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Biomedical subjects

J Dunn

Publications and source records attributed to J Dunn.

At least 109 records · Page 6Linked to original sources
PubMed1996

Why talk about mental states? The significance of children's conversations with friends, siblings, and mothers.

Natural language data from 38 47-month-olds recorded at home in unstructured observations were analyzed and comparisons made of characteristics of mental state term use in child-friend, child-sibling, and child-mother dyads. Significantly more references to mental states were made by the children in conversations with siblings and friends than with mothers. Frequent use of mental state terms by both partners was related to cooperative interaction in both child-friend and child-sibling dyads and several associations were found with measures of language fluency, gender, and maternal education, although these varied across the 2 dyads. Children's use of mental state terms in conversations with siblings and friends was correlated with their performance on two false belief measures. Results highlight the importance of extending investigations into the social implications of the development of children's "theories of mind."

Child↗
PubMed1996

Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development.

Carbohydrate-deficient glycoprotein syndrome (CDGS) type II is a multisystemic congenital disease with severe involvement of the nervous system. Two unrelated CDGS type II patients are shown to have point mutations (one patient having Ser-->Phe and the other having His-->Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N- acetylglucosaminyltransferase II (GnT II), an enzyme essential for biosynthesis of complex Asn-linked glycans. Both mutations caused both decreased expression of enzyme protein in a baculovirus/insect cell system and inactivation of enzyme activity. Restriction-endonuclease analysis of DNA from 23 blood relatives of one of these patients showed that 13 donors were heterozygotes; the other relatives and 21 unrelated donors were normal homozygotes. All heterozygotes showed a significant reduction (33%-68%) in mononuclear-cell GnT II activity. The data indicate that CDGS type II is an autosomal recessive disease and that complex Asn-linked glycans are essential for normal neurological development.

Blotting, Northern↗
PubMed1995

Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals.

This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administration of the corn oil-based soft gel cap (CsA-GC) with those with the microemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadministration of a low- or high-fat breakfast affected the pharmacokinetics of CsA presented in either formulation. Comparisons of the three sets of pharmacokinetic parameters--namely, after fasting or after low-fat or after high-fat diets--demonstrated the CsA-ME formulation to display greater intraindividual reproducibility of the C0 and C12 trough levels (TLs), Cmax, tmax, and area under the concentration-time curve (AUC) than the CsA-GC formulation. Although the degree of interindividual variation in AUC, Cmax and tmax after CsA-ME administration was slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the customarily monitored C0 or C12 TL values. CsA-ME showed higher correlation coefficients of drug exposure (AUC) with C12 than CsA-GC (0.910 versus 0.712). However, CsA-ME administration resulted in only modest improvement over CsA-GC administration in the relationships between drug dose and C0, C12, or AUC--namely, 0.645 versus 0.496, 0.611 versus 0.517, and 0.700 versus 0.501, respectively. Correlation analysis between individual timed samples and AUC determinations revealed that CsA-ME requires significantly less frequent blood monitoring for prediction of total drug exposure than does CsA-GC. Although the clinical utility of this reproducible pharmacokinetic behavior remains to be demonstrated in the de novo transplant setting, the markedly reduced intraindividual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the frequency of subsequent adjustments in, CsA doses.

Corn Oil↗
PubMed1995

Selective inhibition of prostaglandin endoperoxide synthase-1 (cyclooxygenase-1) by valerylsalicylic acid.

Aspirin causes a time-dependent inhibition of prostaglandin endoperoxide H synthases (PGHS)-1 and -2 by acetylating active site serines present in both isozymes. In the case of PGHS-1, aspirin acetylation blocks cyclooxygenase activity, apparently by preventing arachidonate binding to the cyclooxygenase active site. With PGHS-2, acetylation does not block substrate binding but rather alters the enzyme in such a way that the acetylated form of PGHS-2 produces 15R-hydroxyeicosatetraenoic acid (15R-HETE) instead of the usual prostaglandin endoperoxide product. Based on these differences between PGHS-1 and PGHS-2, we reasoned that a salicylate ester containing an acyl group somewhat larger than the acetyl group of aspirin might be a selective inhibitor of PGHS-2. Accordingly, we prepared and tested eight different acyl salicylates as inhibitors of human (h) PGHS-1 and -2 expressed transiently in cos-1 cells. Valeryl(pentanoyl)salicylate (VSA) was the only compound in this series which showed isozyme selectivity, and, surprisingly, VSA inhibited hPGHS-1 much more effectively than hPGHS-2. Inhibition of hPGHS-1 by VSA was time-dependent. VSA also inhibited ovine PGHS-1 but did not inhibit the S530A mutant of ovine PGHS-1. This latter mutant, which lacks the active site serine hydroxyl group, is also refractory to inhibition by acetylsalicylate. Thus, we conclude that VSA acylates the active site serine of PGHS-1. VSA inhibited prostanoid synthesis by serum-starved murine NIH 3T3 cells which express only PGHS-1; in contrast, VSA caused only partial inhibition of prostanoid synthesis by serum-stimulated 3T3 cells which express both PGHS isozymes. Our results establish that VSA can be used as a reasonably selective inhibitor of PGHS-1.

3T3 Cells↗
PubMed1995

Etoposide protein binding in cancer patients.

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r = 0.74), daily dose (r = 0.37) and age (r = -0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.

Administration, Oral↗
PubMed1995

A prospective randomized trial to evaluate different oral dose regimens of medroxyprogesterone acetate in women with advanced breast cancer.

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; chi 2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; chi 2 = 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments.

Administration, Oral↗
PubMed1995

Adenylate compartmentation and storage in coelomic cells of the polychaete Nereis virens

The concentrations of adenine nucleotides (AMP, ADP, ATP) were determined in coelomic cells (eleocytes) of the polychaete Nereis virens. In cells of immature and male animals, total ADP and AMP contents (each 10&shy;15 &micro;mol ml-1 packed cell volume) greatly exceeded that of ATP (0.8 &micro;mol ml-1 packed cell volume). 31P-nuclear magnetic resonance (NMR) studies of living eleocytes showed that the high concentrations of both AMP and ADP are free in solution. Comparisons of in vivo NMR spectra with those obtained from metabolite extracts of eleocytes suggest that the adenylate pools are compartmentalized, with a large pool being in an environment with a pH<6.0 and a small pool being in a domain where pH>6.7. This indicates that eleocytes are capable of storing high concentrations of ADP and AMP without inhibiting energy metabolism by sequestering these compounds into an acidic compartment. The large acidic vacuole characteristic of eleocytes may function as this compartment.

Journal Article↗
PubMed1995

Cytokine treatment of human bone marrow activates anti-leukaemia effector cells: monitoring of purging by polymerase chain reaction and DNA analysis.

The aims of this study were to investigate the role of cytokines (tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma) and interleukin-2 (IL-2) in augmenting graft-versus-leukaemia (GVL). We have investigated the effector cells involved in GVL, by studying the role of these cells in purging of the cell line K562 in short-term bone marrow cultures. The effect of the addition in vitro of rGCSF was also studied. Monitoring of purging was achieved by cytotoxicity assays, DNA analysis and the use of the polymerase chain reaction for the detection of bcr/abl transcripts in the Philadelphia positive (Ph+) K562 cell line. Supernatants from IL-2-treated and non-treated bone marrow were tested for cytokine production (TNF alpha and IFN gamma). The results have shown that the main cytotoxic effector cells in the bone marrow generated by IL-2 have the CD56+ CD8+ phenotype. Overnight incubation of bone marrow was sufficient to generate cytotoxic cells as measured by Chromium51 (Cr51) release assays. Measurable levels of TNF alpha but not IFN gamma were also detected in supernatants. Addition of TNF alpha and IFN gamma to the IL-2 in the bone marrow cultures augmented the cytotoxicity but tended to inhibit progenitor cell growth as measured by granulocyte-macrophage colony-forming unit (GM-CFU) and erythroid blast-forming unit (BFU-e) assays. An estimate of the purging of the marrow could also be achieved by DNA analysis of K562 DNA in bone marrow. The bcr/abl transcript could still be detected by PCR analysis in marrow containing 1% K562 and treated with IL-2 for 24 h, but by 6 days of incubation the bcr/abl transcript was weak or undectable. The results suggest that although reduction in the proportion of leukaemia in contaminated marrow can be detected after incubation with IL-2 for 24 h, complete elimination of minimal residual disease requires longer incubation times.

Biomarkers, Tumor↗
PubMed1995

Individual differences in young children's pretend play with mother and sibling: links to relationships and understanding of other people's feelings and beliefs.

50 33-month-old children were observed at home with their siblings and mothers. Observational measures of pretend play, observer ratings of the child's, mother's, and sibling's behavior, and measures of family discourse about feelings were collected. At 40 months each child was assessed on Bartsch and Wellman's false beliefs task and Denham's affective perspective taking task. Results revealed individual differences in the amount and sophistication of young children's social pretend play and suggested that these individual differences are related to experiences in the relationships that young children have with their mothers and siblings. Results also indicated that early social pretend play was significantly related to the child's developing understanding of other people's feelings and beliefs. The data are interpreted as providing support for the notion that early experience in social pretense is associated with children's mastery of the relation between mental life and real life. The importance of considering the relationship context of social pretense is also discussed.

Awareness↗
PubMed1995

Intersubjectivity in psychoanalysis: a critical review.

The intersubjective critique of the classical model's positivistic tradition is examined. Classical analysis construes the core of mental life as a discrete entity that can be relatively interpretively captured as such. In contrast, the intersubjectivists construe core psychic processes as inseparable from a relational matrix. The intersubjective critique is traced to the theoretical tensions in Freud's concepts of transference/countertransference and ego development. Questions are raised whether the current intersubjective challenges actually constitute changes in clinical activity and process. Noted is the ubiquitous overlap between the intersubjective and classical models in all theories of psychoanalysis, as each seem to capture different aspects of mental functioning. Classical analysis maintains a difference between a stultifying 'idealisation' of a positivistically-based objective orientation and a holding such a possibility as only an 'ideal' to strive for: absolutist approaches to theory are unfounded, as the irreducibility of our subjectivity does not reduce us to total ignorance. Adopting an intersubjective orientation does not stop analysts from idealising 'that theory' and imposing it on the patient in an authoritarian manner. Nothing intrinsic to any theory forestalls self-aggradisement, and answers to such problems may lie in other kinds of theoretical debates than these.

Countertransference↗
PubMed1994

Multiple myeloma.

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Psychological effects of organophosphate pesticides: a review and call for research by psychologists.

Organophosphates are among the most commonly used and most toxic pesticides. They act directly on the nervous system by inhibiting the neurotransmitter acetylcholine. Organophosphates evoke a consistent pattern of physical symptoms. They also have acute psychological and behavioral effects, such as anxiety, depression, and cognitive impairments. Research suggests that moderate levels of acute poisoning may cause persistent problems. Long-term psychological effects of low-level exposure, however, have not been determined satisfactorily. Some research has documented cognitive and emotional deficits due to chronic exposure to organophosphates, but not all studies have found ill effects. To date, psychologists have played only a small role in studying the psychological effects of organophosphates, despite the substantial contribution their expertise could make.

Humans↗
PubMed1994

Monoclonal anti-TNF-alpha suppresses graft vs host disease reactions in an in vitro human skin model.

Graft vs host disease (GVHD) following allogeneic marrow transplant in humans is known to be mediated in part by cytokines. Tumour necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) are considered to be critical in the mechanism. A commercially produced antibody to TNF-alpha (CB0006) was tested in vitro to assess its ability to suppress mixed lymphocyte reactions (MLR). Peripheral blood mononuclear cells treated and untreated with CB0006 were also tested for their ability to elicit a graft vs host reaction (GVHR) in vitro in a human skin-explant model for GVHD. The results showed that CB0006 could inhibit mixed lymphocyte culture (MLC) proliferative responses and that in vitro antibody treated responder cells were less effective in causing GVHR in vitro skin-explant assays. CB0006 was also shown to inhibit MLC supernatant induced GVHR.

Antibodies, Monoclonal↗
PubMed1994

New nonionic triiodinated x-ray contrast media containing the N-(2-hydroxyethyl)aminopropane-2,3-diol side chain.

We have found the amino alcohol (HE)APD to be an effective solubilizing and detoxifying agent for triiodinated benzene XRCM. Most of the compounds containing the (HE)APD moiety displayed good solution properties (low osmolality and viscosity) and relatively low toxicities. A general trend was observed in which compounds with low hydrophilicity were more toxic. High hydrophilicity was found to be necessary for low intracisternal toxicity, but is not the only criterion. Use of the 5-glycolamido group provides compounds with high hydrophilicity. When all the properties were compared, the best compounds in this study were found to be the three asymmetrically substituted isophthalamides containing the (HE)APD and APD side chains (4a-c: MP-1556, MP-1683, and MP-1689). These compounds have excellent solution properties (low osmolality and viscosity) and low intravenous and intracisternal toxicities, and compare favorably to current clinical agents.

Animals↗