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Biomedical subjects

S Harris

Publications and source records attributed to S Harris.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1999

Enovin, a member of the glial cell-line-derived neurotrophic factor (GDNF) family with growth promoting activity on neuronal cells. Existence and tissue-specific expression of different splice variants.

Glial cell-line-derived neurotrophic factor (GDNF), neurturin and persephin are neurotrophic factors involved in neuroneal differentiation, development and maintenance. They act on different types of neuroneal cells and signal through a receptor complex composed of a specific ligand-binding subunit of the GDNF family receptor alpha (GFRalpha) family together with a common signaling partner, the cRET protein tyrosine kinase. We describe the molecular cloning, expression, chromosomal localization and functional characterization of enovin, a fourth GDNF family member almost identical to the recently described artemin. We show the occurence in most tissues of several differently spliced mRNA variants for enovin, of which only two are able to translate into functional enovin protein. Some tissues seem to express only nonfunctional transcripts. These observations may underlie a complex transcriptional regulation pattern. Enovin mRNA expression is detectable in all adult and fetal human tissues examined, but expression levels are highest in peripheral tissues including prostate, placenta, pancreas, heart and kidney. This tissue distribution pattern is in accordance with that of GFRalpha-3, which here is shown to be the preferred ligand-binding receptor for enovin (Kd = 3.1 nM). The human enovin gene is localized on chromosome 1, region p31.3-p32. In vitro, enovin stimulates neurite outgrowth and counteracts taxol-induced neurotoxicity in staurosporine-differentiated SH-SY5Y human neuroblastoma cells. The peripheral expression pattern of enovin and its receptor together with its effects on neuroneal cells suggest that enovin might be useful for the treatment of neurodegenerative diseases in general and peripheral neuropathies in particular.

Adult↗
PubMed1999

The effect of the timing of ethanol exposure during early postnatal life on total number of Purkinje cells in rat cerebellum.

We have previously shown that exposing rats to a high dose of ethanol on postnatal d 5 can affect Purkinje cell numbers in the cerebellum whilst similar exposure on d 10 had no such effect. The question arose whether a longer period of ethanol exposure after d 10 could produce loss of Purkinje cells. We have examined this question by exposing young rats to a relatively high dose (approximately 420-430 mg/dl) of ethanol for 6 d periods between the ages of either 4 and 9 d or 10 and 15 d of age. Exposure was carried out by placing the rats in an ethanol vapour chamber for 3 h per day during the exposure period. Groups of ethanol-treated (ET), separation controls (SC) and mother-reared controls (MRC) were anaesthetised and killed when aged 30 d by perfusion with buffered 2.5% glutaraldehyde. Stereological methods were used to determine the numbers of Purkinje cells in the cerebellum of each rat. MRC, SC and rats treated with ethanol between 10-15 d of age each had, on average, about 254-258 thousand cerebellar Purkinje cells; the differences between these various groups were not statistically significant. However, the rats treated with ethanol vapour between 4-9 d of age had an average of only about 128000+/-20000 Purkinje cells per cerebellum. This value was significantly different from both the MRC and group-matched SC animals. It is concluded that the period between 4 and 9 d of age is an extremely vulnerable period during which the rat cerebellar Purkinje cells are particularly susceptible to the effects of a high dose of ethanol. However, a similar level and duration of ethanol exposure commencing after 10 d of age has no significant effect on Purkinje cell numbers.

Animals↗
PubMed1999

Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide.

AIMS: Glimepiride is a new sulfonylurea for diabetes treatment which is supposed to impact less on extra-pancreatic ATP-dependent K+ channels than the conventional drug glibenclamide. This study was performed to evaluate whether this results in a better maintenance of ATP-dependent K+ channel mediated ischaemic myocardial preconditioning. METHODS AND RESULTS: In a double-blind placebo-controlled study the period of total coronary occlusion during balloon angioplasty of high grade coronary artery stenoses was used as a model to compare the effects of both drugs. Quantification of myocardial ischaemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. All patients underwent three dilatations. The first dilatation (dilatation 1) served to determine the severity of ischaemia during vessel occlusion. During dilatation 2, baseline values were recorded. Thereafter, glimepiride (15 patients: 1.162 mg), glibenclamide (15 patients: 2.54 mg) or placebo (15 patients) were intravenously administered over 12 min. Dilatation 3 started 10 min after the beginning of the drug administration. Mean ST segment shifts in the placebo group decreased by 35% (dilatation 2: 0.23; dilatation 3:0.15 mV; CI -0.55 to 0.00 mV; P=0.049). A similar reduction also occurred in the glimepiride group, in which repetitive balloon occlusion led to a 34% reduction (dilatation 2: 0.35; dilatation 3: 0.23 mV; CI -0.21 to -0.02 mV; P=0.01). There was little influence however, on mean ST segment shifts in the glibenclamide group (dilatation 2 and dilatation 3: 0.24 mV; CI -0.10 to 0.25 mV; P=0.34). Accordingly, time to angina during balloon occlusion slightly increased (by 30%) in the placebo group (dilatation 2: 37 s; dilatation 3: 48 s; CI 0.0 to 15.0 s; P=0.16); increased by 13% in the glimepiride group (dilatation 2: 40 s; dilatation 3: 45 s; CI 0.0 to 14.0 s; P=0023); and remained unchanged in the glibenclamide group (dilatation 2 and dilatation 3: 30 s; CI -7.5 to 7.5 s; P=0.67). CONCLUSION: These results show that glimepiride maintains myocardial preconditioning, while glibenclamide might be able to prevent it.

Adult↗
PubMed1999

Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature.

This report summarizes knowledge accumulated in a long-term study of congenital and maternal cytomegalovirus (CMV) infection in Sweden. Some new findings are included. We considered diagnostic methods, sources of maternal infection (including occupational risks), roles of primary and secondary maternal infections, transmission to foetuses, incidence, symptoms and prognosis of established congenital infection and relative importance of such infection in infantile sensorineural deafness, microcephaly and type 1 diabetes mellitus. Virus isolation testing was done 1977-1985 on 16,474 newborns. 76 (0.5%) congenitally infected infants were found, 22/76 (29%) with transient neonatal symptoms and 11/60 (18%) with neurological symptoms by the age of 7 y. Type of maternal CMV infection was serologically determined in 62/76 cases (30 primary, 32 secondary). CNS disturbances in the infants occurred after both primary (all trimesters) and secondary maternal infections. The negative potential of secondary maternal infections might be an obstacle to preventive vaccination.

Adolescent↗