Biomedical subjects

D G Morgan

Publications and source records attributed to D G Morgan.

At least 37 records · Page 2Linked to original sources

PubMed2000

The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.

Agouti-Related Protein↗

PubMed2000

Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies.

The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.

Animals↗

PubMed2000

The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

Adrenocorticotropic Hormone↗

PubMed2000

Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone.

The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be important in physiological regulation of food intake. We investigated which hypothalamic areas known to express MC4R are involved in the regulation of feeding by using alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R antagonist. Cannulae were inserted into the rat hypothalamic paraventricular (PVN), arcuate (Arc), dorsomedial (DMN), and ventromedial (VMN) nuclei; the medial preoptic (MPO), anterior hypothalamic (AHA), and lateral hypothalamic (LHA) areas; and the extrahypothalamic central nucleus of the amygdala (CeA). Agrp (83-132) (0.1 nmol) and [Nle4, D-Phe7]alpha(-MSH (NDP-MSH) (0.1 nmol), a stable alpha-MSH analog, were administered to fed and fasted rats, respectively. The PVN, DMN, and MPO were the areas with the greatest response to Agrp and NDP-MSH. At 8 h postinjection, Agrp increased feeding in the PVN by 218 +/- 23% (P < 0.005), in the DMN by 268 +/- 42% (P < 0.005), and in the MPO by 236 +/- 31% (P < 0.01) compared with a saline control group for each nucleus. NDP-MSH decreased food intake in the PVN by 52 +/- 6% (P < 0.005), in the DMN by 44 +/- 6% (P < 0.0001), and in the MPO by 55 +/- 6% (P < 0.0001) at 1 h postinjection. Injection into the AHA and CeA resulted in smaller alterations in food intake. No changes in feeding were seen after the administration of Agrp into the Arc, LHA, or VMN, but NDP-MSH suppressed food intake in the Arc and LHA. This study indicates that the hypothalamic nuclei expressing MC4R vary in their sensitivity to Agrp and alpha-MSH with regard to their effect on feeding.

Agouti-Related Protein↗

PubMed2000

Central administration of orexin A suppresses basal and domperidone stimulated plasma prolactin.

Orexin immunoreactive fibres are abundant in the hypothalamus suggesting a neuroendocrine regulatory role. Intracerebroventricular (ICV) administration of orexin A suppressed plasma prolactin in male rats by 71% at 20 min post-injection and 83% at 90 min post-injection (P < 0.005 vs saline at both time points). To investigate whether this effect was through the tuberoinfundibular dopaminergic (TIDA) system, a supra-maximal dose of domperidone, a dopamine receptor antagonist, was injected intraperitoneally (i.p.) prior to ICV injection of orexin A. ICV orexin A significantly suppressed domperidone (9 mg/kg)-stimulated plasma prolactin levels, by up to 40% (i.p. domperidone + ICV orexin A 3 nmol 34.5 +/- 7.4 ng/ml and i.p. domperidone + ICV orexin A 20 nmol 43.5 +/- 4.3 ng/ml, both P < 0.005 vs i.p. domperidone + ICV saline 57.9 +/- 2.7 ng/ml). Orexin A, 100 nM, significantly stimulated release of neurotensin, vasoactive intestinal polypeptide, somatostatin, corticotropin releasing factor and luteinizing hormone releasing hormone, but had no effect on release of dopamine, thyrotropin releasing hormone (TRH), vasopressin or melanin-concentrating hormone from hypothalamic explants in vitro. Orexin A did not alter basal or TRH stimulated prolactin release in dispersed pituitary cells harvested from male rats. The data suggest that ICV administration of orexin A suppresses plasma prolactin in part through a pathway independent of the dopaminergic system.

Animals↗

PubMed1999

Investigation of the feeding effects of melanin concentrating hormone on food intake--action independent of galanin and the melanocortin receptors.

Melanin concentrating hormone (MCH) is recognised as a hypothalamic appetite stimulant. The mechanism of action of MCH is undetermined largely due to lack of identification of hypothalamic MCH receptors. We designed in vivo and in vitro studies to further characterise the feeding effects of MCH in the rat. MCH was injected directly into the paraventricular nucleus (PVN) at the beginning of the light phase. PVN MCH (0.5 microg) produced an increase in 2 h food intake of 272+/-60% vs. saline control (0.7+/-0.2 g), p<0.05. The time course of the effect of intracerebroventricular (i.c.v.) administration of 5 microg MCH on food intake was investigated. An increase in feeding was observed within 15 min from the time of injection and was not sustained beyond half an hour following administration. To investigate a possible interaction with galanin, 5 microg of MCH was injected i.c.v. with or without 10 microg of galanin. The two peptides together increased 1 h feeding above that of either peptide alone, 768+/-62% (compared with the saline group, 0.47+/-0.2 g), p<0.05 vs. 585+/-36%, galanin alone and 317+/-72%, MCH alone. Finally, to investigate if MCH bound to the brain melanocortin receptors, receptor autoradiography was performed on rat brain sections with the stable analogue of alpha MSH, [125I] Nle(4), D-Phe(7)-alphaMSH and unlabeled MCH. MCH did not compete with [125I] Nle(4), D-Phe(7)-alphaMSH binding. Results demonstrate that MCH stimulates feeding via the PVN, has a short onset and duration of action and activates feeding by mechanisms independent to galanin and the melanocortin receptors.

Animals↗

PubMed1999

Rotational symmetry of the C ring and a mechanism for the flagellar rotary motor.

FliG, FliM, and FliN, key proteins for torque generation, are located in two rings. The first protein is in the M ring and the last two are in the C ring. The rotational symmetries of the C and M rings have been determined to be about 34 (this paper) and 26 (previous work), respectively. The mechanism proposed here depends on the symmetry mismatch between the rings: the C ring extends 34 levers, of which 26 can bind to the 26 equivalent sites on the M ring. The remaining 8 levers bind to proton-pore complexes (studs) to form 8 torque generators. Movement results from the swapping of stud-bound levers with M ring-bound levers. The model predicts that both the M and C rings rotate in the same direction but at different speeds.

Bacterial Proteins↗

PubMed1999

Induction of presenilins in the rat brain after middle cerebral arterial occlusion.

In the present study, we have examined the expression of both presenilins in the rat hippocampus, cortex, striatum, and cerebellum after middle cerebral artery occlusion (MCA-O), an animal model of ischemia. The cortex showed the greatest increase in PS mRNA levels (7-10-fold) at 4 and 8 days posttreatment. Presenilin-1 (PS-1) levels in the contralateral cortex were significantly increased 1 day after MCA-O. In comparison, PS mRNA content was only modestly elevated in the hippocampus and striatum at 4 and 8 days after MCA-O (30-100% changes). Other Alzheimer's disease (AD)-related genes, amyloid precursor protein and apolipoprotein E, are induced in brain injury suggesting that these AD-related genes may well be components of a brain-injury response. Thus, a breakdown in this response via cerebrovascular disease and/or genetic mutation may contribute to AD pathology.

Alzheimer Disease↗

PubMed1999

'Please see and advise': a qualitative study of patients' experiences of psychiatric outpatient care.

BACKGROUND: Patient evaluations have become a sensitive indicator of service delivery and the quality of care. In this study they point to a lack of clarity surrounding the role of outpatient psychiatry in relation to primary care, raising questions about the effective integration of services for patients whose needs straddle the boundaries of primary and specialist care. METHODS: Interviews with a consecutive series of 100 new referrals to two outpatient clinics compared their expectations of treatment with their subsequent experiences of psychiatric care. Patients' perception of progress was compared with clinical assessments. Follow-up interviews explored the reasons why patients tended to lapse from care. RESULTS: The majority of patients (74%) hoped for more effective responses to often long-standing problems which had previously been treated with limited success. In approximately one-third of cases this expectation was met; the remainder reported psychiatric intervention was less than helpful (20%), or were unable to say whether it had helped or not. Most of these patients perceived little difference between psychiatric supervision and treatment offered by their GP. Seemingly impersonal consultations and failure to engage with underlying problems contributed to the high drop-out rate. CONCLUSION: The findings indicate a relatively poor fit between the role of the outpatient service and the circumstances that commonly lead to psychiatric referral. The implications are considered in relation to alternative options for managing psychosocial problems within primary care.

Adolescent↗

PubMed1999

Oral versus transdermal selegiline: antidepressant-like activity in rats.

These studies compared the dose-response effects of oral vs. transdermal selegiline on antidepressant-like activity and brain monoamine oxidase (MAO) activities in rats. Rats received selegiline by gavage (0-100 mg/kg) or via transdermal patches (0-4.8 cm2, 0-8.7 mg/kg) daily for 7 days; antidepressant-like activity was determined using the forced-swim test. Following behavioral testing, cerebral cortices were assayed for MAO-A and MAO-B activities. Doses of selegiline that selectively inhibited MAO-B (3 and 10 mg/kg/day by gavage and 0.4 mg/kg/day via patch) did not alter either immobility or latency time. However, the oral administration of 30 or 100 mg/kg/day or the transdermal administration of 8.7 mg/kg/day, doses that led to greater than 70% inhibition of MAO-A, decreased immobility time significantly. The IC50s for inhibition of MAO-A following oral and transdermal administration for 7 days were 19.8 and 1.1 mg/kg, respectively. Results indicate that both oral and transdermal selegiline have antidepressant-like activity as assessed by the forced-swim test, and that transdermal administration, which bypasses first-pass metabolism, allows for using lower doses than oral administration.

Administration, Cutaneous↗

PubMed1999

Primary biliary cirrhosis and type II autoimmune polyglandular syndrome.

A 45-year-old female was diagnosed with Hashimoto's thyroiditis in 1976 and Addison's disease in 1979. At that time, her antimitochondrial antibody (AMA) level was elevated at 1:32. She subsequently developed premature ovarian failure and type I diabetes mellitus. In 1996, she became jaundiced with a cholestatic enzyme pattern. AMA was positive at a titre of 1:256. A liver biopsy confirmed the diagnosis of primary biliary cirrhosis (PBC). She underwent a liver transplantation in January 1998. This is the first report of PBC in association with type II autoimmune polyglandular syndrome. The association of PBC with other organ-specific autoimmune diseases supports an immune-mediated pathogenesis and may have implications in further studies of PBC.

Female↗

PubMed1999

The physical environment of special care units: needs of residents with dementia from the perspective of staff and family caregivers.

To manage the care of increasing numbers of residents with dementia, many long-term care facilities have created special care units (SCUs) designed to meet the unique needs of this group. This article describes results of the qualitative component of a larger research project examining environment-behavior relationships in dementia care settings. Eighteen indepth interviews were conducted with 9 staff and 9 family members of SCU residents. Thematic analysis was conducted using grounded theory techniques. Participants described residents' needs in relation to both the physical and social environments. This article focuses on the five areas of need identified by participants in relation to the physical environment: safety, homelike setting, optimal stimulation, cues, and options for privacy and social interaction.

Aged↗

PubMed1999

Healthcare utilization associated with dyspepsia in patients with arthritis.

OBJECTIVE: To compare gastrointestinal-related healthcare resource utilization in arthritis patients with and without dyspepsia. STUDY DESIGN: A historical cohort study based on a claims database. PATIENTS AND METHODS: Data were obtained from the MarketScan database. Adult patients with a diagnosis of arthritis (International Classification of Diseases, 9th Revision [ICD-9] codes 714.0-715.9) during 1992 and 1993 were included; individuals with a diagnosis of dyspepsia within the first 3 months of their arthritis diagnosis were considered study case patients. Each case patient was matched with 4 nondyspeptic arthritis patients based on age, gender, employment status, and type of insurance plan. Healthcare resource utilization in terms of outpatient services and inpatient admissions during the first year after the initial arthritis diagnosis was compared between the case and control groups. RESULTS: A total of 503 case and 2146 control patients were identified. There were no significant differences in demographic characteristics between the 2 groups. Dyspeptic patients (cases) had a significantly higher rate of claims for endoscopic procedures (odds ratio [OR] = 10.0, P < .01) than nondyspeptic patients (controls). Patients with dyspepsia also had a significantly higher claim rate of gastrointestinal ulcer or bleeding (OR = 4.2, P < .01) and were more likely to be hospitalized at least once (OR = 1.4, P < .01). Dyspeptic patients had overall higher frequencies of use of outpatient services (53.9 vs 32.5 claims per patient, P < .001) and higher costs for both inpatient admission and outpatient services than nondyspeptic patients. CONCLUSION: Dyspeptic arthritis patients have higher healthcare resource utilization and associated costs than nondyspeptic arthritis patients.

Adult↗

PubMed1998

The NPY Y1 receptor antagonist BIBP 3226 blocks NPY induced feeding via a non-specific mechanism.

We have previously shown that intracerebroventricular BIBP 3226 inhibits NPY induced feeding in rats. However, this was associated with abnormal behaviour, likely to be due to interaction with Y1 receptors involved in mechanisms other than the control of food intake. In order to minimise such interactions we investigated the effects of paraventricular nucleus (PVN) injections of BIBP 3226 and its inactive enantiomer BIBP 3435. Intra-PVN injection of NPY (0.1-2.5 nmol/animal) increased food intake, with an EC50 of approximately 0.15 nmol/animal. Injections of BIBP 3226 and BIBP 3435 (0.25-25 nmol) reduced NPY-induced food intake in a dose responsive manner, with BIBP 3226 reducing food intake by 95%, and BIBP 3435 by 65% at the highest dose tested. The reversibility of the effect of BIBP 3226 was investigated by measuring the feeding response to NPY (0.5 nmol) in animals 1 week after BIBP 3226 injection. The response to NPY was less in animals which had received high doses of BIBP 3226. Animals previously injected with saline vehicle alone showed a normal NPY feeding response. These results suggest that BIBP 3226 may be inhibiting NPY-induced food intake in a non-specific manner, not secondary to inhibition of the Y1 receptor. This does not, however rule out a role for the Y1 receptor in the control of food intake by NPY.

Animals↗

PubMed1998

Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line.

To examine the influence of the putative satiety factor (GLP-1) on the hypothalamo-pituitary-gonadal axis, we used GT1-7 cells as a model of neuronal luteinizing hormone- releasing hormone (LHRH) release. GLP-1 caused a concentration-dependent increase in LHRH release from GT1-7 cells. Specific, saturable GLP-1 binding sites were demonstrated on these cells. The binding of [125I]GLP-1 was time-dependent and consistent with a single binding site (Kd = 0.07+/-0.016 nM; binding capacity = 160+/-11 fmol/mg protein). The specific GLP-1 receptor agonists, exendin-3 and exendin-4, also showed high affinity (Ki = 0.3+/-0.05 and 0.32+/-0.06 nM, respectively) as did the antagonist exendin-(9-39) (Ki = 0.98+/-0.24 nM). At concentrations that increased LHRH release, GLP-1 (0.5-10 nM) also caused an increase in intracellular cAMP in GT1-7 cells (10 nM GLP-1: 7.66+/-0.4 vs. control: 0.23+/-0.02 nmol/mg protein; P < 0.001). Intracerebroventricular injection of GLP-1 at a single concentration (10 microg) produced a prompt increase in the plasma luteinizing hormone concentration in male rats (GLP-1: 1.09+/-0.11 vs. saline: 0.69+/-0.06 ng/ml; P < 0.005). GLP-1 levels in the hypothalami of 48-h-fasted male rats showed a decrease, indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance.

Animals↗

PubMed1998

Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells.

Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. 125I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY > [Pro34]-NPY > NPY 3-36 >> NPY 13-36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits 125I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (Gi or Go) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7-36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through Gi to the inhibition of adenylyl cyclase.

Adenylyl Cyclase Inhibitors↗

PubMed1998

A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.

Agouti Signaling Protein↗

PubMed1997

Exaggerated astrocyte reactivity after nigrostriatal deafferentation in the aged rat.

Although clinical experience suggests that brain injury in the aged is associated with a poor prognosis, little research has examined this phenomenon at a cellular or molecular level. Unilateral 6-hydroxydopamine lesions of the nigrostriatal system were produced in 6-, 15- or 24-month-old rats. In the deafferented neostriatum, the time-dependent induction of glial fibrillary acidic protein (GFAP) was larger and persisted longer in the aged rats. The response of middle-aged rats was intermediate. In contrast, no induction of S-100 or glutamine synthetase was observed in any age group. In a second series of rats with stab wounds in the neostriatum, there were substantially larger GFAP inductions than after deafferentation, but fewer effects of age. However, in both lesion paradigms, GFAP staining increased in the contralateral striatum of old rats, but not in young rats. These data support and extend our earlier work describing larger GFAP RNA inductions after fornix transections in aged mouse hippocampus. The consistency of this exaggerated glial reactivity in the aged brain after modest injury suggests the following: 1) aged astrocytes are more sensitive to gliotrophic factors released by terminal degeneration, 2) larger quantities of such factors are produced after injury, 3) clearance of these factors is delayed in old rodents, and/or 4) aged astrocytes are less able to terminate GFAP inductions after activation. Given the potential role of inflammatory reactions as pathogenic mechanisms in Alzheimer's dementia, these data suggest that age-related glial hypersensitivity may independently increase the risk for some degenerative diseases.

Afferent Pathways↗