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Biomedical subjects

G M Brown

Publications and source records attributed to G M Brown.

At least 55 records · Page 3Linked to original sources
PubMed1998

60 Hz magnetic field exposure and urinary 6-sulphatoxymelatonin levels in the rat.

Four separate experiments were carried out to investigate the effect of extremely low frequency magnetic field (MF) exposure (60 Hz, 1 mT rms) on urinary 6-sulphatoxymelatonin (aMT6s) levels in Sprague-Dawley rats. In the first experiment, immature male rats maintained under a regular 12 h daily photoperiod (white fluorescent light) were exposed to a 20 h daily MF exposure for 6 weeks. The second experiment was similar to the first, except that the MF exposure was limited to 10 days. In the third experiment, adult male rats acclimated to a combination of continuous dim red light and regular 12 h daily photoperiod (white fluorescent) were subjected to a single 1 h exposure to intermittent MF (1 min on and 1 min off cycles), 2 h before fluorescent lights went off. The fourth experiment was similar to the third, except that the animals received 2 consecutive days of 20 h daily exposure to intermittent MF, beginning 1 h before the fluorescent lights went off each day. In all four experiments, the circadian profile of urinary aMT6s was examined before, during, and after the MF exposure. No significant effect of 1 mT MF on indoleamine metabolism was observed in any of the above experiments. However, in one of the experiments (no. 4), both the control and the MF groups showed a lower aMT6s level during the exposure days, when compared with that of pre- and post-exposure days, suggesting that the existence of possible effects with lower field strengths at the range of stray field cannot be ruled out.

Animals↗
PubMed1998

A comparative study of the work involved in measuring profiles using an ion chamber, a linear diode array and film.

In this work a method of using Kodak X-Omat V film to measure beam profiles for dynamically wedged fields is presented. Also, the profiles determined by film measurement are compared with those measured with an ion chamber (0.12 cm3 Scanditronix RFA 300 RK) and an array of silicon diodes (11 channel Scanditronix linear diode array). The beam investigated is a 6 MV photon beam from a Varian 2100 C linear accelerator. The geometric method of positioning film and determining the central axis (CAX) position of the beam yielded results which agreed to within 1 mm with the software determined position of the CAX. The profiles measured by film agreed well with the ion chamber measured profiles in terms of overall field size, position, penumbral width, height and position of maximum and profile shape between the 20% dose levels. Film profiles deviated most from ion chamber profiles in the post-penumbra regions. Linear diode array (LDA) measured profiles matched ion chamber profiles in the post-penumbra regions, field size and general profile shape. In the region of maximum dose differences in dose of up to 4% were seen along with horizontal shifts of around 2 mm between LDA and ion chamber profiles.

Biophysical Phenomena↗
PubMed1997

Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. RESULTS: Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. CONCLUSION: Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.

Adolescent↗
PubMed1997

Studies of the renal action of melatonin: evidence that the effects are mediated by 37 kDa receptors of the Mel1a subtype localized primarily to the basolateral membrane of the proximal tubule.

The pineal hormone melatonin controls circadian behavior of a variety of organs in different species, including humans. However, the precise mechanism (or mechanisms) by which this occurs remains largely unknown. At the cellular level its effects are believed to be mediated via interaction with specific melatonin receptors (MR), which have previously been cloned from human brain (Mel1a) and retina (Mel1b). At the tissue level, MR have been investigated primarily through empirical definition of specific binding sites, but so far there has been little success in biochemical or molecular characterization of native MR. In the kidney, there is strong circumstantial evidence that melatonin affects diurnal variations in renal function, but relatively little is known about the overall glomerular vs. tubular contributions to these effects. The strategy behind the present study was to use a panel of peptide-specific antibodies to identify MR proteins in various tissues, and from a determination of the intrarenal distribution of MR, gain insight into the mechanism by which melatonin might regulate kidney function. We used two peptide-specific antibodies directed against different regions of Mel1a to identify MR. Our results show that the native Mel1a receptor is a 37 kilodalton (kDa) protein in human and rat brain. Further, immunofluorescent studies carried out in guinea pig kidney have revealed that anti-Mel1a antibody is also localized to the basolateral membrane (BLM) of the renal cortical epithelium, especially the early proximal tubule. Immunoblotting of purified BLM fractions from guinea pig renal cortex and small intestine using the two different peptide-specific antibodies reveals the presence of a single peptide-blockable band at 37 kDa. These same BLM fractions also demonstrate the presence of high-affinity 2-[125I]iodomelatonin (125I-MEL) binding sites, with the pharmacological specificity of binding expected of the Mel1a receptor subtype, inhibited by guanosine 5'-O-(3'-thiotriphosphate) (GTPgammaS) and pertussis toxin. We conclude that functional MR in guinea pig kidney and small intestine are of the Mel1a subtype, and are expressed as 37 kDa proteins localized to the BLM and coupled to a pertussis toxin-sensitive G-protein (Gi). This localization strongly suggests that the proximal tubule plays a significant role in mediating the renal action of melatonin.

Animals↗
PubMed1997

Differential inhibitory effects of melatonin analogs and three naphthalenic ligands on 2-[125I]iodomelatonin binding to chicken tissues.

We have compared the 50% inhibition values of 2-[125I]iodomelatonin ([125I]Mel) competition curves by melatonin and 3 naphthalenic ligands, N-[2-(7-methoxy-1-naphthyl) ethyl] cyclobutane carboxamide (S20642), N-propyl N-[2-(7-methoxy-1-naphtyl) ethyl] urea (S20753), and N-[2-(7-methoxy-1-naphthyl) ethyl] crotonamide (S20750), using membrane preparations of four tissues (lung, spleen, brain, and kidney) of the chicken simultaneously. In retired breeders, we have demonstrated that the affinities of S20642 were similar in the lung and spleen. However they were 2-fold lower in the brain and 80-fold lower in the kidney. Similar differential binding affinities to the melatonin receptors were observed in the four tissues of young male chicks. This suggests that age and sex have little influence on the differential inhibitory properties of melatonin and S20642 in the tissues studied. The addition of guanosine 5'-O-thiotriphosphate (GTPgammaS), which encouraged the uncoupling of melatonin receptor to the G protein complex, lowered the binding affinity of melatonin and S20642 in the tissues studied but their differential affinities in the four tissues were however maintained. The affinities of 5-methoxy-N-cyclopropanoyltryptamine (CPMT) in the kidney were also 5-10-fold lower than those in the lung, spleen, and brain of young male chicks. The distinctive differential affinities of melatonin, S20642, and CPMT for [125I]Mel binding sites in the chicken lung, spleen, brain, and kidney indicated that the binding sites in these tissues are heterogeneous. Our study implicated that the naphthalenic ligand S20642 may be a useful melatonin analog to distinguish melatonin receptor subtypes in tissues and a possible drug candidate worthwhile for further investigations.

Aging↗
PubMed1997

The developmental and circadian variation of melatonin receptors in the chicken spinal cord.

The developmental variation of 2-[125I]iodomelatonin binding sites in membrane preparations of the chicken spinal cords was investigated. In 19-day-old embryos, the maximum number of binding sites (Bmax) was the highest during the development. With the increase in age posthatch, the Bmax decreased gradually and significantly from 1-day-old to 4-month-old chickens. However, there were no significant changes in equilibrium dissociation constant (Kd) among all age-groups studied. To study the circadian variation, the 2-[125I]iodomelatonin binding sites in the spinal cords of 3-week-old chickens were determined at 4-hour intervals throughout a 24-hour period under a 12-hour light/12-hour dark cycle. There was a diurnal rhythm in both Bmax and Kd of [125I]iodomelatonin binding sites in which Bmax decreased and Kd increased in the dark period. The characteristics of developmental and circadian variation of melatonin receptors in the chicken spinal cord suggest that melatonin may exert a direct action on spinal cord functions and that it plays a more important role in the young animal.

Animals↗
PubMed1997

Comparative efficacy and potency of ipratropium via Turbuhaler and pressurized metered-dose inhaler in reversible airflow obstruction.

Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p<0.05). In conclusion, the efficacy study showed that maximum FEV1 occurred at low doses of IB, negating any opportunity to identify differences between devices. The potency study indicated that the 10 microg dose via TH was of similar efficacy to the 20 microg dose via pMDI, confirming an efficacy ratio of 1.5-2.0:1 for the TH device.

Adult↗
PubMed1997

Studies of melatonin effects on epithelia using the human embryonic kidney-293 (HEK-293) cell line.

The expression of melatonin receptors (MR) of the Mel1a subtype in basolateral membrane of guinea pig kidney proximal tubule suggests that melatonin plays a role in regulating epithelial functions. To investigate the cellular basis of melatonin action on epithelia, we sought to establish an appropriate in vitro culture model. Epithelial cell lines originating from kidneys of dog (MDCK), pig (LLC-PK1), opossum (OK), and human embryo (HEK-293) were each tested for the presence of MR using 2-[125I]iodomelatonin (125I-MEL) as a radioligand. The HEK-293 cell line exhibited the highest specific 125I-MEL binding. By intermediate filament characterization, the HEK-293 cells were determined to be of epithelial origin. Binding of 125I-MEL in HEK-293 cells demonstrated saturability, reversibility, and high specificity with an equilibrium dissociation constant (Kd) value of 23.8 +/- 0.5 pM and a maximum number of binding sites (Bmax) value of 1.17 +/- 0.11 fmol/mg protein (n = 5), which are comparable with the reported Kd and Bmax values in human kidney cortex. Coincubation with GTPgammaS (10 microM) and pertussis toxin (100 ng/ml) provoked a marked decrease in binding affinity (Kd was increased by a factor of 1.5-2.0), with no significant difference in Bmax. Melatonin (1 microM) decreased the forskolin (10 microM) stimulated cAMP level by 50%. HEK-293 cells do not express dopamine D1A receptor. Following transient transfection of HEK-293 cells with human dopamine D1A receptor (hD1A-R), exposure of the cells to dopamine stimulated an increase in the level of cAMP. Similarly, transient transfection of HEK-293 cells with rat glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and PTH type 1 receptors, each resulted in an hormone inducible increase in cAMP levels. Surprisingly, only the stimulatory effect of dopamine could be inhibited by exposure to melatonin. The inhibitory effect of melatonin on dopamine D1-induced increase in cAMP was completely inhibited by pertussis toxin (100 ng/ml, 18 h). Immunoblot and immunocytochemical studies were carried out using two polyclonal antibodies raised against the extra and cytoplasmic domains of Mel1a receptor. Immunoblot studies using antibody against the cytoplasmic domain of Mel1a receptor confirmed the presence of a peptide blockable 37 kDa band in HEK-293 cells. Indirect immunofluorescent studies with both antibodies revealed staining predominantly at the cell surface, but staining with the antibody directed against the cytoplasmic domain required prior cell permeabilization. By RT-PCR, HEK-293 cells express both Mel1a and Mel1b messenger RNAs, but the messenger RNA level for Mel1b is several orders of magnitude lower than for Mel1a. We conclude that HEK-293 cells express MR predominantly of the Mel1a subtype. Our evidence suggests that one of the ways that melatonin exerts its biological function is through modulation of cellular dopaminergic responses.

Animals↗
PubMed1997

Caregivers and HIV infection. Services and issues.

Because of the complexity of their illness, patients infected with HIV may require many services to facilitate the management of the disease. The primary care provider must understand and facilitate the services that are needed and needs to be familiar with the individuals responsible for the care of each patient. There are many stresses that have been identified in HIV caregiving, for informal caregivers and health care workers. These stresses are described, and suggestions for appropriate interventions are outlined.

Adult↗
PubMed1996

Synthetic phospho-oligosaccharide fragments of lipophosphoglycan as acceptors for Leishmania major alpha-D-mannosylphosphate transferase.

Protozoan parasites of the genus Leishmania synthesise lipophosphoglycans, phosphoglycans and proteophosphoglycans that contain phosphosaccharide-repeat units of [-6Gal beta 1-4Man alpha 1-P-]. In this study, a GDP-Man-dependent alpha-mannosylphosphate-transferase activity was detected in washed Leishmania major membranes using synthetic phospho-oligosaccharide fragments of lipophosphoglycan as acceptor substrates. The divalent-cation-dependent alpha-mannosylphosphate-transferase activity had an apparent K(m) for GDP-Man of about 15-20 microM and a pH optimum of 7.0. The activity showed a requirement for a non-reducing terminal beta Gal residue and for one or more phosphodiester units preceding the acceptor site. Based on these results, the activity may be defined as a GDP-Man: Gal beta 1-4Man alpha 1-P-R alpha-mannosylphosphate-transferase. This acceptor specificity is consistent with a role for the alpha-mannosylphosphate transferase in the elongation of phosphosaccharide-repeat domains of Leishmania glycoconjugates rather than in the priming of these domains. An identical or similar activity must exist in the amastigote forms of the Leishmania that produce and secrete proteophosphoglycan material and the activity therefore represents a feasible target for the development of chemotherapeutics.

Animals↗
PubMed1996

Characterization of a non-reducing terminal fragment from bovine articular cartilage keratan sulphates containing alpha(2-3)-linked sialic acid and alpha(1-3)-linked fucose. A sulphated variant of the VIM-2 epitope.

Alkaline-borohydride-reduced keratan sulphate chains were isolated from bovine articular cartilage (6-8-year-old animals) and digested with keratanase II, an endo- beta-N-acetylglucosaminidase. The resulting oligosaccharides were borohydride-reduced and fractionated on a strong anion-exchange column. 1H-NMR spectroscopic analysis of the products revealed one containing both alpha(2-3)-linked sialic acid and alpha(1-3)-linked fucose which was shown to have the structure (I) shown. This structure is a sulphated variant of the VIM-2 epitope (CD65), a putative ligand of E-selectin. No oligosaccharide containing the sialyl-Le(+) structure [NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-] was identified in this study. [equation: see text]

Acetylglucosaminidase↗
PubMed1996

Nocturnal melatonin and 24-hour 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder.

Nine bipolar patients (2 men and 7 women) and 12 healthy control subjects completed overnight sampling for serum melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s). The patients were investigated during manic, depressed, and/or euthymic states. Although serum MT levels did not differ significantly across the bipolar groups, in all cases serum MT levels were significantly lower than in control subjects. Differences in MT levels were also present between bipolar patients who were in a depressed phase and control subjects. There were no statistically significant differences in urinary aMT6s levels among the patients and control subjects, although in all cases nocturnal aMT6s levels were significantly higher than daytime levels. This study provides tentative evidence for decreased serum MT as a trait but not a state marker in bipolar affective disorder.

Adult↗
PubMed1996

Neuromodulation of frontal and temporal cortex by intravenous d-fenfluramine: an [15O]H2O PET study in humans.

This study assessed the modulatory effect of a serotonergic agonist, d-fenfluramine, on localized neuronal firing as indexed by changes in regional cerebral blood flow (rCBF). Previously, we reported the effect of oral d, l-fenfluramine on neuronal activity as measured by change in [18F]fluorodeoxyglucose uptake. Improvements in the current study include: a more specific serotonin agonist, d-fenfluramine; a more reliable administration route, intravenous; and a one session paradigm made possible with the radiotracer [15O]H2O. Changes in relative rCBF (P < 0.001) were observed: increases within the frontal cortex bilaterally and decreases within the temporal cortex bilaterally, and left thalamus. Other significant findings were elevated cortisol and growth hormone; increased euphoria and panic symptoms and decreased tiredness. These results support further investigation with intravenous d-fenfluramine to study the net functional effects of serotonergic stimulation in health and illness.

Adult↗
PubMed1996

Localization and characterization of melatonin receptors in the rabbit spinal cord.

Melatonin receptors in the rabbit spinal cord were studied. Using in vitro quantitative autoradiography we have localized and characterized 2-[125I]iodomelatonin ([125I]MEL) binding sites in the central gray substance (lamina X) of the rabbit spinal cord. Saturation study revealed a single class of high affinity binding sites in the central gray substance with an equilibrium dissociation constant (Kd) of 38.8 +/- 5.25 pM and a maximum number of binding sites of 5.69 +/- 0.84 fmol/mg protein in the mid-light period. These [125I]MEL binding sites were highly specific for melatonin. Coincubation with 10 microM or 50 microM guanosine 5'-O-(3-thiotriphosphate) produced a significant change in Kd. These results suggest that melatonin receptors in the rabbit spinal cord are coupled to a guanine-nucleotide-binding protein (G-protein). Our studies suggest that melatonin exerts a direct action on the rabbit spinal cord.

Animals↗
PubMed1996

Lack of association between thyroid and pineal responses to antidepressant treatment.

With antidepressant treatment for major depression there are decreases in thyroid hormone levels and increases in pineal function. We have conducted a study to examine whether there is a relationship between pineal and thyroid hormone measures as well as between hormone measures and response to treatment in patients treated with desipramine. Measures of thyroid activity included thyroxine, triiodothyronine, T3 resin uptake, and TSH. Pineal function was determined by measurement of 6-suphatoxymelatonin in three consecutive 8 hour pools. Hormone measures as well as Hamilton depression scores were obtained prior to treatment and at the end of 5 weeks of treatment. As in previous studies, thyroid measures decreased, pineal activity increased, and Hamilton scores decreased significantly with treatment. No correlations were found between these measures, suggesting that if there is a relationship between them it is not a direct one.

Adult↗
PubMed1996

Effects of self-generated sad mood on regional cerebral activity: a PET study in normal subjects.

This study investigated the cerebral regions modulated by self-generated sad mood in normal subjects. Eleven healthy men experienced a temporary sad mood by recalling sad personal memories. Two control states were used for comparison: a resting condition, and a condition involving the recall of affectively neutral personal events. Regional cerebral blood flow (rCBF) images were obtained using [15O]-H2O Positron Emission Tomography. A statistical comparison of the images during negative mood and neutral recall conditions revealed that sad mood was associated with a decrease in rCBF in the left dorsolateral prefrontal, left medial prefrontal, and left temporal cortex; no increase in activity was noted in this comparison. Our results are consistent with the noted left prefrontal decrease in metabolism found in depressed patients through a variety of methodologies; however, our results contrast with findings of increased left or bilateral prefrontal activity in transient induced negative mood states reported for women (George et al., 1995, Am J Psychiatry 152:341-341) and for mixed-gender (Pardo et al., 1993, Am J Psychiatry 150:713-719) subject groups. The study brings to light a number of methodological issues, including the crucial importance of the baseline condition used for the isolation of the emotional components of a given task.

Adult↗