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Biomedical subjects

B Butler

Publications and source records attributed to B Butler.

At least 55 records · Page 3Linked to original sources
PubMed1993

A nonpeptidyl growth hormone secretagogue.

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

Amino Acid Sequence↗
PubMed1993

Natural history of blue sclerae in osteogenesis imperfecta.

Scleral hue is an important sign which distinguishes 2 broad groupings of patients, those with and those without blue sclerae with nonlethal osteogenesis imperfecta (OI). Individuals with OI type I have distinctly blue sclerae which remain intensely blue throughout life. In OI type III and OI type IV the sclerae may also be blue at birth and during infancy, but the intensity fades with time such that these individuals have sclerae of normal hue by adolescence and adult life.

Adolescent↗
PubMed1993

An overview of computer software developed to search biological sequence databases.

The scientific community has established a number of databases to receive and maintain the abundant biological sequence information being generated by research investigators worldwide. For researchers in an increasing number of biological disciplines, the information stored in these databases has become an invaluable tool in their daily research endeavors. This article reviews the organization of the largest nucleic acid and protein sequence databases and discusses some of the commonly available computer software that has been developed for searching them.

Amino Acid Sequence↗
PubMed1993

Heat shock-mediated cell cycle blockage and G1 cyclin expression in the yeast Saccharomyces cerevisiae.

For cells of the yeast Saccharomyces cerevisiae, heat shock causes a transient inhibition of the cell cycle-regulatory step START. We have determined that this heat-induced START inhibition is accompanied by decreased CLN1 and CLN2 transcript abundance and by possible posttranscriptional changes to CLN3 (WHI1/DAF1) cyclin activity. Persistent CLN2 expression from a heterologous promoter or the CLN2-1 or CLN3-1 alleles that are thought to encode cyclin proteins with increased stability eliminated heat-induced START inhibition but did not affect other aspects of the heat shock response. Heat-induced START inhibition was shown to be independent of functions that regulate cyclin activity under other conditions and of transcriptional regulation of SWI4, an activator of cyclin transcription. Cells lacking Bcy1 function and thus without cyclic AMP control of A kinase activity were inhibited for START by heat shock as long as A kinase activity was attenuated by mutation. We suggest that heat shock mediates START blockage through effects on the G1 cyclins.

Cell Cycle↗
PubMed1993

A novel non-peptidyl growth hormone secretagogue.

Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.

Animals↗
PubMed1993

Semi-automated cervical smear pre-screening systems: an evaluation of the Cytoscan-110.

This paper reports a test of a system for provision of machine assistance in cervical cytology screening. The hypothesis tested was that if the results of examination by a screener of a small number of high-ploidy cells on specially prepared monolayers, automatically selected and presented by the system, were combined with machine measurement of cell and cell population characteristics, it would be possible to distinguish conditions requiring further action on the part of a cytology service from those in which the patient could safely be signed out. The system appeared broadly capable of this discrimination, with a false-negative error not significantly different (for the numbers tested) on CIN1 and more severe cases to that obtaining for routine screening of the parallel PAP smears, and also to results obtained by a panel of three observers. The machine system appeared to do better than other systems in selecting borderline cases for review, but this may have been an artefact of the method of evaluation used: all results were compared with a 'reference diagnosis', which was computed using statistical techniques to integrate diagnostic information from all available sources. The false-negative error-rate of the system amounted to 5% of high-grade cases, 17% of CIN1's and 29% of borderlines, but were not substantially different from the FN rates for other reporting systems on the same material. The proportion of negative cases referred back for full cytological diagnosis was 34%. Despite this high false-positive rate, the system is potentially cost-effective in use.

Automation↗
PubMed1992

PMA-sensitive protein kinase C is not necessary in TRH-stimulated prolactin release from female rat primary pituitary cells.

In GH3 cells and other clonal rat pituitary tumor cells, TRH has been shown to mediate its effects on prolactin release via a rise of cytosolic Ca2+ and activation of protein kinase C. In this study, we examined the role of protein kinase C in TRH-stimulated prolactin release from female rat primary pituitary cell culture. Both TRH and PMA stimulated prolactin release in a dose-dependent manner. When present together at maximal concentrations, TRH and PMA produced an effect which was slightly less than additive. Pretreatment of rat pituitary cells with 10(-6) M PMA for 24 hrs completely down-regulated protein kinase C, since such PMA-pretreated cells did not release prolactin in response to a second dose of PMA. Interestingly, protein kinase C down-regulation had no effect on TRH-induced prolactin release from rat pituitary cells. In contrast, PMA-pretreated GH3 cells did not respond to a subsequent stimulation by either PMA or TRH. Pretreatment of rat pituitary cells with TRH (10(-7) M, 24 hrs) inhibited the subsequent response to TRH, but not PMA. Forskolin, an adenylate cyclase activator, stimulated prolactin release by itself and in a synergistic manner when incubated together with TRH or PMA. The synergistic effects of forskolin on prolactin release was greater in the presence of PMA than TRH. Down-regulation of protein kinase C by PMA pretreatment abolished the synergistic effect produced by PMA and forskolin but had no effect on those generated by TRH and forskolin. sn-1,2-Dioctanylglycerol (DOG) pretreatment attenuated the subsequent response to DOG and PMA but not TRH. The effect of TRH, but not PMA, on prolactin release required the presence of extracellular Ca2+. In conclusion, the mechanism by which TRH causes prolactin release from rat primary pituitary cells is different from that of GH3 cells; the former is a protein kinase C-independent process whereas the latter is at least partially dependent upon the activation of protein kinase C.

Animals↗
PubMed1991

The use of cervicography in a primary screening service.

The cervicography and concurrent endocervical brush smear results obtained in 1162 women screened at the Marie Stopes Clinic were analysed. Colposcopy and biopsy results were obtained for positive cases. A comparison was made with a group of 1007 women attending the same clinic for routine cytology only. Nearly 10% of women who were screened by cervicography had a technically defective cervicogram, the main single reason being that the view was obscured by blood. Routine cytology was positive in 1%, while cervicography was positive in 13%, where positivity was defined as a result leading to a recommendation for colposcopy. The false positive rate for cervicography was 26%. Even after adjustment, this difference was highly significant (P less than 0.0001).

Acetates↗
PubMed1991

mu-receptor mediates elevated glucose and corticosterone after third ventricle injection of opioid peptides.

Four experiments were done to determine which receptor type(s) mediates the effects of third ventricular microinjections of four opioid peptide agonists on blood levels of glucose, free fatty acids, and corticosterone. Tests were performed in unanesthetized adult male albino rats having chronic intraventricular cannulas; blood samples were taken from the tail tip at 0, 15, 30, 60, 90, and 120 min postmicroinjection. In experiment 1, the agonists DAGO (Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol), beta-endorphin, DSLET (d-Ser2-Leu-enkephalin-Thr), and dynorphin A-(1-17) (0, 0.3, 1, 3, and 10 nmol/rat) produced three distinct patterns of changes in serum glucose, free fatty acid, and corticosterone values. Experiment 2 showed that the effects of DAGO and beta-endorphin were inhibited by prior injection with the opiate-receptor blocker naloxone (1 mg/kg sc) and that the effects of dynorphin were not diminished. Experiment 3 determined that dynorphin effects were also not diminished by naloxone given intraventricularly. Experiment 4 found that blockade of the mu-receptor by intraventricular pretreatment with the specific antagonist beta-funaltrexamine (20 micrograms/rat, 24 h before) completely abolished the effects of DAGO and beta-endorphin on glucose and corticosterone. The mu-receptor is critical to the mediation of the hyperglycemia and hypercorticosteronemia induced by the central administration of opiate agonists. These results imply that mu-opioid binding sites previously identified in central autonomic regions may be involved in the regulation of circulating glucose and corticosterone.

Animals↗
PubMed1991

Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells.

We have recently reported that His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) synergizes with GH-releasing factor (GRF) to increase GH release and cAMP accumulation in rat pituitary cells in vitro. This study was undertaken to further investigate the mechanism of action of GHRP-6 on GH release, particularly the involvement of protein kinase-C. Forskolin (10(-5) M), A23187 (10(-6) M), and phorbol 12-myristate 13-acetate (PMA; 10(-7) M) all stimulated GH release. However, only PMA can mimic the synergistic effects of GHRP-6 on GRF-stimulated GH release and intracellular cAMP accumulation. 4 alpha-Phorbol 12,13-didecanoate, an inactive phorbol ester, was unable to stimulate GH release or potentiate the effect of GRF. Extracellularly added phospholipase-C not only stimulated GH release in a dose-dependent manner, but also potentiated GRF-induced GH release. Phloretin, a protein kinase-C inhibitor, in a concentration range of 10-250 microM had very little or no effect on basal and GRF-stimulated GH release, but markedly inhibited the stimulatory effects induced by either PMA or GHRP-6. Incubation of rat pituitary cells with 10(-6) M PMA for 24 h completely down-regulated protein kinase-C, since such PMA-pretreated cells did not release GH in response to a second dose of PMA. The protein kinase-C-depleted cells had an attenuated GHRP-6 response, but they responded normally to GRF. Moreover, the synergistic effects of GHRP-6 and GRF on GH release and cAMP accumulation were also greatly inhibited by protein kinase-C down-regulation. These data suggest that the effects of GHRP-6 on GH release, either alone or together with GRF, are at least partially mediated via the activation of protein kinase-C.

Amino Acid Sequence↗
PubMed1990

Cochlear microcirculation in young and old gerbils.

Human postmortem studies as well as epidemiologic investigations have implicated the peripheral vascular system as one of the etiologic factors of presbycusis. This study uses the surface dissection microsphere method for regional cochlear blood flow analysis and morphometric techniques for quantifying capillary density in the stria vascularis. In this study 11 old and 10 young gerbils were used. Our results indicate that blood flow in the cochlea was decreased in the old gerbils. This decrease was most obvious in the lateral portion (stria vascularis). The decrease of blood flow in older animals was clearly not related to loss of strial capillaries with aging. The decreased flow to the lateral portion must arise from either decreased perfusion pressure or from increased vascular resistance. This decreased blood flow in the aged animals supports a vascular theory of presbycusis.

Aging↗
PubMed1990

Plasma ratio tryptophan/neutral amino acids in relation to clinical response to paroxetine and clomipramine in patients with major depression.

The pretreatment plasma ratio of tryptophan (Trp) to other large neutral amino acids (LNAA), thought to reflect brain serotonin formation, was determined in 44 inpatients with major depression, who were subsequently treated double-blind on a fixed-dose schedule for 4 weeks with the selective serotonin uptake inhibitor paroxetine (n = 27) or clomipramine (n = 17). The study took place at four clinical centers. Endogenous and non-endogenous depressives were comparable with respect to the ratio Trp/LNAA and clinical improvement and were therefore analyzed together. The clomipramine group showed a significant inverse correlation between ratio Trp/LNAA and improvement, and patients with a ratio Trp/LNAA below the mean showed a trend towards greater improvement than patients with a higher ratio but with comparable serum drug levels. The improvement in the paroxetine group was significantly inversely correlated with the Trp concentration but not with the ratio Trp/LNAA. The findings accord with previous trials of various antidepressant treatments, in which about 25% of the variance in therapeutic response associates with pretreatment plasma amino acid profiles.

Adult↗
PubMed1990

A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects.

GBR 12909 selectively blocks dopamine uptake and its biochemical and pharmacological profiles suggest that it may possess antidepressant activity and be of value in treatment of Parkinson's disease. The tolerance, pharmacokinetics and influence on psychomotor performance of GBR 12909 were investigated in a randomized placebo-controlled double-blind study. Four healthy subjects were administered oral single doses of 100, 200 and 300 mg GBR 12909 and placebo, and four other healthy subjects received, 50, 100 and 150 mg GBR 12909 and placebo once daily for 7 days. The intermediate and highest doses resulted in mild to moderate side-effects such as difficulties in concentrating, asthenia, feeling of drug influence and palpitations. No changes were observed in haematological and clinico-chemical parameters. A dose-related effect on ECG was observed with a slight reduction of the T-wave amplitude. No signs of arrhythmia or decompensation during exercise until exhaustion were observed. Psychomotor performance indicated dose-related sedation in the single-dose study. Only minor deviations from first order kinetics were observed. Elimination half-life was estimated at 1-2 days. Steady-state serum concentrations of GBR 12909 appeared to be attained within 1 week. Based on the results of this study, the estimated therapeutic doses are expected to be well-tolerated in patients.

Adult↗
PubMed1989

Bombesin microinfusion into the rat hypothalamic paraventricular nucleus increases blood glucose, free fatty acids and corticosterone.

Bombesin is a particularly potent hyperglycemic agent when administered intraventricularly or intracisternally in the rat. Because bombesin-like immunoreactivity is found in several forebrain regions implicated in glucoregulation, the ability of direct hypothalamic microinfusions of this peptide to affect serum metabolic fuel levels was tested. Three experiments, using anesthetized, acutely infused rats, or unanesthetized rats with chronic intracranial implants, showed that microinfusion of bombesin into the hypothalamic paraventricular nucleus caused significant, dose-related increases in serum glucose; infusions into the lateral hypothalamus or the caudate nucleus were ineffective. Infusions into the ventromedial nucleus significantly elevated glucose only in acutely anesthetized rats. In unanesthetized rats with chronic intracranial cannulae, bombesin infusions into all 3 hypothalamic sites, but not the caudate-putamen, significantly elevated blood free fatty acids, while only infusions into the paraventricular nucleus caused significant dose-related increases in blood corticosterone. The results demonstrate that the paraventricular nucleus is a sensitive site for bombesin-induced elevation of blood glucose, free fatty acids, and corticosterone. They also imply that the bombesin binding sites and immunoreactive terminals previously identified in these regions may be involved in the central regulation of circulating metabolic fuel levels and the pituitary-adrenal axis, and that the effects of acute surgery may augment the hyperglycemic response to intrahypothalamic bombesin administration.

Animals↗
PubMed1989

Comparison of serum free thyroxine measurements by chemiluminescence and equilibrium dialysis.

A study of 239 patients compared free thyroxine (FT4) measurements made by equilibrium dialysis (ED) with measurements made using the Magic Lite FT4 chemiluminescence (CI) immunoassay (Ciba Corning Immunodiagnostics). Patient groups: 41 normals; 27 hyperthyroid; 29 hypothyroid; 37 sick euthyroid; 10 chronic renal failure (CRF) and 25 pregnant patients; 13 oestrogen; 10 heparin; 12 salicylate; and 9 dilantin-treated patients; 3 lipaemic; 5 haemolysed; 6 hyperbilirubinaemic patients; 6 low thyroid binding protein (TBP) and 6 high TBP level patients. The two assays gave comparable results in most groups. Both assays tended to give elevated values in heparinized patients but FT4-ED results were more obviously affected. Pregnant patients and women on oral oestrogen had higher mean values with FT4-ED. In both assays the sick euthyroid and CRF patients had mean FT4 values similar to healthy euthyroid patients; the range of values in sick euthyroid and CRF patients was similar in both assays but wider than in healthy euthyroid patients. A supplemental study of 81 unselected acutely ill patients using FT4-Cl alone confirmed the wider range of values to be anticipated in sick euthyroid patients.

Adult↗
PubMed1989

The use of case vignettes in studies of interrater reliability of psychiatric target syndromes and diagnoses. A comparison of ICD-8, ICD-10 and DSM-III.

This study is part of the ICD-10 field trials in which the use of case vignettes for interrater agreement has been examined. From our electronic database of 880 consecutively admitted inpatients we selected 24 cases that were transcribed to vignettes covering the first 5 ICD-10 target syndrome of dementia, substance use disorders, schizophrenia, mood and anxiety disorders. ICD-10 was compared with ICD-8 and DSM-III. The results showed that all 3 standard classification systems obtained an acceptable interrater agreement. Among the diagnoses, depressive disorders gave rise to most disagreement between the raters. Discrepancies between the methods of measuring interrater agreement were found when intraclass reliability was compared with consensus calculations for the individual patient.

Humans↗