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R Perkins

Publications and source records attributed to R Perkins.

At least 19 recordsLinked to original sources
PubMed2001

Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens.

Understanding structural requirements for a chemical to exhibit estrogen receptor (ER) binding has been important in various fields. This knowledge has been directly and indirectly applied to design drugs for human estrogen replacement therapy, and to identify estrogenic endocrine disruptors. This paper reports structure-activity relationships (SARs) based on a total of 230 chemicals, including both natural and xenoestrogens. Activities were generated using a validated ER competitive binding assay, which covers a 10(6)-fold range. This study is focused on identification of structural commonalities among diverse ER ligands. It provides an overall picture of how xenoestrogens structurally resemble endogenous 17beta-estradiol (E(2)) and the synthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, five distinguishing criteria were found to be essential for xenoestrogen activity, using E(2) as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the17beta-OH and O-O distance between 3- and 17beta-OH, (3) precise steric hydrophobic centers mimicking steric 7alpha- and 11beta-substituents, (4) hydrophobicity, and (5) a ring structure. The 3-position H-bonding ability of phenols is a significant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17beta-OH contributes as a H-bond donor only. The precise space (the size and orientation) of steric hydrophobic bulk groups is as important as a 17beta-OH. Where a direct comparison can be made, strong estrogens tend to be more hydrophobic. A rigid ring structure favors ER binding. The knowledge derived from this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.

Animals↗
PubMed2000

Predicted changes in pre-mRNA secondary structure vary in their association with exon skipping for mutations in exons 2, 4, and 8 of the Hprt gene and exon 51 of the fibrillin gene.

Exon skipping that accompanies exonic mutation might be caused by an effect of the mutation on pre-mRNA secondary structure. Previous attempts to associate predicted secondary structure of pre-mRNA with exon skipping have been hindered by either a small number of available mutations, sub-optimal structures, or weak effects on exon skipping. This report identifies more extensive sets of mutations from the human and hamster Hprt gene whose association with exon skipping is clear. Optimal secondary structures of the wild-type and mutant pre-mRNA surrounding each exon were predicted by energy minimization and were compared by energy dot plots. A significant association was found between the occurrence of exon skipping and the disruption of a stem containing the acceptor site consensus sequences of exon 8 of the human Hprt gene. However, no change in secondary structure was associated with skipping of exon 4 of the hamster Hprt gene. Using updated energy parameters we found a different structure than that previously reported for exon 2 of the hamster Hprt gene. In contrast to the previously reported structure, no significant association was found between predicted structural changes and skipping of exon 2. For all three Hprt exons studied, there was a significantly greater number of deoxythymidine substitutions among mutations accompanied by exon skipping than among mutations without exon skipping. For exon 8, deoxythymidine substitution was also associated with structural changes in the stem containing the acceptor site consensus sequences. For exon 51 of the human fibrillin gene, structural differences from wild type were predicted for all four mutations accompanied by exon skipping that were not were predicted for a single mutation without exon skipping. Our results suggest that both primary and secondary pre-mRNA structure contribute to definition of Hprt exons, which may involve exonic splicing enhancers.

Animals↗
PubMed2000

Corporate governance of public health services: lessons from New Zealand for the state sector.

New Zealand public hospitals and related services were grouped into 23 Crown Health Enterprises and registered as companies in 1993. Integral to this change was the introduction of corporate governance. New directors, largely from the business sector, were appointed to govern these organisations as efficient and effective businesses. This article presents the results of a survey of directors of New Zealand publicly-owned health provider organisations. Although directors thought they performed well in business systems development, they acknowledged their shortcomings in meeting government expectations in respect to financial performance and social responsibility. Changes in public health sector provider performance indicators have resulted in a mixed report card for the sector six years after corporate governance was instituted.

Delivery of Health Care↗
PubMed2000

The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands.

We have utilized a validated (standardized) estrogen receptor (ER) competitive-binding assay to determine the ER affinity for a large, structurally diverse group of chemicals. Uteri from ovariectomized Sprague-Dawley rats were the ER source for the competitive-binding assay. Initially, test chemicals were screened at high concentrations to determine whether a chemical competed with [3H]-estradiol for the ER. Test chemicals that exhibited affinity for the ER in the first tier were subsequently assayed using a wide range of concentrations to characterize the binding curve and to determine each chemical's IC50 and relative binding affinity (RBA) values. Overall, we assayed 188 chemicals, covering a 1 x 10(6)-fold range of RBAs from several different chemical or use categories, including steroidal estrogens, synthetic estrogens, antiestrogens, other miscellaneous steroids, alkylphenols, diphenyl derivatives, organochlorines, pesticides, alkylhydroxybenzoate preservatives (parabens), phthalates, benzophenone compounds, and a number of other miscellaneous chemicals. Of the 188 chemicals tested, 100 bound to the ER while 88 were non-binders. Included in the 100 chemicals that bound to the ER were 4-benzyloxyphenol, 2,4-dihydroxybenzophenone, and 2,2'-methylenebis(4-chlorophenol), compounds that have not been shown previously to bind the ER. It was also evident that certain structural features, such as an overall ring structure, were important for ER binding. The current study provides the most structurally diverse ER RBA data set with the widest range of RBA values published to date.

Animals↗
PubMed2000

A dose-ranging study of rapacuronium in pediatric patients.

BACKGROUND: The aim of this study was to determine the dose or doses of the new rapid-onset, short-acting, neuromuscular blocking drug rapacuronium that would provide satisfactory conditions for tracheal intubation at 60 s in infants and children. METHODS: Sixty-five infants (< 1 yr), 51 younger children (1-6 yr), and 49 older children (7-12 yr) were studied. Anesthesia was induced with thiopental-nitrous oxide-oxygen. Tracheal intubation was attempted 60 s after administration of one of five doses of rapacuronium (0.5, 1.0, 1.5, 2.0, or 2.5 mg/kg) and intubating conditions were assessed using a four-point scale. Following tracheal intubation, anesthesia was maintained with nitrous oxide-oxygen and alfentanil (12.5-50 microg/kg) as necessary. Neuromuscular transmission was monitored in an uncalibrated fashion using an acceleromyograph. RESULTS: Intubating conditions were good or excellent at 60 s in all infants after doses of 1.5 mg/kg or more and in all younger and older children after doses of 2.0 mg/kg or more. The duration of action of rapacuronium was dose- and age-dependent. Mean times to reappearance of the third twitch of the train-of-four (TOF; T3) were less than 10 min in infants at doses of 1.5 mg/kg or less and in younger and older children at doses of 2.0 mg/kg or less. Recovery of T3 after 1.0-2.0 mg/kg rapacuronium was significantly slower in infants compared with younger (P = 0.001) and older (P = 0.02) children. Five adverse experiences were related to rapacuronium administration: Bronchospasm (two instances), tachycardia (one instance), and increased salivation (two instances). None were serious. CONCLUSIONS: Doses of 1.5 and 2.0 mg/kg rapacuronium can produce satisfactory intubating conditions at 60 s in anesthetized infants and children, respectively, and are associated with a short duration of action.

Age Factors↗
PubMed2000

Ionization and photoelectric smoke alarms in rural Alaskan homes.

OBJECTIVE: To compare rates of nuisance alarms and disconnection between ionization and photoelectric smoke alarms. DESIGN: A prospective cohort study. SETTING: Four Inupiat Eskimo villages in the Northwest Arctic Borough region of Alaska, 48 km (30 mi) above the Arctic Circle. SUBJECTS: Households in 4 communities with similar populations, number of homes, mean income, size of household, and square footage per home. INTERVENTION: Two villages had photoelectric alarms installed (58 homes), and 2 other villages had ionization alarms installed (65 homes) in standard locations. Follow-up household surveys were conducted after 6 months to determine rates of false alarms and detector disconnection. All of the households that could be contacted 104/123 agreed to participate in the follow-up surveys. Main outcome measures The proportion of households experiencing false alarms and the proportion of disabled alarms in households in each of the test communities. RESULTS: Homes with ionization alarms had more than 8 times the rate of false alarms as those with photoelectric alarms. Eleven of the ionization alarms (19%) were disconnected compared with 2 of the photoelectric devices (4%). CONCLUSIONS: In small rural residences, photoelectric smoke alarms have lower rates of false alarms and disconnection. Photoelectric alarms may be the preferred choice for dwellings with limited living space or frequent false alarms.

Alaska↗
PubMed2000

Quantitative comparisons of in vitro assays for estrogenic activities.

Substances that may act as estrogens show a broad chemical structural diversity. To thoroughly address the question of possible adverse estrogenic effects, reliable methods are needed to detect and identify the chemicals of these diverse structural classes. We compared three assays--in vitro estrogen receptor competitive binding assays (ER binding assays), yeast-based reporter gene assays (yeast assays), and the MCF-7 cell proliferation assay (E-SCREEN assay)--to determine their quantitative agreement in identifying structurally diverse estrogens. We examined assay performance for relative sensitivity, detection of active/inactive chemicals, and estrogen/antiestrogen activities. In this examination, we combined individual data sets in a specific, quantitative data mining exercise. Data sets for at least 29 chemicals from five laboratories were analyzed pair-wise by X-Y plots. The ER binding assay was a good predictor for the other two assay results when the antiestrogens were excluded (r(2) is 0.78 for the yeast assays and 0.85 for the E-SCREEN assays). Additionally, the examination strongly suggests that biologic information that is not apparent from any of the individual assays can be discovered by quantitative pair-wise comparisons among assays. Antiestrogens are identified as outliers in the ER binding/yeast assay, while complete antagonists are identified in the ER binding and E-SCREEN assays. Furthermore, the presence of outliers may be explained by different mechanisms that induce an endocrine response, different impurities in different batches of chemicals, different species sensitivity, or limitations of the assay techniques. Although these assays involve different levels of biologic complexity, the major conclusion is that they generally provided consistent information in quantitatively determining estrogenic activity for the five data sets examined. The results should provide guidance for expanded data mining examinations and the selection of appropriate assays to screen estrogenic endocrine disruptors.

Binding, Competitive↗
PubMed1999

Determining clinically meaningful cognitive impairment following traumatic brain injury.

AIMS: To study the reliability and validity of ratings of: neuropsychological impairment with test data from traumatically brain-injured patients. METHODS: Neuropsychological test results from 66 traumatically brain-injured adults and 27 orthopaedic controls were rated for neuropsychological impairment by an experienced neuropsychologist and three undergraduate students provided with brief training in test interpretation. Ratings were based on the discrepancy between a patient's current cognitive level and their estimated premorbid cognitive level. Decision making rules were utilised in making the ratings. The raters, who were blind with respect to the patients diagnostic group membership, independently rated test results. Test results were rerated using the same method approximately two weeks later. RESULTS: The ratings of novice raters were in good to very good agreement with the ratings of an expert. All raters evidenced very good to excellent test-retest reliability. Higher rates of neuropsychological impairment were found in the traumatically brain-injured group than in the orthopaedic control group. Discriminant function analysis suggested that raters employed information from all neuropsychological measures (with the exception of current intellectual level), in making their overall ratings of neuropsychological impairment. CONCLUSION: These findings provide encouraging preliminary evidence in support of the reliability and validity of individual case-based ratings of neuropsychological impairment. The high false positive rate in the control sample may reflect the relatively low specificity of neuropsychological impairment.

Adolescent↗
PubMed1999

Effects of a body image curriculum for college students on improved body image.

OBJECTIVE: This study evaluated the effects of an undergraduate body image course, "Body Traps: Perspectives on Body Image," on decreasing body dissatisfaction, weight concern, and disordered eating behaviors. METHODS: Twenty-four undergraduate females enrolled in the body image course. Measures of body image and disordered eating patterns were assessed at baseline and at postintervention. RESULTS: Subjects significantly decreased the frequency and severity of their body dissatisfaction and disordered eating. No changes in body mass index or global self-esteem were observed. DISCUSSION: This is the first investigation to demonstrate that a formal, academic course can result in the reduction of both attitudinal and behavioral eating disorder risk factors. Future controlled studies need to be undertaken to substantiate this effect.

Adult↗
PubMed1999

A comparison of the impact of hospital reform on medical subcultures in some Australian and New Zealand hospitals.

This article examines similarities and differences in the way that hospital staff in Australia and New Zealand are evaluating efforts to improve quality, clinical effectiveness and service integration, and to strengthen clinical accountability. We draw on data from a cross-national study of hospital staff in Australia and New Zealand. The results highlight the way in which respondents' views about reform are influenced by the interplay of two factors: the impact of respondents' occupational backgrounds (our findings point to differences in the profession-based subcultures of medicine, nursing and general management and the way that these are reflected in respondents' assessments of particular aspects of reform); and the way that the impact of professional subcultures may be mitigated by differences between the systems in which respondents were located, including differences between the programs of reform that have been pursued in each country. The implications of these findings are discussed.

Australia↗
PubMed1999

Comparison of estrogen receptor alpha and beta subtypes based on comparative molecular field analysis (CoMFA).

A substantial body of evidence indicates that both humans and wildlife suffer adverse health effects from exposure to environmental chemicals that are capable of interacting with the endocrine system. The recent cloning of the estrogen receptor beta subtype (ER-beta) suggests that the selective effects of estrogenic compounds may arise in part by the control of different subsets of estrogen-responsive promoters by the two ER subtypes, ER-alpha and ER-beta. In order to identify the structural prerequisites for ligand-ER binding and to discriminate ER-alpha and ER-beta in terms of their ligand-binding specificities, Comparative Molecular Field Analysis (CoMFA) was employed to construct a three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) model on a data set of 31 structurally-diverse compounds for which competitive binding affinities have been measured against both ER-alpha and ER-beta. Structural alignment of the molecules in CoMFA was achieved by maximizing overlap of their steric and electrostatic fields using the Steric and Electrostatic ALignment (SEAL) algorithm. The final CoMFA models, generated by correlating the calculated 3D steric and electrostatic fields with the experimentally observed binding affinities using partial least-squares (PLS) regression, exhibited excellent self-consistency (r2 > 0.99) as well as high internal predictive ability (q2 > 0.65) based on cross-validation. CoMFA-predicted values of RBA for a test set of compounds outside of the training set were consistent with experimental observations. These CoMFA models can serve as guides for the rational design of ER ligands that possess preferential binding affinities for either ER-alpha or ER-beta. These models can also prove useful in risk assessment programs to identify real or suspected EDCs.

Algorithms↗
PubMed1998

An evaluation of services for women with long-term mental health problems.

This paper presents the results of an evaluation study of services for women with long-term mental health problems. The study, which was conducted in a long-term rehabilitation and community care service, examined the adequacy, accessibility, and responsiveness of services provided for women users; explored differences between the men and women using the service and those newly admitted to it; and explored the views and experiences of service providers and the women users themselves. The results of the study confirm and extend those of previous studies and suggest a number of service recommendations. The unevenness in attention to the needs of women across services needs to be addressed. Services should be more attractive to women. Agencies and facilities for women outside mental health services should be supported to ensure that they can accommodate women with long-term mental health problems, and the women themselves need to be offered the support necessary to ensure they have access to such facilities. Finally, efforts must be made to ensure that services both recognize the losses that women with long-term mental health problems have experienced and foster their continued hopes and aspirations for the future.

Adult↗
PubMed1998

'I wanted to be a nurse ... but I didn't get that far': women with serious ongoing mental health problems speak about their lives.

Within mental health services there are fewer women than men with serious mental health problems and there is evidence that their needs are relatively neglected resulting in specific deleterious effects. In research, as in services, the abilities of women with serious mental health problems appear to be under-estimated, and there is almost a total absence of research into the views and experiences of such women. This study aimed to explore the lives of women with serious ongoing mental health problems and their experience of services, to develop understanding of the context and impact of mental distress. In a series of 5 focus group interviews, the women, who were using a range of services for people with long-term mental health problems, described lives which, even before the onset of mental health problems, were marked by material, social and personal disadvantage. Their mental health problems led to numerous losses: loss of homes, jobs, relationships, children and loss of 'normality', yet the women retained hopes and aspirations for the future. The women clearly identified aspects of the service that they valued, in particular the support and company of women workers and other women service users. The implications of these findings are discussed in relation to planning and providing mental health services for women.

Activities of Daily Living↗
PubMed1998

Pharmacokinetics of sparfloxacin in the serum and vitreous humor of rabbits: physicochemical properties that regulate penetration of quinolone antimicrobials.

We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% +/- 12.2% of that in serum. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin. There are two modes of quinolone translocation into and out of the vitreous humor: diffusion into the eye and both diffusion and carrier-mediated elimination out of the vitreous humor.

Animals↗