Partnership in health: beyond the rhetoric.
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Public Health↗
Biomedical subjects
G Williams
Publications and source records attributed to G Williams.
Changes in medical student attitudes as they progress through a medical course.
OBJECTIVES: To explore the way ethical principles develop during a medical education course for three groups of medical students--in their first year, at the beginning of their penultimate (fifth) year and towards the end of their final (sixth) year. DESIGN: Survey questionnaire administered to medical students in their first, fifth and final (sixth) year. SETTING: A large medical school in Queensland, Australia. SURVEY SAMPLE: Approximately half the students in each of three years (first, fifth and sixth) provided data on a voluntary basis, a total of 385 students. RESULTS: At the point of entry, minor differences were found between medical students and first year law and psychology students. More striking were differences between male and female medical students, suggesting early socialization had a substantial impact here. CONCLUSIONS: Results indicate that substantial changes in attitude have developed by the beginning of fifth year with little change thereafter. Gender difference persisted. Some difference in ethical attitudes were found when groups of different ethnic backgrounds were compared. The impact of a move to a graduate medical course, which gives high priority to ethics within a professional development domain, can now be evaluated.
Attitude of Health Personnel↗
Hyperphagia in cold-exposed rats is accompanied by decreased plasma leptin but unchanged hypothalamic NPY.
Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4 degrees C for 21 days weighed 14% less than controls maintained at 22 degrees C (P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter (P < 0.001). Increase BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure.
Acclimatization↗
Qualitative research and evidence-based healthcare.
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Evidence-Based Medicine↗
Rationale and standards for the systematic review of qualitative literature in health services research.
Despite growing recognition of the need for qualitative methods in health services research, there have been few attempts to define quality standards for assessing the results. This article acknowledges the desirability of a plurality of standards. However, it is argued that three interrelated criteria can be identified as the foundation of good qualitative health research: interpretation of subjective meaning, description of social context, and attention to lay knowledge. These criteria can be examined in relation to different dimensions of any research report, including theoretical basis, sampling strategy, scope of data collection, description of data collected, and concern with generalizability or typicality. But if the concern is with the appropriateness of care and with understanding the factors that shape lay and clinical behavior, then these criteria must form the basis of a hierarchy of qualitative research evidence.
Humans↗
Interferon beta in the treatment of multiple sclerosis: mechanisms of action.
Interferon beta (IFN-beta) has been shown in several clinical trials to have efficacy in MS. Its mechanism of action, however, remains unclear. In this review, several biological activities of IFN-beta are highlighted, including its inhibitory effects on proliferation of leukocytes and antigen presentation. Furthermore, IFN-beta may modulate the profile of cytokine production toward that of the anti-inflammatory phenotype, and this appears to occur in the systemic circulation and within the CNS. Finally, IFN-beta can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases. These activities are likely to act in concert to account for the mechanism of IFN-beta in MS.
Adjuvants, Immunologic↗
Community perceptions of health, illness and care: identifying issues for indigenous communities.
Community meetings, interviews with key informants, and focus groups were used to document major health concerns and problems among Indigenous women in Queensland, as part of the Australian Longitudinal Study on Women's Health. In this article, we analyze understandings of "community" as used in Australian health research and among Indigenous women. We then examine health issues as identified and experienced by women and explore the gaps that exist between community concerns, individual health status, and service delivery.
Adolescent↗
Role of ARC NPY neurons in energy homeostasis.
Neuropeptide Y (NPY) is one of the most abundant and widely distributed neurotransmitters in the mammalian brain and appears to be an important regulatory peptide in both the central and peripheral nervous systems. The arcuate nucleus (ARC) is the major site of expression for NPY within neurons in the hypothalamus. The most noticeable effect of NPY is the stimulation of feeding. To date, six NPY receptor subtypes have been cloned and pharmacologically characterized, and there is evidence for further NPY receptor subtypes. The recent isolation and cloning of a rat NPY receptor with the required pharmacology for the feeding response, called the Y(5) receptor, has led to the suggestion that this is the "feeding" receptor. There is, however, still controversy as to whether the Y(5) receptor represents the true "feeding" receptor, since selective Y(1) receptor antagonists are capable of antagonizing NPY-induced hyperphagia. It also is possible that another, as yet unidentified, NPY receptor subtype(s) may mediate the effects of NPY on energy balance. The potency and behavioral specificity of NPY on feeding and its ability to induce obesity, together with the evidence that ARC-NPY neurons operate homeostatically to counteract energy deficits, all suggest that the ARC-PVN projection is important in regulating energy balance. The next few years will tell us whether or not these important physiological lessons will be successfully translated into a safe and effective form of therapy for human obesity.
Journal Article↗
The lack of specificity of neuropeptide Y (NPY) antisense oligodeoxynucleotides administered intracerebroventricularly in inhibiting food intake and NPY gene expression in the rat hypothalamus.
To evaluate the role of neuropeptide Y (NPY), a potent appetite stimulant, in controlling food intake and body weight, we investigated the use of antisense oligodeoxynucleotides (ODNs) to inhibit NPY gene expression in the hypothalamus. We compared the hypothalamic distribution of fluorescein-labelled ODNs administered intracerebroventricularly, and effects on food intake and NPY gene expression, of three different structural modifications of an antisense ODN sequence against NPY. Rats had either the antisense or missense ODNs (24 micrograms/day) or saline infused into the third ventricle by osmotic minipumps for 7 days. The unmodified phosphodiester ODN was not detectable in the hypothalamus after 7 days and had no effects on food intake. The phosphorothioate ODN was widely distributed throughout the hypothalamus but had nonselective effects, with similar changes in food intake and NPY mRNA levels in the antisense and missense groups, and was severely toxic. The propyl-protected ODN appeared to penetrate the hypothalamus well but had no antisense-selective effects on NPY mRNA levels or food intake. Antisense ODNs are increasingly used to inhibit gene expression in vitro and in intact animals. These negative findings underline the need for rigorous evaluation of any effects of antisense ODNs administered into the central nervous system, and raise doubts about the validity of this approach in physiological or pharmacological studies.
Analysis of Variance↗
Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro.
BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insulin-sensitizing agents, which are undergoing clinical evaluation as treatments for NIDDM. Potential side effects of thiazolidinediones include edema and hemodilution. Although the underlying mechanisms are presently unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglitazone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstricted with norepinephrine (NE; 6 micromol/l), troglitazone (n = 22 vessels), but not BRL 49653 (1-100 micromol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 micromol/l; P < 0.01). In the presence of indomethacin (IM; 10 micromol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and replaced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline) similar in magnitude to that produced by troglitazone vehicle (ethanol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (100 micromol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/- 8.0%, respectively; NS). In the presence of IM (10 micromol/l; n = 10), the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4%), although not significantly (NS vs. BRL 49653 alone or ethanol alone). Additional studies in Wistar rat arteries showed a similar vasodilator effect of troglitazone that was not inhibited by L-NAME (100 micromol/l). The alpha-tocopherol moiety alone had no vasorelaxant effect at concentrations up to 300 micromol/l. Thus, in human arterial resistance vessels in vitro, BRL 49653 does not possess the direct, IM-sensitive vasorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.
Adipose Tissue↗
A safety assessment of fixed combinations of acetaminophen and acetylsalicylic acid, coformulated with caffeine.
Overuse and abuse of phenacetin-containing mixed analgesics has contributed to end-stage renal disease. Combination analgesics, especially those coformulated with caffeine, have been implicated as imparting a greater risk of analgesic-associated nephropathy (AAN) than single or coformulated analgesics without caffeine. This has led to a recommendation that the sale of "two plus caffeine" analgesic mixtures be reclassified from over-the-counter to prescription only availability. There is a rational basis for coformulating acetylsalicylic acid (ASA) and acetaminophen (paracetamol) as this reduces the dose of each, without altering efficacy. The coformulation of caffeine with these analgesics has a significant adjuvant effect and increases analgesic efficacy 1.4-1.6-fold. Currently available animal and human data do not support the notion that the nephrotoxic risk from coformulated ASA and acetaminophen is higher than the risk from either ASA or acetaminophen alone, in equivalent analgesic doses. There are no epidemiological data that implicate caffeine in AAN, and only limited evidence that links excessive acetaminophen usage to renal disease. There is no evidence that caffeine increases analgesics papillotoxicity directly. The presence of caffeine in mixtures of analgesics are no more addictive than other sources of caffeine. There is no evidence to suggest that adding caffeine to analgesic mixtures enhances the potential for promoting analgesic misuse in the general population. Thus distinct therapeutic benefits of ASA, acetaminophen and caffeine appear to outweigh any known risk. It is doubtful if preventing the availability of these products will significantly affect the role of analgesic abuse/overuse in end-stage renal disease. Better risk management would come from a focused educational program, developed in a close collaboration between industry, healthcare professionals and consumer organizations, such a program must warn against the potential dangers of analgesic and non-steroidal anti-inflammatory drug misuse.
Acetaminophen↗
Rapid, automated assay for progesterone on the Abbott AxSYM analyzer.
We describe an automated assay for progesterone (P4) in human serum and plasma with the Abbott AxSYM random-access immunoassay analyzer. In this one-step competitive assay, P4 immobilized onto latex microparticles competes with sample P4 for binding to a conjugate of alkaline phosphatase (AP) and anti-P4 antibody. Total CVs ranged from 3.4% to 8.2% in multiple precision studies conducted according to the 20-day NCCLS EP5-T protocol. The detection limit (zero calibrator + 2 SD) was 0.10 microg/L across 36 experiments. Values for diluted samples were 83-116% of expected. Recovery of P4 added to serum specimens was 92-115%. Cross-reactivities with 43 natural and synthetic steroids were 0-6.3%. No significant interference was detected from bilirubin, protein, erythrocytes, hemoglobin, triglycerides, or cholesterol. In a multisite correlation study, AxSYM P4 results compared well with results from a commercial RIA method (n = 1156; r = 0.976; slope = 1.03; y-intercept = 0.04). Assay throughput is >80 tests per hour in batch mode, 60 tests per hour with mixed load list configurations.
Autoanalysis↗
A novel therapy for nocturnal polyuria: a double-blind randomized trial of frusemide against placebo.
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Aged↗
Increased hypothalamic neuropeptide Y concentration or hyperphagia in streptozotocin-diabetic rats are not mediated by glucocorticoids.
Hypothalamic neuropeptide Y containing neurones are overactive and may mediate hyperphagia in insulin-deficient diabetic rats, but the factors stimulating them remain uncertain. To determine the possible role of glucocorticoids, we investigated the effects of the glucocorticoid receptor blocker mifepristone (RU486) on food intake and regional hypothalamic neuropeptide Y concentrations in streptozotocin-diabetic rats. RU486 (30 mg/kg) or corn oil vehicle control was given orally for 3 weeks to diabetic rats. Food intake and neuropeptide Y levels in the hypothalamic arcuate and paraventricular nuclei were increased in untreated diabetic rat groups (P < 0.01), and though RU486 did increase plasma corticosterone levels (P < 0.01) it did not have any effect on either feeding or neuropeptide Y levels (P = NS). These negative findings suggest that glucocorticoids may not be responsible for increasing hypothalamic neuropeptide Y or for hyperphagia in insulin-deficient diabetes.
Animals↗
Distribution of [Leu31,Pro34]NPY-sensitive, BIBP3226-insensitive [125I]PYY(3-36) binding sites in rat brain: possible relationship to Y5 NPY receptors.
Recently, using molecular cloning approaches, three new neuropeptide Y (NPY)/peptide YY (PYY) receptors have been described in rodent brain, with pharmacological profiles that differ from the three previously described Y1, Y2 and Y3 NPY receptors and the Y4 pancreatic polypeptide- (PP-) preferring receptor. Two of these new receptors are spice variants and are called Y5 receptors, whilst a third receptor has been called Y6 and has been suggested to be expressed only in the mouse. In the absence of a totally selective Y5 and/or Y6 radioligands, we have examined [125I]PYY(3-36) binding, which binds Y2 and Y5/Y6 receptors, using homogenate assays and quantitative receptor autoradiography to study the distribution of the three newly discovered Y5/Y6 receptors by masking binding to Y1 receptors with high concentrations of the non-peptidergic selective Y1 antagonist, BIBP3226, and using either [Leu31,Pro34]NPY or human PP to mask binding to Y5 and Y6 receptors, leaving binding to Y2 receptors. Using this approach, [125I]PYY(3-36) labels a small population of Y1 receptors and a larger population of binding sites that are insensitive to BIBP3226, human PP and [Leu31,Pro34]NPY, presumed to be Y2 receptors. There was also [125I]PYY(3-36) binding to sites sensitive to NPY, human PP and [Leu31,Pro34]NPY, but insensitive to BIBP3226, located in the hypothalamus, amygdala, hippocampus and thalamus. As one of the recently cloned Y5 receptors is synthesized in these regions, as shown by in-situ hybridization techniques, we suggest that the small population of [125I]PYY(3-36) binding sites which are sensitive to human PP and [Leu31,Pro34]NPY, but insensitive to BIBP3226, may represent binding to Y5 receptors. We have been unable, however, to visualize a smaller population of Y6 receptors which are labelled by [125I]PYY3-36 and sensitive to [Leu31,Pro34]NPY, but not to BIBP3226 and human PP, confirming that the murine Y6 receptor does not appear to be expressed in rat brain.
Animals↗
Neutralizing epitopes on the extracellular interferon gamma receptor (IFNgammaR) alpha-chain characterized by homolog scanning mutagenesis and X-ray crystal structure of the A6 fab-IFNgammaR1-108 complex.
The extracellular interferon gamma receptor alpha-chain comprises two immunoglobulin-like domains, each with fibronectin type-III topology, which are responsible for binding interferon gamma at the cell surface. The epitopes on the human receptor recognized by three neutralizing antibodies, A6, gammaR38 and gammaR99, have been mapped by homolog scanning mutagenesis. In this way, a loop connecting beta-strands C and C' in the N-terminal domain was identified as a key component of the epitopes bound by A6 and gammaR38, whereas gammaR99 binds to the C-terminal domain in a region including strands A and B and part of the large C'E loop. The epitope for A6 was confirmed in a crystal structure of a complex between a recombinant N-terminal receptor domain and the Fab fragment from A6, determined by X-ray diffraction to 2.8 A resolution. The antibody-antigen interface buries 1662 A2 of protein surface, including 22 antibody residues from five complementarity determining regions, primarily through interactions with the CC' surface loop of the receptor. The floor of the antigen binding cavity is formed mainly by residues from CDR L3 and CDR H3 while a surrounding ridge is formed by residues from all other CDRs except L2. Many potential polar interactions, as well as 13 aromatic side-chains, four in VL, six in VH and three in the receptor, are situated at the interface. The surface of the receptor contacted by A6 overlaps to a large extent with that contacted by interferon-gamma, in the ligand-receptor complex. However, the conformation of this epitope is very different in the two complexes, demonstrating that conformational mobility in a surface loop on this cytokine receptor permits steric and electrostatic complementarity to two quite differently shaped binding sites.
Amino Acid Sequence↗
Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat.
Neuropeptide Y (NPY) potently induces feeding, reduces thermogenesis and induces obesity in rats when injected into the cerebral ventricles. Groups of male Wistar rats were either restricted to 60% of their normal daily food intake over 10 days or made obese by presenting them with a high-calorie diet rich in sugars and fat over 6 weeks. Food restricted rats lost up to 20% of their body weight, compared with control rats and had large reductions in their body fat mass. By contrast, rats with dietary-induced obesity weighed 26% more than controls due mainly to increased body fat mass. Quantitative receptor autoradiography demonstrated reduced [(125)I]PYY binding in the hypothalamic lateral (perifornical) and dorsal areas, hypothalamic ventromedial, arcuate and dorsomedial nuclei, hippocampal CA3 region, centromedial amygdaloid nucleus and thalamic paraventricular and reuniens nuclei in dietary restricted rats compared with controls. By contrast, regional [(125)I]PYY binding was significantly increased in hypothalamic lateral and dorsal areas, hypothalamic arcuate and dorsomedial nuclei, amygdaloid medial and centromedial nuclei, thalamic centromedial and paraventricular nuclei of dietary obese rats versus controls. Masking NPY Y1 receptors with 1 microM BIBP3226, a selective Y1 receptor antagonist, revealed that the changes in [(125)I]PYY binding in brains of food-restricted and dietary-obese rats were due to changes in BIBP3226-insensitive binding sites, presumably Y2 or Y5 NPY receptors. These data suggest that dietary-restriction stimulates NPY release resulting in down-regulation of NPY Y5 'feeding' and/or Y2 receptors and reduced BAT thermogenesis thereby providing an increased drive to eat to restore normal caloric intake whilst reducing thermogenesis in order to conserve fat reserves. By contrast, the up-regulation of NPY Y5 and/or Y2 receptors in dietary-induced obesity is consistent with inhibition of NPY release in the hypothalamus, amygdala and thalamus. Overall, we suggest that there is a regional increase in NPY release during negative energy balance, such as during food-restriction and a reduced regional release of NPY in positive energy balance, such as during hyperphagia associated with the development of obesity.
Amygdala↗
Giving thyroid hormones to clinically hypothyroid but biochemically euthyroid patients. Distinguishing hypothyroid symptoms from common non-specific complaints is difficult.
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Humans↗