Biomedical subjects

D Cooper

Publications and source records attributed to D Cooper.

At least 19 recordsLinked to original sources

PubMed1999

Genetic diversity of Borrelia burgdorferi in lyme disease patients as determined by culture versus direct PCR with clinical specimens.

Two hundred seventeen isolates of Borrelia burgdorferi originally cultured from skin biopsy samples or blood of early Lyme disease patients were genetically characterized by PCR-restriction fragment length polymorphism (RFLP) typing of the 16S-23S ribosomal DNA intergenic spacer. Three major RFLP types were observed. Of the cultured isolates, 63 of 217 (29.0%) were type 1, 85 of 217 (39.2%) were type 2, and 58 of 217 (26.7%) were type 3; mixtures of two RFLP types were obtained in 6.0% (13 of 217) of the cultures. Comparison of typing of B. burgdorferi performed directly on 51 patient skin specimens with typing of cultures originally isolated from the same tissue revealed that a much larger proportion of direct tissue samples had mixtures of RFLP types (43.1% by direct typing versus 5.9% by culture [P < 0.001). In addition, identical RFLP types were observed in only 35.5% (11 of 31) of the paired samples. RFLP type 3 organisms were recovered from blood at a significantly lower rate than were either type 1 or type 2 strains. These studies demonstrate that the genetic diversity of B. burgdorferi patient isolates as determined by cultivation differs from that assessed by PCR performed directly on patient tissue.

Bacteriological Techniques↗

PubMed1998

Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.

OBJECTIVE: To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial. DESIGN: Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml. METHODS: Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated. RESULTS: We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay. CONCLUSION: The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis.

Analysis of Variance↗

PubMed1998

Outcome after treatment of high-risk papillary and non-Hürthle-cell follicular thyroid carcinoma.

BACKGROUND: Treatment of differentiated thyroid cancer has been studied for many years, but the benefits of extensive initial thyroid surgery and the addition of radioiodine therapy or external radiation therapy remain controversial. OBJECTIVE: To determine the relations among extent of surgery, radioiodine therapy, and external radiation therapy in the treatment of high-risk papillary and non-Hürthle-cell follicular thyroid carcinoma. DESIGN: Analysis of data from a multicenter study. SETTING: 14 institutions in the United States and Canada participating in the National Thyroid Cancer Treatment Cooperative Study Registry. PATIENT: 385 patients with high-risk thyroid cancer (303 with papillary carcinoma and 82 with follicular carcinoma). MEASUREMENTS: Death, disease progression, and disease-free survival. RESULTS: Total or near-total thyroidectomy was done in 85.3% of patients with papillary carcinoma and 71.3% of patients with follicular cancer. Overall surgical complication rate was 14.3%. Total or near-total thyroidectomy improved overall survival (risk ratio [RR], 0.37 [95% CI, 0.18 to 0.75]) but not cancer-specific mortality, progression, or disease-free survival in patients with papillary cancer. No effect of extent of surgery was seen in patients with follicular thyroid cancer. Postoperative iodine-131 was given to 85.4% of patients with papillary cancer and 79.3% of patients with follicular cancer. In patients with papillary cancer, radioiodine therapy was associated with improvement in cancer-specific mortality (RR, 0.30 [CI, 0.09 to 0.93 by multivariate analysis only]) and progression (RR, 0.30 [CI, 0.13 to 0.72]). When tall-cell variants were excluded, the effect on outcome was not significant. After radioiodine therapy, patients with follicular thyroid cancer had improvement in overall mortality (RR, 0.17 [CI, 0.06 to 0.47]), cancer-specific mortality (RR, 0.12 [CI, 0.04 to 0.42]), progression (RR, 0.21 [CI, 0.08 to 0.56]), and disease-free survival (RR, 0.29 [CI, 0.08 to 1.01]). External radiation therapy to the neck was given to 18.5% of patients and was not associated with improved survival, lack of progression, or disease-free survival. CONCLUSIONS: This study supports improvement in overall and cancer-specific mortality among patients with papillary and follicular thyroid cancer after postoperative iodine-131 therapy. Radioiodine therapy was also associated with improvement in progression in patients with papillary cancer and improvement in progression and disease-free survival in patients with follicular carcinoma.

Adenocarcinoma, Follicular↗

PubMed1998

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.

BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). CONCLUSIONS: Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.

Anti-HIV Agents↗

PubMed1998

Preclinical characterization of an anti-tat ribozyme for therapeutic application.

A hammerhead ribozyme retroviral construct, denoted RRz2, targeting the coding region of the human immunodeficiency virus type 1 (HIV-1) tat gene, has shown itself to be effective in a range of test systems. Inhibition of the replication of HIV-1 IIIB and primary drug-resistant strains in pooled transduced CEMT4 cells was consistently found to be more than 80% compared with the control-vector transduced cells, whereas a mutant RRz2 gave approximately 45% inhibition. A multiple HIV-1 passage assay showed the absence of emergence of mutations within the specific viral RNA ribozyme target sequences. This lack of generation of ribozyme "escape mutants" occurred despite the almost complete disappearance of a HIV-1 quasi-species in the testing virus. When RRz2 was tested in peripheral blood lymphocytes (PBLs) from HIV-1-infected patients, paired analysis showed that cell viability in the ribozyme-transduced HIV-1-infected PBLs was significantly higher than that in the vector-transduced cells. This difference in viability (vector versus RRz2) was not observed in PBLs from non-HIV-1-infected donors. Taken together, these results indicate that the transfer of an anti-HIV-1 ribozyme gene into human T lymphocytes could have major impact on viral replication and T cell viability in the HIV-1-infected individual.

Base Sequence↗

PubMed1998

Induction-maintenance antiretroviral therapy: proof of concept.

OBJECTIVE: To investigate the concept of aggressive initial combination therapy followed by reduction to a less demanding maintenance regimen with respect to its potential for sustaining viral suppression. DESIGN: Durable viral suppression to < 20 HIV RNA copies/ml plasma was achieved with zidovudine-nevirapine-didanosine (ZDV-NVP-ddl) therapy. Potential for sustained antiviral response was explored for patients who began with ZDV-NVP-ddl and subsequently interrupted ddl. METHODS: Antiretroviral-naive patients were treated with ZDV-NVP, ZDV-ddl, or ZDV-NVP-ddl. Viral load was measured with the Amplicor assay (limit of quantification 400 copies/ml) and by the Ultra Direct assay (limit of quantification 20 copies/ml) when the Amplicor result was < 500 copies/ml. Treatment adherence for each drug was recorded, including all dose adjustments. RESULTS: Five patients who had begun treatment with ZDV-NVP-ddl discontinued ddl for at least 6 weeks after achieving viral load levels below detection. All were documented to have sustained their viral load at < 20 copies/ml during the ddl interruption. Two patients permanently discontinued ddl, both with sustained viral load below detection for more than 1 year while treated with ZDV NVP. In contrast, no patient initially receiving ZDV-NVP was able to maintain viral load below detection for sustained periods; none had viral load below detection after week 12 of treatment. CONCLUSIONS: After induction with ZDV-NVP-ddl, patients were able to sustain viral suppression with a regimen (ZDV NVP) that was only transiently effective as initial therapy. There was no evidence of virologic escape, even with the most sensitive measure of plasma viral load.

Anti-HIV Agents↗

PubMed1998

A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.

CONTEXT: Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA. OBJECTIVE: To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine. DESIGN: Double-blind, controlled, randomized trial. SETTING: University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS). PATIENTS: Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL). INTERVENTION: Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine. MAIN OUTCOME MEASURE: Plasma HIV-1 RNA. RESULTS: Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). CONCLUSIONS: Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.

Adult↗

PubMed1998

Functional redundancy and gustatory development in bdnf null mutant mice

In the mouse nasopalate papilla and in the trenches of the foliate and vallate papillae, taste buds accumulated primarily during the first 2 weeks after birth. Null mutation for brain-derived neurotrophic factor caused extensive death of embryonic taste neurons, with the secondary outcome that most taste buds failed to form. However not all taste neurons died; functional redundancy rescued a variable number. The primary research objective was to identify the likely site of the taste neuron rescue factor that substituted for BDNF. In this quest taste bud abundance served as a useful gauge of taste neuron abundance. The proportion of taste buds that developed was variable and uncorrelated among the nasopalate, vallate, and foliate gustatory papillae within each bdnf null mutant mouse. Thus, in spite of shared IXth nerve innervation, the vallate and foliate papillae independently varied in residual gustatory innervation. This variation rules against the rescue of gustatory neurons by system-wide factors or by factors acting on the IXth ganglion or nerve trunk. Therefore it is likely that surviving BDNF-deprived taste neurons were stochastically rescued by a redundant neurotrophic factor at the level of the local gustatory epithelium. These findings broaden the classic expectation that target tissue supplies only a single neurotrophic factor that can sustain sensory (taste) neurons.

Journal Article↗

PubMed1998

The morphogenesis of mouse vallate gustatory epithelium and taste buds requires BDNF-dependent taste neurons

The developmental absence of brain-derived neurotrophic factor (BDNF) in null mutant mice caused three interrelated defects in the vallate gustatory papilla: sparse innervation, a reduction in the area of the gustatory epithelium, and fewer taste buds. On postnatal day 7, the stunted vallate papilla of bdnf null mutant mice was 30% narrower, the trench walls 35% reduced in area, and the taste buds 75% less abundant compared with wild-type controls. Quantitative assessment of innervation density was carried out to determine if the small trench walls and shortage of taste buds could be secondary consequences of the depletion of gustatory neurons. The diminished gustatory innervation was linearly associated with a reduced trench wall area (r=+0.94) and fewer taste buds (r=+0.96). Residual taste buds were smaller than normal and were innervated by a few surviving taste neurons. We conclude that BDNF-dependent taste neurons contribute to the morphogenesis of lingual gustatory epithelia and are necessary for both prenatal and postnatal mammalian taste bud formation. The gustatory system provides a conspicuous example of impaired sense organ morphogenesis that is secondary to sensory neuron depletion by neurotrophin gene null mutation.

Journal Article↗

PubMed1998

Functional redundancy and gustatory development in bdnf null mutant mice.

Accessory Nerve↗

PubMed1998

The morphogenesis of mouse vallate gustatory epithelium and taste buds requires BDNF-dependent taste neurons.

The developmental absence of brain-derived neurotrophic factor (BDNF) in null mutant mice caused three interrelated defects in the vallate gustatory papilla: sparse innervation, a reduction in the area of the gustatory epithelium, and fewer taste buds. On postnatal day 7, the stunted vallate papilla of bdnf null mutant mice was 30% narrower, the trench walls 35% reduced in area, and the taste buds 75% less abundant compared with wild-type controls. Quantitative assessment of innervation density was carried out to determine if the small trench walls and shortage of taste buds could be secondary consequences of the depletion of gustatory neurons. The diminished gustatory innervation was linearly associated with a reduced trench wall area (r = +0.94) and fewer taste buds (r = +0.96). Residual taste buds were smaller than normal and were innervated by a few surviving taste neurons. We conclude that BDNF-dependent taste neurons contribute to the morphogenesis of lingual gustatory epithelia and are necessary for both prenatal and postnatal mammalian taste bud formation. The gustatory system provides a conspicuous example of impaired sense organ morphogenesis that is secondary to sensory neuron depletion by neurotrophin gene null mutation.

Animals↗

PubMed1998

Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase C.

Utilizing clinostatic rotating wall vessel (RWV) bioreactors that simulate aspects of microgravity, we found phytohemagglutinin (PHA) responsiveness to be almost completely diminished. Activation marker expression was significantly reduced in RWV cultures. Furthermore, cytokine secretion profiles suggested that monocytes are not as adversely affected by simulated microgravity as T cells. Reduced cell-cell and cell-substratum interactions may play a role in the loss of PHA responsiveness because placing peripheral blood mononuclear cells (PBMC) within small collagen beads did partially restore PHA responsiveness. However, activation of purified T cells with cross-linked CD2/CD28 and CD3/CD28 antibody pairs was completely suppressed in the RWV, suggesting a defect in signal transduction. Activation of purified T cells with PMA and ionomycin was unaffected by RWV culture. Furthermore, sub-mitogenic doses of PMA alone but not ionomycin alone restored PHA responsiveness of PBMC in RWV culture. Thus our data indicate that during polyclonal activation the signaling pathways upstream of PKC activation are sensitive to simulated microgravity.

Antigen-Antibody Reactions↗

PubMed1998

Plasma esterase (ES) polymorphism in the tammar wallaby, Macropus eugenii.

The major plasma esterase in the tammar wallaby was identified as a carboxylesterase by inhibition studies and polymorphism with six variants was observed by isoelectric focusing (pH 4.2-4.9), followed by staining for esterase activity. Family studies demonstrated an inheritance of six codominant alleles, ESA,B,C,D,E,F, and population studies revealed marked differences in the allele frequencies in five Australian populations of tammar wallabies.

Animals↗

PubMed1998

Lack of reactivity to CMV pp65 antigenemia testing in a patient with CMV disease following allogeneic bone marrow transplant.

Pre-emptive antiviral therapy based on the early detection of CMV infection is an important strategy for the prevention of CMV disease following allogeneic BMT. Accepted methods for early detection of CMV infection include viral culture of blood or bronchial lavage specimens or CMV pp65 antigenemia testing of peripheral blood specimens. We describe a patient with aplastic anemia with worsening liver transaminases after allogeneic bone marrow transplantation who had repeated negative tests for CMV pp65 antigenemia despite positive viral blood cultures. Re-examination of peripheral blood samples with a different pp65 antibody pool revealed the presence of high levels of CMV in peripheral blood leukocytes, confirming a lack of reactivity to the original antibody pool. Following institution of antiviral therapy, a prompt reduction in the number of pp65 antigen-positive peripheral blood leukocytes paralleled a reduction in abnormal transaminases. The practical implications of these findings are discussed.

Adult↗

PubMed1998

Effects of long-term oral treatment with leflunomide on allergic sensitization, lymphocyte activation, and airway inflammation in a rat model of asthma.

BACKGROUND: Short-term treatment with leflunomide is effective in suppressing antigen-specific antibody production and allergen-induced bronchoconstriction after sensitization. This agent may thus have a role in future primary prevention strategies in allergic disease. OBJECTIVE: The current study aimed to determine whether long-term oral treatment with leflunomide prevents allergic sensitization permanently. METHODS: After sensitization with ovalbumin, six groups of rats (n = 31) were treated daily with leflunomide or diluent for up to 30 days. Ovalbumin-specific IgE and IgG were determined weekly for at least 2 weeks after cessation of treatment. T lymphocytes from another 21 animals were stimulated ex vivo with ovalbumin or concanavalin A. RESULTS: Ovalbumin-specific IgE and IgG were lower during treatment with leflunomide compared with controls (P < 0.002) but increased after the cessation of treatment. Antigen-specific T-cell proliferation was decreased in cells obtained from leflunomide treated animals (P < 0.05), but not when stimulated with concanavalin A. Eosinophil (P < 0.0001) and neutrophil (P < 0.02) numbers in bronchoalveolar lavage 24 h after allergen challenge were lower in the leflunomide treated animals. CONCLUSIONS: Leflunomide prevents antigen-specific immunoglobulin production after sensitization during treatment, inhibits allergen-induced airway inflammation and diminishes antigen-specific T lymphocyte proliferation.

Administration, Inhalation↗

PubMed1998

A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group.

Cytomegalovirus (CMV) disease is a common complication of advanced human immunodeficiency virus (HIV) infection. Administration of oral valaciclovir, a valine ester of acyclovir, achieves sufficient plasma acyclovir levels to inhibit many clinical isolates. Acyclovir has been associated with enhanced survival in AIDS but not with CMV disease prevention. CMV-seropositive patients (1227) with CD4 cell counts <100/mm3 were enrolled in a randomized, double-blind trial. Valaciclovir, 8 g/day, was compared with acyclovir, 3.2 or 0.8 g/day, for CMV prevention; all three arms were compared for survival. The confirmed CMV disease rate was 11.7% among valaciclovir recipients and 17.5% in the pooled acyclovir arms, a 33% reduction in risk. Time to confirmed CMV disease was significantly longer for the valaciclovir group (P = .03). A trend toward earlier mortality for valaciclovir recipients was seen (P = .06). Toxicity and earlier medication discontinuation were more common in this group. Valaciclovir significantly reduces the risk of CMV disease. Further exploration of a better-tolerated dose is warranted.

AIDS-Related Opportunistic Infections↗

PubMed1998

Effects of 14 d of covert substitution of olestra for conventional fat on spontaneous food intake.

We conducted a double-blind, placebo-controlled, within-subject crossover study to investigate the effects of covert substitution of olestra, a non-energy-containing fat replacer, for conventional fat on food selection and energy intake in lean and obese men and women. Fifty-one subjects [BMI (kg/m2): 19-36; age: 25-63 y] were studied during two 14-d treatment periods (olestra and placebo), with a 7-d washout between feeding periods. During the intervention periods all foods were provided to the subjects. The aim was to produce a 10% dilution of total energy intake by replacing conventional triacylglycerol with olestra. To accomplish this, subjects were required to consume core foods providing 20-35 g olestra (depending on estimated energy needs) or the same foods containing placebo triacylglycerol. Additional items could be selected from foods that varied in macronutrient composition. When the two treatment periods were compared, total energy intake was 8% lower and fat intake 11% lower during the olestra period than during the placebo treatment period (P < 0.0001). Overall, subjects compensated for 15% of the fat and 20% of the total energy replaced by olestra. In absolute terms, subjects consumed 32% of total energy from fat during the placebo period and 27% of total energy from fat during the olestra period. Neither carbohydrate nor protein intake (g/d) differed between periods. The results did not differ as a function of BMI (lean compared with obese) or sex. Over a 2-wk period, covert substitution of olestra for conventional fat led to reductions in dietary fat intake and total energy intake in all subjects.

Adult↗

PubMed1998

Improving the yield of blood cultures for patients with early Lyme disease.

This study was designed to improve the recovery of Borrelia burgdorferi from blood. With the techniques used, B. burgdorferi could be recovered from the blood of approximately 25% of patients with early Lyme disease associated with erythema migrans. Serum was a better source of culture material than whole blood. The volume of blood cultured correlated directly with yield, particularly for patients with a single erythema migrans lesion.

Adult↗