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Biomedical subjects

M Davies

Publications and source records attributed to M Davies.

At least 325 records · Page 18Linked to original sources

Proteinases and the glomerulus: their role in glomerular diseases.

Degradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM) in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.

Basement Membrane↗

Dorsal raphe microinjection of 5-HT and indirect 5-HT agonists induces feeding in rats.

Previous work has shown that 5-hydroxytryptamine (5-HT) receptor agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reduce 5-HT neurotransmission and induce feeding in rats. The effects of 8-OH-DPAT appear to be mediated in part in the dorsal raphe nucleus by serotonergic somatodendritic autoreceptors which normally regulate impulse flow in 5-HT dorsal raphe neurons. The present experiments sought to examine whether suppression of dorsal raphe serotonergic neural activity induced by exogenously applied, or endogenously released 5-HT would increase feeding. Free-feeding rats were microinjected in the dorsal raphe with 5-HT, the 5-HT releasing compound d-fenfluramine, the 5-HT re-uptake inhibitor zimelidine, or the type-A monoamine oxidase inhibitor brofaromine. Dose dependent increases in food intake over a 1 h period were found following treatment with 5-HT and the three indirectly acting compounds. Thus, increased serotonergic activity within the dorsal raphe increases feeding, presumably by inhibiting the activity of dorsal raphe 5-HT neurons. In addition the effects of 5-HT were blocked by pretreatment with haloperidol, indicating the involvement of a dopaminergic mechanism in mediating the effects of feeding of a suppression in dorsal raphe 5-HT neural activity. The results are discussed in terms of the general role which serotonergic neurons arising from the dorsal raphe may play in behavioural inhibition.

Animals↗

When in Rome.

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Community Mental Health Services↗

Desferrioxamine as a lipid chain-breaking antioxidant in sickle erythrocyte membranes.

The mechanism of action of desferrioxamine in the inhibition of the catalysis of iron-induced oxidative damage has been ascribed to its ability to chelate available ferric ion (Kb = 10(31)). However, recent work has proposed that the trihydroxamate moiety of desferrioxamine can also be involved in electron transfer reactions involving the superoxide radical, peroxidase/hydrogen peroxide mixtures and ferryl myoglobin radicals. In this study we report evidence for the ability of desferrioxamine to inhibit peroxidative damage to pathological membranes with which non-haem iron is associated through a mechanism of action as a lipid chain breaking antioxidant, independently of its iron chelating properties.

Anemia, Sickle Cell↗

Uncommon troubles in young people: prevalence estimates of selected psychiatric disorders in a nonreferred adolescent population.

A two-stage epidemiologic strategy was used to estimate the lifetime prevalence of selected DSM-III-defined psychiatric disorders in a county-wide secondary school population (N = 5596). Screening tests used in the first stage included items based on DSM-III criteria for eating disorders and panic disorder, as well as the Leyton Obsessional Inventory-Child Version and the Beck Depression Inventory. Based on interviews (n = 356) by clinicians in the second stage, the lifetime prevalence of anorexia nervosa was 0.2%; bulimia, 2.5%; panic disorder, 0.6%; obsessive-compulsive disorder, 1.9%; major depression, 4.0%; dysthymic disorder, 4.9%; and generalized anxiety disorder, 3.7%. While rates of mental health service utilization varied greatly by diagnosis, only 41% of students who were assigned both a diagnosis and a rating of impairment had received any kind of clinical attention.

Adolescent↗

Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142.

Previously, the 5-hydroxytryptamine (5-HT)1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone and the 5-HT3 receptor antagonist ICS 205-930 have been shown to exert anxiolytic-like effects in several animal models. In the experiments reported here the effects of these compounds on feeding behaviour and food preference in a novel environment were examined, and compared with the effects of the anxiolytic drug chlordiazepoxide and the anxiogenic compound FG 7142. Chlordiazepoxide significantly reduced the latency to begin eating and prolonged the total time spent eating; chlordiazepoxide also abolished food neophobia, by significantly increasing the time spent eating novel food items. In contrast, FG 7142 significantly increased eating latency and reduced eating duration. Both 8-OH-DPAT and buspirone significantly enhanced eating duration, but unlike chlordiazepoxide eating was directed only towards the familiar food. In addition buspirone, but not 8-OH-DPAT, reduced eating latency. ICS 205-930 significantly increased eating latency and reduced eating duration; however, these effects were observed only at the lowest dose tested. All of these behavioural effects were observed only when animals were unfamiliar with the testing situation, and cannot be accounted for in terms of changes in mechanisms controlling hunger. The behavioural paradigm used in these experiments may induce a competition between the drives to explore a novel environment and to eat. It is suggested that the tendency of buspirone and 8-OH-DPAT to suppress exploratory activity may thus result in enhanced feeding duration.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

A pharmacological analysis of the eating response induced by 8-OH-DPAT injected into the dorsal raphé nucleus reveals the involvement of a dopaminergic mechanism.

Direct injection of the 5-hydroxytryptamine (5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the dorsal raphé nucleus (DRN) dose dependently increased food intake in free feeding rats. The hypothesis that this effect is mediated by 5-HT1A receptors was tested by investigating the abilities of the putative 5-HT1A antagonists metergoline, propranolol and spiperone to prevent 8-OH-DPAT-induced eating. Metergoline failed to affect 8-OH-DPAT-induced eating when injected either peripherally or into the DRN. Peripherally injected propranolol and spiperone prevented 8-OH-DPAT-induced eating, but these drugs were ineffective when injected into the DRN. These results indicate that 8-OH-DPAT-induced eating may not involve 5-HT1A receptors within the DRN. The ability of peripherally injected spiperone to prevent the eating response to 8-OH-DPAT reflects its dopamine blocking activity since haloperidol was an effective antagonist of 8-OH-DPAT-eating. This result may indicate that 8-OH-DPAT produces a general behavioural activation by reducing the inhibitory influence which 5-HT normally exerts over the nigrostriatal dopamine pathway, and that this behavioural activation is expressed as eating when food is the most salient goal object present.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Human glomerular epithelial cell proteoglycans.

Proteoglycans synthesized by cultures of human glomerular epithelial cells have been isolated and characterized. Three types of heparan sulfate were detected. Heparan sulfate proteoglycan I (HSPG-I; Kav 6B 0.04) was found in the cell layer and medium and accounted for 12% of the total proteoglycans synthesized. HSPG-II (Kav 6B 0.25) accounted for 18% of the proteoglycans and was located in the medium and cell layer. A third population (9% of the proteoglycan population), heparan sulfate glycosaminoglycan (HS-GAG; Kav 6B 0.4-0.8), had properties consistent with single glycosaminoglycan chains or their fragments and was found only in the cell layer. HSPG-I and HSPG-II from the cell layer had hydrophobic properties; they were released from the cell layer by mild trypsin treatment. HS-GAG lacked these properties, consisted of low-molecular-mass heparan sulfate oligosaccharides, and were intracellular. HSPG-I and -II released to the medium lacked hydrophobic properties. The cells also produced three distinct types of chondroitin sulfates. The major species, chondroitin sulfate proteoglycan I (CSPG-I) eluted in the excluded volume of a Sepharose CL-6B column, accounted for 30% of the proteoglycans detected, and was found in both the cell layer and medium. Cell layer CSPG-I bound to octyl-Sepharose. It was released from the cell layer by mild trypsin treatment. CSPG-II (Kav 6B 0.1-0.23) accounted for 10% of the total 35S-labeled macromolecules and was found predominantly in the culture medium. A small amount of CS-GAG (Kav 6B 0.25-0.6) is present in the cell extract and like HS-GAG is intracellular. Pulse-chase experiments indicated that HSPG-I and -II and CSPG-I and -II are lost from the cell layer either by direct release into the medium or by internalization where they are metabolized to single glycosaminoglycan chains and subsequently to inorganic sulfate.

Antibodies, Monoclonal↗

Synthesis of 1,25-dihydroxyvitamin D3 by spleen cells isolated from two patients with myelofibrosis and a normal subject.

The ability to synthesise [3H]1,25(OH)2D3 was studied in spleen cells incubated in short-term primary culture with [3H]25(OH)D3 which were isolated from two patients with idiopathic myelofibrosis and from one normal subject. Formation of a metabolite co-chromatographing with authentic 1,25(OH)2D3 on three different high-performance liquid chromatography systems was observed for cells from all three patients. [3H]1,25(OH)2D3 synthesis was 0.37 and 1.6 fmol/10(6) cells/incubation for cells with a density below that of lymphocyte separating media (1.077 g/ml) for the two myelofibrotic patients respectively and 0.15 fmol/10(6) cells/incubation for the normal subject. The most likely cell type capable of this synthesis were those of the monocyte-macrophage lineage which would have been present in abnormally high numbers in the patients with myelofibrosis. However, the exact identity of the cell-type responsible could not be determined because of the heterogeneity of cell types present. The observation that spleen cells from two patients with myelofibrosis and from a normal accident victim could metabolise [3H]25(OH)D3 to its active form [3H]1,25(OH)2D3 suggests a possible role for this metabolite in spleen haematopoiesis.

Calcitriol↗

Isolation, culture and characterization of human peritoneal mesothelial cells.

This study establishes a reproducible technique for the culture of human peritoneal mesothelial cells. Direct explants, as well as enzymatically degraded specimens, of human omentum have been used as the source of cells. Cells were grown on collagen and gelatin coated matrices and were maintained in supplemented Ham's F-12 medium containing 10% (vol/vol) Fetal calf serum. Morphologically and ultrastructurally, the cells formed a homogeneous population. They were polygonal when confluent and devoid of contaminating fibroblasts, endothelial cells and macrophages. Cultured mesothelial cells co-expressed cytokeratin and vimentin and synthesized laminin, fibronectin, mesosecrin, non-specific esterase and collagen Types I and III but not Type IV. Ultrastructural features included numerous surface microvilli, cytoplasmic vesicles and an abundant endoplasmic reticulum. The stimulation of mesothelial cells by the calcium ionophore A23187 demonstrated that the two major products of arachidonic acid metabolism were prostacyclin and prostaglandin E2. The peritoneal mesothelial cell may be pivotal in the initiation of the inflammatory response during peritonitis and its establishment in culture will provide the basis for an in vitro model of peritoneal inflammation.

Cells, Cultured↗

Activation of the inflammatory response of neutrophils by Tamm-Horsfall glycoprotein.

The activation of human polymorphonuclear leukocytes (PMN) by particulate Tamm-Horsfall glycoprotein (THG) represents an interaction hitherto unrecognized. The potential pathophysiological effect of this phenomenon within the interstitium of the kidney is highlighted by the activation of the respiratory burst, as well as by comprehensive PMN degranulation. Products of the interaction are expressed in terms of phagocytosis, luminol-dependent chemiluminescence, granule marker enzyme release and arachidonic acid metabolism. Significant quantities of the primary, secondary and tertiary granule markers, myeloperoxidase, vitamin B12 binding protein and N-acetyl-beta-D-glucosaminidase, respectively, were secreted in a dose and time-dependent manner. Phagocytosis of the glycoprotein was accompanied by the generation of significant quantities of leukotriene B4. Furthermore, the ability of such a particulate ligand to activate the alternative pathway of complement clearly represents a capacity to augment the inflammatory response. Should the interaction of THG with PMN take place within the interstitium of the kidney, augmented by the deposition of complement proteins on the surface of insoluble aggregates, the resulting inflammatory response may lead to marked tissue damage and eventually result in interstitial fibrosis.

Complement Pathway, Alternative↗

Early childhood bereavement.

Acute bereavement responses in preschool children were prospectively assessed. Parentally bereaved subjects (26, 3- to 6-year-olds) were compared with matched, nonbereaved controls (N = 40). Bereaved subjects, particularly boys, were significantly more symptomatic (Child Behavior Checklist--Parent). On a newly standardized affect interview for preschoolers, bereaved children reported feeling more scared and less happy than controls. Bereaved children, especially girls, reported significantly more sadness when thinking about their parents. The ability to report these grieving emotions correlated significantly with improved functioning. Children from families experiencing a drop in income after the death were more symptomatic. Disturbance among subject parents and children was highly correlated. Issues of developmental capacity to grieve and the impact of environmental mediators are discussed.

Adaptation, Psychological↗

The DSM-III-R field trial of disruptive behavior disorders.

The members of the DSM-III-R Advisory Committee responsible for the diagnostic criteria for the disruptive behavior disorders (attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder) were able to reach agreement on potential items to be included in the final diagnostic criteria. However, there was considerable disagreement about the relative utility of different items for the three disorders and no agreement on how many items should be required from a final list of discriminating items to establish each of the diagnoses. This article describes the method and results of a national field trial of the proposed criteria. Using as a standard the diagnosis of these disorders made by expert clinicians with experience with these disorders, the diagnostic criteria that were finally included in DSM-III-R demonstrated high sensitivity, specificity, and internal consistency.

Attention Deficit Disorder with Hyperactivity↗

Psychopathology and developmental delay in homeless children: a pilot study.

The authors report a survey of 50 parent-child pairs from homeless families housed in New York City hotels. The purpose of the survey was to determine the extent of emotional or behavioral disturbances and of developmental delays in homeless children aged 4 through 10 years, the presence of depression or a history of depression or other psychiatric problems in the parents of these children, and to determine whether the children and adults had mental health needs. The results indicate that nearly all of the children showed some difficulties. Sixty-one percent of the children had receptive verbal functioning at or below the first percentile for age, 29% were functioning at the fifth percentile for age in psychomotor ability, and 38% exhibited emotional and behavioral problems. Twenty-eight percent of the parents exhibited evidence of mild to severe depression; a smaller percentage admitted to past psychiatric problems.

Adult↗

The involvement of 5-hydroxytryptaminergic and dopaminergic mechanisms in the eating induced by buspirone, gepirone and ipsapirone.

1. The roles of 5-hydroxytryptamine (5-HT) and dopamine systems in mediating the increased feeding induced by buspirone, gepirone and ipsapirone were investigated. 2. All three compounds induced dose-dependent increases in food intake when administered subcutaneously to free feeding rats. Buspirone was effective over a narrower dose range than either gepirone or ipsapirone, and the maximal effect observed was smaller than the effects elicited by gepirone and ipsapirone. 3. Depletion of brain 5-HT with parachlorophenylalanine (PCPA) prevented the effects of equi-effective doses of gepirone (2.5 mg kg-1) and ipsapirone (2.5 mg kg-1), but failed to prevent buspirone (1 mg kg-1)-induced eating. Thus buspirone does not appear to interact with 5-HT systems to elicit feeding. 4. Gepirone (0.2 micrograms) and ipsapirone (0.04 and 0.2 micrograms) increased food intake when injected into the dorsal raphé nucleus (DRN), presumably by inhibiting the activity of DRN 5-hydroxytryptaminergic afferents. Buspirone (0.04-5 micrograms) was ineffective when injected into the DRN. 5. Pretreatment with haloperidol (0.1 mg kg-1, 30 min) significantly attenuated the effects of equi-effective doses of buspirone, gepirone and ipsapirone, indicating that these drugs interact with dopaminergic systems to increase feeding. 6. Previously it has been shown that each of these drugs increases striatal dopamine activity. Increased dopaminergic neurotransmission in the striatum induces a general behavioural activation, which under certain conditions facilitates feeding. It is possible that this mechanism underlies the behavioural effects of buspirone, gepirone and ipsapirone. The effects of gepirone and ipsapirone probably involve an indirect action to inhibit the activity of DRN 5-hydroxytryptaminergic afferents, whereas buspirone interacts directly with dopaminergic systems.

8-Hydroxy-2-(di-n-propylamino)tetralin↗