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PubMed2001

Influence of rotational energy barriers to the conformational search of protein loops in molecular dynamics and ranking the conformations.

An adjustable-barrier dihedral angle potential was added as an extension to a novel, previously presented soft-core potential to study its contribution to the efficacy of the search of the conformational space in molecular dynamics. As opposed to the conventional soft-core potential functions, the leading principle in the design of the new soft-core potential, as well as of its extension, the soft-core and adjustable-barrier dihedral angle (SCADA) potential (referred as the SCADA potential), was to maintain the main equilibrium properties of the original force field. This qualifies the methods for a variety of a priori modeling problems without need for additional restraints typically required with the conventional soft-core potentials. In the present study, the different potential energy functions are applied to the problem of predicting loop conformations in proteins. Comparison of the performance of the soft-core and SCADA potential showed that the main hurdles for the efficient sampling of the conformational space of (loops in) proteins are related to the high-energy barriers caused by the Lennard-Jones and Coulombic energy terms, and not to the rotational barriers, although the conformational search can be further enhanced by lowering the rotational barriers of the dihedral angles. Finally, different evaluation methods were studied and a few promising criteria found to distinguish the near-native loop conformations from the wrong ones.

Computational Biology↗
PubMed1994

Faculty--agents of change.

In medical schools and residencies, the faculty in all settings and through all facets of the curriculum influence learners' skills, attitudes, and behaviors. Mentorship and role modeling are powerful forces in shaping a professional. To positively affect the number of students seeking to enter the generalist specialties, the faculty community will need reevaluation, expansion, and professional development. This paper discusses some of the hurdles for institutional leaders and offers pragmatic suggestions for beginning the process of retooling the faculty. A matrix is presented to describe the multifaceted faculty required for educating the generalist.

Adult↗
PubMed2000

Gene therapy in transplantation in the year 2000: moving towards clinical applications?

Transplantation faces several major obstacles that could be overcome by expression of immunomodulatory proteins through application of gene therapy techniques. Gene therapy strategies to prolong graft survival involve gene transfer of immunosuppressive or graft-protecting molecules. Very promising results have been obtained in small animal experimental models with inhibitors of co-stimulatory signals on T cells, immunosuppressive cytokines, donor major histocompatibility antigens and regulators of cell apoptosis or oxidative stress. The application of gene therapy techniques to transplantation offers a great experimental and therapeutic potential. Local production of immunosuppressive molecules may increase their therapeutic efficiency and reduce their systemic effects. When compared with other clinical situations, gene therapy in transplantation offers several potential advantages. Gene transfer into the graft can be performed ex vivo, during the transit between the donor and the recipient, thus avoiding many of the hurdles encountered with in vivo gene transfer. Furthermore, the difficulties associated with immune responses to the gene transfer vectors and transient gene expression may be easier to overcome when gene therapy protocols are applied to transplantation than when applied to other clinical situations. The next century should witness a rapid increase in the application of gene therapy techniques to large animal pre-clinical models of transplantation and later to clinical trials. Gene Therapy (2000) 7, 14-19.

Apoptosis↗
PubMed1998

Viral vectors, tools for gene transfer in the nervous system.

Viral vectors are becoming increasingly important tools to investigate the function of neural proteins and to explore the feasibility of gene therapy to treat diseases of the nervous system. This gene transfer technology is based on the use of a virus as a gene delivery vehicle. In contrast to functional analysis of gene products in transgenic mouse, viral vectors can be applied to transfer genes to somatic, post-mitotic cells of fully developed animals. To date, five viral vector systems are available for gene transfer in the nervous system. These include recombinant and defective herpes viral vectors, adenoviral vectors, adeno-associated viral vectors and lentiviral vectors. Of these vectors herpes and adenoviral vectors are the most common in use. To date, one of the main hurdles in applying these two vector systems is the focal immune response that occurs following intraparenchymal infusion. Despite this limitation, herpes and adenoviral vectors have been used successfully to modify the physiological response to injury in several rodent models of neurodegeneration. The first purpose of this review is to describe the principles of the generation of viral vectors and to discuss the advantages and disadvantages of the viral vector systems currently in use for gene transfer in the nervous system. Secondly, we give an overview of the performance of these vectors following direct infusion in the nervous system and review the results obtained with these vectors in animal models of neurodegeneration and regeneration. The results of these initial studies have provided a framework for future experiments based on gene transfer strategies with viral vectors to study normal physiology and pathology of the nervous system.

Adenoviridae↗
PubMed2006

Defining and maintaining a high quality screening collection: the GSK experience.

Understanding the quality of a screening collection is the first step to improving it and, as a result, the quality of the screening process. This article outlines how this issue was approached at GlaxoSmithKline and some of the hurdles that needed to be overcome to achieve success. The article focuses specifically on the necessary software and hardware infrastructure needed, and at some of the extra benefits of such a project in terms of data mining and data modelling.

Chromatography, High Pressure Liquid↗
PubMed2004

Trans-splicing adeno-associated viral vector-mediated gene therapy is limited by the accumulation of spliced mRNA but not by dual vector coinfection efficiency.

Therapeutic application of recombinant adeno-associated virus (AAV) has been limited by its small carrying capacity. To overcome this limitation trans-splicing vectors were developed recently. However, the transduction efficiency of trans-splicing vectors is considerably lower than that of a single intact vector in skeletal muscle. To improve trans-splicing vectors for skeletal muscle gene therapy, we examined whether coinfection efficiency is a rate-limiting factor in the mdx mouse, a model for Duchenne muscular dystrophy. Two different AAV viruses were delivered to the mdx muscle. Similar to previous reports in normal muscle, coinfection efficiency reached approximately 90% in the diseased muscle. This result suggests that coinfection is not a hurdle in dystrophic muscle. Another critical step in the trans-splicing method is the transcription and splicing across the inverted terminal repeat (ITR) junction in the reconstituted genome. To test whether this represented a significant obstacle, we systematically evaluated the transcription, pre-mRNA stability and splicing, and translation in a synthetic lacZ construct that mimicked the reconstituted genome. Although inserting an intron in the lacZ gene had no effect on its expression, inclusion of the ITR junction in the intron reduced expression by 50%. In construct containing the ITR junction, the mRNA transcript level was significantly reduced. This mRNA level reduction was associated with decreased pre-mRNA stability. These data suggest that the accumulation of mRNA is a rate-limiting factor in trans-splicing vector-mediated gene therapy.

Animals↗
PubMedDate not supplied

Prototype antiepileptic drug clinical development plan.

Antiepileptic drug (AED) development has been generally difficult owing to many factors: regulatory requirements for demonstration of efficacy and safety, subject availability, traditional trial designs, and physicians' beliefs about epilepsy and its treatment. The U.S. Food and Drug Administration (FDA) regulations require a new drug to be shown safe and effective for its intended use before it can be marketed. The unambiguous proof required is a formidable hurdle for AED development. We report a recent clinical development plan highlighting innovations in clinical trial design that have addressed these requirements, discuss alternative endpoints, and compare the results of various trial designs at various stages of development. This model clinical development plan includes trials relevant to all three clinically relevant contexts in which an AED might be used: as an adjunct to an existing regimen, as a substitution for much of an existing AED regimen, and as monotherapy.

Anticonvulsants↗
PubMed2006

Current science of regenerative medicine with stem cells.

Regenerative medicine with stem cells holds great hope for the treatment of degenerative disease. The medical potential of embryonic stem cells remains relatively untapped at this point, and significant scientific hurdles remain to be overcome before these cells might be considered safe and effective for uses in patients. Meanwhile, adult stem cells have begun to show significant capabilities of their own in repair of damaged tissues, in both animal models and early patient trials.

Animals↗
PubMed2006

Dose and outcome: the hurdle of neutropenia (Review).

The development of chemotherapy in the early 1970s resulted in the availability of curative therapeutic strategies for hematological malignancies and several types of solid tumors. It is evident that drugs should be used at their optimal dose and schedule, and drug combinations should be given at consistent intervals. According to the mathematical models that suggested the direct dose-response relationship in the improvement of outcomes in cancer chemotherapy, the dose intensity and, more recently, the dose-dense approach was considered one of the most important tools in conventional chemotherapy. Anticancer drugs are often associated with myelotoxicity, and reducing the dose or increasing the time interval between each cycle of treatment is a frequent empiric approach. Unfortunately, a dose reduction of >or=20% causes a loss of 50% in the cure rate, particularly in chemosensitive tumors. To accelerate bone marrow recovery and prevent the onset of severe myelosuppression and its complications, the standard use of granulocyte colony-stimulating factors (G-CSF), such as filgrastim and the long-acting pegfilgrastim, is recommended. The aim of this review is to analyze how dose intensification concepts and dose-dense regimens are able to increase the cure rate of chemosensitive solid tumors and lymphomas.

Antineoplastic Agents↗
PubMed2000

Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer.

Replication-selective oncolytic adenoviruses represent a novel cancer treatment platform. Clinical studies have demonstrated the safety and feasibility of the approach, including the delivery of adenovirus to tumors through the bloodstream (Heise et al., 1999b; Reid et al., 1999; Nemunaitis et al., 1999). The inherent ability of replication-competent adenoviruses to sensitize tumor cells to chemotherapy was a novel discovery that has led to chemosensitization strategies. These data will support the further development of adenoviral agents, including second-generation constructs containing exogenous therapeuitc genes to enhance both local and systemic antitumoral activity (Heise and Kirn, 2000; Hermiston, 2000; Agha-Mohammadi and Lotze, 2000). In addition to adenovirus, other viral species are being developed including herpesvirus, vaccinia, reovirus and measles virus (Kirn, 2000a; Martuza, 2000; Norman and Lee, 2000; Mastrangelo et al., 2000; Coffey et al., 1998; Martuza et al., 1991; Kirn, 2000b; Lattime et al., 1996). Since intratumoral spread also appears to be a substantial hurdle for viral agents, inherently motile agents such as bacteria may hold great promise for this field (Low et al., 1999; Sznol et al., 2000). Given the unknown predictive value of in vitro cell-based assays and murine tumor model systems for the efficacy and therapeutic index of replication-selective oncolytic adenoviruses in patients, we believe that encouraging adenoviral agents must be tested in well-designed clinical trials as soon as possible. Only then can the true therapeutic potential of these agents be realized.

Adenovirus E1A Proteins↗
PubMed1999

Effect of thermal injury with Pseudomonas aeruginosa infection on pulmonary and systemic bacterial clearance.

BACKGROUND: Despite improvements in burn wound care, infections, particularly pneumonia, remain a major hurdle to recovery from thermal injury. After burns, a variety of systemic immune and inflammatory changes contribute to the risk of infection. Clinically, infection coupled with burn injury seems to adversely affect susceptibility to subsequent infection. METHODS: Using a mouse model of 10% total body surface area, full-thickness, third-degree burns with quantitative bacterial cultures of multiple tissues, the effect of graded intratracheal and intraperitoneal infections with Pseudomonas aeruginosa on the development of infection was assessed. RESULTS: P. aeruginosa infection of blood and lung were demonstrated in burned mice 4 hours after they received 1 to 7.2x10(5) P. aeruginosa intratracheally but not in unburned control mice. Disseminated infection from endogenous bacterial species (Proteus, Enterococcus, Streptococcus) involving the lungs, liver, blood, and subeschar space was observed in mice that received both burns and infection with P. aeruginosa (intraperitoneally and intratracheally) but not with infection or burn alone (p<0.01). After burns, pulmonary bacterial clearance was delayed in association with both pulmonary infection (7.2x10(5) P. aeruginosa intratracheally) and intraperitoneal infection (10(7) P. aeruginosa intraperitoneally). Histologically, diffuse pneumonitis was observed in mice that received burns and infection but not in mice with either infection or burns alone. CONCLUSION: Small thermal injuries coupled with transient infection of the lungs or peritoneum delay the clearance of bacteria from the lungs and contribute to infection of the lungs, liver, burn site, and blood by endogenous organisms. These studies support the synergy of relatively small thermal injuries with infectious exposures in the pathogenesis of pneumonia and systemic infections after burns.

Animals↗
PubMed2002

The protein folding problem: a biophysical enigma.

Protein folding, the problem of how an amino acid sequence folds into a unique three-dimensional shape, has been a long-standing problem in biology. The success of genome-wide sequencing efforts has increased the interest in understanding the protein folding enigma, because realizing the value of the genomic sequences rests on the accuracy with which the encoded gene products are understood. Although a complete understanding of the kinetics and thermodynamics of protein folding has remained elusive, there has been considerable progress in techniques to predict protein structure from amino acid sequences. The prediction techniques fall into three general classes: comparative modeling, threading and ab initio folding. The current state of research in each of these three areas is reviewed here in detail. Efforts to apply each method to proteome-wide analysis are reviewed, and some of the key technical hurdles that remain are presented. Protein folding technologies, while not yet providing a full understanding of the protein folding process, have clearly progressed to the point of being useful in enabling structure-based annotation of genomic sequences.

Animals↗
PubMed1998

Vector development: a major obstacle in human gene therapy.

Gene therapy has been proposed for a wide variety of human conditions including monogenic disorders, such as the haemoglobinopathies and immunodeficiency syndromes, cancer and many other diseases. Prerequisites for the success of this approach include the ability to deliver the therapeutic gene intact to the target cell, persistent levels of transgene expression sufficient to correct the disease phenotype, lack of unwanted side-effects associated with vector exposure or gene transfer and relative simplicity allowing the widespread use of this methodology. Although substantial progress has been made in animal models since the inception of genetic therapy in the early 1980s, significant obstacles remain for human therapy, most notably in the area of vector development. The first generation of gene therapy vectors has failed to overcome many of the biological hurdles cited above necessitating the development of alternate means of gene delivery and expression.

Adenoviridae↗
PubMed2001

Healthcare e-commerce: connecting with patients.

Electronically connecting with patients is a challenging frontier at which technical hurdles are probably exceeded by political, legal, and other barriers. The rise of consumerism, however, compels a response focused more on revenue and strategic advantage than on pure cost savings. Among the difficulties faced by providers is choosing among various models of connectivity and component function. Emerging models include "free-floating" personal medical records largely independent of the office-based physician, systems with compatible and intertwined physician and consumer relationships using an application services provider office practice system, and systems that connect patients and providers through e-mail, office triage, prescription refills, scheduling, and so on. This article discusses these and other combinations of technology that significantly overcome the barriers involved and that may be woven together to provide solutions uniquely suited to various competitive situations.

Commerce↗
PubMed2001

Evaluation of 60 continuous quality improvement projects in French hospitals.

OBJECTIVE: To evaluate the feasibility of implementing continuous quality improvement (CQI) projects in French health care organizations. DESIGN: The French Ministry of Health issued two calls for CQI projects (in 1995 and 1996). ANAES was commissioned to monitor and evaluate the projects, and to provide advice. SETTING: ANAES in collaboration with French public hospitals. STUDY PARTICIPANTS: A jury selected 64 projects from 483 submissions. The first series of projects related to safety issues (e.g. blood transfusions), the second related chiefly to patient management. INTERVENTIONS: ANAES instructed project leaders in process analysis (modified four-step FOCUS-PDCA model), convened regular meetings between leaders and performed on-site visits. MAIN OUTCOME MEASUREMENTS: Objective outcomes: goal achievement, extension of projects to other topics and departments, allocation of resources. Subjective outcomes: changes in attitudes. Statistics were obtained from two questionnaires completed by project leaders. RESULTS: Four projects were discontinued; 82% (49 out of 60) met more than half their objectives. The CQI method was adopted by other departments in 65% and 50% (1st and 2nd series respectively) of cases. Hospital management often chose to provide continued support (81%/88%), offer training (59%/80%), create a CQI unit (62%/73%), and allocate a budget (61%/65%). A positive impact on staff attitudes was noted in over 75% of projects. CONCLUSION: ANAES' co-ordinated initiative to acquaint a hard core of French public hospitals with CQI proved successful. Identification of the factors for success and of potential hurdles helped pave the way for the national hospital accreditation procedure currently underway.

Attitude of Health Personnel↗
PubMed2006

Application of the CIT concept in the clinical environment: hurdles, practicalities, and clinical benefits.

Basic neuroscience research on brain plasticity, motor learning, and recovery has stimulated new concepts in motor rehabilitation. Combined with the development of methodological goal standards in clinical outcome research, these findings have effectuated the introduction of a double-paradigm shift in physical rehabilitation: (a) the move toward evidence-based procedures and disablement models for the assessment of clinical outcome and (b) the introduction of training-based concepts that are theoretically founded in learning theory. A major drive for new interventions has further come from recent findings on the adaptive capacities of neural networks and their linkage to perception, performance, and long-term recovery. In this context, constraint-induced movement therapy, an intervention initially designed for upper-limb hemiparesis, represents the theoretically and empirically most thoroughly founded training concept. Several clinical trials on constraint-induced therapy (CIT) have shown its efficacy in higher functioning patients; however, the transfer of the treatment into standard health care seems slow. Survey research further suggests a rather poor acceptance of CIT among clinical staff and it seems that the implementation of CIT is hindered by barriers constructed of beliefs and assumptions that demand a critical and evidence-based discussion. Within this context, we have conducted a series of experiments on amended CIT protocols and their application in the clinical environment which addressed the following issues: (1) massed practice: are 6 hours of daily training inevitable to achieve clinical benefits? (2) practicality: what is feasible in the standard care setting and what are the clinical benefits achieved by "feasible compromise CIT protocols?" (3) apprehensions: are concerns on increased muscular tone and pathologic movement patterns justified, and (4) learned nonuse: is the assumption of "hidden" residual abilities valid so that it warrants the constraint condition? In the present paper, the key findings of these studies will be summarized and critically discussed.

Brain Damage, Chronic↗
PubMed1993

Antilisterial activity of pediocin AcH in model food systems in the presence of an emulsifier or encapsulated within liposomes.

The listericidal activity of pediocin AcH was evaluated in slurries (5, 10, or 25% in dH2O) of nonfat dry milk, butterfat, beef muscle tissue, or beef tallow. Slurries were inoculated with Listeria monocytogenes (2-strain mixture; 2.5 x 10(6) cfu/ml) and then with pediocin AcH (30,000 arbitrary units (AU) per ml of slurry). Although pediocin activity was reduced in slurries, sufficient pediocin remained to decrease the listeriae population. For all slurries tested, the greatest decrease in counts of Listeria (1.2-1.8 log10 cfu decrease) and decrease in pediocin activity (12-54% recovery of original activity) occurred within 1.5 min of addition of pediocin to slurries. Thereafter, counts of Listeria did not change appreciably, but pediocin activity continued to decrease in most treatments for up to 60 min. In general, greater activity was recovered from: (i) slurries of lower (5%) compared to higher (25%) concentrations of food; and (ii) dairy- compared to meat-based slurries. Next, pediocin AcH was encapsulated within phosphatidyl-choline-based liposomes before addition to slurries (10%), or was used unencapsulated in slurries (10%) containing the emulsifier Tween 80. Greater pediocin activity (29-62% increase; average over all concentrations) was recovered from slurries containing encapsulated compared to free pediocin AcH. Likewise, greater pediocin activity was recovered from slurries containing an emulsifier (4-90% increase; average over all concentrations) compared to otherwise similar slurries without Tween 80. The additional recovery of pediocin activity afforded by liposomes or Tween 80 underscores the potential for direct application of biopreservatives to provide another hurdle for L. monocytogenes in foods.

Animals↗