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Biomedical subjects

D Manning

Publications and source records attributed to D Manning.

At least 37 records · Page 2Linked to original sources
PubMed1995

Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells.

The Alzheimer amyloid precursor protein (APP) undergoes complex processing resulting in the production of a 4-kDa amyloid peptide (A beta) which has been implicated in the pathogenesis of Alzheimer's disease. Recent studies have shown that cells can secrete carboxyl terminus truncated APP derivatives (APP-S) in response to physiological stimulus. We have used human central nervous system neurons (NT2N) derived from a teratocarcinoma cell line (NT2) to study the signal transduction pathways involved in APP-S secretion and A beta production. Muscarinic receptors (m2 and m3) as well as the heterotrimeric GTP-binding protein Gq and the beta 1 isoform of phospholipase C were present in NT2N neurons. Stimulation of the muscarinic receptor with carbachol resulted in phospholipase C activation as shown by a transient increase in the second messengers 1,2-diacyl-sn-glycerol and inositol 1,4,5-trisphosphate. Carbachol also caused an increase in intracellular Ca2+ levels measured in single NT2N neurons. Under these conditions, carbachol caused a time-dependent 2-fold increase in APP-S secretion into the medium. In contrast, prolonged treatment with carbachol caused a decrease in A beta production into the medium. These results suggest that APP-S secretion and A beta production in NT2N neurons are regulated by the muscarinic/phospholipase C signal transduction pathway. Furthermore, activation of this pathway results in dissociation of APP-S secretion and A beta production.

Alzheimer Disease↗
PubMed1995

Predictors of recidivism to a juvenile assessment center.

We report the results of a study of the predictors of recidivism to a Juvenile Assessment Center in Hillsborough County, Florida, involving over 2,000 youths processed at the center during its first 8 months of operation. Consistent with previous research, younger aged youths, youths with abuse or neglect histories, with previous arrests for property, violence, or drug offenses, with potential vocational, leisure-recreation, and family problems, or who were arrested on property felony charges were likely to recidivate. The program activity and policy implications of these results are discussed.

Adolescent↗
PubMed1994

Making the new deal for junior doctors happen.

How can the new deal for juniors be implemented in today's overstretched health service? How do you get clinicians and management to work together? On the Wirral falling house officer morale and recruitment stimulated a new approach, action learning, which proved to be highly successful. Action learning is not a new approach in management terms, but it is rarely used in the health service. Guided by an experienced facilitator, a group of people learn management skills by exploring and resolving practical problems relevant to them. A group of general practitioners and consultants used action learning to teach themselves more about management and at the same time to make changes which addressed many of the junior doctors' difficulties and solved the hospital recruiting problem.

Group Processes↗
PubMed1994

Comparison of serum osteocalcin with total and bone specific alkaline phosphatase and urinary hydroxyproline:creatinine ratio in patients with Paget's disease of bone.

Osteocalcin or bone Gla protein (BGP) is secreted by osteoblasts, and its serum concentration is elevated in a number of conditions with high bone turnover. A comparison of serum osteocalcin with total (TALP) and bone specific alkaline phosphatase (BALP) and urinary hydroxyproline/creatinine (OHP/Cr ratio) was performed in 13 patients with active Paget's disease of bone. BGP did not correlate significantly with either BALP or TALP, but did show a significant correlation with OHP/Cr ratio (r = 0.76; P < 0.01). BGP does not appear to be as sensitive a marker as BALP or TALP in Paget's disease.

Aged↗
PubMed1993

The hemoglobins of the bullfrog, Rana catesbeiana. Deoxygenation-linked association of tetrameric components B and C to form the trimer BC2: sedimentation analysis and oxygen equilibria.

Hemolysates from the adult bullfrog, Rana catesbeiana, show an unusually high degree of cooperativity of oxygen binding with Hill coefficients greater than 4. The principal components of the tetrameric hemoglobin, B and C, do not show this high cooperativity when isolated, but it reappears when the components are mixed. Sedimentation velocity measurements show that the unusual behavior results from the mixed association of components B and C to form complexes larger than tetramers. Computer simulation of the sedimentation behavior of mixtures of deoxygenated B and C components shows that the gradient profiles can be satisfactorily described in terms of an equilibrium between the B and C tetramers and a BC2 trimer. The simplest model consistent with the results is the mixed association: B + C<-->BC and BC + C<-->BC2, with the second binding constant being higher than the first, indicating significant cooperativity. The extent of association is highest at low pH and low temperature. The dissociation of the B.C complex with low oxygen affinity to higher affinity B and C molecules during oxygenation results in greatly increased cooperativity of oxygen binding with higher Hill coefficients than possessed by either component alone in equilibria measured between 5 and 25 degrees C and between pH 6 and 8.

Animals↗
PubMed1993

The classification of panic disorders: from Freud to DSM-IV.

The authors trace the history of the classification of anxiety disorders, beginning with a detailed discussion of Freud's work on anxiety-neurosis as a basis for subsequent work. They discuss how anxiety disorders were described in DSM-I and DSM-II where Freud's concept of the anxiety neurosis was used as a major organizing principle. The revolutionary change in DSM-III is described in which the term and organizing principle of neurosis was dropped. The controversies that have arisen as a result of changes in DSM-III-R are discussed, particularly as they relate to compatibility with the International Classification of Diseases-10 (ICD-10) and especially with respect to the relationship and priority of panic and agoraphobia. Finally the authors discuss the process by which decisions will be made in DSM-IV where changes will be based on systematic reviews of empirical evidence whenever possible.

Anxiety Disorders↗
PubMed1992

Deoxygenation-linked association of a tetrameric component of chicken hemoglobin.

Deoxygenation-dependent association of hemoglobin tetramers appears to be widespread among amphibians, reptiles, and possibly all or most birds. The evidence for this conclusion depends largely on oxygen equilibria of whole blood which have Hill coefficients that reach values as high as 5-7 at 80-90% oxygenation. Computer simulation of the sedimentation velocity behavior of the major components A and D of chicken hemoglobin shows that component D but not A self-associates to form dimers of tetramers. The gradient profiles at pH 7.5 were satisfactorily fitted with an association constant of 1.26 x 10(4) M-1 and sedimentation coefficients of 4.63 and 7.35 S for tetramer and (tetramer)2, respectively. Since components A and D share common beta chains we conclude that tetramer-tetramer contacts must depend on surface residues of the alpha chains. Comparison of the amino acid sequences of the alpha D and alpha A chains of the hemoglobins from 12 avian species ranging from sparrow to ostrich shows that 20 residues are conserved in the alpha D chains but not in the alpha A chains. Nine of these (45%) are clustered between positions E20 and FG2. Four of the latter, Lys71 (E20), Asn75 (EF4), Gln78 (EF7), and Glu82 (F3) are conserved in all alpha D chains even though they do not appear to participate in intratetramer contacts. Molecular modeling indicates that residues Lys71, Gln78, and Glu82 of the alpha chain are strong candidates for the primary tetramer-tetramer contacts.

Amino Acids↗
PubMed1992

Relationship of anxiety and depression.

There has been considerable controversy regarding the relationship between depression and anxiety. We review briefly the descriptive, longitudinal, genetic, biological, and treatment response data indicating that there is overlap between depression and anxiety. Several possible models are explored that provide different conceptions of how this relationship may best be understood: (1) that there are a variety of more or less discrete, but sometimes coexisting, syndromes within the spectrum of anxiety and depression; (2) that symptoms of depression and anxiety represent different external manifestations of a more basic underlying cause; (3) that one condition may predispose to the other; (4) that the association may be due to artifactual definitional overlap, particularly since the instruments used to measure depression and anxiety share so many items. All these propositions are supported. An important, practical question is discussed--should the mixed anxiety/depressive disorder that has been suggested by ICD-10 be included in DSM-IV?

Anxiety↗
PubMed1992

[Evaluation of a peptide preparation (milk) in the care of infants with various gastrointestinal intolerances].

The use of an enteral peptide feed based on hydrolysed whey protein (Pepti Junior, Cow and Gate/Nutricia Ltd.) was evaluated in 17 patients with complex GIT intolerance. Nine post surgical neonates were weaned onto the feed either following a period of parenteral nutrition (8) or after demonstrating intolerance of both breast milk and a lactose-free soy based formula. Eight infants admitted to a gastroenterology ward with multiple protein intolerances were also studied. Patients were fed to their nutritional requirements with the milk containing/100 ml; 67 kcal (280 kJ), 2.0 g protein, 3.7 g fat (50% MCT, 50% vegetable oil) and 6.7 g carbohydrate (98% maltodextrins). Patients were maintained on the feed for 7-45 weeks (mean 21 weeks). Full nutritional support was possible with the new formula in all but 2 children who had jejunostomies; in these patients > 50% of nutritional requirement were supplied by the enteral feed. All patients gained weight (mean 0.16 kg/week) (SD 0.09). With the exception of subclinical selenium deficiency, no abnormalities of haematological, biochemical or vitamin states were observed. Post prandial plasma amino-acid concentrations were within acceptable limits and similar to those reported on standard whey based infant formulae. The feed appeared well tolerated in infants with GIT intolerances with no major complications in long term usage.

Evaluation Studies as Topic↗
PubMed1991

Pertussis toxin-sensitive Gi protein involvement in epidermal growth factor-induced activation of phospholipase C-gamma in rat hepatocytes.

Treatment of rat hepatocytes with epidermal growth factor (EGF) produced an enhanced tyrosine phosphorylation of the EGF receptor and phospholipase C-gamma (PLC-gamma) in conjunction with the mobilization of Ca2+. Approximately 30% of the total PLC-gamma was tyrosine-phosphorylated with a maximum being reached after 30 s of incubation with EGF. Pretreatment of the rats with pertussis toxin prior to isolation of the hepatocytes blocked EGF-induced tyrosine phosphorylation of PLC-gamma and Ca2+ mobilization but had no effect on autophosphorylation of the EGF receptor or Ca2+ responses elicited by angiotensin II or phenylephrine. Under these conditions Gi protein alpha subunits were fully ADP-ribosylated. A 41-kDa Gi protein alpha subunit was found to be present in the anti-PLC-gamma immune complex after EGF stimulation as shown by in vitro ADP-ribosylation using [32P]NAD+ and activated pertussis toxin. The kinetics of association between PLC-gamma with Gi alpha protein reached a maximum after 1 min of incubation with EGF. Antibodies specific for the EGF receptor also coimmunoprecipitated a Gi protein alpha subunit. Treatment of hepatocytes with EGF caused first an increase and then a decrease in the amount of Gi protein alpha subunit associated with the EGF receptor. In contrast, studies with cultured rat liver (WB) cells, a cell line in which EGF stimulation of phosphoinositide hydrolysis is not inhibited by pertussis toxin, showed that a stable complex of Gi alpha was not formed with either PLC-gamma or EGF receptor immunoprecipitates. These results indicate that a pertussis toxin-sensitive Gi protein is uniquely involved in the signal transduction pathway mediating EGF-induced activation of PLC-gamma and Ca2+ mobilization in hepatocytes.

Adenosine Diphosphate Ribose↗
PubMed1991

Identification of the subunits of GTP-binding proteins coupled to somatostatin receptors.

Somatostatin (SRIF) induces its biological effects by interacting with membrane-bound receptors that are linked to cellular effector systems via G proteins. We have studied SRIF receptor-G protein associations by solubilizing the SRIF receptor from rat brain and AtT-20 cells and immunoprecipitating the receptor-G protein complex with peptide-directed antisera against the different subunits of the G protein heterotrimer. Antiserum 8730, which selectively interacts with all Gi alpha subtypes, maximally and specifically immunoprecipitated SRIF receptor-Gi alpha complexes. To identify the subtypes of Gi alpha that are coupled to SRIF receptors, the subtype-selective antisera 3646, 1521, and 1518, which specifically interact with Gi alpha 1, Gi alpha 2, and Gi alpha 3, respectively, were used to immunoprecipitate SRIF receptor-Gi alpha complexes. Antiserum 3646 immunoprecipitated SRIF receptor-Gi alpha 1 complexes from both brain and AtT-20 cells. Antiserum 1521 immunoprecipitated Gi alpha 2 from both brain and AtT-20 cells but did not immunoprecipitate SRIF receptors from these tissues. Antiserum 1518 immunoprecipitated AtT-20 cell SRIF receptors but uncoupled brain SRIF receptor-G protein complexes. This result was confirmed with another peptide-selective antiserum, SQ, directed against Gi alpha 3. The findings from these studies indicate that Gi alpha 1 and Gi alpha 3 are coupled to SRIF receptors, whereas Gi alpha 2 is not. Even though brain and AtT-20 cell SRIF receptors were both coupled to Gi alpha, the receptors from these tissues differed in their coupling to Go alpha. Antiserum 2353, which is directed against Go alpha, immunoprecipitated SRIF receptors from AtT-20 cells, but did not immunoprecipitate or uncouple SRIF receptor-G protein complexes from rat brain. To determine the beta subunits associated with the SRIF receptor, antisera directed against G beta 36 and G beta 35 were used to immunoprecipitate SRIF receptor-G protein complexes from brain. Peptide-directed antiserum against G beta 36 selectively immunoprecipitated solubilized brain SRIF receptors. However, antiserum directed against the G beta 35 subunit did not immunoprecipitate brain SRIF receptors, suggesting that brain SRIF receptors may preferentially associate with G beta 36. In addition to coimmunoprecipitating with Gi alpha and G beta, brain SRIF receptors coimmunoprecipitated the G protein gamma subunits, G gamma 2 and G gamma 3. These results provide the first evidence that SRIF receptors are coupled to different subunits of G proteins and suggest that selectivity exists in the association of different G protein subunits with the SRIF receptor.

Amino Acid Sequence↗
PubMed1991

The influence of detergents on the availability of pertussis toxin substrates.

Pertussis toxin-dependent ADP-ribosylation of rat heart and human mononuclear leukocyte membranes was found to be markedly enhanced in the presence of detergents. The order of potency for this effect of detergents was Triton X-100 approximately Lubrol PX greater than digitonin much greater than cholate greater than 3-[(3-cholamidopropyl)dimethylammonia]propanesulfonic acid. Exposure of membranes to increasing concentrations of detergents increased the proportion of pertussis toxin substrate demonstrable in the supernatant fraction whereas the substrate remaining in the pellet fraction demonstrated a complicated relationship with the concentration of detergent. In complementary experiments, it was found that immunochemical detection of G proteins in the pellet fraction from suspensions previously incubated with a maximal concentration of detergent revealed a reduced presence of G proteins with a concomitant increase in the concentration of G proteins in the supernatant fraction; this situation was not observed at submaximal concentrations of detergent during the preincubation of myocardial membranes. The results suggest that the detergent-mediated enhancement of pertussis toxin's action to ADP-ribosylate susceptible G proteins is a complicated process that includes concentration-dependent creation of conditions favorable to the actions of the toxin as well as solubilization of the substrates for the toxin.

Adenosine Diphosphate Ribose↗
PubMed1990

Solubilization of active somatostatin receptors from rat brain.

Rat brain somatostatin (SRIF) receptors were solubilized in an active form with the detergent 3-[(cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Solubilized SRIF receptors were detected with the stable SRIF analog 125I-MK 678. CHAPS solubilized approximately 30% of membrane-bound SRIF receptors. 125I-MK 678 binding to the solubilized SRIF receptors reached equilibrium by 90 min and dissociated from the receptor with a t1/2 of 60 min. The binding of 125I-MK 678 to the solubilized SRIF receptor was of high affinity and was selective. The characteristics of 125I-MK 678 binding to the solubilized and membrane-bound SRIF receptors were similar. The solubilized brain SRIF receptor specifically bound to a wheat germ agglutinin-Sepharose column, suggesting that it is a glycoprotein. Analysis of the solubilized SRIF receptor by gel exclusion chromatography on an AcA 34 Ultrogel column revealed that its molecular mass is approximately 400 kDa. This mass is probably representative of the receptor complexed with other proteins or molecules. Further characterization of the fractionated 400-kDa species by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting indicated that Gi and Go may be associated with the solubilized SRIF receptor. This is supported by the finding that guanosine-5'-O-(3-thio)triphosphate abolished 125I-MK 678 binding to the solubilized SRIF receptor. Antibodies directed against a synthetic peptide corresponding to a region of the C-terminal of Gia, which specifically immunoprecipitate Gia, immunoprecipitated over 24% of the solubilized SRIF receptor, suggesting that the receptor, in part, is coupled to Gi. These studies describe for the first time the characterization of the solubilized SRIF receptor in an active form. The ability to solubilize the SRIF receptor should allow for further characterization of its physical properties.

Animals↗
PubMed1989

Susceptibility to AIDS: what college students do and don't believe.

In-depth, qualitative discussion using the nominal group technique examined freshmen's perceived susceptibility to AIDS and barriers to prevention. Groups were led by dormitory resident advisors as a follow-up to a survey questionnaire of college students' knowledge and beliefs about AIDS. Students' comments showed that many misunderstandings lay behind an apparent understanding of the facts about AIDS. These findings underscore how imperative it is that college health education programs be attuned to the needs and address the deficiencies of the particular student body. In-depth, qualitative research techniques such as the nominal group are described as useful in tailoring AIDS prevention to the specific campus audience and are an appropriate introduction to an AIDS-education session. Suggestions, based on students' comments, are made for improving AIDS-prevention programs on campus.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Diagnostic criteria for dysthymic disorder.

The DSM-III (American Psychiatric Association 1980) criteria for dysthymic disorder selected a heterogeneous group of patients who overlapped with major depression and personality disorders in ways that were difficult to interpret. DSM-III-R (American Psychiatric Association 1987) revised the dysthymia criteria by (1) distinguishing early from late age of onset; (2) providing separate designations for primary and secondary states of dysthymia; (3) including a category of chronic major depression; and (4) revising the specific content of criteria. The performance characteristics of the new criteria set are yet to be tested--a necessary next step to inform the discussions that will culminate in DSM-IV. The remaining areas of greatest controversy are whether (1) early onset, primary dysthymic disorder should be redefined as depressive personality and placed on Axis II; (2) "double-depression" represents a real clinical phenomenon or a definitional artifact; and (3) the content of the diagnostic criteria can be made more specific for chronic depressions. The implications of possible changes and the workings of the DSM-IV Affective Disorders Work Group are discussed.

Depressive Disorder↗
PubMed1988

Pertussis toxin modifies the characteristics of both the inhibitory GTP binding proteins and the somatostatin receptor in anterior pituitary tumor cells.

The effects of pertussis toxin treatment on the characteristics of somatostatin receptors in the anterior pituitary tumor cell line AtT-20 were examined. Pertussis toxin selectively catalyzed the ADP ribosylation of the alpha subunits of the inhibitory GTP binding proteins in AtT-20 cells. Toxin treatment abolished somatostatin inhibition of forskolin-stimulated adenylyl cyclase activity and somatostatin stimulation of GTPase activity. To examine the effects of pertussis toxin treatment on the characteristics of the somatostatin receptor, the receptor was labeled by the somatostatin analog [125I]CGP 23996. [125I]CGP 23996 binding to AtT-20 cell membranes was saturable and within a limited concentration range was to a single high affinity site. Pertussis toxin treatment reduced the apparent density of the high affinity [125I]CGP 23996 binding sites in AtT-20 cell membranes. Inhibition of [125I]CGP 23996 binding by a wide concentration range of CGP 23996 revealed the presence of two binding sites. GTP predominantly reduced the level of high affinity sites in control membranes. Pertussis toxin treatment also diminished the amount of high affinity sites. GTP did not affect [125I]CGP 23996 binding in the pertussis toxin-treated membranes. The high affinity somatostatin receptors were covalently labeled with [125I] CGP 23996 and the photoactivated crosslinking agent n-hydroxysuccinimidyl-4-azidobenzoate. No high affinity somatostatin receptors, covalently bound to [125I]CGP 23996, were detected in the pertussis toxin-treated membranes. These results are most consistent with pertussis toxin uncoupling the inhibitory G proteins from the somatostatin receptor thereby converting the receptor from a mixed population of high and low affinity sites to only low affinity receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗