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At least 289 records · Page 16Linked to original sources
PubMed2006

The role of pre-emptive re-transplant in graft and recipient outcome.

BACKGROUND: The effect of the pre-emptive re-transplant, and of inter-transplant waiting time generally, on graft and recipient survival is not well established. METHODS: Analysis of the United States Renal Data System (USRDS) data (1/1/90 through 12/31/00; n = 92,844) was performed. Cox regression was used to analyse time to event, with an additional analysis to stratify by transplant era. RESULTS: Having a prior transplant, as well as the total number of transplants, was related to an increased risk of graft failure [hazard ratio (HR) 1.24, P<0.001 for history of prior transplant; HR 1.35 per transplant, P<0.001], but not to recipient death. The time waiting for re-transplant slightly worsened the risk for recipient mortality in the entire patient population and in the recipients of single re-transplant (HR 1.003 and 1.004 per month respectively, P<0.001), and for graft failure only in recipients of single re-transplant (HR 1.001 per month, P<0.05). Pre-emptive re-transplant (dialysis-free re-transplant or transplant within 6 days of last graft failure) increased the risk of graft failure (HR 1.36, P<0.001) and did not have any statistically significant effect on recipient survival. The longer duration of prior graft survival but not the type of the graft (living vs deceased) had protective effect on the consecutive graft and recipient survival. CONCLUSIONS: With the potential caveats associated with retrospective data analysis, these results suggest that pre-emptive re-transplantation is associated with increased risk of graft failure, while longer time on dialysis in between transplants is associated with negative effect upon graft and recipient survival in most patient subgroups. The optimal time in between graft failure and re-transplant was not evaluated in this study. Further prospective studies might be needed to confirm the observed effects.

Adolescent↗
PubMed2002

The role of defensins in lung biology and therapy.

Innate host defence, involving both cellular and humoral mediators, is a prominent function of the human airways. Cellular mediators of innate immunity include dendritic cells, natural killer cells, cytotoxic T cells, macrophages and neutrophils, while humoral mediators of innate immunity consist of components of the epithelial lining fluid (ELF) covering the airways. Microbicidal substances in the ELF can selectively disrupt bacterial cell walls and membranes, sequester microbial nutrients or act as decoys for microbial attachment. Antimicrobial components of airway secretions include lysozymes, lactoferrin, secretory leukoprotease inhibitor, defensins and cathelicidins. Defensins are the most widely studied family of antimicrobial peptides present in airway fluid. Humans produce at least 10 different defensin molecules, six alpha-defensins and four beta-defensins similar in structure and function. Direct evidence that defensins have central roles in host defense has only recently become available. Some defensins and defensin-like molecules could serve as templates for the development of pulmonary pharmaceuticals. As potential therapeutics, they possess several desirable properties, including the ability to kill a broad spectrum of micro-organisms while permitting little development of microbial resistance. Many peptides can also neutralize effects of lipopolysaccharide on macrophages and other host defense cells and decrease the release of proinflammatory cytokines thereby giving protection against septic shock. Protegrin-1 is a minidefensin isolated from pig leukocytes and has proved to be an attractive template for large-scale development of antibacterials. One such protegrin analog, iseganan is in phase III clinical trials for the treatment of oral mucositis secondary to systemic chemotherapy. Other prospective uses of iseganan include control of respiratory pathogens in patients with cystic fibrosis and reduction of oral bacteria to prevent ventilator-associated pneumonia. However, in order to advance the production and clinical testing of peptide-based therapeutics, technical hurdles of synthesizing large quantities of complexly folded peptides must be first overcome. Strategies to develop potent peptide-based microbicides are promising in the struggle against increasingly resistant pathogens.

Amino Acid Sequence↗
PubMed2005

Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data.

Genome wide association studies using high throughput technology are already being conducted despite the significant hurdles that need to be overcome (Nat Rev Genet 6:95-108, 2005; Nat Rev Genet 6:109-118, 2005). Methods for detecting haplotype association signals in genome wide haplotype datasets are as yet very limited. Much methodological research has already been devoted to linkage disequilibrium (LD) fine mapping where the focus is the identification of the disease locus rather than the detection of a disease signal. Applications of these approaches to genome wide scanning are limited by the strong model assumptions of the sharing process, which lead to computational complexity. We describe a new algorithm for the initial identification of disease susceptibility loci in genome wide haplotype association studies. Excess sharing of ancestral haplotypes, which indicates the presence of a disease locus, is detected with a simple, easy to interpret, chi2 based statistic. The method allows genome wide scanning for qualitative traits within reasonable computational timeframes and can serve as a first pass analysis prior to the usage of likelihood based methods, providing candidate regions and inferred susceptibility haplotypes. Our method makes no assumptions regarding the population history or the pattern of background LD. Statistical significance is evaluated with permutation tests. The method is illustrated on simulated and real data where it is applied to simple (cystic fibrosis) and complex disease (multiple sclerosis) examples. The statistic has low type I error and greater power to map disease loci over conventional single marker tests for low to moderate levels of LD.

Algorithms↗
PubMed2003

Pharmacological strategies for muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal, genetic disorder whose relentless progression underscores the urgency for developing a cure. Although Duchenne initiated clinical trials roughly 150 years ago, therapies for DMD remain supportive rather than curative. A paradigm shift towards developing rational therapeutic strategies occurred with identification of the DMD gene. Gene- and cell-based therapies designed to replace the missing gene and/or dystrophin protein have achieved varying degrees of success. However, pharmacological strategies not designed to replace dystrophin per se appear promising, and can circumvent many hurdles hampering gene- and cell-based therapy. Here, we will review present pharmacological strategies, in particular those dealing with functional substitution of dystrophin by utrophin and enhancing muscle progenitor commitment by myostatin blockade, with a view toward facilitating drug discovery for DMD.

Animals↗
PubMed2005

Myostatin propeptide-mediated amelioration of dystrophic pathophysiology.

Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.

Animals↗
PubMed1999

Water activity and temperature effects on germination and growth of Eurotium amstelodami, E. chevalieri and E. herbariorum isolates from bakery products.

This study investigated the effect of temperature (5-30 degrees C), water activity (0.775-0.90 aw) and their interactions on the temporal rates of germination and mycelial growth of three species of Eurotium on flour wheat sucrose medium. Germination was quite rapid at aw >0.85, with an almost linear increase with time for all isolates. However, under more extreme water stress, germination was slower. The aw minima for germination were usually lower than those for growth and varied with temperature. The effect of aw x temperature interactions on the lag phases (h) prior to germination and on the germination rates (h-1) were predicted using the Gompertz model modified by Zwietering. Eurotium spp. had shown short lag times at 0.90 aw over a wide range of temperatures. At marginal temperatures, lag phases were significantly longer, especially at >15 degrees C. The temperature x aw profiles for mycelial growth varied between species in terms of rates (mm d(-1)). Predictions of the effect of important environmental factors, such as temperature, aw and their interactions on lag times to germination, germination rates and mycelial growth, are important in the development of hurdle technology approaches to predict fungal spoilage in food products.

Ascomycota↗
PubMed2026

Bridging Organ-on-a-Chip and Omics: A Multi-Dimensional Frontier in Biomedical Research.

Organ-on-a-Chip (OOC) technology offers a powerful platform for replicating human tissue-specific microenvironments, thereby narrowing the translational gap between conventional biomedical models and actual human physiology. Concurrently, omics technologies deliver comprehensive molecular-level insights into biological systems. This review highlights the transformative potential of integrating OOC platforms with high-throughput omics methodologies. We systematically examine the classification, structural configurations, and engineering principles underlying OOC systems, alongside the defining attributes of key omics domains-genomics, transcriptomics, proteomics, and metabolomics. The convergence of dynamic OOC models with advanced omics technologies enables high-resolution, multi-dimensional analyses across numerous biomedical applications, including drug metabolism, disease mechanisms, environmental toxicity assessments, and host-microbiome interactions. This interdisciplinary integration is driving a paradigm shift in precision and translational medicine. However, several challenges remain to be addressed, such as the development of whole-organ mimetics, adaptation of sample collection techniques, and real-time artificial intelligence-based integration of biosensor data with multi-omics datasets. Addressing these hurdles will be vital for unlocking the full potential of this technological synergy in biomedical science.

Multiomics↗
PubMed2000

Gene therapy approaches for treating rheumatoid arthritis.

Current gene therapy approaches for treating rheumatoid arthritis have made use of gene transfer technology as an improved delivery system for emerging proteins and other biologicals whose activities may have therapeutic value. Preclinical research has focused on two primary directions, evaluation of methods of gene delivery and identification of gene products with antiarthritic potential. Although there are reports involving systemic gene delivery, the bulk of effort has focused on local, intraarticular administration using ex vivo and in vivo methods. Viral-based vectors, including adenovirus, adeno-associated virus and herpes simplex virus have the greatest efficiency of gene delivery after intraarticular injection and are capable of generating relevant levels of gene products in several animal models of disease. However, there are limitations to existing generations of these systems that currently preclude their clinical application. Those gene products found to be efficacious in animal models of rheumatoid arthritis include proteins that specifically block the activity of the primary inflammatory cytokines, and include interleukin-1 receptor antagonist and soluble receptors for tumor necrosis factor and interleukin-1. Delivery and expression of genes encoding certain cytokines such as interleukins -4, -10, and -13 and viral interleukin-10, that block synthesis of inflammatory mediators and downregulate aspects of cellular and humoral immune pathways have been found beneficial. Although significant progress has been made, leading to Phase I clinical trials, there remain several hurdles to the routine practice of gene therapy for treatment of rheumatoid arthritis.

Animals↗
PubMed2005

Crafting identities and accessing opportunities post-Brown.

Decades following Brown v. Board of Education (1954), issues regarding the effects of skin color, poverty, and racial differences in the availability of protective factors persist. For a multiethnic sample of mainly African American (56%), female (69%), and high-achieving (65%) youths, a dual-axis model of vulnerability is used to compare four groups of youths identified as high, masked, low, and undetermined vulnerability on the basis of the presence of risk and protective factors. Risks included level of poverty, number of parents in home, and skin-color pigmentation. Protective factors included youths' perceptions of school climate, parental monitoring, and consonance between skin pigmentation and preferred skin color. The author suggests that 50 years post-Brown, issues concerning White privilege, color stereotyping, power discrepancies, and economic disparities maintain "invisible" and persistent hurdles for vulnerable youths who vary on available protective factors. Findings confirm the impact of vulnerability on psychosocial and achievement outcomes.

Adolescent↗
PubMed2001

Gene therapy for inherited hyperbilirubinemias.

Crigler-Najjar syndrome type 1 (CN-1) is a potentially lethal condition, and is the only inherited disorder of bilirubin metabolism that needs treatment beyond the neonatal period. Currently, orthotopic liver transplantation is the only available cure for CN-1. Because the liver architecture is not disturbed in CN-1 and partial correction of bilirubin-UDP-glucuronosyltransferase (UGT1A1) activity is expected to be sufficient for protection against kernicterus, cell and gene therapies are being developed using the Gunn rat as an animal model of the disease. Ex vivo gene therapy based on the transplantation of genetically manipulated hepatocytes and in vivo gene transfer using recombinant adenovirus and Simian virus 40 (SV40)-based vectors have yielded significant success. The novel strategy of in vivo site-directed mutagenesis has also resulted in modest, but significant, correction of the genetic abnormality. Newer viral and nonviral gene delivery methods are being explored and have been discussed in brief. In summary, effective gene therapy methods have been validated in Gunn rats. Despite considerable remaining hurdles, gene therapy for CN-1 could become a clinical reality by the turn of this decade.

Animals↗
PubMed2005

Combinatorial chemistry in glycobiology.

The application of combinatorial chemistry to glycobiology historically has proven challenging due to numerous synthetic hurdles. The advent of novel methodologies has enabled the production of natural as well as mimetic analogues for proof-of-concept experiments and SAR. This review highlights some of the recent synthetic advances in combinatorial carbohydrate synthesis. The application of carbohydrate libraries in glycobiology is also discussed.

Biology↗
PubMed1996

Active barnase variants with completely random hydrophobic cores.

The central structural feature of natural proteins is a tightly packed and highly ordered hydrophobic core. If some measure of exquisite, native-like core packing is necessary for enzymatic function, this would constitute a significant obstacle to the development of novel enzymes, either by design or by natural or experimental evolution. To test the minimum requirements for a core to provide sufficient structural integrity for enzymatic activity, we have produced mutants of the ribonuclease barnase in which 12 of the 13 core residues have together been randomly replaced by hydrophobic alternatives. Using a sensitive biological screen, we find that a strikingly high proportion of these mutants (23%) retain enzymatic activity in vivo. Further substitution at the 13th core position shows that a similar proportion of completely random hydrophobic cores supports enzyme function. Of the active mutants produced, several have no wild-type core residues. These results imply that hydrophobicity is nearly a sufficient criterion for the construction of a functional core and, in conjunction with previous studies, that refinement of a crudely functional core entails more stringent sequence constraints than does the initial attainment of crude core function. Since attainment of crude function is the critical initial step in evolutionary innovation, the relatively scant requirements contributed by the hydrophobic core would greatly reduce the initial hurdle on the evolutionary pathway to novel enzymes. Similarly, experimental development of novel functional proteins might be simplified by limiting core design to mere specification of hydrophobicity and using iterative mutation-selection to optimize core structure.

Amino Acid Sequence↗
PubMed2004

Horse injuries and racing practices in National Hunt racehorses in the UK: the results of a prospective cohort study.

A prospective cohort study was conducted on horses starting in hurdle and steeplechase races on six UK racecourses in 2000 and 2001. Trainers or carers were questioned on the horses' pre-race routine and observational data were collected in the stables and parade ring. Some practices were common to many starters, such as withholding food and water before racing whereas other practices, such as schooling frequency, were more variable. There was a total of 2879 starts and a total of 83 injuries or medical events (28.8/1000 starts). The commonest types of injury were tendon/suspensory injuries and lacerations/wounds. Multivariable logistic regression models were used to identify the relationship between predictor variables and the risk of injury. Risk of injury or medical event was associated with distance of the race and weight carried. The risk of injury, excluding medical events, was associated with the speed of the race and foot conformation.

Animal Husbandry↗
PubMed2006

Semiautomatic 3-D prostate segmentation from TRUS images using spherical harmonics.

Prostate brachytherapy quality assessment procedure should be performed while the patient is still on the operating table since this would enable physicians to implant additional seeds immediately into the prostate if necessary thus reducing the costs and increasing patient outcome. Seed placement procedure is readily performed under fluoroscopy and ultrasound guidance. Therefore, it has been proposed that seed locations be reconstructed from fluoroscopic images and prostate boundaries be identified in ultrasound images to perform dosimetry in the operating room. However, there is a key hurdle that needs to be overcome to perform the ultrasound and fluoroscopy-based dosimetry: it is highly time-consuming for physicians to outline prostate boundaries in ultrasound images manually, and there is no method that enables physicians to identify three-dimensional (3-D) prostate boundaries in postimplant ultrasound images in a fast and robust fashion. In this paper, we propose a new method where the segmentation is defined in an optimization framework as fitting the best surface to the underlying images under shape constraints. To derive these constraints, we modeled the shape of the prostate using spherical harmonics of degree eight and performed statistical analysis on the shape parameters. After user initialization, our algorithm identifies the prostate boundaries on the average in 2 min. For algorithm validation, we collected 30 postimplant prostate volume sets, each consisting of axial transrectal ultrasound images acquired at 1-mm increments. For each volume set, three experts outlined the prostate boundaries first manually and then using our algorithm. By treating the average of manual boundaries as the ground truth, we computed the segmentation error. The overall mean absolute distance error was 1.26 +/- 0.41 mm while the percent volume overlap was 83.5 +/- 4.2. We found the segmentation error to be slightly less than the clinically-observed interobserver variability.

Algorithms↗
PubMed2001

The application of a fermented food ingredient containing 'variacin', a novel antimicrobial produced by Kocuria varians, to control the growth of Bacillus cereus in chilled dairy products.

AIMS: The feasibility of applying variacin, a lantibiotic produced by Kocuria varians in the form of a spray-dried fermented ingredient to control the growth of psychrotrophic Bacillus cereus strains in chilled dairy foods, was evaluated. METHODS AND RESULTS: A range of chilled dairy food formulations modelling commercially-available products were fabricated, to which were added varying amounts of active ingredient. These were subsequently challenged with a B. cereus spore cocktail over a range of abuse temperatures. This work was validated by the inclusion of the fermented ingredient to commercial products. CONCLUSION: Results demonstrate the functionality of the bacteriocin at refrigeration abuse temperatures, and indicate the robust nature of the proteinaceous antimicrobial agent with regard to processing. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates the applicability of fermented food ingredients containing naturally-occurring antimicrobials as additional hurdles in food preservation.

Actinomycetales↗
PubMed2007

Development of new RNAi therapeutics.

RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of "RNAi drug" could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limitations need to consider for achieving effective therapeutics. Major hurdles include the intrinsic poor pharmacokinetic property of siRNA and major biological restrictions include off-target effects, interferon response and the interference with endogenous miRNA. Recent innovations in nucleic acid chemistry, formulations and delivery methods have gradually rendered it possible to develop effective RNAi-based therapeutics. Careful design based on the newest RNAi/miRNA biology can also help to minimize the potential tissue toxicity. If successful with systemic application, RNAi drug will no doubt revolutionize the whole drug development process. This review attempts to describe the progress in this area, including applications in preclinical models and recent favorable experience in a number of human trials of local diseases, along with the discussion on the potential limitations of RNAi therapeutics.

Animals↗
PubMed2006

Feeling the digital pulse: Consumer-centered approach to individual health profiling.

New technologies from the new digital era are overcoming temporal, spatial and physical hurdles in the development and realization of individual health profiling and consumer health monitoring devices. Mature wireless and networking technologies promise more accessibility and portability of health data and records, and health monitoring. The increase in convenience and efficiency underlie the technological foundation for development of telehealth systems, which make personal health care available anytime, anywhere. On the one hand, advances in information technology are aiding in the creation of lifelong health records and hence in the tracking and understanding of the health history of individuals, which in turn will help shift the public health care delivery model toward more primary and secondary care and prevention from the current emphasis on curing. On the other, health monitoring devices are also benefiting from technological progress, and are increasingly moving toward more self-assistive, compact and appealing to consumers. However, although most of the necessary hardware and technologies are already mature and widely available, they have yet to be fully exploited for personal health care, and the general public also need to be educated and encouraged to adopt the concepts of individual health profiling and regular health monitoring into their lives. In this regard, the School of Nursing at The Hong Kong Polytechnic University has been working proactively on two fronts. First, a telehealth system has been installed in community-based venues such as clinics, hospitals and, most important, schools and youth centers in order to promote lifelong health profiling for all individuals. Second, the School of Nursing is committed to utilizing advanced technologies for developing more compact and user-friendly consumer health monitoring devices such as non-invasive meters. This is with a view to encourage individuals to take more responsibility for their own health and behavior, which fits in with the Hong Kong government's aim of shifting the burden of public health care provision away from hospitals to community-based primary and secondary care. The ultimate goal of the School of Nursing's efforts in telehealth and consumer health monitoring devices is the wide adoption of home-based telehealth systems that will subsequently spur individual health profiling, which will in turn encourage personal responsibility for improving one's health.

Consumer Behavior↗
PubMed2004

Localized delivery of growth factors for bone repair.

Delivery of growth factors for tissue (e.g. bone, cartilage) or cell repair (e.g. nerves) is about to gain important potential as a future therapeutic tool. Depending on the targeted cell type and its state of differentiation, growth factors can activate or regulate a variety of cellular functions. Therefore, strictly localized delivery regimens at well-defined kinetics appear to be logical prerequisites to assure safe and efficacious therapeutic use of such factors and avoid unwanted side effects and toxicity, a major hurdle in the clinical development of growth factor therapies so far. This review summarizes various approaches for localized growth factor delivery as focused on bone repair. Similar considerations may apply to other growth factors and therapeutic indications. Considering the vast number of preclinical studies reported in the area of growth factor-assisted bone repair, it surprises though that only two medical products for bone repair have so far been commercialized, both consisting of a collagen matrix impregnated with a bone morphogenetic protein. The marked diversity of the reported growth factors, delivery concepts and not yet standardized animal models adds to the complexity to learn from past preclinical studies presented in the literature. Nonetheless, it is now firmly established from the available information that the type, dose and delivery kinetics of growth factors all play a decisive role for the therapeutic success of any such approach. Very likely, all of these parameters have to be adapted and optimized for each animal model or clinical case. In the future, systems for localized growth factor delivery thus need to be designed in such a way that their modular components are readily adaptable to the individual pathology. To make such customized systems feasible, close cooperative networks of biomedical and biomaterials engineers, pharmaceutical scientists, chemists, biologists and clinicians need to be established.

Animals↗