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PubMed2006

Characterization of an immuno 'stealth' derivative of the herpes simplex virus thymidine-kinase gene.

The cellular immune response against transgene-encoded neoantigens is a potential hurdle in gene therapy applications where long-term expression of transgenes is desired. Here a new optimized derivative of the herpes simplex virus 1-thymidine-kinase (HSV1-TK) gene is described. The HSV-TK gene is frequently used in experimental studies on gene-directed enzyme prodrug therapy. In the optimized gene, the HSV-TK coding region is fused with the codons for the Gly-Ala repeat of the Epstein-Barr virus nuclear-antigen 1 to prevent proteasomal degradation of the HSV-TK. To measure the protective effect in vitro, a model cytotoxic T lymphocyte epitope derived from the ovalbumin was inserted in the TK. Cells expressing the GAr-modified TK do not present TK-derived peptides in the major histocompatibility complex. Furthermore, conservative nucleotide substitutions were introduced, which prevent splicing, as well as mutations that render the TK-expressing cells more sensitive to ganciclovir (GCV). The GAr HSV-TK fusion protein is fully functional in vitro. This HSV-TK gene may be especially useful in those gene therapy applications where an immune response against the transgene-encoded product would frustrate the treatment.

Antigen Presentation↗

PubMed2000

The shape of life: how much is written in stone?

Considering the enormous diversity of living organisms, representing mostly untapped resources for studying ecological, ontogenetic and phylogenetic patterns and processes, why should evolutionary biologists concern themselves with the remains of animals and plants that died out tens or even hundreds of millions of years ago? The reason is that important new insights into some of the most vexing evolutionary questions are being revealed at the interfaces of palaeontology, developmental biology and molecular biology. Attempts to synthesise information from these disciplines, however, often encounter their greatest hurdles in considerations of the radiation of the Metazoa. Ongoing challenges relate to the origins of body plans, the relationships of the metazoan phyla and the timing of major evolutionary radiations. Palaeontology not only has its own unique contributions to the study of evolutionary processes, but provides a lynchpin for many of the emerging techniques.

Animals↗

PubMed2005

Predicting drug-hERG channel interactions that cause acquired long QT syndrome.

Avoiding drug-induced cardiac arrhythmia is recognized as a major hurdle in the successful development of new drugs. The most common problem is acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K(+) channels, delay cardiac repolarization and increase the risk of torsades de pointes arrhythmia (TdP). Not all hERG channel blockers induce TdP because they can also modulate other channels that counteract the hERG channel-mediated effect. However, hERG channel blockade is an important indicator of potential pro-arrhythmic liability. The molecular determinants of hERG channel blockade have been defined using a site-directed mutagenesis approach. Combined with pharmacophore models, knowledge of the drug-binding site of hERG channels will facilitate in silico design efforts to discover drugs that are devoid of this rare, but potentially lethal, side-effect.

Animals↗

PubMed2000

American Association for Cancer Research: dendritic cells: strategies and vaccines. April 1-5, 2000, San Francisco, CA, USA.

Several major sessions on dendritic cells (DCs) reflected the importance of these members of the immune system within cancer research. Technical hurdles to their routine propagation were largely overcome within the past decade, so the study of precursors, as well as the numerous types of dendritic cells, is the focus of intense research. In vitro studies were presented that described further refinements in dendritic cells are collected and culture. Cytokines and other growth factors have been analysed to assess their contribution to the ability of dendritic cells to intake, process and present antigen. In some instances, the dendritic cells themselves are genetically altered to improve their natural biological activity. Many studies have advanced from in vitro work and demonstrated utility in various animal models. Ultimately, there is the hopeful, steady progress into the increasing numbers of experimental immunotherapies against human cancer.

Cancer Vaccines↗

PubMed2005

Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy.

Motor recovery after proximal nerve injury remains extremely poor, despite advances in surgical care. Several neurobiological hurdles are implicated, the most fundamental being extensive cell death within the motorneuron pool. N-acetyl-cysteine almost completely protects sensory neurons after peripheral axotomy, hence its efficacy in protecting motorneurons after ventral root avulsion/rhizotomy was investigated. In adult rats, the motorneurons supplying medial gastrocnemius were unilaterally pre-labelled with retrograde tracer (true-blue/fluoro-gold), prior to L5 and 6 ventral root avulsion, or rhizotomy. Groups received either intraperitoneal N-acetyl-cysteine (ip, 150 or 750 mg/kg/day), immediate or delayed intrathecal N-acetyl-cysteine treatment (it, 2.4 mg/day), or saline; untreated animals served as controls. Either 4 (avulsion model) or 8 (rhizotomy model) weeks later, the pre-labelled motorneurons' mean soma area and survival were quantified. Untreated controls possessed markedly fewer motorneurons than normal due to cell death (avulsion 53% death; rhizotomy 26% death, P<0.01 vs. normal). Motorneurons were significantly protected by N-acetyl-cysteine after avulsion (ip 150 mg/kg/day 40% death; it 30% death, P<0.01 vs. no treatment), but particularly after rhizotomy (ip 150 mg/kg/day 17% death; ip 750 mg/kg/day 7% death; it 5% death, P<0.05 vs. no treatment). Delaying intrathecal treatment for 1 week after avulsion did not impair neuroprotection, but a 2-week delay was deleterious (42% death, P<0.05 vs. 1-week delay, 32% death). Treatment prevented the decrease in soma area usually found after both types of injury. N-acetyl-cysteine has considerable clinical potential for adjuvant treatment of major proximal nerve injuries, including brachial plexus injury, in order that motorneurons may survive until surgical repair facilitates regeneration.

Acetylcysteine↗

PubMed2003

Particle-based vaccines for HIV-1 infection.

The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in pre-clinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.

AIDS Vaccines↗

PubMed2005

[New era of cardiac stem cell therapy in heart failure].

Despite of plethora of reports on stem cell transplantation leading to neovascularization in infarct models, whether sustaining clinical benefit in post-myocardial infarction patients is manifested by myocyte repair remains unclear. Cardiac muscle regeneration in adult heart is thought to occur through the mobilization and differentiation of mesenchymal stem cells in bone marrow origin, however, recent studies have suggested that substantial cardiac stem cells may exist in the heart itself, repopulating the damaged cardiac muscle during injury or aging processes. The implications of cardiac stem cells-based myocyte plasticity have recently begun to define in human heart, neither arisen from bone marrow nor circulating precursors. Introduction of cardiac stem cells may improve myocardial function, but several hurdles exist and should be coaxed far beyond the clinical application of cardiac regenerative therapies. On-going investigations may lead to the discovery of mediators of cardiac stem cells migration, proliferation and differentiation that, in turn, might result in the mending of the broken heart after injury.

Cell Fusion↗

PubMed1998

Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies.

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.

Brain-Derived Neurotrophic Factor↗

PubMed1998

Primary cares. Messages from the frontline.

The biggest hurdle in the establishment of primary care groups is practices' reluctance to co-operate. GPs will want compensation for the time spent on administration. There is little awareness of the fact that PCG budgets may run out. The development of PCGs is expected to lead to an increase in salaried GPs. Current IT systems are seen as inadequate for PCGs.

Budgets↗

PubMed2025

Redundant and Singular Regulatory Elements Underlie the Rapidly Evolving Pigmentation of Drosophila.

A major hurdle in understanding the molecular changes responsible for metazoan diversity is the characterization of cis-regulatory elements (CREs) for gene regulatory networks (GRNs). CRE changes are suspected to be commonplace in trait evolution, since such changes circumvent the deleterious effects of pleiotropy. A growing list of genes, though, is known to be regulated by redundant CREs. Such redundant CRE architectures complicate the characterization of GRN evolution, as they compound the effort to characterize each locus, and raise the questions of how and whether genes with redundant architectures evolve expression. Here, we used the evolution of sexually dimorphic abdomen pigmentation of Drosophila (D.) melanogaster as a model to study the function and evolution of CREs. Numerous sequences were evaluated that were previously predicted as potential abdomen CREs. Most of these predictions were validated, including two, four, and ten that, respectively, reside in the homothorax, grainy head, and Eip74EF transcription factor loci. The homothorax CREs were found to be partially redundant for this gene's pigmentation function, and pupal-stage Homothorax expression and the CRE activities were conserved among Drosophila species with the derived dimorphic and ancestral monomorphic phenotypes. Similarly, the Eip74EF CREs were conserved in the monomorphic D. willistoni. Thus, this gene's extensive CRE spatiotemporal redundancy has been conserved for over 30 million years, predating the dimorphic trait. Pigmentation evolution has been connected elsewhere to changes in nonredundant CREs. When these traits evolve, GRN changes may be biased towards the genes with singular nonredundant CREs, while the expression of redundantly regulated genes remains conserved.

Animals↗

PubMed1996

Predictors of non-urgent utilization of hospital emergency services in Kuwait.

Utilization of the emergency rooms (ERs) in Kuwait has increased considerably during the last decade. Such an increase is a concern for health planners because of the burden on ER services, lack of continuous service provided by the ER and the higher cost of such services. Based on a study of 2011 patients attending the medical ERs in the six government hospitals in early 1993, the predictors of non-urgent utilization were analyzed. Patients were asked about their reasons for visiting the ER rather than the primary health care (PHC) centre. Both patients and doctors were asked to rate the urgency of the visit. According to the doctors' judgement, 61% of the visits were for non-urgent problems that did not require emergency care, while 23% of the patients viewed their visits to be non-urgent. Multiple logistic regression analysis indicated that perceived urgency of the visit was the most important predictor of a non-urgent visit to the ER, after controlling for several predisposing and enabling factors. Patients who perceived their visit to the ER to be non-urgent were about four times more likely to visit the ER for a non-urgent condition as judged by the doctor. The level of education had a significant, positive effect on non-urgent utilization among both Kuwaiti nationals and expatriates. Several factors may explain the above finding. Employment of educated persons in the hospital was one route through which education facilitated ER use. It is also likely that educated persons had more influential contacts or wasta in the hospital. Also, the less educated might have delayed seeking care while the educated consulted for non-urgent reasons as soon as they noticed the symptoms. Like education, the level of non-urgent utilization was higher among Kuwaiti nationals with higher incomes. Thus, a higher social class seems to facilitate ER use for non-urgent reasons. Among the non-Kuwaitis, lack of registration at the PHC centre was a significant reason for non-urgent use of the ER. It is recommended that hurdles in the utilization of PHC facilities should be removed. Registration of non-Kuwaitis at the PHC must be improved, and referrals to the PHC back from the ER should be instituted to ensure the necessary follow-up care.

Adult↗

PubMed1998

Flat, hurdle and steeple racing: risk factors for musculoskeletal injury.

A retrospective case-control study was conducted to identify and quantify risk factors for serious musculoskeletal injury sustained at 4 Australian metropolitan racetracks. During the period of study (August 1988-July 1995) there were 196 cases from flat racing, 52 cases from hurdle racing and 53 cases from steeplechases. The incidences of fatal musculoskeletal injuries per start for flat, hurdle and steeple races were 0.06, 0.63 and 1.43% respectively. Logistic regression identified harder track surfaces, horses being older than age 3 years, one racecourse (Flemington) and jumping races as significant risk factors which increased the risk of musculoskeletal breakdown. The incidence of fatal musculoskeletal injuries for flat races at the 4 study tracks was similar to that reported in the UK but less than the USA. Death rates for hurdle and steeple races in the study population were higher than in the UK. Strategies to reduce the incidence of serious musculoskeletal injuries may include avoidance of excessively hard track surfaces through closer regulation of track moisture content; implementation of more rigorous prerace lameness examinations of horses, particularly older horses; and altering the design and number of jumps in hurdle and steeple races. The quantification of risk, as we have reported here, is the first step towards addressing the causes of musculoskeletal breakdown and should help in applying a reasoned approach to intervention measures that may be effective in reducing racing injuries.

Analysis of Variance↗

PubMed2025

Foundations of Artificial Intelligence in Hepatology: What a Clinician Needs to Know.

This review focuses on foundational knowledge about artificial intelligence (AI) in hepatology, exploring how AI, including machine learning and deep learning, leverages large-scale clinical data to transform the diagnosis, risk assessment, prognostication, and management of liver diseases. Online resources are described to offer fundamental AI knowledge and essential technical skills and to facilitate clinician participation across the entire AI lifecycle, ensuring they contribute not only as end users but also in development and deployment. Unlike traditional statistical approaches that prioritize interpretable parameters and clinical insight, AI focuses on maximizing predictive accuracy by identifying complex, often non-linear patterns using high-dimensional data, albeit often at the cost of model interpretability. AI is demonstrating clinical utility in liver histopathology and radiological imaging, significantly improving detection accuracy for cirrhosis, clinically significant portal hypertension, and hepatocellular carcinoma. Beyond diagnostics, AI-driven prediction models are emerging to provide personalized risk stratification for the development of liver-related complications and treatment guidance, based on complex data including longitudinal laboratory results, comorbidities, and co-medication use to monitor disease progression and therapy response. The field is rapidly expanding into novel areas such as analyzing patient-reported outcomes, genomic data, and real-time liver function monitoring, offering deeper mechanistic insights alongside clinical tools. Despite the potential to revolutionize hepatology practice and research, successful integration into routine care faces challenges. These include seamless workflow integration with existing electronic health records, establishing clear liability frameworks, and guaranteeing protection of patient privacy. Addressing these hurdles requires collaborative efforts from clinicians, researchers, and regulators to develop best practices and governance. Understanding the transformative capabilities, current applications, emerging frontiers, and essential implementation considerations is crucial for clinicians navigating the evolving AI landscape and responsibly utilizing its power for improved patient outcomes.

PROBAST+AI↗

PubMed1998

Models for early chemoprevention trials in breast cancer.

Several models are being explored for use in the phase I and phase II evaluation of breast cancer chemoprevention agents. The short-term DCIS/small invasive cancer model is probably best used in late phase I trials in conjunction with agents likely to have activity in the progression phase of neoplastic development in addition to activity in earlier phases. The core biopsy or FNA hyperplasia models may be best used with drugs that are likely to have activity primarily in the promotion phase of neoplastic development and that are suitable for longer duration trials lasting several months to years. Morphology currently is the key surrogate endpoint biomarker for assessing efficacy in phase II trials. Other biomarkers that may undergo modulation will have to be validated, in that modulation will have to be shown to be directly related to decreased cancer risk in subsequent phase III trials. Only then can they be considered as validated surrogate endpoint biomarkers and used as stand-alone efficacy markers in phase II trials. Despite accrual challenges and technologic hurdles, interest in phase I and phase II chemoprevention trials is high.

Breast Neoplasms↗

PubMed1983

Management education and training of nurses: research study.

The model of more pro-active management with a more analytical and deliberative approach has considerable implications for the roles of all managers within the National Health Service today. Nurse managers, in particular, will now be faced with developing different managerial roles than they have had in the years since the 1974 reorganization. Nurse management courses in the past were more concerned with the overt training of behavioural skills and less concerned with the quantitative and analytical aspects of management. This paper investigates in what areas nurse managers perceived their training to have been deficient and argues for a continuous process of education, as opposed to the existing intermittent 'hurdle process' which, in the main, is the basis of nurse management development at the present time.

Administrative Personnel↗

PubMed1995

Decategorizing health services: interim findings from the Robert Wood Johnson Foundation's Child Health Initiative.

Although results from the evaluation are preliminary thus far, certain tentative conclusions can be reached. First, both care coordination on a small scale and the production of community health report cards are achievable within the relatively short life of a foundation grant. Moreover, both efforts can result in tangible improvements for children and their families. Report cards associated with the initiative have made children's issues more prominent and appear to have led many community leaders to focus greater attention on children's needs. Likewise, many of the care coordination systems developed under the initiative have produced real change for children and their families by guiding them to needed health care and other services. It is important, however, to keep these accomplishments in perspective. While of significant benefit to demonstration communities, the monitoring and care coordination components of this initiative are not unique. A large number of communities have adopted monitoring and reporting programs in recent years. Similarly, care coordination efforts are well established in many communities. What is unique about the RWJF initiative is its attempt at decategorization, and much less progress has been demonstrated for this component. The less-than-hoped-for progress in implementing decategorization at the original sites appears to be the product of a number of interrelated factors. These include an absence of existing models and appropriate technical assistance; political difficulties in gaining cooperation from multiple local agencies involved in service provision; limited progress in establishing needed connections with the state and federal agencies that have authority over categorical programs; and difficulties in implementing major programatic changes when the health care system itself is undergoing rapid change. In combination, these barriers have proven to be largely insurmountable for the originally funded sites, although it is too early in the project to determine which of these factors is predominantly responsible for the lack of success. Whether the newer sites can learn from the experience of the first group and adapt strategies to overcome the multiple hurdles involved remains to be seen. Decategorization is a tool that has the potential to rationalize a fragmented service system by facilitating the coordination of services, especially for children and families with multiple needs. The need for decategorization of funds will not disappear, even if the federal government chooses to combine more of its grant programs to the states into block grants.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗

PubMed1992

Helping chronic psychiatric patients adjust to sociopolitical changes in Poland.

According to the stress-diathesis model, persons with serious mental disorders, such as schizophrenia, have cognitive and psychophysiological vulnerabilities that under conditions of stress, lead to psychotic symptoms and diminished interpersonal functioning (Nuechterlein and Dawson 1984; Zubin and Spring 1977). Pharmacological and psychosocial treatments provide buffers to disease vulnerabilities by compensating for neurotransmitter abnormalities, directly reducing the experience of stress, teaching a range of social and instrumental skills that help patients cope with life problems, and dispersing patients' stress through a well-functioning support network (Liberman et al. 1984). To conduct psychosocial treatments well, clinicians must have knowledge regarding the community stressors that impact upon the patient, the range of skills necessary to navigate the hurdles of everyday life (Goldfried and D'Zurilla 1969), and the interpersonal factors that facilitate formation and maintenance of support systems (Tolsdorf 1976). Clinicians can develop individual rehabilitation plans that reflect patients' strengths and weaknesses in each of these areas.

Adult↗

PubMed2001

Blood pumps: technologies and markets in transformation.

The heart failure industry or sector of blood pump technologies comprised of scientists, medicine, and business has inadequate attention from the financial community due to the perception of unmet market potential and regulatory hurdles. There are more than 20 mechanical circulatory support technologies currently in some stage of development. The application is defined initially for emerging technologies as bridge-to-transplant whereas more mature devices have focused on bridge-to-recovery and alternative-to-transplant. Regulatory hurdles and financing resources have dictated this initial application strategy. Whether a technology has valves, bearings, is magnetically suspended, acts as a pressure cuff, and so on, the future will belong in large part to those technologies that are less expensive, have improved ergonomics, are simpler in surgical application, and can demonstrate efficacy levels that are an improvement over today's approved devices. Today's devices have provided a valuable platform for the emerging technologies. However, there has been little market expansion over these past years, relative to the potential market. The cardiologist is the patient's gatekeeper, and drugs appear to be the therapy of choice as options are considered. Technologies without a business model will have a difficult time attracting much needed funding, the result being protracted development times or project termination. MicroMed has modified its ventricular assist device (VAD) focus, with a broader look at treating the heart failure patient. MicroMed recently entered into an agreement with Chrysalis Biotechnology, Inc., Galveston, TX, covering a synthetic peptide technology (Chrysalin) that when injected into tissue has demonstrated an angiogenic effect without the concerns inherent in recombinant angiogenic/growth factors. We believe a combination therapy of the DeBakey VAD-synthetic peptide could provide sufficient revascularization for bridge-to-recovery or as an alternative-to-transplant in certain patients.

Angiogenesis Inducing Agents↗