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Biomedical subjects

S A Thomas

Publications and source records attributed to S A Thomas.

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

A patient determined general practice satisfaction questionnaire.

OBJECTIVES: To develop and explore the use of a patient satisfaction questionnaire based on patient perceptions of items which influence satisfaction and to explore patient and practitioner characteristics which influence the results. METHOD: Twenty focus groups identified 39 items which were then assembled into a questionnaire which was evaluated by attendees at 133 Australian general practices. MAIN OUTCOME MEASURES: Overall satisfaction with general practitioner services and the appropriateness of the 39 items identified by focus group participants; socio-demographic characteristics of patients and practitioners and the impact of these characteristics on the results; factor analysis of the relationship of the items to each other and to overall satisfaction. RESULTS: Questionnaires were completed by 12,605 patients of 133 general practices. Seventy-three percent of these patients reported they were overall very satisfied with the care they received and 26% were satisfied. There were five individual items for which an average of more than 10% of patients reported they were not satisfied: waiting time at the surgery (18%); ease of obtaining home visits (17%); ease of seeing the doctor out of normal hours (15%); cost of drugs (12%) and facilities for children in the waiting room (10%). Factors which were more likely to result in a report of patients being very satisfied included: patients being older; if patients had visited recently; if they had attended the practice for a long time; if they visited only one general practice and had more consultations in the past 12 months. Patients of solo practitioners were more likely to report they were satisfied with individual items and patients of practices of three or more practitioners were least likely. No significant differences between practices of different sizes in the level of overall satisfaction were detected. Factor analysis identified three major factors which we have described as containing interaction, technical and accessibility items. These three factors explained 44.4% of the variance in results. CONCLUSION: This project found the items patients identified were similar to those identified by practitioners, and reiterated previous findings that there is substantial variability in the levels of satisfaction reported by patients of Australian general practices.

Adolescent↗
PubMed1998

Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction.

BACKGROUND: Myocardial conduction depends on intercellular transfer of current at gap junctions. Atrial myocytes express three different gap junction channel proteins-connexin43 (Cx43), connexin45 (Cx45), and connexin40 (Cx40)-- whereas ventricular myocytes express only Cx43 and Cx45. However, the physiological roles of individual connexins are unknown. We have previously shown that mice heterozygous for a null mutation in the gene encoding Cx43 (Cx43(+/-) mice) express 50% of the normal amount of Cx43 in ventricular myocardium and exhibit marked slowing of ventricular conduction. METHODS AND RESULTS: To determine whether atrial conduction is affected in Cx43(+/-) mice, we measured atrial conduction velocity in isolated hearts, performed detailed ECG and electrophysiological studies in intact animals, and determined the amount of cardiac connexins in atrial and ventricular tissue. Ventricular conduction velocity was reduced by 38% in Cx43(+/-) mice compared with wild-types, but atrial conduction velocity in the same hearts was normal. QRS duration was significantly greater in Cx43(+/-) mice than in wild-types, but P-wave duration and amplitude did not differ. Atrial expression of Cx43 was reduced by 50%. CONCLUSIONS: These results indicate that Cx43 is a principal conductor of intercellular current in the ventricle because ventricular conduction is significantly slowed when Cx43 content is reduced by only 50%. In contrast, a similar reduction in Cx43 content in atrial muscle has no effect on atrial conduction, suggesting that Cx40 (which is expressed in atrial but not ventricular myocytes) is a major electrical coupling protein in atrial muscle. Thus, Cx43 and Cx40 may be chamber-specific determinants of myocardial conduction.

Animals↗
PubMed1998

Transport of opioid peptides into the central nervous system.

Peptide hormones and neurotransmitters play crucial roles in the maintenance of physiological function at both the cellular and organ level. Although peptide neuropharmaceuticals have enormous potential in the treatment of disease states, the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain either by enzyme degradation or by specific properties of the BBB. Peptides that act at opioid receptors are currently being designed for analgesia and to reduce the unwanted side effects associated with morphine, such as addiction and inhibition of gastric motility. It has been the focus of our group to produce stabile peptide analogues of Met-enkephalin, that lead to analgesia without side effects. In this paper we present the methodologies that have been used to elucidate the transport mechanisms of three peptides across the BBB. Using a primary endothelial cell culture model of the BBB, in situ perfusion, and kinetic analysis we show that D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) crosses the BBB via diffusion, [D-penicillamine2,5]enkephalin uses a combination of diffusion and a saturable transport mechanism, and biphalin ([Tyr-D-Ala-Gly-Phe-NH]2) uses diffusion and the large neutral amino acid carrier. Understanding BBB transport mechanisms for peptides will aid in the rational design of peptides targeted to the brain.

Animals↗
PubMed1998

The transport of the anti-HIV drug, 2',3'-didehydro-3'-deoxythymidine (D4T), across the blood-brain and blood-cerebrospinal fluid barriers.

1. The brain is a site of infection, viral replication and sanctuary for HIV-1. The treatment of HIV-1 infection therefore requires that an effective agent be delivered to the brain. 2',3'-Didehydro-3'-deoxythymidine (D4T) is a nucleoside analogue which has been shown to have beneficial clinical effects in the treatment of HIV infection. However, although D4T has been detected in human CSF, the ability of this drug to cross both the blood-brain and blood-cerebrospinal fluid (CSF) barriers and gain entrance into the brain tissue is not known. 2. This study examined the CNS entry of D4T by means of the bilateral vascular brain perfusion technique in the anaesthetized guinea-pig. 3. The results indicated that [3H]-D4T had a limited ability to cross the blood-brain barrier (BBB), which was not significantly greater than D-[14C]-mannitol (a slowly penetrating marker molecule). Although D4T was found to cross the blood-CSF barrier, the presence of D4T in the CSF did not reflect levels of the drug in the brain tissue. 4. These results can be related to the measured low lipophilicity of D4T, the higher paracellular permeability characteristics of the choroid plexus (blood-CSF barrier) compared to the BBB, and the sink action nature of the CSF to the brain tissue. 5. In conclusion, these animal studies suggest that D4T may only penetrate the brain tissue to a limited extent and consideration should be given to these findings in the clinical situation.

Analysis of Variance↗
PubMed1998

Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase.

Mice with a targeted disruption of the dopamine beta-hydroxylase (DBH) gene are unable to synthesize norepinephrine (NE) and epinephrine. These mice have elevated levels of dopamine in most tissues, although the levels are only a fraction of those normally found for NE. It is noteworthy that NE can be restored to normal levels in many tissues after a single injection of the synthetic amino acid precursor of NE, L-threo-3,4-dihydroxyphenylserine (DOPS). In other tissues, NE can be restored to normal levels after multiple injections of DOPS, whereas in the midbrain and cerebellum, restoration of NE is limited to 25-30% of normal. NE levels typically peak approximately 5 h after DOPS administration and are undetectable by 48 h. Epinephrine levels are more difficult to restore. The elevated levels of dopamine fall modestly after injection of DOPS. S(-)-Carbidopa, which does not cross the blood-brain barrier, inhibits aromatic L-amino acid decarboxylase and effectively prevents restoration of NE by DOPS in the periphery, while allowing restoration in the CNS. Ptosis and reductions in male fertility, hind-limb extension, postdecapitation convulsions, and uncoupling protein expression in dopamine beta-hydroxylase-deficient mice are all reversed by DOPS injection.

Animals↗
PubMed1998

Preventive care and continuity of attendance. Is there a risk?

OBJECTIVE: To explore whether there are associations between continuity of care and the provision of items of preventive care in Australian general practice. METHOD: Patient completed questionnaires from a 'consecutive' sample of Australian general practitioners enrolled in the Patient Participation Program of the Quality Assurance and Continuing Medical Education Program of the Royal Australian College of General Practitioners. MAIN OUTCOME MEASURES: An association was sought between the length of time patients reported attending their practitioner, whether they regularly attended more than one practice, and whether they were provided with preventive care. RESULTS: Data from 12,605 questionnaires, completed by patients from 133 practices throughout Australia found that patients who reported only visiting one practice on a regular basis were significantly more likely to report the provision of: blood pressure screening within the past 12 months; cholesterol screening in the past 5 years; adequate smoking cessation information if required; to have discussed the benefits of diet and exercise; to have received a cervical smear in the past 2 years; and to have received adequate instruction in the technique of breast self examination. Patients attending the same practices for longer periods were significantly more likely to have received the above items with the exception of adequate information to enable them to stop smoking if they desired; and cervical smears in the past 2 years. Such patients were less likely to report the provision of tetanus immunisation in the past 10 years and cervical smears in the past 2 years. CONCLUSIONS: Patients reporting greater continuity of care measured by only consulting at one practice or visiting the practice for a longer time period reported a greater provision of preventive care than patients who did not report these characteristics.

Australia↗
PubMed1997

Impaired maternal behavior in mice lacking norepinephrine and epinephrine.

The roles of norepinephrine (NE) and epinephrine in behavior were investigated by targeted disruption of the dopamine beta-hydroxylase (Dbh) gene, thereby eliminating these compounds in vivo. Most heterozygous pups born to Dbh-/- females died within several days of birth and were often found scattered within the bedding. Potential causes including deficits in olfaction and lactation were not apparent. A deficit in maternal behavior was confirmed by the lack of pup retrieval exhibited by Dbh-/- virgin females. Restoration of NE shortly before but not after birth induced females that previously abandoned their litters to act maternally. Our results suggest that NE is responsible for long-lasting changes that promote maternal behavior during both development and parturition in mice.

Animals↗
PubMed1997

Saturation kinetics, specificity and NBMPR sensitivity of thymidine entry into the central nervous system.

It was not until the development of a technique that could measure the brain uptake of slowly moving substrates, that the saturable transport system at the blood-brain barrier (BBB) for the pyrimidine deoxyribonucleoside, thymidine, was demonstrated. The aim of this present study was to further characterize this saturable uptake system at the blood-brain and blood-CSF barriers in terms of specificity, 6-(4-nitrobenzyl)thio-9-beta-D-ribofuranosylpurine (NBMPR) sensitivity and saturation kinetics by means of the in situ brain perfusion technique in anaesthetized guinea pigs. The results indicated that the transport system identified for [3H]thymidine can also transport other pyrimidine deoxyribonucleosides (deoxycytidine) and pyrimidine ribonucleosides (uridine) and is partially NBMPR-sensitive. In addition, guanosine, monocarboxylic acids, hexoses or amino acids were not substrates for the transport system. Further studies revealed that the transport system for [3H]thymidine at the BBB has a low affinity (Km 0.20 +/- 0.06 mM), but a relatively high capacity (Vmax 1.06 +/- 0.08 nmol min(-1) g(-1)). Overall, this study is indicative of a NBMPR-sensitive (es) facilitative transport system for [3H]thymidine and the likely presence of a NBMPR-insensitive and/or sodium-dependent transport system of the N2 (cit) type at the blood-brain and blood-CSF barriers of the guinea pig.

Affinity Labels↗
PubMed1997

Norepinephrine facilitates the development of the murine sweat response but is not essential.

During development, the sympathetic neurons innervating sweat glands undergo a neurotransmitter switch from noradrenergic to cholinergic between postnatal day (P) 4, when the sympathetic neurons first contact the sweat glands, and P21. Several in vitro experiments suggest that norepinephrine (NE), produced by sympathetic neurons, stimulates sweat glands to produce a factor that then induces the phenotypic switch. We tested this hypothesis in vivo using dopamine beta-hydroxylase-deficient mice (DBH -/-), which are unable to synthesize NE and epinephrine, and tyrosine hydroxylase-deficient mice (TH -/-), which are unable to synthesize any catecholamines. The cholinergic agonist pilocarpine and electrostimulation of the sciatic nerve both elicited a sweat response in adult DBH -/- mice that was indistinguishable from the response of controls, and the cholinergic antagonist atropine effectively blocked these responses. We did note, however, a 1- to 2-week delay in the acquisition of the sweat response in DBH -/- mice. Although diminished in magnitude, a sweat response to pilocarpine was also noted in TH -/- mice at P21. Immunohistochemistry demonstrated that TH and vasoactive intestinal peptide were detectable at P14 and increased to adult levels by P21 in DBH +/- and DBH -/- mice. These observations indicate that NE is not essential for the acquisition of the cholinergic phenotype, but it may facilitate its postnatal development.

Acetylcholine↗
PubMed1997

Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.

Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose tissue occurs in response to cold and overeating (diet induced), and there is an inverse relationship between diet-induced thermogenesis and obesity both in humans and in animal models. As a potential model for obesity, we generated mice that cannot synthesize noradrenaline or adrenaline by inactivating the gene that encodes dopamine beta-hydroxylase. These mice are cold intolerant because they have impaired peripheral vasoconstriction and are unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP1). The mutants have increased food intake but do not become obese because their basal metabolic rate is also elevated. The unexpected increase in basal metabolic rate is not due to hyperthyroidism, compensation by the widely expressed uncoupling protein UCP2, or shivering.

Adipose Tissue↗
PubMed1997

Disruption of the metallothionein-III gene in mice: analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures.

Metallothionein-III (MT-III), a brain-specific member of the metallothionein family of metal-binding proteins, is abundant in glutamatergic neurons that release zinc from their synaptic terminals, such as hippocampal pyramidal neurons and dentate granule cells. MT-III may be an important regulator of zinc in the nervous system, and its absence has been implicated in the development of Alzheimer's disease. However, the roles of MT-III in brain physiology and pathophysiology have not been elucidated. Mice lacking MT-III because of targeted gene inactivation were generated to evaluate the neurobiological significance of MT-III. MT-III-deficient mice had decreased concentrations of zinc in several brain regions, including hippocampus, but the pool of histochemically reactive zinc was not disturbed. Mutant mice exhibited normal spatial learning in the Morris water maze and were not sensitive to systemic zinc or cadmium exposure. No neuropathology or behavioral deficits were detected in 2-year-old MT-III-deficient mice, but the age-related increase in glial fibrillary acidic protein expression was more pronounced in mutant brain. MT-III-deficient mice were more susceptible to seizures induced by kainic acid and subsequently exhibited greater neuron injury in the CA3 field of hippocampus. Conversely, transgenic mice containing elevated levels of MT-III were more resistant to CA3 neuron injury induced by seizures. These observations suggest a potential role for MT-III in zinc regulation during neural stimulation.

Aging↗
PubMed1997

Bone mass and bone turnover in power athletes, endurance athletes, and controls: a 12-month longitudinal study.

Strain magnitude may be more important than the number of loading cycles in controlling bone adaptation to loading. To test this hypothesis, we performed a 12 month longitudinal cohort study comparing bone mass and bone turnover in elite and subelite track and field athletes and less active controls. The cohort comprised 50 power athletes (sprinters, jumpers, hurdlers, multievent athletes; 23 women, 27 men), 61 endurance athletes (middle-distance runners, distance runners; 30 women, 31 men), and 55 nonathlete controls (28 women, 27 men) aged 17-26 years. Total bone mineral content (BMC), regional bone mineral density (BMD), and soft tissue composition were measured by dual-energy X-ray absorptiometry. Bone turnover was assessed by serum osteocalcin (human immunoradiometric assay) indicative of bone formation, and urinary pyridinium crosslinks (high-performance liquid chromatography) indicative of bone resorption. Questionnaires quantified menstrual, dietary and physical activity characteristics. Baseline results showed that power athletes had higher regional BMD at lower limb, lumbar spine, and upper limb sites compared with controls (p < 0.05). Endurance athletes had higher BMD than controls in lower limb sites only (p < 0.05). Maximal differences in BMD between athletes and controls were noted at sites loaded by exercise. Male and female power athletes had greater bone density at the lumbar spine than endurance athletes. Over the 12 months, both athletes and controls showed modest but significant increases in total body BMC and femur BMD (p < 0.001). Changes in bone density were independent of exercise status except at the lumbar spine. At this site, power athletes gained significantly more bone density than the other groups. Levels of bone formation were not elevated in athletes and levels of bone turnover were not predictive of subsequent changes in bone mass. Our results provide further support for the concept that bone response to mechanical loading depends upon the bone site and the mode of exercise.

Adolescent↗
PubMed1997

Disruption of the dopamine beta-hydroxylase gene in mice suggests roles for norepinephrine in motor function, learning, and memory.

Mice unable to synthesize norepinephrine (NE) were created by targeted disruption of the dopamine beta-hydroxylase (DBH) gene. DBH-deficient (DBH -/-) mice display normal home cage activity; however, they swim more slowly than their littermates, and some drown. The mutant mice also perform less well on a rapidly rotating rod, and approximately 20% do not learn to walk when the rod begins to turn. Restoration of NE with dihydroxyphenylserine eliminated these motor deficits. DBH -/- mice exhibit normal learning and retention of a passive avoidance paradigm; however, they do not master an active-avoidance paradigm as readily as controls and exhibit more rapid extinction of the active-avoidance task. DBH -/- mice learn to find the hidden platform in the Morris water maze in spite of their slower swim speed and show normal preference for the correct quadrant in the transfer test immediately after training. However, this preference declines relative to controls during the next 2 days.

Animals↗
PubMed1997

Brain and spinal cord distribution of biphalin: correlation with opioid receptor density and mechanism of CNS entry.

Biphalin [(Tyr-D-Ala-Gly-Phe-NH)2] is a bivalent, opioid peptide containing two pharmacophores linked by a hydrazine bridge. When administered intracerebroventricularly, it has been shown to be more potent than morphine and etorphine at eliciting antinociception. Biphalin has also been shown to cross both the blood-brain and blood-cerebrospinal fluid barriers. To understand the basis of biphalin's potency, regional brain and spinal cord distribution studies with [125I-Tyr1]biphalin were performed 5, 20, and 40 min after intravenous bolus injections. A statistically greater amount of [125I-Tyr1]biphalin was detected in the nucleus accumbens compared with other brain regions (p < 0.05). This correlates with the high density of delta- and mu-opioid receptor mRNA and binding sites shown to be expressed in the nucleus accumbens. Also, a statistically greater amount of [125I-Tyr1] biphalin was detected in two other circumventricular organs, the choroid plexus and pituitary, when compared with other brain regions. These studies provide evidence that biphalin can reach not only brain sites, but also spinal sites to elicit antinociception. The overall CNS distribution of [125I-Tyr1]biphalin was decreased with naloxone, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, or naltrindole pretreatment, showing that biphalin detected in the brain and spinal cord is binding to delta- and mu-opioid receptors. Additional in situ brain perfusion experiments identified a saturable component contributing to CNS entry of [125I-Tyr1]biphalin, which could be described by Michaelis-Menten kinetics with a Km of 2.6 +/- 4.8 microM, Vmax of 14.6 +/- 2.89 pmol(-1) x min(-1) x g(-1), and Kd of 0.568 +/- 0.157 microl x min(-1) x g(-1). Brain entry of [125I-Tyr1]biphalin was sensitive to 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid and L-phenylalanine, suggesting use of the large neutral amino acid carrier. This work provides evidence that biphalin is a promising, potent analgesic that has a unique mechanism for reaching both spinal and supraspinal opioid receptor sites.

Analgesics↗
PubMed1997

Decision polarization among rehabilitation team recommendations concerning discharge housing for stroke patients.

This study sought to identify if decision polarization effects were operating in rehabilitation teams when making discharge housing recommendations for stroke patients. Using a Social Judgment Theory approach, individual clinicians were asked to nominate discharge housing for stroke patients. Teams were then assembled and clinicians repeated the task. The research was conducted at a sample of seven in-patient rehabilitation hospitals. The subjects were 74 clinicians who formed 13 teams. All subjects were volunteers, and represented the following professions: medicine, nursing, occupational therapy, physical therapy, speech therapy, and social work. A casebook which described 50 hypothetical stroke patients in terms of eight attributes was devised for the study. Subjects made housing recommendations to these patients using a 7-point scale. When compared to individual clinicians' recommendations, it was found that team housing recommendations made by all 13 teams polarized towards both more supported and, in the other extreme, more independent types of housing. However, teams placed a stronger emphasis on supported housing when compared with individual clinician decisions. This decision polarization suggests that housing recommendations made to patients may reflect team processes as well as patient needs. Rehabilitation teams should be aware of this negative team dynamic so that steps to minimize decision polarization can be taken.

Australia↗