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Biomedical subjects

S M Dunn

Publications and source records attributed to S M Dunn.

At least 55 records · Page 3Linked to original sources
PubMed1999

Predictors of breast cancer in women recalled following screening.

BACKGROUND: Established risk factors are associated with between 25 and 56% of breast cancer cases, but the relative importance and relevance to different age groups is unclear. METHODS: This case-control study examines established risk factors in 298 women with breast cancer and 1926 women without breast cancer aged 40-87 who were recalled for assessment following routine mammography. RESULTS: The cancer group were significantly older than the non-cancer group (F1,222 = 107.6; P < 0.0001). Postmenopausal obesity increased the odds of developing breast cancer (OR: 2.35; CI: 1.33-4.16). The breast cancer group were more likely to have used oral contraceptives (OR: 1.50; CI: 1.09-2.05), and women who used contraceptives for more than 10 years in total were at the highest risk (OR: 1.73; CI: 1.13-2.65). Daily consumption of alcohol was also associated with increased risk of developing breast cancer (OR: 1.62; CI: 1.13-2.33). Reproductive factors and a family history of breast cancer did not affect the odds of developing breast cancer and the reasons for these findings are explored. CONCLUSIONS: Results suggest that the effects of weight reduction in reducing postmenopausal breast cancer risk should be assessed.

Adult↗
PubMed1999

Doctors' participation in randomized trials of adjuvant systemic therapy in breast cancer: how does it relate to their recommendations for standard therapy in breast cancer?

A cross-sectional survey of all medical and radiation oncologists in Australia was undertaken, plus surgeons listed as participants of the ANZ Breast Cancer Trials Group, to examine whether doctors' participation in randomized trials of adjuvant systemic therapy for breast cancer, is associated with their recommendations for adjuvant therapy in two clinical scenarios. Two-hundred and sixty-nine questionnaires were returned (response rate 71%). Fifty-six per cent of respondents, were participating in current adjuvant systemic therapy trials. Radiation oncologists were significantly more likely than surgeons or medical oncologists to recommend radiotherapy, while medical oncologists and surgeons were significantly more likely than radiation oncologists to recommend chemotherapy, in both clinical scenarios. In a multivariate analysis adjusting for the differences between specialist groups, respondents recommending chemotherapy were more likely to be high accruers to clinical trials (OR 3.6, 95% CI 0.93 to 13.9, P=0.08) in scenario 1, or participants of a breast cancer trials organization (OR 3.1, 95% CI 1.6 to 5.9, P=0.001) in scenario 2. Some of the variation in adjuvant systemic therapy recommendations is associated with participation in adjuvant systemic therapy trials. However, this study is unable to determine if trial participation influences opinions about adjuvant therapy, or opinions influence trial participation.

Journal Article↗
PubMed1999

Psychosocial predictors of survival in metastatic melanoma.

PURPOSE: Research interest in psychosocial predictors of the onset and course of cancer has been active since the 1950s. However, results have been contradictory and the literature is noted for methodologic weaknesses. In this prospective study, we aimed to systematically obtain data on psychosocial factors associated with human response to illness. PATIENTS AND METHODS: One hundred twenty-five patients with metastatic melanoma completed questionnaires measuring cognitive appraisal of threat, coping, psychologic adjustment, perceived aim of treatment, social support, and quality of life (QOL). Questionnaires were completed, where possible, every 3 months for 2 years after diagnosis. Survival was measured from date of study entry to date of death or was censored at the date of last follow-up for surviving patients. RESULTS: In a multivariate Cox regression analysis of baseline data, which controlled for demographic and disease predictors, the psychologic variables of perceived aim of treatment (P <.001), minimization (P <. 05), and anger (P <.05) were independently predictive of survival. Patients who were married (P <.01) and who reported a better QOL (P <.05) also survived longer. CONCLUSION: The prognostic significance of psychologic and QOL scores remained after allowance for conventional prognostic factors. If these associations reflect an early perception by the patient or doctor of disease progression, then measures are at least valuable early indicators of such progression. If psychologic processes have a more direct influence on the course of the underlying illness, then it may be possible to manipulate them for therapeutic effect. We are now conducting a randomized controlled trial of a psychologic intervention to further elucidate these issues.

Adaptation, Psychological↗
PubMed1999

Mutagenesis of the rat alpha1 subunit of the gamma-aminobutyric acid(A) receptor reveals the importance of residue 101 in determining the allosteric effects of benzodiazepine site ligands.

The gamma-aminobutyric acid(A) (GABA(A)) receptor contains a binding site (or sites) for benzodiazepines and related ligands. Previous studies have shown that the residue occupying position 101 (rat numbering) of the alpha subunit is particularly important in determining how some of these compounds interact with the receptor. We have made multiple substitutions (F, Y, K, Q, and E) of the histidine at this position of the rat alpha1 subunit and coexpressed the mutant subunits with beta2 and gamma2 subunits in Xenopus oocytes. The effects of flunitrazepam, Ro15-1788, and Ro15-4513 on GABA-gated currents were then examined using electrophysiological techniques. Three substitutions (F, Y, and Q) had little effect on the ability of flunitrazepam to potentiate GABA-induced currents and had relatively modest effects on the EC(50) value of the flunitrazepam response. Other mutations (K and E) resulted in drastic reduction of flunitrazepam recognition. All substitutions also affected the EC(50) values for Ro15-1788 and Ro15-4513, and some led to dramatic changes in their efficacy. For example, H101Y, H101K, and H101Q produced receptors at which Ro15-1788 acted as a partial agonist (maximum potentiation of 164, 159, and 130%, respectively), whereas Ro15-4513 acted as a partial agonist at H101F, H101K, and H101E (potentiation of 122, 138, and 110%, respectively) and an antagonist at H101Y and H101Q. These results indicate that the characteristics of the residue at position 101 of the alpha1 subunit play a crucial role in determining the efficacy of benzodiazepine-site ligands.

Allosteric Regulation↗
PubMed1998

Identification of a unique domain in bovine brain GABAA receptors that is photoaffinity labelled by [3H]Ro15-4513.

We have used photoaffinity labelling and protein cleavage techniques to identify the site of photoincorporation of [3H]Ro15-4513 into the alpha subunit of the bovine gamma-aminobutyric acid type A (GABAA) receptor. Bovine brain membranes were photoaffinity labelled with [3H]Ro15-4513 and after solubilization and denaturation, proteins were specifically cleaved at either cysteine or tryptophan residues. Peptides were resolved by sodium dodecyl sulphate polyacrylamide gel electrophoresis. Cleavage at cysteine residues generated a labelled peptide of Mr 6.5K, while cleavage at tryptophan residues generated a labelled peptide with an Mr of 5K. Cleavage products of this size indicate that the site of [3H]Ro15-4513 incorporation occurs between the end of the first transmembrane domain and the first four amino acids of the third transmembrane domain (residues 247-289). This region of the GABAA receptor has not previously been implicated in the formation of the benzodiazepine binding site and may be part of a unique recognition domain for inverse agonists.

Affinity Labels↗
PubMed1998

The use of unproven methods of treatment by cancer patients. Frequency, expectations and cost.

The use of unproven therapies is of concern for a number of reasons, including the lack of scientific evidence of support them, their potential financial costs and the possibility of interference with conventional treatment. This study explored the prevalence, predictors and experiences of unproven therapy use by cancer patients attending an oncology clinic at an Australian teaching hospital. A questionnaire was administered to patients whilst they were waiting for a consultation with their oncologist. A total of 173 patients were invited to participate, and 156 consented to complete the survey (90%). Over half the patients (81, 52%) had used at least one unproven therapy since their diagnosis, and 28% had used three or more. Patients most commonly practised mediation/relaxation, changed their diet and used multi-vitamins. Most expected that the therapies would aid their conventional treatments and make them feel more in control of their situation. Benefits reported were largely psychological, such as an increased sense of control or a reduction in anxiety. Younger patients, those with early stage or advanced metastatic disease and those who had used unproven therapies prior to developing cancer were more likely to use unproven therapies. Health professionals involved in the care of cancer patients should be prepared to discuss the use of unproven therapies and try to identify and deal with unmet needs to help patients to cope with their illness.

Adult↗
PubMed1998

The Notch signalling pathway in hair growth.

The Notch signalling pathway is an important mediator of cell fate selection whose involvement in epidermal appendage formation is now becoming recognised. Hair follicle development and hair formation involve the co-ordinated differentiation of several different cell types in which Notch appears to have a role. We report intricate expression patterns for the Notch-1 receptor and three ligands, Delta-1, Jagged-1 and Jagged-2 in the hair follicle. Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1 is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode. Expression of Jagged-1 or Jagged-2 overlaps Notch-1 expression at all stages. In mature follicles, Jagged-1 and Jagged-2 are expressed in complementary patterns in the follicle bulb and outer root sheath, Jagged-1 in suprabasal cells and Jagged-2 predominantly in basal cells. In the follicle bulb, Jagged-2 is localised to the inner (basal) bulb cells next to the dermal papilla which do not express Notch-1, whereas Jagged-1 expression in the upper follicle bulb overlaps Notch-1 expression and correlates with bulb cell differentiation into hair shaft cortical and cuticle keratinocytes.

Animals↗
PubMed1998

Structural requirements for ligand interactions at the benzodiazepine recognition site of the GABA(A) receptor.

His101 of the GABA(A) receptor alpha1 subunit is an important determinant of benzodiazepine recognition and a major site of photolabeling by [3H]flunitrazepam. To investigate further the chemical specificity of the residue in this position, we substituted it with phenylalanine, tyrosine, lysine, glutamate, glutamine, or cysteine. The mutant alpha subunits were coexpressed with the rat beta2 and gamma2 subunits in TSA201 cells, and the effects of the substitutions on the binding of benzodiazepine site ligands were examined. [3H]Ro 15-4513 bound to all mutant receptors with equal or greater affinity than to the wild-type receptor. However, flunitrazepam and ZK93423 recognition was adversely affected by substitutions of the amino acid in this position. The binding of the antagonists, Ro 15-1788 and ZK93426, was also sensitive to the mutations, with the largest decreases in affinity occurring with the tyrosine, lysine, and glutamate substitutions. In all mutants that recognized flunitrazepam, GABA potentiated the binding of this ligand to a similar extent, suggesting that it is a full agonist at these receptors. The effects of GABA on the binding of Ro 15-1788 and Ro 15-4513 suggest that their efficacies may have been changed by some of the substitutions. This study further emphasizes the importance of the residue at position 101 in both ligand recognition and pharmacological effect.

Allosteric Site↗
PubMed1998

Intrathecal sufentanil versus epidural lidocaine with epinephrine and sufentanil for early labor analgesia.

UNLABELLED: Intrathecal sufentanil provides approximately 2 h of excellent labor analgesia with minimal motor blockade. Epidural sufentanil has received less scrutiny but may provide the same benefits as intrathecal sufentanil. In this study, we compared epidural sufentanil 40 microg after a lidocaine with an epinephrine test dose with intrathecal (i.t.) sufentanil 10 microg with respect to onset and duration of analgesia, degree of motor block, side effect profile, and mode of delivery. Seventy ASA physical status I or II parturients in early labor (< or = 4 cm cervical dilation) were randomized to receive either i.t. sufentanil 10 microg with a combined spinal-epidural technique (CSE) or epidural sufentanil 40 microg (e.p.) after epidural catheter placement and testing with 3 mL of 1.5% lidocaine with epinephrine (15 microg). After the administration of analgesia, pain scores and side effects were recorded for each patient at 5, 10, 15, 20, and 30 min, and every 30 min thereafter, by an observer blinded to the technique used. The study period was completed when the patients requested additional analgesia. All patients, except one, achieved adequate analgesia with the initial study dose and satisfactorily completed the study. There were no demographic differences between the two groups. Pain relief was rapid for all patients; pain scores were significantly lower at 5 and 10 min in the i.t. group versus the e.p. group. The mean duration of analgesia was similar between the e.p. group (127 +/- 40 min) and the i.t. group (110 +/- 48 min). No patient experienced any motor block. Side effects were similar between the two groups, except for pruritus-both the incidence and severity were significantly more profound at 5, 10, 15, 20, and 30 min in the i.t. group. There was no difference in time from analgesic to delivery, incidence of operative or assisted delivery, or cervical dilation at the time of redose. For early laboring patients, epidural sufentanil 40 microg after a lidocaine test dose provides analgesia comparable to that of i.t. sufentanil 10 microg with less pruritus. IMPLICATIONS: We compared the efficacy and side effects of intrathecal sufentanil with epidural sufentanil with a local anesthetic test dose for analgesia during labor. Analgesia was equally good, although the intrathecal group experienced more itching.

Adult↗
PubMed1998

Gastric contents in children presenting for upper endoscopy.

UNLABELLED: Previous studies of gastric contents in children presenting for surgery specifically excluded those with gastrointestinal disorders. Because these children often need sedation or anesthesia for procedures such as upper endoscopy, it is important to determine the gastric fluid volume and pH in this group to better characterize their risk of aspiration. We therefore analyzed the gastric fluid volume and pH of children with a variety of gastrointestinal symptoms presenting for upper endoscopy. After obtaining institutional review board approval, the stomach contents of 248 children (aged 2 mo to 18 yr) presenting for upper endoscopy were prospectively measured under direct endoscopic vision. Children were fasted for both solids and liquids for at least 6 h (<6 mo) or 8 h (>6 mo). Gastric fluid pH was measured using pH paper. Children received either deep sedation or general anesthesia and were grouped according to their presenting diagnosis. Results were analyzed by using analysis of variance, Kruskal-Wallis, and correlation (P value < 0.05). The mean gastric fluid volume was 0.35 +/- 0.45 mL/kg (range 0-3.14 mL/kg), and the mean gastric fluid pH was 1.37 +/- 1.6 (range 1-7). Of the children, 33% had gastric fluid volumes >0.4 mL/kg, 87% had gastric fluid pH <2.5, and 30% had gastric fluid volume >0.4 mL/kg and pH <2.5. Children with the presenting complaint of abdominal pain had the largest gastric fluid volumes. These data are not appreciably different from historical controls (healthy children fasted for an equivalent period of time who did not have gastrointestinal symptoms). IMPLICATIONS: When fasted for at least 6-8 h, children with a history of gastrointestinal symptoms presenting for upper endoscopy did not have gastric contents with increased volume and acidity compared with previously published groups of children without gastric symptoms who were fasted the same length of time. These results do not support the argument that children with gastrointestinal symptoms pose an increased anesthetic risk for aspiration.

Adolescent↗
PubMed1998

Regulation of a hair follicle keratin intermediate filament gene promoter.

During hair growth, cortical cells emerging from the proliferative follicle bulb rapidly undergo a differentiation program and synthesise large amounts of hair keratin proteins. To identify some of the controls that specify expression of hair genes we have defined the minimal promoter of the wool keratin intermediate filament gene K2.10. The region of this gene spanning nucleotides -350 to +53 was sufficient to direct expression of the lacZ gene to the follicle cortex of transgenic mice but deletion of nucleotides -350 to -150 led to a complete loss of promoter activity. When a four base substitution mutation was introduced into the minimal functional promoter at the binding site for lymphoid enhancer factor 1 (LEF-1), promoter activity in transgenic mice was decreased but specificity was not affected. To investigate the interaction of trans-acting factors within the minimal K2.10 promoter we performed DNase I footprinting analyses and electrophoretic mobility shift assays. In addition to LEF-1, Sp1, AP2-like and NF1-like proteins bound to the promoter. The Sp1 and AP2-like proteins bound sequences flanking the LEF-1 binding site whereas the NF1-like proteins bound closer to the transcription start site. We conclude that the LEF-1 binding site is an enhancer element of the K2.10 promoter in the hair follicle cortex and that factors other than LEF-1 regulate promoter tissue- and differentiation-specificity.

Animals↗
PubMed1998

Effects of propofol and pentobarbital on ligand binding to GABAA receptors suggest a similar mechanism of action.

The GABAA receptor is allosterically modulated by a number of anesthetics and barbiturates. We have examined the effects of propofol and pentobarbital on the binding of the receptor agonist [3H]muscimol and the benzodiazepine modulators [3H]flunitrazepam and [3H]Ro15-4513 to bovine brain membranes. Both agents potentiated the binding of [3H]muscimol (5 nM), with EC50 values of 18.7 and 276 microM, respectively. The binding of [3H]muscimol is heterogeneous, suggesting the presence of both high (Kd approximately 10 nM) and low (Kd approximately 0.1-1.0 microM) affinity sites. The major effect of both propofol and pentobarbital was to increase the affinity of the lower affinity sites without changing the total binding capacity. In contrast, the steroid anesthetic alphaxalone did not affect the affinity of these sites, suggesting that this drug has distinct effects on the GABAA receptor. Propofol and pentobarbital also increased the binding of the benzodiazepine agonist [3H]flunitrazepam and decreased the binding of the inverse agonist [3H]Ro15-4513. The results of these studies demonstrate that propofol and pentobarbital modulate the binding of ligands to the GABAA receptor in a similar manner, suggesting that these drugs may have a common mechanism of action.

Allosteric Site↗
PubMed1997

Agonist binding to the Torpedo acetylcholine receptor. 1. Complexities revealed by dissociation kinetics.

Examination of the kinetics of dissociation of [3H]acetylcholine and [3H]suberyldicholine from the membrane-bound acetylcholine receptor from Torpedo californica has revealed complexities in the high-affinity binding of nicotinic agonists. Each agonist binds to two high-affinity sites per receptor with an equilibrium dissociation constant of approximately 15 nM. When dissociation of [3H]acetylcholine from the receptor complex was triggered by dilution, dissociation occurred as a monophasic process with an apparent rate of 0.023 +/- 0.010 s(-1). However, when micromolar concentrations of unlabeled agonists (acetylcholine, carbamylcholine or suberyldicholine) were included in the dilution buffer this rate increased about 5-fold. This accelerating effect occurred even when the two high-affinity sites were initially saturated with the radioligand. This suggested the presence of an additional site (or subsite) for agonist with affinity in the micromolar range. However, at concentrations of 0-20 microM, no additional sites for [3H]acetylcholine were detected at equilibrium. To explain these results, we propose that each high-affinity site is made up of two subsites, A and B, which are mutually exclusive at equilibrium. With [3H]acetylcholine initially occupying site A, occupancy of site B by unlabeled ligand reduces the affinity for site A and accelerates the dissociation of the radioligand. Studies of dissociation of [3H]suberyldicholine, a large bis-quaternary agonist, provide some clue as to the possible physical nature of these subsites. Whereas its dissociation rate was similar to that of [3H]acetylcholine (0.028 +/- 0.012 s(-1)), this rate was only marginally, if at all, affected by the presence of unlabeled ligands. These results, in addition to those presented in the accompanying manuscript, lead to the proposal that [3H]suberyldicholine is able to cross-link the two subsites or at least sterically occlude the second site.

Acetylcholine↗
PubMed1997

Agonist binding to the Torpedo acetylcholine receptor. 2. Complexities revealed by association kinetics.

The binding of suberyldicholine to membrane-bound Torpedo acetylcholine receptor has been monitored by fluorescence changes of covalently bound 5-iodoacetamidosalicylic acid (IAS). At equilibrium, suberyldicholine binds to two high-affinity binding sites (Kd approximately 20 nM). Kinetic experiments reveal that there is rapid formation of an initial complex (Kd approximately 2 microM) which undergoes sequential fast (k(app) approximately 1 s(-1)) and slow (k(app) approximately 0.05 s(-1)) conformational changes. These kinetics differ from those reported for other agonists [Blanchard, S. G., Dunn, S. M. J., & Raftery, M. A. (1982) Biochemistry 24, 6258-6264] in that, for suberyldicholine, there is no evidence for a second pathway involving the binding of an additional agonist molecule. These results, considered together with the observed dissociation kinetics (accompanying manuscript), suggest that each high-affinity site for acetylcholine is made up of two subsites, which suberyldicholine is able to bridge, thus occluding the binding of a second ligand. The kinetic mechanism for acetylcholine binding has been re-examined to accommodate the complexities of the [3H]-acetylcholine dissociation kinetics and the observation that, at equilibrium, no more than two occupied binding sites are detected [accompanying manuscript: Dunn, S. M. J., & Raftery, M. A. (1997) Biochemistry 36, 3846-3853]. It is suggested that, for each acetylcholine binding site, a second ligand is able to bind but that the ternary complex is transient since one of the two bound ligands again dissociates in the formation of the equilibrium mono-liganded complex. To further probe the physical nature of the two subsites, the binding of a series of bis-quaternary suberyldicholine analogues, (CH3)3N+CH2CH2OCO(CH2)n-COOCH2CH2N+(CH3)3, to IAS-labeled receptor preparations has been examined. Analogues in which n < 5 behave like acetylcholine, i.e., a second ligand binding pathway is observed, but longer ligands (n = 5-10) act like suberyldicholine and may be long enough to cross-link the sites.

Acetamides↗
PubMed1997

The dynamics of change: cancer patients' preferences for information, involvement and support.

BACKGROUND: While the importance of providing individualised communication to cancer patients is now well recognised, little is known about the stability and validity of patients' expressed preferences for information and involvement in decision-making. This study explored the stability and possible predictors of such preferences over time. PATIENTS AND METHODS: Cancer patients seeing two Medical Oncologists in an out-patient clinic at an Australian teaching hospital completed a questionnaire battery before and directly after one consultation, and before their next consultation. Eighty consecutive patients with heterogeneous cancers participated in the study. Preferences for general and specific information, involvement and support were elicited at each assessment. Locus of control and patient familiarity with the clinic were measured before the first consultation. Patient satisfaction with the consultation was assessed directly after the consultation. Demographic and disease data were recorded for each patient. RESULTS: General preferences for information and involvement were relatively stable, at least in the short term; however there was considerable variability in preferences for specific topics of information. Patients whose condition had recently worsened were more likely to want progressively less involvement in decision-making. Gender, the doctor seen and religion were also predictive of patient preferences. CONCLUSIONS: Situational factors, such as change in disease status, may alter a patient's preferences for information and involvement. If we wish to match the provision of information and support to the expressed needs of patients, we must ask patients at each consultation what those needs are.

Adolescent↗