Search PubMed⌕ Search

Biomedical subjects

S Harris

Publications and source records attributed to S Harris.

At least 37 records · Page 2Linked to original sources
PubMed2000

Novel interactions between urokinase and its receptor.

Urokinase-type plasminogen activator (uPA) binds to its receptor (uPAR) with a K(d) of about 1 nm. The catalytic activity of the complex is apparent at uPA concentrations close to K(d). Other functions of the complex, such as signal transduction, are apparent at much higher concentrations (35-60 nm). In the present study, we show that uPA and recombinant soluble uPAR (suPAR), at concentrations that exceed the K(d) and the theoretical saturation levels (10-80 nm), establish novel interactions that lead to a further increase in the activity of the single-chain uPA (scuPA)/suPAR and two-chain uPA (tcuPA)/suPAR complexes. Experiments performed using dynamic light scattering, gel filtration, and electron microscopy techniques indicate that suPAR forms dimers and oligomers. The three techniques provide evidence that the addition of an equimolar concentration of scuPA leads to the dissociation of these dimers and oligomers. Biacore data show that suPAR dimers and oligomers bind scuPA with decreased affinity when compared with monomers. We postulate that uPAR is present in equilibrium between oligomer/dimer/monomer forms. The binding of uPA to suPAR dimers and oligomers occurs with lower affinity than the binding to monomer. These novel interactions regulate the activity of the resultant complexes and may be involved in uPA/uPAR mediated signal transduction.

Fibrinolysis↗
PubMed2000

The bovine papillomavirus E2 transactivator is stimulated by the E1 initiator through the E2 activation domain.

Bovine papillomavirus type 1 (BPV-1) encodes two regulatory proteins, E1 and E2, that are essential for viral replication and transcription. E1, an ATP-dependent helicase, binds to the viral ori and is essential for viral replication, while the viral transcriptional activator, E2, plays cis-dominant roles in both viral replication and transcription. At low reporter concentrations, E1 stimulates E2 enhancer function, while at high reporter concentrations, repression results. An analysis of cis requirements revealed that neither replication nor specific E1-binding sites are required for the initiators' effect on E2 transactivator function. Though no dependence on E1-binding sites was found, analysis of E1 DNA binding and ATPase mutants revealed that both domains are required for E1 modulation of E2. Through the use of E2 fusion-gene constructs we showed that a heterologous DNA-binding domain could be substituted for the E2 DNA-binding domain and this recombinant protein remained responsive to E1. Furthermore, E1 could rescue activation domain mutants of E2 defective for transactivation. These data suggest that E1 stimulation of E2 involves interactions between E1 and the E2 activation domain on DNA. We speculate that E1 may allosterically interact with the E2 activation domain, perhaps stabilizing a particular structure, which increases the enhancer function of E2.

Animals↗
PubMed2000

Synthesis and antiviral activity of acyclovir-5'-(phenyl methoxy alaninyl) phosphate as a possible membrane-soluble nucleotide prodrug.

We describe a synthesis of acyclovir-5'-(phenyl methoxy alaninyl) phosphate (2) from acyclovir (1). This compound was designed to act as a lipophilic, membrane-soluble prodrug of the free nucleotide. However, the biological activities of this derivative against a range of viruses indicated poor intracellular phosphate delivery, in marked contrast to the earlier successful delivery of several dideoxy anti-HIV nucleotides.

Acyclovir↗
PubMed2000

Flexible spatial organization of urban foxes, Vulpes vulpes, before and during an outbreak of sarcoptic mange.

The social and spatial organization of urban fox groups prior to and during an outbreak of sarcoptic mange was compared with predictions derived from the resource dispersion hypothesis (RDH). We investigated the availability of three key resources. Neither daytime rest sites nor breeding sites appeared to be limited in availability. The availability of food deliberately supplied by local householders was examined by questionnaire surveys. The daily and weekly amount of food supplied was greatly in excess of the minimum requirements of a pair of foxes, but was consistent between territories. The availability of this food source increased markedly as a result of more people feeding the foxes. In agreement with the RDH, group size prior to the outbreak of mange increased from 2.25 animals (N=4) to 6.57 animals (N=7). Before the outbreak of mange, two territories were divided. Increased scavenge availability on smaller territories may have promoted these changes. Excluding these spatial changes, territories were very stable between years. After the outbreak of mange, group size declined as a direct result of mange-induced mortality. Surviving animals increased their ranges only after neighbouring groups had died out. Ranges did not increase in size in response to a decline in food availability. Nor were the increases in range size associated with the relinquishment of parts of the existing territory. These postmange changes are contrary to the RDH. Three factors may have promoted these changes: the elimination of interstitial space, the forced dispersal of young or future division of the territory. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2000

A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group.

PURPOSE: We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. SUBJECTS AND METHODS: A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group. RESULTS: During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43- to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1. 5%, P<0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo. CONCLUSION: Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.

Aged↗
PubMed2000

Adjuvant interferon-alpha in malignant melanoma: current status.

High-risk surgically resected primary or loco-regional cutaneous malignant melanoma, although uncommon, can be associated with less than 50% 5-year survival; adjuvant therapy of proven efficacy is therefore appropriate. Since immunological control mechanisms seem to be important in the natural history of melanoma, biological agents have been the subject of many adjuvant studies. Most popular has been recombinant interferon. Well over 4000 patients have been entered into randomized studies. Results suggest that there may be a clinical benefit, most clearly in relapse-free but also perhaps in overall survival. More precise estimates of the magnitude of any benefits are needed. The doses, schedules and cost-benefits have yet to be fully evaluated. Interferon cannot yet be recommended as standard adjuvant therapy in high-risk malignant melanoma.

Combined Modality Therapy↗
PubMed2000

Random population dispersal in a linear hostile environment.

We consider the Fisher equation and its generalization for an asocial population in a linear, hostile environment. The method of center manifold analysis is used to obtain the time-dependent solution of the former, nonlinear equation. The correct critical habitat size is obtained; in addition, the result for the steady state central density compares favorably with the exact result for relatively large population sizes (up to one half of the carrying capacity). For a model of asocial growth we obtain the expanded criteria for survival. This includes the habitat size, the population size at which positive growth begins, and also the minimum initial central density.

Environment↗
PubMed2000

Ankle biomechanics during impact landings on uneven surfaces.

Inversion sprains of the lateral ligaments of the ankle are one of the most common of all sporting injuries. While the strains in the anterior talofibular (ATFL) and calcaneofibular (CFL) ligaments have been measured in quasi-static conditions, the dynamic strains during an actual traumatic event have not been determined. The present investigation determined the strains and strain rates in the ATFL and CFL during an in vitro inversion sprain. The ATFL tended to have higher strain and strain rate values than the CFL, which may explain why it is more often injured than the CFL.

Ankle Injuries↗
PubMed2000

Transgenic gene knock-outs: functional genomics and therapeutic target selection.

The completion of the first draft of the human genome presents both a tremendous opportunity and enormous challenge to the pharmaceutical industry since the whole community, with few exceptions, will soon have access to the same pool of candidate gene sequences from which to select future therapeutic targets. The commercial imperative to select and pursue therapeutically relevant genes from within the overall content of the genome will be particularly intense for those gene families that currently represent the chemically tractable or 'drugable' gene targets. As a consequence the emphasis within exploratory research has shifted towards the evaluation and adoption of technology platforms that can add additional value to the gene selection process, either through functional studies or direct/indirect measures of disease alignment e.g., genetics, differential gene expression, proteomics, tissue distribution, comparative species data etc. The selection of biological targets for the development of potential new medicines relies, in part, on the quality of the in vivo biological data that correlates a particular molecular target with the underlying pathophysiology of a disease. Within the pharmaceutical industry, studies employing transgenic animals and, in particular, animals with specific gene deletions are playing an increasingly important role in the therapeutic target gene selection, drug candidate selection and product development phases of the overall drug discovery process. The potential of phenotypic information from gene knock-outs to contribute to a high-throughput target selection/validation strategy has hitherto been limited by the resources required to rapidly generate and characterise a large number of knock-out transgenics in a timely fashion. The offerings of several companies that provide an opportunity to overcome these hurdles, albeit at a cost, are assessed with respect to the strategic business needs of the pharmaceutical industry.

Animals↗
PubMed1999

Stimulation of bone formation in vitro and in rodents by statins.

Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.

Animals↗
PubMed1999

Bone morphogenetic protein 2 inhibits platelet-derived growth factor-induced c-fos gene transcription and DNA synthesis in mesangial cells. Involvement of mitogen-activated protein kinase.

Bone morphogenetic proteins (BMPs) play an important role in nephrogenesis. The biologic effect and mechanism of action of these proteins in the adult kidney has not yet been studied. We investigated the effect of BMP2, a member of these growth and differentiation factors, on mitogenic signal transduction pathways induced by platelet-derived growth factor (PDGF) in glomerular mesangial cells. PDGF is a growth and survival factor for these cells in vitro and in vivo. Incubation of mesangial cells with increasing concentrations of BMP2 inhibited PDGF-induced DNA synthesis in a dose-dependent manner with maximum inhibition at 250 ng/ml. Immune complex tyrosine kinase assay of PDGF receptor beta immunoprecipitates from lysates of mesangial cells treated with PDGF showed no inhibitory effect of BMP2 on PDGF receptor tyrosine phosphorylation. This indicates that the inhibition of DNA synthesis is likely due to postreceptor events. However, BMP2 significantly inhibited PDGF-stimulated mitogen-activated protein kinase (MAPK) activity that phosphorylates the Elk-1 transcription factor, a component of the ternary complex factor. Using a fusion protein-based reporter assay, we also show that BMP2 blocks PDGF-induced Elk-1-mediated transcription. Furthermore, we demonstrate that BMP2 inhibits PDGF-induced transcription of c-fos gene, a natural target of Elk-1 that normally forms a ternary complex that activates the serum response element of the c-fos gene. These data provide the first evidence that in mesangial cells, BMP2 signaling cross-talks with MAPK-based transcriptional events to inhibit PDGF-induced DNA synthesis. One target for this inhibition is the early response gene c-fos.

Animals↗
PubMed1999

Factors affecting broadband ultrasound attenuation results of the calcaneus using a gel-coupled quantitative ultrasound scanning system.

This study aimed to assess the factors that may influence the distribution and description of broadband ultrasound attenuation (BUA) and to identify specific criteria for diagnostic consideration when collecting BUA reference data. Two hundred Caucasian women (aged 20-79 years) without a history of atraumatic fractures or medicines known to affect bone metabolism were selected for this study. Medical and menstrual history, medication usage, family history of osteoporosis (FHO), physical activity, activities of daily living (ADL), dietary calcium intake, as well as smoking and alcohol consumption were obtained. Broadband ultrasound attenuation (BUA, dB/MHz) was determined in the right foot using a new gel-coupled ultrasound system. BUA was significantly associated with age (p<0.001), body weight (p<0.001), level of physical activity (p = 0.024) and dietary calcium intake (p = 0.023). Smoking, alcohol and coffee consumption and ADL were not associated with BUA (p>0.05). There were no differences in BUA (p>0.05) between those women who reported taking medications or had diseases (known to not affect bone metabolism), were using contraceptives, taking vitamin/mineral supplements and/or had traumatic fractures and their counterparts who did not report these characteristics. Premenopausal women with a FHO had significantly lower BUA values compared with those without a FHO (p = 0.013). When those participants with a FHO were removed from the sample, the peak BUA value was 1.1-4.4% higher and the variability (SD) was reduced by about 3.3-9.3% depending on which age range was used to define the peak BUA value. Consequently, an additional 4.5% of the population were classified as having a T-score <-2. Our results suggest that the impact on BUA of risk factors such as a FHO, body weight, physical activity and dietary calcium intake is similar to that on bone mineral density obtained by dual-energy X-ray absorptiometry (DXA), and thus provides further information on the comparability of quantitative ultrasound and DXA for assessment of risk of fracture. The criteria for calculating the T-score need further study to determine whether young adults with FHO should be included and what cutoff age range should be used in collecting peak values of quantitative ultrasound parameters.

Adult↗
PubMed1999

Theories and intervention approaches to health-behavior change in primary care.

CONTENT: Providers typically rely on health information and their professional status to convince patients to change. Health-behavior theories and models suggest more effective methods for accomplishing patient compliance and other behavior change related to treatment regimens. Behavior modification stresses the remediation of skill deficits or using positive and negative reinforcement to modify performance. Like behavior modification, the Health Belief Model stresses a reduction of environmental barriers to behavior. Social Learning Theory suggests that perceptions of skills and reinforcement may more directly determine behavior. Self-management models put the above theories into self-change actions. Social support theories prioritize reinforcement delivered through social networks, whereas the Theory of Reasoned Action emphasizes perceptions of social processes. Finally, the Transtheoretical Model speaks of the necessity to match interventions to cognitive-behavioral stages. Strategies derived from each of these theories are suggested herein.

Behavior Therapy↗
PubMed1999

Quantifying the risks of TB infection to cattle posed by badger excreta.

Despite strong circumstantial evidence to suggest that the main route of TB transmission from badgers to cattle is via contaminated badger excreta, it is unclear whether the associated risks are high enough to account for the prevalence of the disease in south-west England. To decide whether this was a viable route of transmission, cattle contact with badger excreta was investigated using a deterministic approach to quantify the risks to cattle posed by badger excreta. Levels of investigative and grazing contacts between cattle and badger urine and faeces could each account for the disease prevalence in south-west England. An infection probability of 3.7 x 10(-4) per bite from pasture contaminated with badger urine infected with Mycobacterium bovis could account for the prevalence of TB in cattle in south-west England. Infection probabilities of 6.9 x 10(-7) per investigation and 1.1 x 10(-7) per bite from badger latrines could each account for the prevalence of TB in cattle in the south-west. When considering only the high risk areas of south-west England these bounds fell by a factor of eight. However, badger excreta may still constitute a high level of risk to cattle. The levels of cattle contact with badger excreta are far higher than previously thought, suggesting that it is the probability of infection per given contact with infected badger excreta which has the greater influence on the probability of transmission and not the level of contact. The infection probability per cattle contact with infected badger excreta is in all likelihood extremely low.

Animals↗