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Biomedical subjects

C Donaldson

Publications and source records attributed to C Donaldson.

At least 19 recordsLinked to original sources
PubMed1995

Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor.

Corticotropin-releasing factor (CRF), a peptide first isolated from mammalian brain, is critical in the regulation of the pituitary-adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses. Fish urotensin I and amphibian sauvagine were considered to be homologues of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. We have characterized another mammalian member of the CRF family and have localized its urotensin-like immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors in brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.

Adrenocorticotropic Hormone↗
PubMed1995

Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart.

Corticotropin-releasing factor (CRF; corticoliberin) regulates the secretion of corticotropin (ACTH) and beta-endorphin and has a broad range of effects on the nervous, endocrine, reproductive, cardiovascular, gastrointestinal, and immune systems. Recently, human, rat, and mouse CRF receptors (CRF-R) have been cloned and functionally and anatomically characterized. We report here the cloning of a second CRF-R cDNA (CRF-RB), which encodes a protein of 431 amino acids, which is 16 amino acids longer and 68% similar to the previously cloned CRF-R, CRF-RA. When transiently expressed in COS-M6 cells, CRF-RB binds CRF with high affinity [Kd = 1.2 (0.57-2.5)nM] and transduces the CRF-stimulated signal of the accumulation of intracellular cAMP, which is inhibited by a CRF antagonist. Comparison of the amino acid sequences of CRF-RB and the previously cloned receptor reveals major differences in the N-terminal domain and in the extracellular loops, whereas the sequences of the intracellular loops are nearly identical. CRF-RB and related transcripts are expressed in the heart, as well as in other tissues, including the gastrointestinal tract, epididymis, and brain.

Amino Acid Sequence↗
PubMed1995

Human S100b protein: formation of a tetramer from synthetic calcium-binding site peptides.

Human brain S100b protein is a unique calcium-binding protein comprised of two identical 91-amino acid polypeptide chains that each contain two proposed helix-loop-helix (EF-hand) calcium-binding sites. In order to probe the assembly of the four calcium-binding sites in S100b, a peptide comprised of the N-terminal 46 residues of S100b protein was synthesized and studied by CD and 1H NMR spectroscopies as a function of concentration and temperature. At relatively high peptide concentrations and in the absence of calcium, the peptide exhibited a significant proportion of alpha-helix (45%). Decreasing the peptide concentration led to a loss of alpha-helix as monitored by CD spectroscopy and coincident changes in the 1H NMR spectrum. These changes were also observed by 1H NMR spectroscopy as a function of temperature where it was observed that the Tm of the peptide was lowered approximately 14 degrees C with a 17-fold decrease in peptide concentration. Sedimentation equilibrium studies were used to determine that the peptide formed a tetramer in solution in the absence of calcium. It is proposed that this tetrameric fold also occurs in S100b and is a result of the interaction of portions of all four calcium-binding sites.

Amino Acid Sequence↗
PubMed1995

Hormone replacement therapy: compliance and cost after screening for osteoporosis.

OBJECTIVE: To assess HRT compliance and cost 1 year after population screening for low bone density. DESIGN: Postal questionnaire sent out to women 1 year after having a bone density scan. MAIN OUTCOME MEASURES: Compliance with HRT, type of HRT and cost. RESULTS: Compliance with HRT after screening for women with low bone density was 48% for postmenopausal women and 59% for women with a simple hysterectomy. The most often used form of HRT was Estraderm (49%) for women with a hysterectomy, whilst for women with an intact uterus Prempak-C (54%) was the most popular. The average annual cost of treating women who had had a hysterectomy was 67 pounds whilst for women with an intact uterus it was 61 pounds, a non-significant difference. CONCLUSIONS: Approximately 50% of women with low bone density had started HRT within 1 year of having a densitometry examination. Previous reports of the cost advantage of treating women who had had a hysterectomy relative to those who had not has been overstated.

Bone Density↗
PubMed1995

Differential effects of CGS 12066B and CP-94,253 on murine social and agonistic behaviour.

Although it has been previously proposed that 5-HT1B agonism specifically attenuates rodent agonistic behaviour, more recent investigations have indicated that such influences may be ancillary to an anxiogenic effect. The present study examined the influences of two 5-HT1B agonists, CGS 12066B and CP-94,253, on murine agonistic behaviour. In a resident-intruder paradigm, CGS 12066B (0.5-5.0 mg/kg) decreased resident offensive aggression, social interest, and exploration while dose-dependently enhancing defensive behaviours across the dose range tested. CP-94,253 (2.5-10.0 mg/kg) also reduced elements of resident offensive behaviour whereas defensive behaviours were largely unchanged. Some elements of resident nonsocial and social behaviour were enhanced at 2.5 and 5.0 mg/kg but decreased at 10.0 mg/kg. The behavioural profile of CP-94,253, but not CGS 12066B, supports the proposal that 5-HT1B receptors inhibit agonistic behaviour without concomitant sedative or anxiogenic effects. Findings are discussed in relation to 5-HT1A/1B/2C receptors involved in agonistic behaviour and anxiety.

Agonistic Behavior↗
PubMed1995

Costs of intrapartum care in a midwife-managed delivery unit and a consultant-led labour ward.

OBJECTIVE: to investigate whether there are differences between the cost of intrapartum care for women at low obstetric risk in a midwife-managed labour and delivery unit and that in a consultant-led labour and delivery ward. DESIGN: cost analysis based on the findings of a randomised controlled trial comparing two alternative types of intrapartum care. SETTING: Aberdeen Maternity Hospital, Grampian. SUBJECTS: the number of women 'booked' for care in the Midwives' Unit in a standard year and a comparable group of women cared for in the consultant-led labour ward. PRIMARY OUTCOME MEASURE: the cost 'outcome' is the extra (or reduced) cost per woman resulting from the introduction of a midwife-managed delivery unit. FINDINGS: the baseline extra cost of the introduction of the Midwives' Unit was found to be 40.71 pounds per woman. Depending on the scenario used, this ranged from a cost saving of 9.74 pounds per woman to an additional cost of 44.23 pounds per woman. CONCLUSIONS: this study has shown that, in terms of costs incurred during the intrapartum period, the marginal cost of caring for women at low obstetric risk alongside women at high obstetric risk in a standard labour ward is small. However, the impact of establishing a separate midwife-managed delivery unit, requiring an increase in midwifery staffing levels, can be significant.

Cost-Benefit Analysis↗
PubMed1995

Stepwise or couple antenatal carrier screening for cystic fibrosis?: women's preferences and willingness to pay.

Several antenatal cystic fibrosis carrier screening trials have offered women testing by either the stepwise or the couple method. In this study, both approaches were described to women attending an antenatal clinic, who were then asked which method they preferred. An estimate of the value to women of each type of test was also ascertained using a "willingness to pay" (WTP) method. Of 450 women, 279 (62%) preferred stepwise screening, 117 (26%) preferred couple screening, and 54 (12%) had no preference. Mean WTP for stepwise screening was 19 pounds (95% CI 17.50 pounds-20.50 pounds), and that for couple screening was 18 pounds (95% CI 16.50 pounds-19.50 pounds). The majority of women preferred stepwise screening although the average WTP for each method was similar.

Anxiety↗
PubMed1995

Analysis of cord blood CD34+ cells purified after cryopreservation.

Many practical issues regarding processing blood samples for cord blood banking remain. After cryopreservation, a reduction in clonogenicity has been reported, although it is unknown whether this is associated with lower potential for long-term engraftment. CD34+ cell purification of cryopreserved cord blood (CB) may be important for the clinical application of in vitro expansion. We compared purity, yield, clonogenicity, and growth in long-term stromal-based culture of fresh and cryopreserved CD34+ purified cells (n = 12) using the miniMACS separation system. Mean purity of CD34+ cells was 93% when processed before and 73% when processed after cryopreservation. Fresh CD34+ cells had higher clonogenic potential than cryopreserved cells (45 vs 20%, p < 0.05) in CFU-Mix assays, indicating that progenitor cell loss during cryopreservation is due in part to reduced cloning efficiency of viable CD34+ cells. In long-term culture (LTC) on irradiated normal human bone marrow stroma (n = 7), CFU-GM production in the two groups was the same over 12 weeks, suggesting identical long-term culture-initiating cell (LTC-IC) numbers. We conclude that apparent clonogenic cell loss during cryopreservation is associated with relative sparing of the more primitive LTC-ICs. CFU-Mix assays may therefore underestimate the transplant potential of cryopreserved CB. Purification of CD34+ cells following cryopreservation gives sufficient purity for detailed evaluation of CD34+ cells and for stem cell expansion.

Antigens, CD34↗
PubMed1994

Midwife managed delivery unit: a randomised controlled comparison with consultant led care.

OBJECTIVE: To examine whether intrapartum care and delivery of low risk women in a midwife managed delivery unit differs from that in a consultant led labour ward. DESIGN: Pragmatic randomised controlled trial. Subjects were randomised in a 2:1 ratio between the midwives unit and the labour ward. SETTING: Aberdeen Maternity Hospital, Grampian. SUBJECTS: 2844 low risk women, as defined by existing booking criteria for general practitioner units in Grampian. 1900 women were randomised to the midwives unit and 944 to the labour ward. MAIN OUTCOME MEASURES: Maternal and perinatal morbidity. RESULTS: Of the women randomised to the midwives unit, 647 (34%) were transferred to the labour ward antepartum, 303 (16%) were transferred intrapartum, and 80 (4%) were lost to follow up. 870 women (46%) were delivered in the midwives unit. Primigravid women (255/596, 43%) were significantly more likely to be transferred intrapartum than multi-gravid women (48/577, 8%). Significant differences between the midwives unit and labour ward were found in monitoring, fetal distress, analgesia, mobility, and use of episiotomy. There were no significant differences in mode of delivery or fetal outcome. CONCLUSIONS: Midwife managed intrapartum care for low risk women results in more mobility and less intervention with no increase in neonatal morbidity. However, the high rate of transfer shows that antenatal criteria are unable to determine who will remain at low risk throughout pregnancy and labour.

Consultants↗
PubMed1994

Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary.

Corticotropin-releasing factor (CRF) is a major hypophysiotropic peptide regulating pituitary-adrenal response to stress, and it is also widely expressed in the central nervous system. The recent cloning of cDNAs encoding the human and rat CRF receptors has enabled us to map the distribution of cells expressing CRF receptor mRNA in rat brain and pituitary by in situ hybridization. Receptor expression in the forebrain is dominated by widespread signal throughout all areas of the neo-, olfactory, and hippocampal cortices. Other prominent sites of CRF receptor mRNA expression include subcortical limbic structures in the septal region and amygdala. In the diencephalon, low levels of expression are seen in a few discrete ventral thalamic and medial hypothalamic nuclei. CRF receptor expression in hypothalamic neurosecretory structures, including the paraventricular nucleus and median eminence, is generally low. In the brainstem, certain relay nuclei associated with the somatic (including trigeminal), auditory, vestibular, and visceral sensory systems, constituted prominent sites of CRF receptor mRNA expression. In addition, high levels of this transcript are present in the cerebellar cortex and deep nuclei, along with many precerebellar nuclei. In the pituitary, moderate levels of CRF receptor mRNA expression were detected throughout the intermediate lobe and in a subset of cells in the anterior lobe identified as corticotropes by concurrent immunolabeling. Overall, the central distribution of CRF receptor mRNA expression is similar to, though more expansive than, that of regions reported to bind CRF, and it shows limited overlap with loci expressing CRF-binding protein. Interestingly, CRF receptor mRNA is low or undetectable in several cell groups implicated as central sites of CRF action.

Adrenocorticotropic Hormone↗
PubMed1994

An economic view of high compliance as a screening objective.

Accepted wisdom holds that high compliance is essential for a screening programme to be successful. Indeed, a reason that the national breast screening programme is not routinely offered to women aged 65 or more is on the grounds of predicted poor compliance by older women. Increasing compliance is often associated with increased costs. These costs represent a lost opportunity for screening alternative target populations. We question the need for screening programmes to achieve high compliance, and we argue that a screening programme can be efficient with very low levels of compliance. Adopting compliance as a screening objective and as a measure of the success of screening may be detrimental to the efficiency of a screening programme.

Breast Neoplasms↗
PubMed1994

Population screening for low bone mineral density: do non-attenders have a lower risk of osteoporosis?

Poor compliance may be detrimental to the effectiveness of a screening programme if those at greatest risk of the disease do not attend. Therefore we undertook a study to test whether non-attenders to a screening programme for low bone density, a risk factor for osteoporosis, were at a differential risk of low bone density compared with attenders. Seven hundred and eighty-nine women aged 45-49 years living within 32 km of Aberdeen were selected at random from the Community Health Index and invited to attend for screening for low bone density as a risk of factor for osteoporosis. Attenders and non-attenders were surveyed regarding their risk factors for osteoporosis. Non-attenders were significantly heavier than attenders. In addition, 6 non-attenders who subsequently chose to attend had significantly higher body weight and bone mineral density, at Ward's triangle, than initial attenders. Non-attenders to a screening service for bone density may be at lower risk of developing osteoporosis. Non-attendance, therefore, would not be detrimental to the cost-effectiveness of a screening service for bone density. However, this study indicates there is a potential for response bias in studies of bone density and osteoporosis.

Bias↗
PubMed1993

Recruitment methods for screening programmes: the price of high compliance.

High population compliance is seen as a prerequisite for an equitable screening service. To achieve high compliance fixed appointments are usually advocated. However, the costs of achieving high compliance have not previously been described. To assess the costs of achieving high compliance we have used a randomised trial of two common appointment methods: 800 women aged 45-49 living within 20 miles of Aberdeen were selected at random from the Community Health Index. They were randomly assigned to receive one of two letters--one offering a fixed appointment, the other inviting them to telephone to make an appointment. For a defined population fixed appointments achieved high compliance but only by reducing the opportunities for screening; for every 100 women screened, 110 additional women were denied the opportunity of a screening test. In contrast the open letters of invitation achieved efficiency by increasing the number of women screened with given resources within a larger population. Thus for screening services with fixed budgets, high compliance is achieved only by screening fewer people.

Appointments and Schedules↗