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PubMed2002

Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: unexpected reactivity to a protein paralogue.

DNA vaccination against tissue-restricted antigens is a strategy for cancer therapy. Immune tolerance and ignorance of self antigens has been a hurdle for this approach. We have shown that immunization with xenogeneic DNA orthologues elicits tumor immunity. One model that we have developed entails immunization of mice against tyrosinase-related protein-2 (Tyrp2) using cDNA encoding homologous human Tyrp2. A subset of mice immunized with human Tyrp2 developed antibody responses to Tyrp1. Unexpectedly, this was not simply due to cross-reactivity, as mice with anti-Tyrp1 antibodies were not usually the same animals with anti-Tyrp2 antibodies. Although autoimmune vitiligo was frequently observed in mice that had been immunized with Tyrp2, its occurrence was not correlated with the development of antibodies to Tyrp1. This implies that the appearance of anti-Tyrp1 antibodies was not simply a consequence of the destruction of melanocytes by T-cells recognizing Tyrp2. This represents an example of intermolecular determinant recognition, but is not simply due to epitope spreading since antibodies against the antigen targeted by DNA vaccination are not typically detected.

Animals↗
PubMed1994

End-of-life family decision-making from disclosure of HIV through bereavement.

End-of-life decision-making is conceptualized as the foreground against the background of a family, transitional model of illness with the human immunodeficiency virus (HIV). Both foreground and background represent new knowledge and theory development emerging from six research studies over a 7-year period. The research was phenomenological, longitudinal, ethnographic, descriptive survey, narrative, and grounded using the constant comparative method. In all, 100 families were studied in their home settings in the District of Columbia and 29 states across the United States. Throughout the transitional process from disclosure of HIV through bereavement, families engaged in end-of-life decision-making. Their decision-making style was primarily cognitive or primarily emotional or somewhere in between. Families using a cognitive style of decision-making were less disrupted and more able to surmount hurdles and move toward goals. Exemplars from 23 families illustrated family decision-making and components of the transitional, family model.

Adaptation, Psychological↗
PubMed2005

Modulation of angiogenesis with siRNA inhibitors for novel therapeutics.

Cancer and many other serious diseases are characterized by the uncontrolled growth of new blood vessels. Recently, RNA interference (RNAi) has reinvigorated the therapeutic prospects for inhibiting gene expression and promises many advantages over binding inhibitors, including high specificity, which is essential for targeted therapeutics. This article describes the latest developments using small-interfering RNA (siRNA) inhibitors to downregulate various angiogenic and tumor-associated factors, both in cell-culture assays and in animal disease models. The majority of research efforts are currently focused on understanding gene function, as well as proof-of-concept for siRNA-mediated anti-angiogenesis. The prospects for siRNA therapeutics, both advantages and looming hurdles, are evaluated.

Cell Adhesion Molecules↗
PubMed1994

Newer aspects of micronutrients in chronic disease: copper.

Cu ions are pro-oxidants when added to biological material in vitro and excessive levels of Cu in the body, such as in Wilson's Disease (Yarze et al. 1992) promote oxidant-related pathologies. In contrast there is now substantial evidence that an optimum level of Cu is required to maintain antioxidant defence and that Cu deficiency in animals increases oxidant stress. There are abundant mechanistic relationships linking Cu deficiency and processes associated with IHD, some of which do not directly involve oxidant damage. These mechanistic relationships, however, have mostly been demonstrated in animal models and more information is urgently required concerning possible chronic mild Cu deficiencies in human populations. A major hurdle to advances in this area is the lack of indices of Cu status which are sensitive enough to detect marginal Cu deficiency in humans. The question, therefore, of whether or not there is a role for mild Cu deficiency in the onset of chronic disease processes, including IHD, remains unanswered.

Animals↗
PubMed2005

Large-scale extraction of gene regulation for model organisms in an ontological context.

This paper presents an approach using syntactosemantic rules for the extraction of relational information from biomedical abstracts. The results show that by overcoming the hurdle of technical terminology, high precision results can be achieved. From abstracts related to baker's yeast, we manage to extract a regulatory network comprised of 441 pairwise relations from 58,664 abstracts with an accuracy of 83 - 90%. To achieve this, we made use of a resource of gene/protein names considerably larger than those used in most other biology related information extraction approaches. This list of names was included in the lexicon of our retrained partof- speech tagger for use on molecular biology abstracts. For the domain in question an accuracy of 93.6 - 97.7% was attained on Part-of-speech-tags. The method can be easily adapted to other organisms than yeast, allowing us to extract many more biologically relevant relations. The main reason for the comparable precision rates is the ontological model that was built beforehand and served as a guiding force for the manual coding of the syntactosemantic rules.

Abstracting and Indexing↗
PubMed2002

Inhibition of acyl coenzyme A-cholesterol acyltransferase: a possible treatment of atherosclerosis?

Our full understanding of atherosclerosis and our ability to prevent its sequellae are incomplete. As a result, further investigation of novel antiatherosclerotic mechanisms and agents continues. Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibition has been evaluated as a potential mechanism by which the current treatment arsenal may be expanded. ACAT is present in a variety of tissues and is responsible for catalyzing the conversion of free cholesterol to the more readily stored cholesteryl esters. Impressive lipid effects demonstrated in animals have not generally been demonstrated in human clinical trials. Partial ACAT inhibition with specific agents has resulted in lesion regression and decreased progression, whereas complete ACAT inhibition via genetic alterations has led to an exacerbation of cholesterol deposition in tissues in animal models. No ACAT inhibitor has yet been fully evaluated in human clinical trials for its impact on atherosclerotic disease progression. Several hurdles, such as sample size requirements needed to detect effect over background therapy and lack of sensitive surrogate efficacy markers, have served as a deterrent to the development of this class of investigational drug. However, with recent technologic advancements, more sensitive methods of measuring disease progression may be available. Human clinical trials are currently underway, with several agents reported in Phase II clinical trials. Within the next few years, results from these trials may determine whether or not ACAT inhibitors will be added to the list of treatment options for the prevention of atherosclerotic disease progression.

Animals↗
PubMed2005

AAV-mediated gene transfer for treatment of hemophilia.

Adeno-associated viral (AAV) gene transfer of coagulation factor VIII and IX to skeletal muscle and liver of murine and canine models of hemophilia A and B have resulted in sustained systemic expression and, in several studies, in complete cure of the bleeding disorder. These impressive results prompted initiation of two Phase I/II clinical trials to evaluate the safety of AAV-factor IX gene transfer to muscle and liver of patients with severe hemophilia B. Herein, we have reviewed results from studies in animals with hemophilia, early experience with the vector system in the clinic, recent innovative approaches in vector design and delivery, and strategies to circumvent immunological limitations. Taken together, these studies provide much encouragement for the possibility of future clinical success, but also point out hurdles that still have to be overcome.

Animals↗
PubMed2006

An investigation of the Gamma hypothesis: a predictive modelling study of the effect of combined inhibitors (salt, pH and weak acids) on the growth of Aeromonas hydrophila.

The Gamma hypothesis, that multiple inhibitory factors combine independently, is the underlying hypothesis for the quantification of the Hurdle concept used in food manufacture. The literature, however, is confused as to whether interactive effects exist and under which circumstances they occur, if at all. Using the method of time to detection (TTD), the inhibitory effect of pH, salt and specific weak acids (acetic, propionic, sorbic and benzoic) and combinations of these with respect to the growth of Aeromonas hydrophila (ATCC 7966) were analysed. A model based on the relative rate to detection described all combinations analysed as having independent effects on the TTD. No synergistic interactions were found between pH and salt, between pH and individual weak acids or between combinations of weak acids and pH for any of the systems under study. This study supports the validity of the Gamma concept -- that individual environmental effects act independently and should, in turn, facilitate attempts to model the growth of other microorganisms under a variety of conditions.

Acids↗
PubMed1993

Product line management. Formalizing clinical product lines as part of patient focused restructuring.

Patient Focused Care is entirely consistent with clinical Product Line Management. In fact, as with Patient Focused Care and CQI/TQM, these two initiatives are better together than apart. To take advantage of this opportunity, you may have to modify your existing mechanism for Product Line Management. But the added benefits of more successful Product Line Management will make any modifications a temporary distraction. Down goes the perceived hurdle.

Cardiology Service, Hospital↗
PubMed2005

Alternatives to antibiotics: chemical and physical antimicrobial interventions and foodborne pathogen response.

Successful control of foodborne pathogens requires placement of chemical and physical hurdles in the preharvest and postharvest food production sectors. Pathogens may also encounter indigenous antimicrobials in foods including certain botanical compounds that have historically been used for flavor enhancement as well as preservation. Chemical additives have traditionally included organic acids to control microbial contamination in foods and feeds. However, there is some concern that continuous application of certain chemical antimicrobials can lead to a buildup of microbial resistance. This creates problems if foodborne pathogens survive and develop resistance to a variety of environmental stressors encountered in pre- and postharvest animal production. To expand the diversity of potential antimicrobials that have practical application to food animal production requires exploring the interaction between the food matrix and foodborne pathogens. There is potential for isolating antimicrobial compounds that exhibit mechanisms unrelated to conventional antimicrobial compounds. However, understanding the potential for novel antimicrobial compounds in foods and feeds will require the physiological examination of foodborne pathogen response under experimental conditions comparable to the environment where the pathogen is most likely to occur. Research on foodborne Salmonella pathogenesis is extensive and should provide a model for detailed examination of the factors that influence antimicrobial effectiveness. Analysis of pathogen response to antimicrobials could yield clues for optimizing hurdle technologies to more effectively exploit vulnerabilities of Salmonella and other foodborne pathogens when administering antimicrobials during food and feed production.

Animal Feed↗
PubMed2003

The use of health economic information by reimbursement authorities.

The increasing costs of health-care and the need for cost containment have resulted in a 'fourth hurdle' in the establishment of drug approval and reimbursement policies. This hurdle is the demonstration of a drug's cost-effectiveness through the process of economic evaluation. The role of models in the economic evaluation of pharmaceuticals is becoming increasingly accepted with the recent trend towards developing models with greater transparency and clinical relevance. However, health-care decisions do not, and should not, rely solely on the cost-effectiveness of a drug or intervention. Factors such as disease severity, availability of alternative treatment strategies, cost of drugs to patients, compliance with therapy and patients' satisfaction with overall treatment effectiveness should also be considered, and in some cases can be incorporated into economic evaluation. The Arthritis Cost Consequences Evaluation System (ACCES) is provided as an example of the attributes and limitations that should be considered in determining the usefulness of a model for economic evaluations with the purpose of determining reimbursement policy decisions.

Cost-Benefit Analysis↗
PubMed2006

ABO-incompatible allotransplantation as a basis for clinical xenotransplantation.

The 8th Congress of the International Xenotransplantation Association (IXA), held in Goteborg in September, 2005, immediately followed the 2nd International Symposium on ABO-Incompatibility in Transplantation, both congresses organized by Michael Breimer and Lennart Rydberg. The Proceedings of the Symposium on ABO-Incompatibility in Transplantation have been published (Xenotransplantation 2006; 13 (2)). The present paper provides an overview of a workshop held at the 8th Congress of the IXA, and highlights the immunological concepts emerging from ABO-incompatible allotransplants and discusses them in relation to xenotransplantation. Using specified immunomodulatory protocols, ABO-incompatible solid organ allotransplantation has become a clinical reality for a small number of patients over the last two decades. ABO-incompatible adult kidney and infant heart transplants have similar patient and graft survivals as their ABO-compatible counterparts. In contrast, ABO-incompatibility is present in up to 30% of all patients receiving hematopoietic stem cell transplants in the absence of specific immunomodulation, without affecting overall survival. Consequently, ABO-incompatible solid organ transplants and hematopoietic stem cell transplants may serve as in vivo models to elucidate the immunological mechanisms of accommodation and/or tolerance in the clinical setting. Because of similarities in the immunological hurdles that need to be overcome, knowledge obtained from ABO-incompatible allotransplantation might further promote advances in the field of xenotransplantation. The similarities and differences between ABO-incompatible allotransplantation and xenotransplantation are discussed.

ABO Blood-Group System↗
PubMed2005

Risk factors for epistaxis on British racecourses: evidence for locomotory impact-induced trauma contributing to the aetiology of exercise-induced pulmonary haemorrhage.

REASONS FOR PERFORMING STUDY: The proposed biological mechanisms for exercise-induced pulmonary haemorrhage (EIPH) are many and varied. Better knowledge of risk factors should lead to achievable measures to reduce the incidence. OBJECTIVES: To identify risk factors associated with epistaxis following racing in UK Thoroughbreds, to gain possible insights into the pathogenesis of the condition and to investigate the association between epistaxis and race finishing position. METHODS: The association of epistaxis occurring on UK racecourses between 1996 and 1998 with a wide range of race-, horse- and start-level variables was examined in multivariable mixed effect logistic regression analyses. Four multivariable analyses were conducted, one for all race types considered collectively and one each for flat, hurdle and steeplechase race types considered separately. RESULTS: Risk of epistaxis was significantly increased for hurdle and steeplechase race types compared to both flat and National Hunt flat races. In 3 of the 4 final models, there was a significant biological trend for increasing risk of epistaxis with increasing ground hardness ('going') and accumulated years spent racing. However, in flat races epistaxis was such a rare outcome (0.33 cases per 1000 starts) that this subset analysis had insufficient power to measure the detectable effect of 'going' as statistically significant. Horses with epistaxis were significantly more likely to have a poorer finishing position than those without blood at the nostrils. CONCLUSIONS: Findings were consistent with the theory that locomotory impact-induced trauma contributes to exercise-induced epistaxis. Further validation of this hypothesis through application of similar methods to endoscopically visible EIPH and through biomechanical studies is warranted. POTENTIAL RELEVANCE: Knowledge of significant risk factors should allow formulation of practical measures, such as track watering, to reduce the risks of EIPH and epistaxis in racehorses.

Animals↗
PubMed2004

Learning to work together: using the presage, process, product (3P) model to highlight decisions and possibilities.

Collaborative practice is seen as a core aspect of professional practice and, therefore, a focus of professional education. Current interprofessional and quality assurance literature provides enumeration and discussion of a range of competencies required for effective collaborative practice. Case studies of education and training related to collaborative competences rarely discuss the nature of influences on development, delivery and learning. Barriers to development and delivery have been identified for interprofessional education, but we want to move beyond the mental picture of climbing over or moving around fixed hurdles. Learning opportunities are complex dynamic systems, seeking equilibrium. The creative tension of influences provides opportunities for insightful management. This paper uses the systems-form 3P (presage-process-product) model of learning and teaching (Biggs, 1993) to help examine the nature of educational opportunities designed to promote collaborative working. Presage, process and product factors are identified and discussed. We argue that untangling (or at least seeing) the web of influences on learning to work together promotes critical awareness and encourages more informed and timely decisions.

Cooperative Behavior↗
PubMed2005

Finite element analysis in functional morphology.

This article reviews the fundamental principles of the finite element method and the three basic steps (model creation, solution, and validation and interpretation) involved in using it to examine structural mechanics. Validation is a critical step in the analysis, without which researchers cannot evaluate the extent to which the model represents or is relevant to the real biological condition. We discuss the method's considerable potential as a tool to test biomechanical hypotheses, and major hurdles involved in doing so reliably, from the perspective of researchers interested in functional morphology and paleontology. We conclude with a case study to illustrate how researchers deal with many of the factors and assumptions involved in finite element analysis.

Anatomy↗
PubMed2005

The therapeutic potential in targeting CCR5 and CXCR4 receptors in infectious and allergic pulmonary disease.

Targeting chemokines and chemokine receptors in various acute and chronic pulmonary diseases remains a vibrant area of basic and clinical research despite major hurdles including cross-species barriers, toxicity, and redundancy. In this review, we draw upon our basic research with a murine model in which innate and acquired immunity are linked in the development and maintenance of chronic asthma due to Aspergillus fumigatus. Using intact and genetically altered mice, studies have also been undertaken to elucidate safe and effective therapeutic strategies that interrupt the initiation and amplification of inflammatory and immune events that follow the intrapulmonary introduction of Aspergillus into A. fumigatus-sensitized mice. These events include resident immune cell activation, immune and inflammatory cell recruitment to the airways, changes in lung physiology, and profound changes in the architecture of the airway due to the activation of lung resident cells. The expression of 2 major chemokine receptors, namely, CC chemokine receptor (CCR) 5 and CXC chemokine receptor (CXCR) 4, has been identified and their roles in innate and acquired immune events during fungal asthma have been explored. CCR5 and CXCR4 are best known for their roles in human immunodeficiency virus-1 (HIV-1) infection, but both are attractive targets in the context of overt inflammatory and remodeling responses in the lung. This avenue of research is markedly enhanced by the existence of numerous small molecule antagonists that are available to selectively target these receptors.

Adenoviridae↗
PubMed2003

CD8+ T cells, NK cells and IFN-gamma are important for control of tumor with downregulated MHC class I expression by DNA vaccination.

One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-gamma knockout mice revealed that IFN-gamma was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-gamma in generating this antitumor effect.

Animals↗
PubMed1999

DNA vaccines: a ray of hope.

Vaccines represent the most commonly employed immunologic intervention in medicine today. DNA vaccination or genetic immunization is a rapidly developing technology that offers new approaches for the prevention of disease. This method of vaccination provides a stable and long-lived source of the protein vaccine, and it is a simple, robust, and effective means of eliciting both antibody- and cell-mediated immune responses. Furthermore, DNA vaccines have a number of potential advantages such as they can address several diseases in one vaccine, they are cheap and easy to produce and have no special cold storage requirement because they are extremely stable. It has proven to be a generally applicable technology in various preclinical animal models of infectious and noninfectious diseases, and several DNA vaccines have now entered phase I/II, human clinical trials. There are several hurdles that need to be overcome on the road to the use of DNA vaccines widely. These include the technical challenges of improving delivery and/or potency so that low doses of DNA can achieve the efficacy of conventional vaccines.

Antibody Formation↗