal tracking in vivo. Inverse PCR and/or a ligation-mediated PCR procedure have demonstrated that a large number of transduced clones (over 50) contribute to multiple lineages in vivo for up to at least 2 years post-transplantation. Thus far we have little evidence for rapid clonal succession or lineage-restricted engraftment of transduced cells. These and other advances should result in successful gene therapy for a variety of acquired and congenital disorders affecting HSCs and their progeny lineages.

Animals↗
PubMed2006

Selective inhibitors of hepatitis C virus replication.

Worldwide over 170 million people are chronically infected with the hepatitis C virus and hence at high risk to develop fatal liver disease. There is no vaccine available and the standard therapy [(pegylated) interferon alfa plus ribavirin] is only effective in 50-60% of patients and is associated with important side-effects. The discovery of novel antiviral strategies to selectively inhibit HCV replication has long been hindered by the lack of convenient cell culture models for the propagation of HCV. This hurdle has been overcome first with the establishment of the HCV replicon system in 1999 and, in 2005, with the development of robust HCV cell culture models. In recent years also mouse models have been elaborated that will be instrumental in assessing the in vivo efficacy of novel drugs. The viral serine protease and the viral RNA dependent RNA polymerase have shown to be excellent targets for selective anti-HCV therapy. Clinical studies with a limited number of HCV protease and polymerase inhibitors resulted in encouraging results. However, and not unexpected, preclinical evidence suggest that the virus may become rapidly resistant to such inhibitors. Combination therapy of drugs with different mode of action and resistance profiles may thus be required. Alternative strategies, such as the use of non-immunosuppressive cyclosporin A analogues with potent anti-HCV activity, may prove important, in particular since such compounds may have a resistance profile that is very different from that of protease or polymerase inhibitors.

Animals↗
PubMed1998

Evaluating community efforts to decategorize and integrate financing of children's health services.

Publicly funded categorical programs for children often differ in eligibility rules, allowable services, and criteria for provider participation, making it necessary for families to navigate through several programs to piece together care for their children. Recognizing these problems, the Robert Wood Johnson Foundation launched a national demonstration project in 1991 with the goal of decategorizing children's health services in nine communities. It was hoped that by releasing funds from categorical restrictions on their use, scarce public resources could be directed where they might have the greatest impact. However, the demonstration sites confronted a number of challenges in designing and implementing decategorization strategies: an absence of existing models and effective technical assistance; political hurdles in gaining cooperation from the multiple local agencies engaged in service provision; and difficulties in carrying out major programmatic changes when the health care system itself was rapidly being transformed. The proposition that decategorization holds promise as a tool for improving access to health care deserves further investigation.

Adolescent↗
PubMedDate not supplied

In silico modelling of hazard endpoints: current problems and perspectives.

Major scientific hurdles in the acceptance of quantitative structure-activity relationships (QSAR) for regulatory purposes have been identified. First, when quantifying important features of chemical structure complexities of molecular structure have often been ignored. More mechanistic modelling of chemical structure should proceed on two fronts: by developing a more in-depth understanding and representation of the multiple states possible for a single chemical by achieving greater rigor in understanding of conformational flexibility of chemicals; and, by considering families of activated metabolites that are derived in biological systems from an initial chemical substrate. Second, QSAR research is severely limited by the lack of systematic databases for important risk assessment endpoints, and despite many decades of research, the ability to cluster reactive chemicals by common toxicity pathways is in its infancy. Finally, computational tools are lacking for defining where a specific QSAR is applicable within the domain (universe) of chemical structures that are to be regulated. This paper describes some of the approaches being taken to address these needs. Applications of some of these new approaches are demonstrated for the prediction of chemical mutagenicity, where considerations of both molecular flexibility and metabolic activation improved the QSAR predictability and interpretations. Lastly, the applicability domain for a specific QSAR predicting estrogen receptor binding is presented in the context of a mechanistically-defined chemical structure space for large heterogeneous chemical datasets of regulatory concern. A strategic approach is discussed to selecting chemicals for model improvement and validation until regulatory acceptance criteria for risk assessment applications are met.

Endpoint Determination↗
PubMed2005

Oligonucleotide-mediated gene modification and its promise for animal agriculture.

One of the great aspirations in modern biology is the ability to utilise the expanding knowledge of the genetic basis of phenotypic diversity through the purposeful tailoring of the mammalian genome. A number of technologies are emerging which have the capacity to modify genes in their chromosomal context. Not surprisingly, the major thrust in this area has come from the evaluation of gene therapy applications to correct mutations implicated in human genetic diseases. The recent development of somatic cell nuclear transfer (SCNT) provides access to these technologies for the purposeful modification of livestock animals. The enormous phenotypic variety existent in contemporary livestock animals has in many cases been linked to quantitative trait loci (QTL) and their underlying point mutations, often referred to as single-nucleotide polymorphisms (SNPs). Thus, the ability for the targeted genetic modification of livestock animals constitutes an attractive opportunity for future agricultural applications. In this review, we will summarize attempts and approaches for oligonucleotide-mediated gene modification (OGM) strategies for the site-specific modification of the genome, with an emphasis on chimeric RNA-DNA oligonucleotides (RDOs) and single-stranded oligonucletides (ssODNs). The potential of this approach for the directed genetic improvement of livestock animals is illustrated through examples, outlining the effects of point mutations on important traits, including meat and milk production, reproductive performance, disease resistance and superior models of human diseases. Current technological hurdles and potential strategies that might remove these barriers in the future are discussed.

Animal Diseases↗
PubMed1999

Tech talk on multistate licensure.

Professional nursing associations, unions, state regulatory boards, and even Congress are hotly debating the topic of multistate licensure. This article discusses several hurdles to implementing a multistate licensure model and explains how technology can help to overcome them.

Humans↗
PubMed2003

Cell-mediated cytotoxicity to porcine aortic endothelial cells is not dependent on galactosyl residues when baboon peripheral blood lymphocytes are previously primed with pig xenoantigens.

BACKGROUND: In the pig-to-baboon model, acute vascular rejection remains the main hurdle for successful long-term xenograft survival. The production of galactosyl knockout pigs could solve concomitantly the problem of hyperacute and acute vascular rejection. This work studies in vitro the cell-mediated cytotoxicity of natural killer (NK) and T cells after priming of baboon peripheral blood lymphocytes (PBLs) with pig antigens to evaluate whether cytotoxicity is galactosyl-dependent. MATERIAL AND METHODS: PBLs from naive and primed baboons were used as effectors on primary porcine aortic endothelial cells (PAECs) to assess cytotoxicity. Untreated or galactosidase-digested PAECs were used to evidence the role of galactosyl residues on cell-mediated cytotoxicity. Two rat-anti baboon monoclonal antibodies were tested to inhibit either T+NK cells (LO-CD2b) or NK cells alone (LO-CD94). RESULTS: When using PBLs from naive animals, spontaneous lysis occurred and was inhibited by both LOCD-2b and LO-CD94. In comparison, lysis of PAECs was significantly higher when baboon PBLs were first primed in vivo with pig xenoantigens. In this case, cytotoxicity was completely inhibited by LO-CD2b but only partially by LO-CD94. Reduction of galactosyl residues by galactosidase digestion showed that PAEC lysis almost completely disappeared with naive baboon PBLs but not with primed baboon PBLs, thereby indicating that anti-pig T-cell response is not dependent on galactosyl residues. CONCLUSION: Galactosyl knockout pigs could solve hyperacute rejection and also prevent the activation of NK cells even after xenogeneic priming. T cells will then be the next hurdle for the success of xenografting.

Animals↗
PubMed2007

Structure-based maximal affinity model predicts small-molecule druggability.

Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.

Algorithms↗
PubMed2004

Transcriptional blocks limit adenoviral replication in primary ovarian tumor.

PURPOSE: Despite the success of conditionally replicating adenoviruses in tumor models, clinical success has been limited when they are used as a single modality agent. Overcoming the disparity in efficacy between in vivo animal models and human use is a key hurdle for better conditionally replicating adenovirus therapy in humans. We endeavored to identify biological blocks to adenoviral infection and replication in tumor cells. EXPERIMENTAL DESIGN: We hypothesized that the differences in adenoviral replication between ovarian cancer cell lines and patient tumor samples are the result of a block in viral RNA transcription. To test this hypothesis, established ovarian cancer cell lines and purified patient ovarian cancer cells were infected with wild-type adenovirus. RNA for early adenoviral genes E1A and E1B as well as the late transcripts for fiber and hexon were measured using real-time PCR. RESULTS: Established ovarian cancer cell lines treated with wild-type virus had a lower E1A:E1B ratio than the patient samples. Additionally, the levels of fiber and hexon relative to E1A were also decreased in the patient samples compared with the established cell lines. These findings were consistent with an early- to late-phase block in the adenovirus replication cycle. CONCLUSIONS: These data suggest that the biology of abortive infection in the patient samples may be linked to a defect in the production of early and late viral transcripts. Identification of factors leading to abortive infection will be crucial to understanding the low viral replication in patient samples.

Adenoviridae↗
PubMed2003

Security issues in the electronic transmission of prescriptions.

The UK government has stated within its plan of reform for the National Health Service that a secure system for the Electronic Transfer of Prescriptions will be available by 2004. The objectives of this paper are to highlight the significant barriers faced in securing an ETP system, to provide a critical analysis of the security mechanisms in the models currently being piloted and to suggest an alternative revised model which overcomes the identified deficiencies and security hurdles. To identify the significant security issues relevant to the adoption of ETP, the authors have combined their analysis of present prescription processing practice with their knowledge of computer security. The authors identify and describe how the issues of patient confidentiality, authorization, identity authentication, audit, scalability, availability and reliability are significant barriers to the adoption of ETP, particularly if they effect ease of use. The paper's contribution to the field of ETP is to suggest solutions to each of the identified security issues and to combine the solutions together in a revised and developed model.

Computer Security↗
PubMed2006

Clinical hurdles for the transplantation of cardiomyocytes derived from human embryonic stem cells: role of molecular imaging.

Over the past few years, human embryonic stem cells (hESCs) have gained popularity as a potentially ideal cell candidate for tissue regeneration. In particular, hESCs are capable of cardiac lineage-specific differentiation and confer improvement of cardiac function following transplantation into animal models. Although such data are encouraging, there remain significant hurdles before safe and successful translation of hESC-based treatment into clinical therapy, including the ability to assess cells following transplant. To this end, molecular imaging has proven a reliable methodology for tracking the long-term fate of transplanted cells. Imaging reporter genes that are introduced into the cells before transplantation enable non-invasive and longitudinal studies of cell viability, location and behaviour in vivo. Therefore, molecular imaging is expected to play an increasing role in characterizing the biology and physiology of hESC-derived cardiac cells in living subjects.

Cell Differentiation↗
PubMed2007

Selection and fusion of color models for image feature detection.

The choice of a color model is of great importance for many computer vision algorithms (e.g., feature detection, object recognition, and tracking) as the chosen color model induces the equivalence classes to the actual algorithms. As there are many color models available, the inherent difficulty is how to automatically select a single color model or, alternatively, a weighted subset of color models producing the best result for a particular task. The subsequent hurdle is how to obtain a proper fusion scheme for the algorithms so that the results are combined in an optimal setting. To achieve proper color model selection and fusion of feature detection algorithms, in this paper, we propose a method that exploits nonperfect correlation between color models or feature detection algorithms derived from the principles of diversification. As a consequence, a proper balance is obtained between repeatability and distinctiveness. The result is a weighting scheme which yields maximal feature discrimination. The method is verified experimentally for three different image feature detectors. The experimental results show that the fusion method provides feature detection results having a higher discriminative power than the standard weighting scheme. Further, it is experimentally shown that the color model selection scheme provides a proper balance between color invariance (repeatability) and discriminative power (distinctiveness).

Algorithms↗
PubMed2006

The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy.

Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that overexpressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗