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Biomedical subjects

S M Dunn

Publications and source records attributed to S M Dunn.

At least 19 recordsLinked to original sources
PubMed1999

Misunderstanding in cancer patients: why shoot the messenger?

AIM: We aimed to document the prevalence of misunderstanding in cancer patients and investigate whether patient denial is related to misunderstanding. PATIENTS AND METHODS: Two hundred forty-four adult cancer outpatients receiving treatment completed a survey assessing levels of understanding and denial. Doctors provided the facts against which patient responses were compared. Multiple logistic regression analyses determined the predictors of misunderstanding. RESULTS: Most patients understood the extent of their disease (71%, 95% CI: 65%-77%) and goal of treatment (60%, 95% CI: 54%-67%). Few correctly estimated the likelihood of treatment achieving cure (18%, 95% CI: 13%-23%), prolongation of life (13%, 95% CI: 8%-17%) and palliation (18%, 95% CI: 10%-27%). Patient denial predicted misunderstanding of the probability that treatment would cure disease when controlling for other patient and disease variables (OR = 2.20, 95% CI: 0.99-4.88, P = 0.05). Patient ratings of the clarity of information received were also predictive of patient understanding. CONCLUSIONS: Patient denial appears to produce misunderstanding, however, doctors' ability to communicate effectively is also implicated. The challenge that oncologists face is how to communicate information in a manner which is both responsive to patients' emotional status and sufficiently informative to allow informed decision-making to take place.

Adaptation, Psychological↗
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↗
PubMed1997

Amyotrophic lateral sclerosis immunoglobulins are ineffective in altering calcium influx through presynaptic voltage-sensitive calcium channels.

Recent work has suggested that one factor in the etiology of the neuromuscular disease, amyotrophic lateral sclerosis (ALS), may be an autoimmune mechanism in which presynaptic voltage-sensitive calcium channels are an antigenic target. We have developed a fluorescence technique to measure rapid Ca2+ influx through presynaptic calcium channels in isolated nerve terminals (synaptosomes) from rat cerebral cortex. Depolarization of the synaptosomes by elevated external K+ concentration caused a rapid increase in cytoplasmic Ca2+, as measured by a change in fluorescence of the Ca2+ chelating dye, Fura-2, which was loaded inside the synaptosomes. Pharmacological characterization suggests that the P- and Q-subtypes of voltage-sensitive calcium channels mediate the majority of this Ca2+ influx. The synaptosome preparation has been used as a model system to investigate the effects of IgG, purified from eight ALS patients, on presynaptic calcium channel function. IgG (1 microgram ml-1 to 1 mg ml-1) was preincubated with the synaptosomes prior to depolarization. IgG, from these eight ALS patients, had no systematic effects on presynaptic Ca2+ influx. Thus, using this system, we find no evidence for an effect of ALS IgG on the function of presynaptic calcium channels.

Adult↗
PubMed1997

Medicaid AIDS waivers: seeking cost effective financing of AIDS care.

The epidemic of Acquired Immunodeficiency Syndrome (AIDS) emerged at a time of transition in American health care and health care policy. The waiver of traditional Medicaid limitations on home and community-based health care services for persons with AIDS has been utilized by several states attempting to demonstrate models of care where quality of life as well as financial concerns are addressed. The Medicaid AIDS Waiver programs in New Jersey and Florida note promising results in the cost-effectiveness of such programs when compared with traditional Medicaid. Variations in patient participation by geographic area and demographic characteristics indicate areas for future improvement in program accessibility.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Processor quality assurance using digital imaging.

The purpose of this study was to develop and test a computer imaging method for assessing longitudinal processor variability. A technique called adaptive histogram equalization was used to test deviation in automatic processing when a test film is compared with a time-temperature processed standard at two different kVp's and film speeds. In a 14-day study we found that the density ranges for the standard film did not change, while the density range of the automatically processed films changed by a factor of two. These results suggest that if automatic processing is to be used for films taken as part of a longitudinal study-for example, subtraction-then processor variation can potentially lead to incorrect inference of bone gain or loss.

Absorptiometry, Photon↗