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Biomedical subjects

D Walker

Publications and source records attributed to D Walker.

At least 109 records · Page 6Linked to original sources
PubMed1998

Triptorelin acetate administration in early pregnancy: case reports and review of the literature.

When using a long protocol with cycle day 23 gonadotrophin-releasing hormone agonists (GnRH-a) administration, an elevated estradiol level or a missed period 10-14 days after initiating pituitary downregulation should alert the physician to the possibility of a pregnancy. We report 4 pregnancies occurring during pituitary downregulation with Triptorelin acetate in 366 in-vitro fertilization (IVF) cycles resulting in 3 deliveries of 4 normal neonates at term and 1 first trimester abortion. This supports published data reporting a 1% spontaneous pregnancy incidence in women undergoing pituitary desensitization GnRH-a during the luteal phase prior to planned IVF treatment, a 15.9% abortion rate and a 1.7% malformation rate. Our cases together with other published data suggest that pregnancy outcome is not adversely affected by GnRH-a administration during the luteal phase of the conception cycle. However, long term follow-up of these babies is still lacking and the number of reported cases is too small adequately to rule out the possibility of any detrimental effect related GnRH-a administration in pregnancy.

Abortion, Spontaneous↗
PubMed1998

Intranuclear trafficking and gene targeting by members of the steroid/nuclear receptor superfamily.

Upon binding to regulatory elements in mammalian chromosomes, steroid receptors induce specific transitions in the nucleoprotein structure of the template. These transitions reflect, in part, the reorganization of chromatin structure to permit interaction of secondary factors with target sequences in promoter regulatory regions. Steroid receptors represent a class of transcriptional activators that are able to interact with repressed nucleoprotein templates and recruit necessary activities for chromatin remodeling. The ligand-induced movement of nuclear receptors from inactive states, either in the cytoplasm or in the nucleus, to productive interactions with chromatin is complex and likely reflects the interaction with multiple protein complexes and subcellular structures. Regulation of gene expression by nuclear receptors is thus mediated through the subcellular distribution of inactive receptors, the redistribution of activated receptor complexes to appropriate nuclear domains, the reorganization of chromatin structures for interaction with soluble components of the nucleoplasm, and direct protein-protein contacts between receptors and the basal transcription apparatus.

Animals↗
PubMed1998

Species differences in size discrimination in the paracellular pathway reflected by oral bioavailability of poly(ethylene glycol) and D-peptides.

Animal models are frequently used to aid prediction of intestinal absorption in humans. However, there is little comparative quantitative information on species differences in paracellular permeation, which is an important route for oral absorption of small to medium-sized hydrophilic drug molecules. This study addresses this issue by comparing the molecular mass (MM) dependency in oral bioavailability between rat and dog of poly(ethylene glycol) (PEG), a polydispersed model mixture commonly used to characterize paracellular absorption, and of a series of eight D-peptides (based on D-phenylalanine). Fasted rats and dogs received PEG (400/900) and the D-peptides (MM 236-406 Da), orally and intravenously, with total 24-48 h urine collection to estimate oral bioavailability. After HPLC separation, the individual PEG oligomers and D-peptides were determined using radiometric detection, for radiolabeled material, and LC-MS, for unlabeled (PEG) material. All compounds were predominantly excreted unchanged following intravenous administration. After oral administration, the predominant peak in the radiochromatogram was unchanged material, indicating stability of the compounds in the gastrointestinal tract. A clear molecular mass dependency in oral bioavailability was seen with both series, but with absorption much greater in dog than rat. Thus, for PEG in rat, bioavailability decreased sharply from 79 to around 2% with increasing MM between 282 and 591 Da, and then tapered to around 1. 5% up to 1295 Da. Whereas in dog, bioavailability remained around 100% for oligomers up to 600 Da and then decreased quite sharply with increasing MM, tending to plateau around 13% beyond 900 Da. Likewise, for the d-peptides in rat, bioavailability decreased from 30 to 1% with increasing MM between 236 and 406 Da, whereas in dog it was 100%, declining to 16% over the same molecular range. This species difference appears to be due to a larger pore size and greater frequency of pores in the paracellular pathway of dog compared to rat. Furthermore, on the basis of comparison with literature data for PEG and selected drugs, rat would appear to be a better predictor than dog of absorption of hydrophilic compounds in human.

Absorption↗
PubMed1998

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.

Adolescent↗
PubMed1998

Efficacy of CI-1020, an endothelin-A receptor antagonist, in hypoxic pulmonary hypertension.

We previously showed that CI-1020, an endothelin (ET)-A-selective receptor antagonist, dose-dependently blocked acute hypoxic pulmonary hypertension (PH) in rats. In this study we show that CI-1020 can reverse existing PH and prevent progression of right ventricular hypertrophy (RVH) in rats exposed to chronic hypoxia. Male Sprague-Dawley rats were exposed to 20 days of hypoxia (10% O2) with CI-1020 treatment (20 or 40 mg/kg/day) starting on day 10. On day 20 of hypoxia, the rats were instrumented under anesthesia with a pulmonary artery cannula and allowed to recover to consciousness before measurement of mean pulmonary arterial pressure (MPAP). Blood samples were then collected for plasma ET-1 measurements, the rats killed, and their hearts dissected, dried, and weighed. RV/LV + septum ratio (g/g) was used as an index of RVH (RVHi). Normoxic rats and rats exposed to hypoxia for only 10 days were also evaluated as controls. Normoxic rats had MPAPs of 13 +/- 1 mm Hg, plasma ET-1 levels of 2.1 +/- 0.1 pg/ml, and an average RVHi of 0.29 +/- 0.03. Rats exposed to 10 or 20 days of hypoxia had MPAPs of 33 +/- 2 and 44 +/- 0 mm Hg, plasma ET-1 levels of 4.2 +/- 0.8 and 4.6 +/- 0.8 pg/ml, and average RVHis of 0.47 +/- 0.05 and 0.52 +/- 0.03, respectively. In comparison, rats treated with CI-1020 had MPAPs that were 37% (20 mg/kg/day) and 44% (40 mg/kg/day) lower than untreated 20-day hypoxic rats. Furthermore, rats dosed with 40 mg/kg/day of CI-1020 had MPAPs that were significantly lower (24%) than control 10-day hypoxic rats, indicating a significant reversal of PH. Along with this reversal in PH, their average RVHi was 23% lower (p < 0.05) relative to untreated 20-day hypoxic rats.

Animals↗
PubMed1998

Rickettsia honei sp. nov., the aetiological agent of Flinders Island spotted fever in Australia.

The name Rickettsia honei, strain RBT, has been proposed for a unique spotted fever group (SFG) agent which is pathogenic for humans. This agent has previously been compared to the other SFG agents and was shown to be distinct in protein structure by SDS-PAGE and by immunoblotting. Genetic comparisons of the 16S rRNA, rompA, gltA and the 17 kDa antigen genes with the other SFG rickettsiae confirmed the phylogenetic distance between R. honei and the previously described species. Genetically, Rickettsia honei is more closely related to the Thai tick typhus (TT-118) rickettsia than to any other member of the SFG. Indeed, it is proposed that TT-118 is a strain of R. honei which was previously isolated in Thailand. These results elucidate the presence of a unique SFG rickettsial species in Australasia.

Antigens, Bacterial↗
PubMed1998

Improving musculoskeletal clinical skills teaching. A regionwide audit and intervention study.

OBJECTIVE: To identify factors that influence medical students' perceptions of the quality of a clinical skills course; to apply these factors to the course at one hospital; to measure the effect of this change. DESIGN: Cross sectional questionnaire survey; application of identified factors; repeat questionnaire survey. SETTING: Three teaching hospitals and five district general hospitals in north east England. SUBJECTS: Third year medical students attending locomotor clinical skills courses in two consecutive years. MAIN OUTCOME MEASURES: Score awarded by students in five categories; numbers of patients seen by each student; comparisons with other clinical skills weeks. RESULTS: Response rates were 71 of 150 and 89 of 161. Factors associated with a high awarded score were: organisation of the course by a rheumatologist (p < 0.01); teaching from a rheumatologist (p < 0.01); higher number of patients seen (r = 0.76). Mean number of patients seen varied widely, from 7 per student at one hospital to 20.4 at another. Teaching hospitals scored poorly. In the second year, after making changes at one teaching hospital the mean total score improved (p < 0.01), and students saw more patients (p < 0.01). The ranking of this hospital rose from 6 to 1. The additional cost of the modified course was 640 pounds per student. CONCLUSIONS: The standard of teaching of locomotor clinical skills varies widely and can be improved by application of factors identified in this survey, although additional costs are incurred.

Clinical Competence↗
PubMed1998

A three-decade perspective on community and public psychiatry training in Oregon.

The public psychiatry training program at Oregon Health Sciences University, established in 1973, educates psychiatric residents to work in community mental health centers and state hospitals. The authors present a brief history of this program, which spans three decades, and describe recent developments in its operation, with special attention to financing, administrative structure, and educational elements. Several program graduates have chosen careers in public-sector work. The program is founded on the principle that just as dollars should follow patients in health care systems, so should residents in training follow patients. Administrative and fiscal arrangements must be flexible to support this mobility.

Career Choice↗
PubMed1998

Maternal, umbilical, and amniotic fluid concentrations of tryptophan and kynurenine after labor or cesarean section.

A major route of tryptophan metabolism is via the hepatic and cerebral synthesis of kynurenine, a substance subsequently used by astrocytes in the brain for the production of the neuroactive substances kynurenic acid and quinolinic acid. Both kynurenic and quinolinic acids have been implicated in modulating the activity of excitatory amino acid pathways in the brain, the former as a neuroprotectant because of its antagonist properties, and the latter as an excitotoxin because of its agonist actions, at NMDA receptors. We therefore determined the concentrations of tryptophan and kynurenine in maternal venous and umbilical cord blood, and in amniotic fluid, of infants after labor and vaginal delivery, and after delivery by cesarean section. Concentrations of tryptophan and kynurenine were significantly higher in umbilical vein plasma compared with maternal venous plasma. Tryptophan and kynurenine concentrations in umbilical vein plasma and amniotic fluid were significantly higher after labor, compared with samples obtained from infants of the same gestational age delivered by cesarean section. There was no umbilical vein-to-artery concentration difference for kynurenine in samples obtained after either labor or cesarean section, but there was a significant gradient for tryptophan in samples obtained after vaginal delivery, indicating increased transfer of this amino acid during labor. There was a significant correlation between umbilical vein tryptophan and kynurenine concentrations for both the labor and cesarean section groups, and plasma kynurenine concentrations were also significantly correlated with both umbilical vein cortisol concentrations and the duration of the second stage of labor in the vaginally delivered infants. These results suggest that the placental transfer of tryptophan and the fetal synthesis of kynurenine are increased during labor. These findings have implications for understanding the vulnerability of the infant brain to ischemic/hypoxic damage in the perinatal period. By analogy with the adult brain, the molar ratio of these substances is likely to determine the susceptibility of the brain to seizure and excitotoxic damage.

Adult↗
PubMed1998

Formative design of a virtual learning environment.

Current technology for 3D visualization, modeling and interaction allows the construction of attractive virtual environments for study of anatomy, surgery and other biomedical fields. The formative methodology for designing such environments is uncharted, but necessary before committing to large scale development. We present one such methodology undertaken during the design of a learning environment for biology for high school and middle school students. We expect to extend this design methodology to the development of environments for the teaching of medical subjects.

Animals↗
PubMed1998

Management of psychiatric symptoms in medically ill patients in the homecare setting.

Nurses with critical care knowledge and experience increasingly provide technologically advanced care to patients at home who often present comorbid psychiatric symptoms. Failure to accurately recognize and provide appropriate intervention can be devastating for patients because these symptoms can exacerbate the medical condition and may lead to mortality. The Biopsychosocial Model and the Transactional Model of Stress were presented as guides for nursing practice. Practice is directed at 1) understanding the patient's perception of events, 2) involving the caregiver(s) in the patient's recovery, and 3) enhancing the individual's adaptive coping efforts and resources. The article attempts to guide nurses in making decisions on when to consult and collaborate with an APPN to achieve desired patient outcomes.

Community Health Nursing↗
PubMed1997

Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the alpha1A subunit of the P/Q-type calcium channel.

Synaptotagmins are synaptic vesicle proteins containing two calcium-binding C2 domains which are involved in coupling calcium influx through voltage-gated channels to vesicle fusion and exocytosis of neurotransmitters. The interaction of synaptotagmins with native P/Q-type calcium channels was studied in solubilized synaptosomes from rat cerebellum. Antibodies against synaptotagmins I and II, but not IV co-immunoprecipitated [125I]omega-conotoxin MVIIC-labelled calcium channels. Direct interactions were studied between in vitro-translated [35S]synaptotagmin I and fusion proteins containing cytoplasmic loops of the alpha1A subunit (BI isoform). Gel overlay revealed the association of synaptotagmin I with a single region (residues 780-969) located in the intracellular loop connecting homologous domains II and III. Saturable calcium-independent binding occurred with equilibrium dissociation constants of 70 nM and 340 nM at 4 degrees C and pH 7.4, and association was blocked by addition of excess recombinant synaptotagmin I. Direct synaptotagmin binding to the pore-forming subunit of the P/Q-type channel may optimally locate the calcium-binding sites that initiate exocytosis within a zone of voltage-gated calcium entry.

Amino Acid Sequence↗
PubMed1997

Identification of brainstem neurons responding to hypoxia in fetal and newborn sheep.

Hypoxia causes a reversible decrease in the level of respiratory, oculomotor and postural muscle activity in fetal sheep, an effect not seen in newborn lambs. We have used Fos immunohistochemistry to identify neurons which are activated by hypoxia and which may mediate this motor inhibition in the fetus. Pregnant sheep of either 117 or 138 days gestation were made hypoxic by allowing them to breathe 8-9% O2 for 2 h. Compared to age-matched control fetuses, hypoxia caused a significant increase in Fos-immunoreactivity in several medullary nuclei including the nucleus tractus solitarius, lateral reticular nucleus and the rostral ventrolateral medulla and also in the lateral parabrachial nucleus, locus coeruleus and subcoeruleus region in the pons. Hypoxia in newborn lambs, 7-18 days old, resulted in Fos staining in the same medullary and pontine nuclei with the exception of the subcoeruleus region which was devoid of Fos-immunoreactivity. In newborn lambs in which the carotid sinus nerves had been sectioned bilaterally, Fos-immunoreactivity was increased in the nucleus tractus solitarius in the medulla and in the locus coeruleus, lateral parabrachial and Kölliker-Fuse nuclei in the pons when compared to intact control newborn lambs. When carotid sinus nerve denervated-lambs were subjected to hypoxia the pattern of Fos-ir was similar to the pattern seen in the denervated control lambs but in addition staining was present in the subcoeruleus. These results suggest that a specific set of pontine neurons are activated by low oxygen levels in the fetus but not in the newborn lamb in the presence of an intact innervation from the carotid sinus. We hypothesise that: (a) in the fetus hypoxia activates neurons in the region of the subcoeruleus and this causes cessation of breathing movements and muscle atonia; and (b) that after birth stimulation of the carotid chemoreceptors by hypoxia normally inhibits activation of these subcoeruleus neurons.

Aging↗