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Biomedical subjects

D Dunn

Publications and source records attributed to D Dunn.

At least 55 records · Page 3Linked to original sources
PubMed1996

Detection of virus in vertically exposed HIV-antibody-negative children.

BACKGROUND: HIV-infected mothers can transmit their infection to their children in utero or at delivery (vertical transmission). There have been cases of children who were reported as acquiring infection vertically and later clearing the infection. We report the frequency of this phenomenon in a European cohort study. METHODS: In four centres of the European Collaborative Study of children born to HIV-infected mothers, 299 children became HIV-antibody-negative and 264 of these had been followed up with virus culture and PCR for viral DNA at least once. FINDINGS: Nine of the 264 children were positive by virus culture or PCR, and subsequently seroreverted. Two of the nine tested virus-positive after they became antibody-negative. Six cases were virus-positive early in life and became negative thereafter, which is consistent with clearance of infection. The pattern was less clear in the other three. The nine cases had had their last virus test at age 16-101 months. All nine children had been bottlefed only. Eight had been delivered vaginally. The children had no HIV-related symptoms and received no anti-HIV treatments. Based on only those children who had two or more positive virological tests, we estimate that 2.7% (6/219) cleared or "tolerated" the virus. INTERPRETATION: The detection of virus or viral DNA in "uninfected" children born to HIV-infected mothers was rare and was not associated with clinical disease or immunological abnormalities. The timing of samples will affect the documentation of clearance since, in uninfected children of HIV-positive mothers who cleared the virus, viraemia was intermittent. Current paediatric opinion is to inform parents of children who serorevert that the child is not HIV-infected.

Child, Preschool↗
PubMed1996

The active site specificity of the Yersinia protein-tyrosine phosphatase.

Yersinia protein-tyrosine phosphatase substrates have been synthesized employing an expedient methodology that incorporates phosphorylated non-amino acid residues into an active site-directed peptide. While the peptidic portion of these compounds serves an enzyme targeting role, the nonpeptidic component provides a critical assessment of the range of functionality that can be accommodated within the active site region. We have found that the Yersinia phosphatase hydrolyzes both L- and D-stereoisomers of phosphotyrosine in active site-directed peptides, with the former serving as a 10-fold more efficient substrate than the latter. In addition, this enzyme catalyzes the hydrolysis of a variety of aromatic and aliphatic phosphates. Indeed, a peptide bearing the achiral phosphotyrosine analog, phosphotyramine, is not only the most efficient substrate described in this study, it is also one of the most efficient substrates ever reported for the Yersinia phosphatase. Straight chain peptide-bound aliphatic phosphates of the general structure, (Glu)4-NH-(CH2)n-OPO3(2-) (n = 2-8), are also hydrolyzed, where the most efficient substrate contains seven methylene groups. Finally, a comparison of the substrate efficacy of the peptide-bound species with that of the corresponding non-peptidic analogs, reveals that the peptide component enhances kcat/Km by up to nearly 3 orders of magnitude.

Binding Sites↗
PubMed1996

Anemia and the transition of nomadic hunter-gatherers to a sedentary life-style: follow-up study of a Kalahari community.

Iron profiles of communities of hunter-gatherers and former hunter-gatherers conducted between 1969 and 1987 at Dobe in the Kalahari Desert of Botswana exhibited pronounced differences during periods of rapid culture change. The loss of good health and particularly the increase in anemia through time was attributed to notable changes in diet, although changes in mobility patterns were considered a secondary cause. In 1988 and 1989, studies were conducted at Kutse, also in the Kalahari Desert of Botswana, to ascertain the frequency of anemia at a recently sedentary community in which residents still relied primarily on wild animals for meat. Although not identical, the hematological presentation in 1989 was similar to that in 1988. The studies together suggest that our findings characterize the pattern of health and disease at Kutse, which is unrelated to any specific year or to diet. Additional measures of disease, specifically ESR (erythrocyte sedimentation rate) and oral temperatures, support an interpretation of anemia of chronic disease as the cause of hypoferremia at Kutse. Morbidity is high, in spite of adequate diets, because the residents are transitional from a nomadic to a sedentary lifestyle and from a relatively dispersed to an aggregated settlement pattern. These changes have introduced new health problems.

Adult↗
PubMed1996

Determining factors for the outcome of peripheral blood progenitor cells harvests.

This is a pilot retrospective study to investigate the factors that may affect the collection of peripheral blood progenitor cells (PBPC). Sixty-nine PBPC harvests in 18 cancer patients (median age 39.5; 8 males and 10 females) were performed during marrow recovery after chemotherapy and hematopoietic growth factors. Median number of nucleated cells (MNC) collected were 13.3 (range 2.3-44.5) x 10(9) per session. Median CFU-GM was 362 colonies (range 63-1,720) per 500,000 MNC. Neither sex, body weight, diagnosis, nor the number of days into leukapheresis was significantly associated with MNC and CFU-GM. Older patients tend to have higher CFU-GM in the PBPC harvests (P = .0437). Higher WBC on the day of harvest is significantly associated with higher yield of MNC after leukapheresis (P < .0001). Patients without any evidence of disease have significantly higher yield of MNC than those having local/distant metastases with or without marrow involvement (P = .0302 and .0446). For patients with metastatic disease, those with bone marrow involvement tend to have higher CFU-GM than those without bone marrow involvement although the difference is not statistically significant (P = .0559). Those patients who have received only one, or three and more chemotherapy regimens have a higher yield of MNC than those who have only two previous chemotherapy regimens (P = .036 and .0324). The mechanism of PBPC mobilization is also discussed. In view of the limited patient number in this study, the results should be confirmed by larger studies.

Adolescent↗
PubMed1996

Characteristics of pregnant HIV-1 infected women in Europe. European Collaborative Study.

There is a growing number of infected women in Europe and an increasing proportion of these have acquired their infection through heterosexual contact. Most infected women are of childbearing age and thus increasing numbers of children are at risk of acquiring infection. In this paper we examine the socio-demographic characteristics and trends in mode of acquisition of infection of 1690 infected women from 7 countries enrolled in the European Collaborative Study, a prospective multi-centre study of children born to women known to be HIV infected at or before the time of delivery. The majority of women were white, primiparae, married or cohabiting and born in Europe. Two-thirds had a history of injecting drug use (IDU), most commonly involving heroin. Although patterns of transmission varied by centre, there was a relative increase in heterosexual transmission over the study period. A history of needle-sharing among IDUs was common, but needle-sharing during pregnancy significantly declined between 1987 and 1994.

Adult↗
PubMed1996

Possible role of nitric oxide in the development of L-2-chloropropionic acid-induced cerebellar granule cell necrosis.

1. L-2-Chloropropionic acid (L-CPA) produces selective neuronal cell necrosis in rat cerebellum when administered orally at 750 mg kg-1 that is mediated in part through activation of N-methyl-D-aspartate (NMDA) receptors. Cerebellar granule cell death occurs between 30 and 36 h following L-CPA administration exhibiting a number of features in common with excitatory amino acid-induced cell death. We have used this in vivo model to examine the neurochemical processes following L-CPA-induced activation of NMDA receptors leading to neuronal cell death in the rat cerebellum. 2. The effects of a number of compounds which potently block nitric oxide synthase in vitro were examined on L-CPA-induced neurotoxicity 48 h following L-CPA dosing, to discover whether the neuronal cell death is mediated in part by excessive nitric oxide generation. Four inhibitors were studied, NG-nitro-L-arginine (L-NOARG), NG-nitro-L-arginine methyl ester (L-NAME), NG-iminoethyl-L-ornithine (L-NIO) and 3-bromo-7-nitroindazole (BrNI). 3. L-NAME (50 mg kg-1, i.p. twice daily) and BrIN (50 mg kg-1, i.p. twice daily) administration prevented the L-CPA-induced loss of granule cells which can reach up to 80-90% of the total cell number in rats treated with L-CPA alone. L-NOARG (50 mg kg-1, i.p. twice daily) and L-NIO administered at either 25 or 100 mg kg-1, twice daily did not produce any significant protection against L-CPA-induced neurotoxicity. 4. Both L-NAME and BrIN also prevented the L-CPA-induced increase in cerebellar water content and sodium concentrations. L-NIO when administered at the highest doses prevented the increase in cerebellar sodium concentration but not water content. L-NIO and L-NOARG were ineffective in preventing the L-CPA-induced increases in cerebellar water and sodium concentrations. 5. L-CPA-induced reductions in cerebellar aspartate and glutamate concentrations and increases in glutamine and GABA concentrations were prevented by L-NAME and BrIn, but not by L-NIO or L-NOARG. Also reductions in L-[3H]-glutamate binding to glutamate ionotrophic and metabotrophic receptors in the granule cell layer of rat cerebellum was prevented by L-NAME and BrIN, but not L-NIO or L-NOARG. 6. In conclusion, the neuroprotection offered by L-NAME and BrIN suggests that L-CPA-induced cerebellar granule cell necrosis is possibly mediated by or associated with excessive generation of nitric oxide. The inability of nitric oxide synthase inhibitors, L-NOARG and L-NIO to afford protection may result from their limited penetration into the brain (L-NIO) or rapid dissociation from the enzyme.

Animals↗
PubMed1996

Evidence for mediation of L-2-chloropropionic acid-induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase.

1. Delayed neuronal cell death elicited by excess excitatory amino acid concentrations has been strongly implicated in many neurological disorders including head trauma, stroke, motor neurone disease and Huntington's disease. We have used the neurotoxin, L-2-chloropropionic acid (L-CPA) to model cellular events in vivo leading to delayed neuronal cell loss which is confined to the cerebellar cortex and can be prevented by inhibitors of nitric oxide synthase such as NG-nitro-L-arginine methyl ester. 2. Experiments were performed to determine whether the constitutive nitric oxide synthase (NOS) or inducible form of NOS (iNOS) was responsible for the neuronal cell death. Activation of NOS was confirmed by a 39% increase in cerebellar total nitrate and nitrite concentrations in L-CPA-treated brains, as compared to controls (controls = 2.53 +/- 0.10; L-CPA treated = 3.51 +/- 0.31 nmol mg-1 protein, P < 0.01 Student's t tests, n = 6, mean +/- s.e.mean). Biochemical measurements of total NOS activity were made in homogenates of cerebellum 6 h and 48 h following L-CPA administration, times at which L-CPA concentrations are maximal in brain and a time when there is a high proportion of cerebellar granule cell death, respectively. NOS activity as measured by the amount of [3H]-arginine converted to [3H]-citrulline, did not reveal any difference between controls (rats dosed with water) and animals dosed with L-CPA at either 6 or 48 h following dosing. Furthermore the ability of three NOS inhibitors, NG-nitro-L-arginine, 7-bromo-3-nitroindazole and S-methylisothiourea to block the conversion of [3H]-citrulline to [3H]-arginine was identical at 6 and 48 h time points in control and L-CPA treated rats. 3. Quantitative autoradiography using [3H]-NG-nitro-L-arginine was used to measure the relative anatomical distribution and amount of NOS enzyme in the cerebellum of controls and L-CPA-treated rats 48 h following dosing. There was no significant alteration in the binding of [3H]-NG-nitro-L-arginine to granular and molecular layers of the cerebellum of control and L-CPA-treated rat brains. 4. Western blotting using antibodies against the inducible NOS enzyme failed to detect the protein in cerebellums of L-CPA-treated rats when measured 48 h after L-CPA dosing. 5. In conclusion, the increase in cerebellar nitrate/nitrite concentrations in L-CPA-treated rats provides further evidence for activation of NOS in the cerebellum following administration of L-CPA. The failure to demonstrate an increase in NOS activity at 6 or 48 h in L-CPA-treated rats as compared to controls suggests that the source of nitric oxide responsible for the granule cell death must originate from the constitutive NOS enzyme, probably the neuronal form which is highly enriched in the cerebellum. This hypothesis was further substantiated by Western blotting and quantitative autoradiography.

Animals↗
PubMed1996

Health care 1999: a National Bellwether.

To provide a framework to understand managed care's effect on inpatient utilization, "Health Care 1999: A National Bellwether," was created by the Sachs Group, a health care information firm based in Evanston, Illinois. The study outlines estimated changes in discharges, patient days, and average lengths of stay in the aggregate, product line, and regional levels from 1994 to 1999. To develop this study, Sachs created a model reflecting inpatient utilization for a group model HMO. The model is based on current practice patterns in California, recognized as the most aggressive managed care marketplace.

Bed Occupancy↗
PubMed1995

Use of polymerase chain reaction and quantitative antibody tests in children born to human immunodeficiency virus-1-infected mothers.

The diagnosis of human immunodeficiency virus (HIV) infection in children born to HIV-infected mothers is complicated by the presence of passively acquired maternal antibodies, and exclusion of infection in these infants remains problematic. The use of genome detection by polymerase chain reaction (PCR) amplification and the quantification of anti-HIV-1 antibodies were examined as methods for early diagnosis. Blood samples were taken from 84 non-breast-fed infants of HIV-infected mothers in five Italian and Spanish centres, a subgroup of children enrolled in the European Collaborative Study (ECS) for whom clinical and immunological information has been documented from birth. Whole blood was added to glycigel cryopreservative, stored, and tested in the United Kingdom by a nested PCR method. Antibody to HIV-1 was detected and quantified by titration using a gelatin particle agglutination test. PCR sensitivity and specificity were assessed. Twenty-one of the 84 children tested were infected. The estimated PCR sensitivity ranged from 0% (95% CI 0-26%) on day 1, 57% (19-85) on day 7, to 63% (33-92) on day 30. The negative predictive value of PCR ranged from 85% (83-88) on day 0 to 98% (94-100) at 3 months of age. On average, the level of maternal antibody halved every 33 days (31-36.5) in uninfected children. Between 6 and 9 months of age, increases in antibody titres in infected children were not more informative than absolute levels. These findings suggest that antibody measurement may supplement genomic diagnosis and that this collection method provides an alternative to the use of dried blood spots.

Age Factors↗
PubMed1995

The cyclic dilemma: organic, functional, and environmental interaction in a young teenager.

This Grand Rounds considers an early-adolescent female who demonstrated a mixed clinical picture including rapid cycling of psychotic behavior. The case presents issues commonly faced in hospital practice and provides an example of the use of standardized instruments in assessment and monitoring treatment, as well as a discussion of issues germane to inpatient child and adolescent psychiatrists and related treatment team members.

Adolescent↗
PubMed1995

The European Collaborative Study: clinical and immunological characteristics of HIV 1-infected pregnant women.

OBJECTIVE: To describe the changing clinical and immunological characteristics and timing of diagnosis of HIV-infected pregnant women enrolled in the European Collaborative Study. DESIGN: A prospective study of the mothers of children enrolled in the European Collaborative Study on children born to HIV-infected women. SETTING: Twenty-one European centres in seven countries. SUBJECTS: One thousand six hundred and ninety HIV-infected women and their 1754 deliveries. RESULTS: The proportion of women in whom HIV infection had been diagnosed before pregnancy increased significantly over time, from 7% in 1984-1985 to 65% in 1994 (P < 0.001). The prevalence of breastfeeding, which was related to the timing of diagnosis, significantly declined over the study period. The mean CD4 count was 510 cells/mm3, and there was a significant decline in average CD4 count over the study period. Black women had a significantly lower CD4 count than white women. From survival analysis it is estimated that five years after delivery 14% of women will have died and 24% will have developed CDC stage IV disease. CONCLUSIONS: Timing of diagnosis is of critical importance if mother-to-child transmission is to be reduced through avoidance of breastfeeding and zidovudine therapy and effective antenatal screening policies have become increasingly important. The rate of progression of maternal disease highlights the implications of HIV infection for their children, both infected and uninfected.

Antiviral Agents↗