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Biomedical subjects

R F Walker

Publications and source records attributed to R F Walker.

At least 37 records · Page 2Linked to original sources
PubMed1990

Chronobiology in laboratory medicine: principles and clinical applications illustrated from measurements of neutral steroids in saliva.

A number of chronobiological principles, as they pertain to the practice of laboratory medicine, have been discussed. Without doubt, salivary steroid assays are valuable tools for use in clinical studies, not necessarily as a single time-qualified sample but more often as a series of samples that will describe the underlying endocrinological time-structure. It is also important to appreciate that melatonin, certain drugs, and many dietary constituents such as phyto-oestrogens, are among the myriad of substances that can be monitored, and so hold great promise for the chronobiologist interested in the use of saliva as a sampling medium, both in the present and in the future.

Adrenal Glands↗
PubMed1990

Potential value of salivary steroids in chronoepidemiological and endocrine-related studies.

Experience from Institute studies has clearly demonstrated the advantages of salivary steroids in clinical endocrinological research and their potential value in chronoepidemiological studies of many kinds that may involve hormones. Of course, the examples and suggestions for areas of research involve many more covariates than those mentioned; but sufficient evidence has been presented to indicate the chronobiological potential of salivary steroid assays in studies of mental health, aggression and behaviour, stress, the endocrine changes occurring from birth to old age and those relating to endocrine cancer. The pioneering studies of Halberg et al (1981) and Haus et al. (1987) have demonstrated the feasibility of carrying out international epidemiological studies as they relate to breast cancer risk and studies of the general population. The potential value of salivary steroid assays in clinical, physiological and epidemiological studies is judged to be considerable.

Chronobiology Phenomena↗
PubMed1989

Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites.

The drug SK&F 110679 (His-D-Trp-Ala-Trp-D-Phe-LysNH2), is an enkephalin-derived hexapeptide, which specifically releases growth hormone in a wide variety of species in vivo and in vitro. Previous binding studies, using ligands which are specific for mu and delta opioid binding sites, demonstrated an inverse relationship between the opioid binding potency and the potency in releasing growth hormone of a series of peptides related to SK&F 110679. In an attempt to understand its mode of action better, a binding assay for the peptide was established using a ligand which had been tritium labelled at the D-Trp2 residue. Membrane fragments from both the hypothalamus and anterior pituitary tissue were found to contain sites to which [3H]SK&F 110679 reversibly and saturably bound. The binding curves for [3H]SK&F 110679 to membrane fragments of both hypothalamus and anterior pituitary were resolved into two binding components with the computer program LIGAND. The Kd's obtained were in the 10(-8) M and 10(-5) M range. The relationship of these binding sites to the growth hormone-releasing activity of the peptide was explored by examining the relationship between the binding and potency in releasing growth hormone of a series of peptides related to SK&F 110679. For sites in both the hypothalamus and pituitary, a significant correlation between binding and the release of growth hormone was obtained. Thus, these binding sites appeared to be involved in the release of growth hormone by SK&F 110679-related peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Implementation of a primary screen for developmental neurotoxicity.

A battery of tests to evaluate physical growth/development and neurobehavioral function was conducted with 78 litters of control Sprague-Dawley rats given purified water by intubation. The objectives of this study were to optimize test methods and to document the range and variability of the experimental endpoints. Data are presented for maternal evaluations (body weight gain, food consumption), gestation length, litter size, and postnatal survival. Pup body weight was used to assess postnatal somatic growth rate from birth to 85 days of age, while whole and regional brain weight measurements at 7, 28, and 85 days provided a more specific measure of physical growth relevant to a neurobehavioral study. Physical landmarks of development evaluated were pinna unfolding, incisor eruption, and eye opening while reflex landmarks of development evaluated were the negative geotaxis and pupillary reflexes. The mean percentage of litters acquiring a physical trait or reflex increased sigmoidally with age, and the data suggest that the potential to detect developmental delays would be optimal when ca. 90% of control litters reach the test landmark. Functional evaluations were arranged according to four testing subsets so that each litter was evaluated in each test (1 pup/sex/litter), but repeated testing on pups was minimized. Auditory and tactile startle reflexes, as well as prepulse inhibition, were measured at ages 22 days and 60-64 days and found to increase with age. A passive avoidance paradigm (age 40-43 days) was used to assess exploratory behavior (approach) and memory (avoidance). Swimming performance in a water maze was used to evaluate learning. In this test, escape times and error rates improved to their highest level by five or six trials and showed acceptable degrees of variability. Spontaneous motor activity was monitored for 23 hr at age 54-61 days to evaluate exploratory activity, photoperiod entrainment, and catecholamine-induced locomotion (amphetamine challenge). Finally, landmarks of sexual maturation (balanopreputial separation evident at 45 days of age, vaginal perforation evident at 33 days) and estrous cyclicity (4.8 cycles per 21 days) were evaluated as measures of reproductive neuroendocrine function. In sum, the test battery provided an efficient yet comprehensive screen for evaluating effects on physical growth/development and neurobehavioral function which meets practical criteria for preclinical testing of pharmaceutical agents.

Animals↗
PubMed1989

Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer.

Thirty-eight premenopausal breast cancer patients were treated for periods up to 12 months with a sustained-release formulation of the luteinizing hormone-releasing hormone agonist goserelin [Zoladex, (D-Ser(But)6Azgly10-LH-RH); 3.6 mg depot every 4 weeks] either alone or in combination with the antioestrogen tamoxifen citrate (Nolvadex 40 mg/day). In both treatment groups serum gonadotrophin concentrations fell durig the first month of therapy and were suppressed on continued treatment. In patients treated with the combination therapy FSH concentrations were significantly reduced in comparison with goserelin alone. Relatively normal ovarian activity was observed during the first few weeks of therapy. Thereafter, oestradiol and progesterone concentrations rapidly declined in both treatment groups. Slightly lower serum oestradiol concentrations were recorded in patients receiving combination therapy. No significant adverse side-effects were recorded in either group of patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Cyclic enkephalin analogues containing alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid at positions 2 or 5.

Analogues of the highly potent and delta-receptor-selective enkephalins 1-4 were prepared with alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid (Apmp) replacing the beta,beta-dimethylcysteine (Pen) at positions 2 or 5. The peptides 5-8 were prepared by employing D,L-Apmp and, following oxidative cyclization, the resulting diastereomeric peptides were separated and purified by preparative high performance liquid chromatography. Compounds 7 and 8, with D- or L-Apmp substituted at position 5 are approximately 5 orders of magnitude more potent in the MVD assay than analogues 5 or 6 with D- or L-Apmp at position 2. While displaying less delta-receptor selectivity than the corresponding Pen-containing compounds, 7 and 8 are an order of magnitude more potent. All the analogues showed diminished delta-receptor selectivity in the rat brain binding assay. Compounds 7 and 8 displayed delta-receptor affinity comparable to the corresponding Pen-containing analogues.

Amino Acids, Sulfur↗
PubMed1989

Salivary testosterone levels and the progress of puberty in the normal boy.

Salivary testosterone (ST) levels were measured in 84 boys aged 7.3-16.2 from the Edinburgh Growth Study. The correlation coefficient between matched plasma/saliva samples was 0.88. Six samples were collected over the course of one day from 0900 to 2100 h each month in the majority of the children for 4 consecutive months. Mean daily ST levels showed a significant rise between each pubertal stage (genital (G) and pubic hair (PH]. The rise in ST became more rapid once a mean testicular volume (MTV) of 10 ml had been reached. The diurnal rhythm was assessed by individual curve fitting on the log scale and by cosinor analysis. A rhythm was present prepubertally and developed into a pattern similar to that of the adult rhythm by stage G3. The monthly rate of rise of ST was greatest at stage G4. A significant rise in ST levels was detectable immediately prior to an increase in MTV to 3 ml. This allowed earlier recognition of the clinical onset of puberty at testicular volume of 3 ml, which in this group occurred at 10.9 (SD 0.9) years. ST is a non-invasive and sensitive method for the serial monitoring of gonadal function in the prepubertal and adolescent boy.

Adolescent↗
PubMed1989

Salivary steroids and psychometric parameters in male marathon runners.

Testosterone and cortisol in male marathon runners (n = 11) were determined in saliva samples (n = 28) collected during the three rest days preceding a competitive marathon and in the samples collected at 08.00h on the race day. An Eysenck Personality Inventory was completed on the first rest day and psychological state was assessed on rest days and on the morning of the marathon by completion of visual analogue scales for anxiety, depression, hostility and libido at four times each day. Anxiety, depression and hostility were positively inter-correlated. Extraversion and depression were negatively correlated. At 08.00h on the day of the marathon, anxiety and hostility scores were significantly higher than those on rest days, but depression and libido scores were unchanged. No relationship was found between depression or libido and any hormonal parameter. Race day cortisol correlated negatively with hostility, and changes in cortisol (09.00h) between the race day and the mean rest-day levels correlated with the corresponding changes in anxiety.

Adult↗
PubMed1989

Review of the endocrine actions of luteinising hormone-releasing hormone analogues in premenopausal women with breast cancer.

The endocrinological actions of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex (goserelin) in premenopausal women with advanced breast cancer are reviewed. LHRH analogues are an interesting addition to the currently available treatments for hormone-sensitive breast cancer in premenopausal women. Their modest side effects and ease of administration are in contrast to the risks and morbidity of surgical endocrine therapy.

Adult↗
PubMed1989

Design of a primary screen for developmental neurotoxicity.

A battery of tests was devised for routine use as a primary screen for developmental neurotoxicity. The battery was divided into preweaning and postweaning tests using rats as subjects. Since the rat CNS is structurally incomplete at birth, preweaning tests were predominantly physical, using specific landmarks of somatic maturation and regional brain growth as indices of normal development. Pupillary responses to light and positional responses to gravity (negative geotaxis) were also included in the preweaning battery to monitor reflex behavior, a relatively simple CNS function. The postweaning battery predominantly contained functional tests to evaluate higher order behaviors that develop after completion of neurogenesis. The postweaning tests were divided into 4 subsets designed to evaluate (I) neuromuscular function, (II) memory, (III) problem solving, and (IV) neuroendocrine function, respectively. Curiosity, rhythmicity, patency of monoamine neurons, and physical measures of brain growth were included within the subsets so as to evaluate a spectrum of CNS functions. Preliminary findings suggest that tests and instrumentation selected for the proposed battery provide an informative, objective, comprehensive and cost-efficient means to screen for developmental neurotoxicity.

Aging↗
PubMed1988

Ovarian effects of an anti-inflammatory-immunomodulatory drug in the rat.

The purpose of this study was to determine whether a 30-day administration of SK&F 86002-A2, an inhibitor of cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism, adversely affected reproductive cycles, ovarian structure, and/or pituitary/ovarian hormone secretion. Cyclooxygenase and 5-lipoxygenase enzymes catalyze the reactions leading to the synthesis of prostaglandins and leukotrienes, respectively, which are physiological regulators of ovarian function. Female rats were dosed once daily by gavage with 0, 1, 5, 10, 30, or 60 mg (base)/kg/day of SK&F 86002-A2 for 30 consecutive doses beginning on the day of vaginal proestrus. Vaginal smears were then examined daily until necropsy, when ovaries and uteri were collected for macroscopic and histological examination. In addition, serum concentrations of estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and prolactin were estimated by radioimmunoassay. Estrous cycle irregularity, resulting from a dose-related lengthening of the interestrous interval, significantly (p less than 0.05) reduced the number of cycles in rats receiving 60 mg/kg/day of SK&F 86002-A2 compared to controls. Furthermore, the ovaries from this group of rats weighed significantly more (p less than 0.05) than controls, apparently due to an increased occurrence of enlarged, cystic follicles that occasionally contained blood. Luteinized follicles with entrapped ova were also detected during histological examination. Dilatation of the uterine lumen was observed in some rats receiving doses of SK&F 86002-A2 greater than 1 mg/kg/day. Serum progesterone in rats receiving 60 mg/kg/day of SK&F 86002-A2 was significantly (p less than 0.05) lower than controls. In contrast, mean levels of serum estradiol were elevated in rats receiving 30 mg/kg/day of SK&F 86002-A2. Serum concentrations of FSH, LH, and prolactin were not significantly different in any group. The results of this study suggest that SK&F 86002-A2 disrupts cyclic ovarian function by a local, cumulative action that inhibits ovulation and alters steroid secretion.

Animals↗
PubMed1988

Ovarian effects of SK&F 86002-A2 in the rat: site of action.

In a preliminary 30-day study, oral administration of SK&F 86002-A2, an inhibitor of prostaglandin and leukotriene synthesis, blocked ovulation and altered ovarian structure and hormone production in rats. The purpose of the present study was to determine if the locus of action of SK&F 86002-A2 for these effects was the ovary or some other site in the female reproductive system, using a number of experimental approaches. A single sc or intraovarian injection of SK&F 86002-A2 did not block spontaneous or gonadotropin-induced ovulation in proestrous rats, whereas indomethacin, a positive control, acutely disrupted the ovulatory process. Since neither route of administration blocked ovulation, integrated pituitary and ovarian events were not negatively affected by a single injection of SK&F 86002-A2 at doses which caused ovarian dysfunction when administered repeatedly for 30 days. In contrast to a single dose, oral administration of SK&F 86002-A2 to hypophysectomized rats for 2 weeks suppressed follicular growth and estradiol production in response to sc administration of pregnant mare serum gonadotropin. Although ovarian function was suppressed in hypophysectomized rats, LH surges induced by estradiol in ovariectomized rats were not affected by administration of SK&F 86002-A2 for 2 weeks. Thus, hypothalamic/pituitary dysfunction did not contribute to the ovarian effects of SK&F 86002 that occurred after repeated dosing. In conclusion, these results indicate that disruption of ovarian cycles by SK&F 86002-A2 is related to a direct effect on the ovary, and not to altered hypothalamic/pituitary function and LH release. Specifically, SK&F 86002-A2 may suppress the ovarian response to gonadotrophin, retarding follicular growth and estrogen production. The ovarian effects are consistent with a pharmacological expression of the inhibitory action of SK&F 86002-A2 on prostaglandin and leukotriene synthesis.

Administration, Oral↗
PubMed1988

Non-insulin-dependent diabetic patients (NIDDMs) do not demonstrate the dawn phenomenon at presentation.

A dawn rise of plasma glucose (PG) and/or insulin, the 'dawn phenomenon', has been commonly reported in treated diabetic patients and normal subjects. To evaluate the effect of treatment on this phenomenon in non-insulin-dependent diabetics (NIDDMs), PG, C peptide, immunoreactive insulin (IRI), growth hormone (GH), cortisol, epinephrine, and norepinephrine were measured hourly between 24.00 and 09.00 h in 17 newly diagnosed untreated NIDDMs (group 1). The study was repeated in 11 patients after a year of treatment (group 2). The PG levels did not change significantly at any time from 03.00 to 08.00 h in group 1 but increased continuously from 6.7 +/- 0.5 mmol/l at 04.00 h to 7.8 +/- 0.5 mmol/l at 08.00 h (P less than 0.01) in group 2. IRI and C peptide decreased significantly after 07.00 h in both groups. GH and catecholamine changes were similar in group 1 and group 2. Cortisol levels showed a nadir at 02.00 h and a peak after 07.00 h in both groups. Our results demonstrate no dawn rise of mean PG, IRI and C peptide in newly diagnosed untreated NIDDMs but a significant rise of PG in the early morning period in NIDDMs after a year of treatment with diet alone and diet plus sulphonylureas. Therefore other factors such as treatment and/or duration of the diabetes may play an important role in the pathogenesis of the dawn phenomenon.

Blood Glucose↗