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Biomedical subjects

S Harris

Publications and source records attributed to S Harris.

At least 19 recordsLinked to original sources
PubMed2001

Transgenic knockouts as part of high-throughput, evidence-based target selection and validation strategies.

The worldwide genome sequencing projects are helping to define the size and complexity of the expressed genome and are thereby identifying an unprecedented number of genes of uncertain disease alignment and unknown function. It is widely recognized that, within the pharmaceutical industry, a significant commercial advantage will accrue to those companies that most effectively gather and integrate additional biological information into their therapeutic target selection and drug progression strategies. This article presents the rationale for including comparative phenotypic information obtained from transgenic gene knockouts as an integral part of any future therapeutic target selection strategy.

Journal Article↗
PubMed2001

Lifestyles, diets, and Native American exposure factors related to possible lead exposures and toxicity.

Lead exposure is still a national concern, and it is possible that Native Americans who live on reservations and pursue traditional lifestyles may be at higher risk through both their unique exposure profiles and their potentially greater sensitivity. A major component of the exposure assessment is the diet. For tribal members, traditional lifestyles that include native foods, medicines, and traditional practices have evolved and proven to be the most healthful over many thousands of years of coexistence with the environment. However, a completely traditional diet may not be fully available for a variety of reasons; so, one must also consider the adverse health consequences caused by the loss of healthy native foods and medicines, the contamination of remaining native foods, the inability to practice one's religion, and the possibly lower quality of the substitute diet. Health evaluations of lead exposure on reservations should therefore consider at least two types of diets in addition to the typical suburban diet: (a) traditional diets composed of native foods and medicines that would result in increased exposure if the plants and animals are contaminated and (b) disadvantaged or commodity food diets that result in widespread vitamin and mineral deficits of the sort known to increase absorption of and response to lead. Additional exposure to lead might come from reservation housing which is often older, although the prevalence of lead-based paint on reservations is unknown. The degree of physiological response could also be affected by widespread exposures to other neurotoxins (such as mercury and PCBs in fish), underlying disease patterns, and genetics. Although each of these factors is plausible, their prevalence singly or in combination is unknown. Any correlation between these risk factors and blood lead levels on reservations is also unknown. This paper begins to address these gaps by discussing the range of traditional and current diets that may exist among tribes and methods for developing a whole-lifestyle exposure scenario that is appropriate for an individual tribe. Some of the factors discussed in this paper may not apply to the large population of Native Americans who live in urban situations.

Adult↗
PubMed2001

Fine mapping of Ath6, a quantitative trait locus for atherosclerosis in mice.

Ath6 is a novel quantitative trait locus associated with differences in susceptibility to atherosclerosis between C57BL/6J (B6) and C57BLKS/J (BKS) inbred mouse strains. Combining data from an intercross and a backcross (1593 meioses) between mice from B6 and BKS strains and from The Jackson Laboratory interspecific backcross panels, (C57BL/6J x Mus spretus) F1 x C57BL/6J and (C57BL/6J x SPRET/Ei) F1 x SPRET/Ei, we constructed a consensus genetic map and narrowed Ath6 to a 1.07 +/- 0.26 cM interval between the anonymous DNA marker D12Pgn4 and the gene Nmyc1. This region is near the proximal end of murine Chromosome (Chr) 12, which is homologous to the human chromosomal region 2p24-p25. Marker order in the Ath6 region was concordant among the two crosses and The Jackson Laboratory interspecific backcross panels. This high resolution map rules out candidate genes encoding apolipoprotein B, syndecan 1, and Adam17. The two Ath6 crosses have a combined potential resolution of 0.06 cM.

Alleles↗
PubMed2001

Dietary habits and dental health over the first 18 months of life.

OBJECTIVES: The main objective of this study was to describe the dental health of infants and toddlers with special reference to their dietary habits and oral hygiene behaviour over the first 18 months of life. METHODS: The longitudinal dietary data were obtained at 6, 12 and 18 months of age by using a 3-day weighed diet diary. Dental examinations were carried out at 12, and again at 18 months of age. The information on demographic factors and oral hygiene behaviours over the first 18 months of life was gathered by using a structured questionnaire at 12 and 18 months. RESULTS: 163 children were studied. Visible dental plaque was present in 18% and 25% of children at 12 and 18 months of age, respectively. No child had dental caries at either 12 or 18 months of age. There was a statistically significant correlation between visible plaque measured as plaque index at 12 months and the mean daily eating/drinking episodes at 6 months (r=0.25, P=0.001) and 12 months (r=0.15, P=0.05). The correlations between plaque index at 18 months and the mean eating/drinking episodes at both 12 months (r=0.2, P=0.04) and 18 months (r=0.2, P=0.02) were low but statistically significant. Nevertheless, there was no significant correlation between accumulation of plaque at either 12 or 18 months and the mean daily frequency consumption of food and drink containing non-milk extrinsic sugars (NMES) at any age. Children who brushed their teeth themselves were more likely to have visible plaque compared with children whose teeth were cleaned by their parents. The partial correlation showed that positive relation between mean daily eating/drinking episodes and plaque was not influenced by tooth brushing.

Analysis of Variance↗
PubMed2001

Immunohistochemical expression of cell cycle proteins E2F-1, Cdk-2, Cyclin E, p27(kip1), and Ki-67 in normal placenta and gestational trophoblastic disease.

The role of cell cycle protein expression in gestational trophoblastic disease is poorly understood. In this study we investigated the immunostaining patterns of G(1) restriction point and G(1)-S regulatory proteins E2F-1, Cdk2, cyclin E, p27(kip1), and the proliferation marker Ki-67 on routinely processed sections of 29 hydatidiform moles (10 partial moles and 19 complete moles, including 9 persistent moles), 7 choriocarcinomas, and 7 normal placentas. Ki-67 trophoblast staining decreased with increasing gestational age of the placenta, and showed maximal expression in gestational trophoblastic disease. Cyclin-dependent kinase activity, as reflected by Cdk2 expression patterns, also decreased with placental maturation. E2F-1 was uniquely expressed by trophoblasts of moles and choriocarcinoma. Cyclin E was maximally expressed by complete moles and choriocarcinomas, and showed an inverse relationship with the cyclin-dependent kinase inhibitor p27(kip1). Abnormal trophoblastic proliferations may be mediated through interactions of Cdk-2, E2F-1, cyclin E, and p27(kip1). Overexpression of cyclin E was associated with more aggressive forms of gestational trophoblastic disease. However, we did not find distinguishing features between complete moles that spontaneously resolved after evacuation and persistent moles that required chemotherapy. The different expression patterns of cyclin E and E2F-1 in partial and complete moles may be useful in distinguishing these two entities. Furthermore, loss of p27(kip1) in malignant trophoblast may represent a necessary step in the development of choriocarcinoma.

CDC2-CDC28 Kinases↗
PubMed2001

A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II.

An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of candesartan cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to candesartan cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of randomised treatment, the doses of candesartan cilexetil and losartan were doubled to 32 mg and 100 mg once daily and continued respectively for 6 weeks. At week 8, candesartan cilexetil lowered the blood pressure (BP) at 24 h (trough), 6 h (peak) and 48 h post dose to a significantly greater extent (P < 0.05) than losartan: candesartan cilexetil lowered trough BP by 13.4/10.5 mm Hg, peak BP by 15.5/12.9 mm Hg and 48-h BP by 10.5/9.9 mm Hg compared to a reduction of trough BP by 10.1/9.1 mm Hg, peak BP by 12.0/9.5 mm Hg, and 48-h BP by 5.9/7.0 mm Hg by losartan. The responder and control rates were numerically higher in the candesartan cilexetil group, but the differences did not reach statistical significance; the responder rates were 58.8% for the candesartan cilexetil group and 52.1% for the losartan group and control rates were 49.0% for the candesartan cilexetil group and 44.6% for the losartan group. Overall, both treatment regimens were well tolerated. A total of 15 of the 611 (2.5%) patients withdrew from the study due to an adverse event, including nine (2.9%) in the candesartan cilexetil group and six (2.0%) in the losartan group. In conclusion, this forced titration study confirms that candesartan cilexetil is more effective in lowering BP than losartan when compared at once daily maximum doses.

Antihypertensive Agents↗
PubMed2001

Analysis of badger urine volatiles using gas chromatography-mass spectrometry and pattern recognition techniques.

The potential for badger urine to signal olfactory information relating to sex, age class and seasonality was investigated by performing GCMS headspace analysis followed by pattern recognition statistical analysis on 84 urine samples collected from different categories of animal. Approximately 300 compounds were identified using library searching, and GCMS peak areas were recorded for the 33 most common. PCA was performed on the normalised and standardised data from all badgers, through which significant seasonal trends and groupings of homologous series of compounds were detected. PCA was also performed on the three subgroups of adults in the spring, summer and autumn, and a level of sexual discrimination was possible during the latter two seasons. Malanobis distances on the scores of the first five principal components provided good discrimination for these three subgroups, but discrimination was poor when all samples were analysed together. This, combined with the initial results of the PCA, confirms that a strong seasonal trend is imposed upon the sexual trend in this dataset. Our initial analysis indicates that badger urine potentially contains olfactory cues relating to sex and season. The relevance of these findings to understanding olfactory communication in mammals is discussed.

Animals↗
PubMed2001

Potassium titanyl phosphate laser treatment of resistant port-wine stains.

BACKGROUND: The pulsed dye laser (PDL; 585 nm, 450 micros pulse) has been established as the treatment of choice for port-wine stains (PWS), but only few patients have total clearance. A modulated potassium titanyl phosphate (KTP) laser (532 nm) has been developed that allows the adjustment of energy fluences within the 5-50 J cm-2 range with laser pulse widths between 1 and 50 ms at pulse rates from 1 to 20 pulses s(-1). OBJECTIVES: To determine the efficacy and side-effect rate of the KTP laser in treating PDL-resistant PWS. METHODS: Thirty patients were recruited. The site and colour of the PWS were recorded and assessed with erythemameter readings, videomicroscopy and photography both before and after treatment. All patients had test areas treated on their first visit and were then reviewed at 2-monthly intervals. Repeat treatments were given if no adverse effects had occurred and if the treated areas had shown between 25 and 100% lightening. RESULTS: Thirty patients were assessed, age range 11-63 years (mean 35.4) with 19 females. The PWS affected the face in 21 (70%) patients, leg in five (17%) and other sites in four (13%). Patients had one to four tests or treatments (mean 2.2) with the KTP laser. Overall, 16 (53%) patients showed > 25% response and five (17%) showed > 50% response to treatments with the KTP laser. Best responses were found with fluences ranging from 18 to 24 J cm(-2) with pulse width 9-14 ms. No correlation was found with the colour of the PWS or the number of previous treatments with PDL. Patients preferred the KTP laser treatments compared with the PDL (visual analogue score mean 9.8; n = 5) with less discomfort during treatments and minimal purpura post-treatment. Six patients (20%) developed side-effects: scarring (n = 2, 7%), hyperpigmentation (n = 3, 10%) and prolonged healing phase of over 4 weeks (n = 1, 3%). CONCLUSIONS: We have shown that the KTP laser can further lighten PDL-resistant PWS and that it is a useful addition to the laser treatment of PWS. Further studies need to assess the efficacy and side-effects of the KTP laser in previously untreated PWS.

Adolescent↗
PubMed2001

Reflecting on the use of student portfolios.

The use of portfolios in nursing has increased during recent years. We reflect upon the design and implementation of a portfolio for pre-registration nursing students in the School of Care Sciences(1)at the University of Glamorgan. The portfolio was introduced as the result of the need to address the theory-practice divide and to provide nurse students with the skills to maintain a professional profile upon registration. We also discuss other potential benefits associated with using the portfolio. These include the use of a portfolio as a focus for discussion between the student and their preceptor or personal tutor, a vehicle for the development of reflective skills and a means of assessment. We acknowledge that along with benefits, there are a number of potential problems and limitations in their use, for example, an increase in the workload for the student, preceptor and personal tutor. We include preliminary findings of an evaluation of our portfolio, revealing that both students and staff value the introduction of the portfolio, although currently it is not a high priority in terms of the course as a whole.

Documentation↗
PubMed2001

Provision of Internet-based rheumatology education (http://rheuma.bham.ac.uk).

OBJECTIVES: The Internet is becoming an important way of delivering medical information, and if used appropriately may assist in improving patients' self-management of their disease. We have established an arthritis education website ('Arthritis Help') and investigated its use over the last 2 yr. METHODS: Computer-generated log-file analysis and on-line questionnaires were used to create user profiles of our website. RESULTS: An average of 288 people visited our site each day, predominantly from America and the UK (49% of users). The typical questionnaire respondent (n = 770) was an American female with arthritis, aged 30+ yr, accessing the Internet from home. Typically, respondents had previously obtained information from medical staff or in written form, but were now more likely to use the Internet. One hundred and sixty-seven out of 585 respondents found our site to be useful, prompting them to seek more information (29%), change their behaviour or engage in more effective discussions with their physician (15%). CONCLUSIONS: These data indicate that it is possible to use the Internet to deliver medical information to its target audience, and that this process can have some impact on the way disease is self-managed. This information may aid more focused website design to maximize the use and potential benefits of such a resource.

Age Distribution↗
PubMed2001

Withdrawal from methadone maintenance treatment: prognosis and participant perspectives.

OBJECTIVE: To determine the proportion of clients engaged in methadone maintenance treatment who have favourable prognosis for withdrawal, and to examine client perceptions and expectations of withdrawal. METHODS: A broad cross-section of 856 methadone clients was sampled across Melbourne, Sydney and Brisbane. Self-complete surveys were developed for the clients, their clinic staff or pharmacists, and methadone prescribers. The client survey examined aspects of the clients' perspectives of withdrawal, and the surveys for the service providers collected information about each client's current treatment episode. Informed consent was provided by clients to obtain information from their clinic staff member or pharmacist, and their methadone prescriber. RESULTS: Most clients (70%) were at least very interested in methadone withdrawal. Clients were also more optimistic about their own post-withdrawal outcomes (in terms of opioid use) than both their clinic staff and prescribing doctors. Clinical criteria indicated that 31% of clients had a reasonable prognosis for withdrawal. However, when considering all factors, 17% had good withdrawal prognosis, were interested in methadone withdrawal, and believed it was very likely they would remain opioid-free for three months post-withdrawal. CONCLUSIONS: Despite the likely continued increase in client numbers in substitution maintenance treatment, the majority of methadone clients have a poor prognosis for withdrawal and should not be encouraged to cease treatment. IMPLICATIONS: Clients who do not meet key clinical criteria are likely to have poor clinical outcomes regardless of how withdrawal is attempted.

Adult↗
PubMed2000

Granulation rescue and developmental marking of juxtaglomerular cells using "piggy-BAC" recombination of the mouse ren locus.

Mice lacking a functional Ren-1(d) gene exhibit a complete lack of renal juxtaglomerular cell granulation and atypical macula densa morphology. Transgenic mice carrying a 145-kilobase BAC clone encompassing the Ren-1(d) and Ren-2 loci were generated, characterized, and backcrossed with Ren-1(d-/-) mice. Homozygous Ren-1(d)-null mice expressing the BAC clone exhibited complete restoration of normal renal structure. Homologous recombination in Escherichia coli was used to generate a modified version of the BAC clone, in which an IRESbeta-geo cassette was inserted specifically into the Ren-1(d) gene. When introduced into the germline, the modified clone provided a marker for juxtaglomerular cell differentiation and beta-geo was expressed appropriately in juxtaglomerular cells throughout development. Parallel backcross experiments onto the Ren-1(d)-null background demonstrated that the juxtaglomerular cells expressed the modified Ren-1(d) locus in the absence of regranulation. These data demonstrate that the nongranulated cells constitute bona fide juxtaglomerular cells despite their altered morphology, that overexpression of renin-2 cannot compensate for the loss of renin-1(d), and that primary structural differences between the two isoforms are responsible for the differences in granulation. The use of BAC modification as part of functional complementation studies illustrates the potential for in vivo molecular dissection of key physiological mechanisms.

Animals↗
PubMed2000

Clinical outcomes, quality of life, and costs in the North Thames Dialysis Study of elderly people on dialysis: a prospective cohort study.

BACKGROUND: Evidence-based health policy is urgently needed to meet the increasing demand for health services among elderly people, particularly for expensive technologies such as renal-replacement therapy. Age has been used to ration dialysis, although not always explicitly, despite the lack of rigorous empirical evidence about how elderly people fare on dialysis. We undertook a comprehensive assessment of outcomes in patients 70 years or over. METHODS: We did a 12-month prospective cohort study of outcomes in 221 patients with end-stage renal failure aged 70 years or over recruited from four hospital-based renal units. We assessed 1-year survival in 125 incident patients (70-86 years) and disease burden (hospital admissions, quality of life, costs) in 174 prevalent patients (70-93 years). FINDINGS: 1-year survival rates were: 71% overall; 80%, 69%, and 54% in patients 70-74 years, 75-79 years, and 80 years and older, respectively (p=0.008); and 88%, 71%, and 64% in patients with no, one, or two or more comorbid conditions, respectively (p=0.056). Cox regression analyses showed that mortality was significantly associated with age 80 years and older (relative risk 2.79 [95% CI 1.28-6.93]) and peripheral vascular disease (2.83 [1.29-6.17]), but not with diabetes, ischaemic heart disease, cerebrovascular disease, chronic obstructive airways disease, sex, or treatment method. In terms of disease burden, hospital admissions represent a low proportion of costs and was not required by a third of patients, mental quality of life in elderly dialysis patients was similar to that of elderly people in the general population, and the average annual cost per patient of 20802 (US$31200) (68% dialysis treatment, 1% transport, 19% inpatient hospital admissions, 12% medications) was within the range of other life-extending interventions. INTERPRETATION: Our results suggest that age alone should not be used as a barrier to referral and treatment and emphasise the need to consider the benefits of dialysis in elderly people. Indicators of the ability to benefit from treatment, rather than chronological age, should be used to develop policies that ensure equal access to care for all.

Aged↗
PubMed2000

Induction of labour: a continuous quality improvement and peer review program to improve the quality of care.

This article describes a program developed to improve the process of planned induction of labour and to reduce the rates of inappropriate induction. The setting is a tertiary-care maternity hospital in urban Vancouver, BC, in which 7000 deliveries take place annually. Approximately 65% of these can be considered primary care; the remainder are secondary- or tertiary-level cases. Continuous quality improvement (CQI) methods were used by a multidisciplinary team, which included nursing staff, physicians, health records personnel and a CQI facilitator. Interventions included the development of a new induction-booking process, clear criteria for induction, feedback to caregivers about changes and a peer review system to oversee and maintain improvement. The overall induction rate for the institution decreased, and this change has been maintained.

British Columbia↗
PubMed2000

A region in domain II of the urokinase receptor required for urokinase binding.

The urokinase receptor is composed of three homologous domains based on disulfide spacing. The contribution of each domain to the binding and activation of single chain urokinase (scuPA) remains poorly understood. In the present paper we examined the role of domain II (DII) in these processes. Repositioning DII to the amino or carboxyl terminus of the molecule abolished binding of scuPA as did deleting the domain entirely. By using alanine-scanning mutagenesis, we identified a 9-amino acid continuous sequence in DII (Arg(137)-Arg(145)) required for both activities. Competition-inhibition and surface plasmon resonance studies demonstrated that mutation of Lys(139) and His(143) to alanine in soluble receptor (suPAR) reduced the affinity for scuPA approximately 5-fold due to an increase in the "off rate." Mutation of Arg(137), Arg(142), and Arg(145), each to alanine, leads to an approximately 100-fold decrease in affinity attributable to a 10-fold decrease in the apparent "on rate" and a 6-fold increase in off rate. These differences were confirmed on cells expressing variant urokinase receptor. suPAR-K139A/H143A displayed a 50% reduction in scuPA-mediated plasminogen activation activity, whereas the 3-arginine variant was unable to stimulate scuPA activity at all. Mutation of the three arginines did not affect binding of a decamer peptide antagonist of scuPA known to interact with DI and DIII. However, this mutation abolished both the binding of soluble DI to DII-III in the presence of scuPA and the synergistic activation of scuPA mediated by DI and wild type DII-DIII. These data show that DII is required for high affinity binding of scuPA and its activation. DII does not serve merely as a spacer function but appears to be required for interdomain cooperativity.

Animals↗
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↗