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PubMed2006

Development and application of three-tiered nuclear genetic markers for basal Hexapods using single-stranded conformation polymorphism coupled with targeted DNA sequencing.

BACKGROUND: Molecular genetic approaches have much to offer population biology. Despite recent advances, convenient techniques to develop and screen highly-resolving markers can be limiting for some applications and taxa. We describe an improved PCR-based, cloning-free, nuclear marker development procedure, in which single-stranded conformation polymorphism (SSCP) plays a central role. Sequence-variable alleles at putative nuclear loci are simultaneously identified and isolated from diploid tissues. Based on a multiple allele alignment, locus-specific primers are designed in conserved regions, minimizing 'null' alleles. Using two undescribed endemic Australian Collembola as exemplars, we outline a comprehensive approach to generating and validating suites of codominant, sequence-yielding nuclear loci for previously unstudied invertebrates. RESULTS: Six markers per species were developed without any baseline genetic information. After evaluating the characteristics of each new locus via SSCP pre-screening, population samples were genotyped on the basis of either DNA sequence, restriction site, or insertion/deletion variation, depending on which assay was deemed most appropriate. Polymorphism was generally high (mean of nine alleles per locus), and the markers were capable of resolving population structuring over very fine spatial scales (<100 km). SSCP coupled with targeted DNA sequencing was used to obtain genotypic, genic and genealogical information from six loci (three per species). Phylogeographic analysis identified introns as being most informative. CONCLUSION: The comprehensive approach presented here feasibly overcomes technical hurdles of (i) developing suitably polymorphic nuclear loci for non-model organisms, (ii) physically isolating nuclear allele haplotypes from diploid tissues without cloning, and (iii) genotyping population samples on the basis of nuclear DNA sequence variation.

Animals↗
PubMed2005

Criteria for determining a basic health services package. Recent developments in The Netherlands.

The criterion of medical need figures prominently in the Dutch model for reimbursement decisions as well as in many international models for health care priority setting. Nevertheless the conception of need remains too vague and general to be applied successfully in priority decisions. This contribution explores what is wrong with the proposed definitions of medical need and identifies features in the decision-making process that inhibit implementation and usefulness of this criterion. In contrast to what is commonly assumed, the problem is not so much a failure to understand the nature of the medical need criterion and the value judgments involved. Instead the problem seems to be a mismatch between the information regarding medical need and the way in which these concerns are incorporated into policy models. Criteria--medical need, as well as other criteria such as effectiveness and cost-effectiveness--are usually perceived as "hurdles," and each intervention can pass or fail assessment on the basis of each criterion and therefore be included or excluded from public funding. These models fail to understand that choices are not so much between effective and ineffective treatments, or necessary and unnecessary ones. Rather, choices are often between interventions that are somewhat effective and/or needed. Evaluation of such services requires a holistic approach and not a sequence of fail or pass judgments. To improve applicability of criteria that pertain to medical need we therefore suggest further development of these criteria beyond their original binary meaning and propose meaningful ways in which these criteria can be integrated into policy decisions.

Cost-Benefit Analysis↗
PubMed2022

Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies.

The FDA has predicted that at least 10-20 gene therapy products will be approved by 2025. The surge in the development of such therapies can be attributed to the advent of safe and effective gene delivery vectors such as adeno-associated virus (AAV). The enormous potential of AAV has been demonstrated by its use in over 100 clinical trials and the FDA's approval of two AAV-based gene therapy products. Despite its demonstrated success in some clinical settings, AAV-based gene therapy is still plagued by issues related to host immunity, and recent studies have suggested that AAV vectors may actually integrate into the host cell genome, raising concerns over the potential for genotoxicity. To better understand these issues and develop means to overcome them, preclinical model systems that accurately recapitulate human physiology are needed. The objective of this review is to provide a brief overview of AAV gene therapy and its current hurdles, to discuss how 3D organoids, microphysiological systems, and body-on-a-chip platforms could serve as powerful models that could be adopted in the preclinical stage, and to provide some examples of the successful application of these models to answer critical questions regarding AAV biology and toxicity that could not have been answered using current animal models. Finally, technical considerations while adopting these models to study AAV gene therapy are also discussed.

Animals↗
PubMed2001

How the open-source development model can improve medical software.

The current system of proprietary software development for healthcare applications is inadequate to meet the needs of providers, administrators, and patients. A recent advance in the field of Internet programming is the release of large-scale software projects as "open-source". The advantages of this method of development include higher quality, lower cost, and increased adherence to established standards. There are several hurdles to be overcome before the healthcare field can take full advantage of this development model. The implementation of open-source development of medical software could greatly improve clinical and research software and elevate the academic standards of the field of medical informatics.

Copyright↗
PubMedDate not supplied

Improving the selective neonatal BCG program.

OBJECTIVES: The aim of the work was to develop and implement an improved selective neonatal Bacille-Calmette-Guerin (BCG) vaccine program in which neonates are systematically assessed, and those identified as at "high risk of being exposed to tuberculosis" are given neonatal BCG. DESIGN: Service models used in other parts of the country were assessed and their limitations and difficulties were carefully considered. Possible service models for local use were then considered. A selective neonatal BCG program involving universal neonatal screening was implemented. SAMPLE: A program was implemented offering BCG to high-risk neonates. RESULTS: As has been the case with other health trusts, developing a new neonatal BCG service met with obstacles and hurdles. Means of overcoming some of the difficulties are presented. Preliminary findings regarding the service model, including neonatal BCG uptake rates, were positive. CONCLUSION: A successful neonatal BCG program was implemented.

BCG Vaccine↗
PubMed2000

Viral vector delivery in solid-state vehicles: gene expression in a murine prostate cancer model.

BACKGROUND: Although there are increasingly more clinical trials involving gene therapy, efficient gene transfer remains a major hurdle to success. To enhance the efficiency of delivery of viral vectors in gene therapy protocols, we evaluated the effect of various matrices to act as a vehicle for recombinant virus during intratumoral injection. METHODS: The ability of several vehicles (catgut spacer, polyglycolic acid, chromic catgut, and gelatin sponge matrix) to deliver the canarypox virus ALVAC to the cells of the murine prostate cancer cell line RM-1 was studied in vitro and in vivo. ALVAC recombinants encoding the murine cytokines interleukin 2 (IL-2), interleukin 12 (IL-12), and tumor necrosis factor-alpha (TNF-alpha) were used to assess enhancement of antitumor activity after intratumoral inoculation. Confirmatory experiments were conducted by use of another mouse prostate cancer cell line, RM-11, and a mouse bladder cancer cell line, MB-49. All statistical tests were two-sided. RESULTS: The gelatin sponge matrix proved to be the most effective solid-state vehicle for delivering viral vectors to cells in culture. In addition, this matrix statistically significantly enhanced expression of ALVAC-delivered reporter genes in tumor models when compared with fluid-phase delivery of virus (P =.037 for the RM-1 model and P =.03 for the MB-49 model). Statistically significant growth inhibition of established tumors was observed when a combination of the three recombinant ALVAC viruses expressing IL-2, IL-12, and TNF-alpha was delivered with the matrix in comparison with 1) fluid-phase intratumoral injection of the ALVAC recombinants, 2) no treatment, or 3) treatment with parental ALVAC (all P<.05). CONCLUSIONS: Viral vector delivery in a solid-state vehicle resulted in improved recombinant gene expression in vivo and translated to greater inhibition of tumor growth in an immunotherapy protocol for heterotopic tumor nodules. The efficient delivery of reporter genes described herein may prove useful in many solid tumor gene therapy protocols.

Animals↗
PubMed2006

A comparison of survival models for assessing risk of racehorse fatality.

Survival analysis was used to assess risk factors for fatal injuries on UK race courses. This allowed assessment of variation due to temporal horse-level effects, including previous racing intensity and historical distribution of race types, as well as race-level factors. Comparisons were made between measuring survival time as number of days and as number of races to injury from the first race. Two related models were presented for time as number of races to injury: a Cox regression model fitted using partial likelihood, with the Efron approximation to handling ties, and a discrete-time logit model fitted using maximum likelihood. The latter approach had the advantages of being computationally more efficient and enabling the testing of different functional forms for the dependence of hazard on time. Retrospective data were available from all race starts on the 59 courses in Britain from 1990 to the end of 1999, as analysed by . The analysis was conducted on the data for the 47,424 horses that had started racing in the UK: 538,895 starts with 1,228 fatal injuries. Horses starting racing abroad were excluded, but some included horses would have raced abroad at some stage during their racing career. The results for the selected models were broadly consistent with each other and with previously published studies. Steeplechase and hurdle races had a higher risk of fatal injury than flat races (relative hazards 1.5 and 1.7, respectively). Risk increased with the firmness of surface, age and race distance (reaching a plateau at 20 furlongs) and decreased with previous racing intensity (reaching a plateau after seven races run in the last 12 months). Horses running their first race of a new type were also found to be at higher risk (relative hazard 1.5). The main difference between the models for time as number of days and number of races concerned the role of age: age at race was identified as the more important factor in the latter model, whereas, age at first race was more significant in the former model.

Age Factors↗
PubMed2000

Eukaryotic DNA replication: a model for a fixed double replisome.

To duplicate their genomes, eukaryotic cells have to overcome some formidable chemical and topological hurdles, considering the number of nucleotides that have to be polymerized faithfully and the sheer physical size of the DNA molecules that have to be disentangled and partitioned in an orderly way. This article tackles one particular aspect of the process: the organization of the apparatus that advances the replicative growing forks along the DNA molecule. Here, I suggest a solution to the difficulty of separating the daughter molecules in an orderly way and propose an alternative to the current models, which reconciles the use of a single polarity of synthesis by the DNA polymerases with the need for parallel polymerization of two strands of opposite polarity.

DNA↗
PubMed2004

Development and characterization of five cell models for chemoresistance studies of human ovarian carcinoma.

Platinum agents and paclitaxel (taxol) are among the most effective drugs currently available for treatment of ovarian cancer. One of the hurdles with taxol and platinum- based therapy is the clinical development of resistance to these agents. To investigate the mechanism of drug resistance in human ovarian cancer, we developed and characterized 5 cell models for chemoresistance studies of cisplatin, carboplatin and taxol. We report in this study that these human ovarian carcinoma cell model systems include 2 models for cisplatin resistance, 2 models for carboplatin resistance, and 1 model for taxol resistance. The biological and biochemical characteristics of the models showed that (i), the IC50 values of the drugs for all these resistant cell models were 3 times (or more) higher than those for the parental tumor cells. There also exist varying degrees of cross-resistance to several other chemotherapeutic agents in these systems. Moreover, the intracellular drug accumulations in these cells were significantly reduced as compared to those in the parental cells. (ii), The proliferation rates of these resistant cells were markedly decreased. However, there were no obvious changes in cell cycle distribution in these model systems. (iii), Our results for the expression of a few major drug resistance-related genes revealed that the expression of p53, lrp-1 and mrp-1 was decreased, while the expression of pkc, topo I and topo II beta was increased in the resistant tumor cells as compared with the parental cells. In contrast, no significant alterations in gst-pi and topo II alpha expression were found. Interestingly, the levels of mdr-1 expression were elevated in some models, but were reduced in others, thus suggesting that different pathways are involved in the formation of drug resistance in different cell model systems, and that different mechanisms are responsible for the development of different drug resistances in tumor cells. Taken together, our findings indicate that these models may be potentially used to assess the biochemical and genetic mechanisms of drug resistance in human ovarian cancer and to identify new drug resistance-related genes.

Antineoplastic Agents↗
PubMed2003

Experimental evaluation of an elastic foundation model to predict contact pressures in knee replacements.

Computational wear prediction is an attractive concept for evaluating new total knee replacement designs prior to physical testing and implementation. An important hurdle to such technology is the lack of in vivo contact pressure predictions. To address this issue, this study evaluates a computationally efficient simulation approach that combines the advantages of rigid and deformable body modeling. The hybrid method uses rigid body dynamics to predict body positions and orientations and elastic foundation theory to predict contact pressures between general three-dimensional surfaces. To evaluate the method, we performed static pressure experiments with a commercial knee implant in neutral alignment using flexion angles of 0, 30, 60, and 90 degrees and loads of 750, 1500, 2250, and 3000N. Using manufacturer CAD geometry for the same implant, an elastic foundation model with linear or nonlinear polyethylene material properties was implemented within a commercial multibody dynamics software program. The model's ability to predict experimental peak and average contact pressures simultaneously was evaluated by performing dynamic simulations to find the static configuration. Both the linear and nonlinear material models predicted the average contact pressure data well, while only the linear material model could simultaneously predict the trends in the peak contact pressure data. This novel modeling approach is sufficiently fast and accurate to be used in design sensitivity and optimization studies of knee implant mechanics and ultimately wear.

Compressive Strength↗
PubMed2001

Inhibitory effects of spices and herbs towards Shigella sonnei and S. flexneri.

The use of spices and herbs, their essential oils or their active compounds as means of control of pathogens constitutes an alternative to chemical additives In the present study the antibacterial activities of cloves, thyme, oregano, rosemary and basil on Shigella have been established. Although in a model system in agar media addition of 1% basil could contribute to the 'hurdle' principle and delay outgrowth of Shigella sp. this was not confirmed in real food conditions: the presence of 1% basil did not affect growth of Shigella in potato puree at 22 degrees C or survival at 7 degrees C in spaghetti sauce. Thyme and essential oils and thymol and carvacrol showed inhibition of Shigella sp. in the agar well diffusion method (MIC 0.1-1.0%) and they have potential to be used as a desinfectant in the washing water e.g. in the process line of minimal processed vegetables. However, more studies combining sensoric properties with microbial analysis are needed to investigated the possible use of these compounds.

Colony Count, Microbial↗
PubMed2005

Feedback dynamics and cell function: Why systems biology is called Systems Biology.

A new paradigm, like Systems Biology, should challenge the way research has been conducted previously. This Opinion article aims to present Systems Biology, not as the application of engineering principles to biology but as a merger of systems- and control theory with molecular- and cell biology. In our view, the central dogma of Systems Biology is that it is system dynamics that gives rise to the functioning and function of cells. The concepts of feedback regulation and control of pathways and the coordination of cell function are emphasized as an important area of Systems Biology research. The hurdles and risks for this area are discussed from the perspective of dynamic pathway modelling. Most of all, the aim of this article is to promote mathematical modelling and simulation as a part of molecular- and cell biology. Systems Biology is a success if it is widely accepted that there is nothing more practical than a good theory.

Computational Biology↗
PubMed2006

Agrobacterium-mediated delivery of marker genes to Phanerochaete chrysosporium mycelial pellets: a model transformation system for white-rot fungi.

The lack of an efficient transformation system in filamentous fungi is one of the major problems in carrying out cloning and expression of genes to produce a value-added product at the commercial level. Therefore an attempt has been made to develop an efficient, convenient and expeditious genetic transformation system for successful transfer of transferred DNA, carrying the genes coding for GUS (beta-glucuronidase) (uidA), green fluorescent protein (gfp) and hygromycin phosphotransferase (hpt) to the nuclear genome of Phanerochaete chrysosporium, a widely studied lignin-degrading white-rot fungus. The transformation of the marker gene was confirmed through GUS, PCR and Southern-blot hybridization. Transformation with acetosyringone, in the presence of light with partial bleaching for 1 h, were found to be a better combination for fungal transformation with 48% efficiency. The agro-transformation method to transform the modified mycelial pellets offers a practical means for exploiting transgenic approaches in genetic manipulation and improvement of P. chrysosporium, a model white-rot fungus. Moreover, it has the potential to overcome the technical hurdles in genetic manipulation to bio-technologically exploit many other filamentous fungi of industrial importance.

Gene Targeting↗
PubMedDate not supplied

Focusing technology assessment using medical decision theory.

Combining medical decision theory and epidemiologic information, the authors have developed a strategy to assess diagnostic technologies. For any patient, patient utilities with new diagnostic information are compared with the preferred fallback action absent that diagnostic information. After determination of whether the expected value of diagnostic information (EVDI) justifies its cost, the method adds across the eligible population to determine whether the global EVDI justifies the technology's deployment, employing a screen (Hurdle 1) that assumes that the diagnostic device has perfect accuracy. This preliminary evaluation relies on published data on treatment efficacy, population probabilities of illness, etc., but not on new clinical trials. If the technology is not sufficiently cost-effective, even with this optimistic assumption, the strategy recommends against its use. Otherwise, the next step is Hurdle II, in which the critical clinical studies, identified by the decision-theory model, are undertaken. These commonly include measuring the actual diagnostic accuracy of a device, with which the cost-effectiveness is recalculated. These studies in general do not require randomized controlled trials.

Algorithms↗
PubMed2003

Nuclear transfer: progress and quandaries.

Cloning mammals by nuclear transfer is a powerful technique that is quickly advancing the development of genetically defined animal models. However, the overall efficiency of nuclear transfer is still very low and several hurdles remain before the power of this technique will be fully harnessed. Among these hurdles include an incomplete understanding of biologic processes that control epigenetic reprogramming of the donor genome following nuclear transfer. Incomplete epigenetic reprogramming is considered the major cause of the developmental failure of cloned embryos and is frequently associated with the disregulation of specific genes. At present, little is known about the developmental mechanism of reconstructed embryos. Therefore, screening strategies to design nuclear transfer protocols that will mimic the epigenetic remodeling occurring in normal embryos and identifying molecular parameters that can assess the developmental potential of pre-implantation embryos are becoming increasingly important. A crucial need at present is to understand the molecular events required for efficient reprogramming of donor genomes after nuclear transfer. This knowledge will help to identify the molecular basis of developmental defects seen in cloned embryos and provide methods for circumventing such problems associated with cloning the future application of this technology.

Animals↗
PubMed1997

Early experience of the European Medical Devices Vigilance System.

The new European system for the regulation of medical devices is currently being introduced incrementally, having begun in 1993 with a view to completion around the turn of the century. Although still it its relative infancy there has already been valuable experience gained in relation to certain device types. The system is based upon three EC Directives; the first covering active implantable devices is now fully in force; with the second covering most other devices, currently within a transition phase. The Directives fully recognise the importance of stringent post market surveillance, one key element of which involves the reporting of certain device related incidents to and between the regulatory authorities of Member States (Competent Authorities). The objective behind the reporting requirements, or "Vigilance System", is to protect patients and other users by reducing the chance of the same types of incidents reoccurring in different places across the European Economic Area (EEA). As Competent Authority for the UK, the Medical Devices Agency was one of the first to put the System into effect and continues to play a leading role. In broad terms, Vigilance requires manufacturers to notify Competent Authorities of incidents, known as Vigilance Cases, in which a device led to or might have led to the death or serious injury of patients or users. In addition they must also provide similar notification of device recalls undertaken for a technical or medical reason. For their part, Competent Authorities are required to share certain details of Vigilance Cases between each other, and with the European Commission. While mandatory incident reporting is not a new concept outside Europe, Vigilance is unique in attempting to coordinate this across nineteen different countries with different languages and cultures. Even after four years, there remains some confusion among industry and regulators alike over exactly what is required and how best to achieve it. In particular there is an element of concern among manufacturers over apparent variations in interpretation being demonstrated by different Competent Authorities. Although derived from an inherently sensible and straight forward objective, in practice Vigilance raises a myriad of questions such as when, how and to whom should reports be made, and perhaps most fundamentally, exactly which incidents should be reported. The Directives themselves offer little clarification, and in recognition of this the Commission drew up the EC Guidelines on the Medical Devices Vigilance System. These Guidelines, while not legally binding offer practical and invaluable answers to these and many other important questions. Ongoing improvements to the Guidelines appear to be the best way to try to "level the playing field" across the EEA. Considerable effort continues to be made to fine tune this document with input representing regulatory and industry interests and it is hoped that a second revision may be available next year. Vigilance is gaining popularity as a model for adoption outside the EEA, particularly as it begins to overcome the operational hurdles characteristic of the first "live running" of any new system.

Equipment and Supplies↗
PubMed2004

A prospective cohort study to investigate risk factors for horse falls in UK hurdle and steeplechase racing.

REASONS FOR PERFORMING STUDY: Equine fatalities during racing continue to be a major welfare concern and falls at fences are responsible for a proportion of all equine fatalities recorded on racecourses. OBJECTIVES: To identify and quantify risk factors for horse falls in National Hunt (NH) racing and to report the frequency of falling and falling-associated fatalities. METHODS: A prospective cohort study was conducted on 2879 horse starts in hurdle and steeplechase races on 6 UK racecourses. Any horse that suffered a fall at a steeplechase or hurdle fence during the race was defined as a case. Data were obtained by interview and observations in the parade ring and from commercial databases. Multivariable logistic regression models, allowing for clustering at the level of the track, were used to identify the relationship between variables and the risk of falling. RESULTS: There were 124 falling cases (32 in hurdling and 92 in steeplechasing) identified. The injury risk of fallers was 8.9% and fatality risk 6.5%. Duration of journey to the racecourse, behaviour in the parade ring and weather at the time of the race were associated with falling in both hurdle and steeplechase racing. Age, amount of rainfall and going were also associated with falling in steeplechase racing. CONCLUSIONS: Falls at fences are significant contributors to equine fatalities during NH racing. Potentially modifiable risk factors identified were the condition of track surfaces and journey time to the racecourse. POTENTIAL RELEVANCE: It is hoped that information from this study may be used in future interventions to improve horse and jockey safety in racing. The study has also identified areas requiring further research, such as equine behaviour and its effect on racing performance, and the effect of light conditions on jumping ability.

Accidental Falls↗
PubMed1998

Stereotactic mechanical percutaneous renal access.

Obtaining accurate percutaneous renal access when treating intrarenal disease requires substantial skill. Robotic devices have been used in a variety of surgical applications and have been successful in facilitating percutaneous puncture while improving accuracy. Laboratory models of robotic devices for percutaneous renal access have also been developed. However, several technical hurdles need to be addressed. One relates to the device-patient interface. As a first step in creating a complete robotic system, a mechanical arm (PAKY) with active translational motion for percutaneous renal access has been developed and clinically assessed. The PAKY consists of a passive mechanical arm mounted on the operating table and a radiolucent needle driver that uses a novel active translational mechanism for needle advancement. The system utilizes real-time fluoroscopic images provided by a C-arm to align and monitor active needle placement. In vitro experiments to test needle placement accuracy were conducted using a porcine kidney suspended in agarose gel. Seven copper balls 3 to 12.5 mm diameter were placed in the collecting system as targets, and successful access was confirmed by electrical contact with the ball. The PAKY was then used clinically in nine patients. The number of attempts, target calix location, calix size, and time elapsed were evaluated. In the in vitro study, successful needle-ball contact occurred the first time in all 70 attempts, including 10 attempts at the 3-mm balls. Clinically, percutaneous access to the desired calix was attained on the first attempt in each case. The mean target calix diameter was 14.7 mm (range 7-40 mm). The mean time elapsed while attempting access was 8.2 minutes. No perioperative complications attributable to needle access occurred. Early experience indicates that the PAKY provides a steady needle holder and an effective and safe end-effector for percutaneous renal access. This device may provide the mechanical platform for the development of a complete robotic system capable of creating percutaneous renal access.

Adult↗