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A Davidson

Publications and source records attributed to A Davidson.

At least 73 records · Page 4Linked to original sources
PubMed1997

Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors.

Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin-UDP-glucuronosyltransferase-1 (BUGT1)-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 x 10(9) pfu of a recombinant adenovirus-expressing human BUGT1 (Ad-hBUGT1) resulted in hepatic expression of human BUGT1 (hBUGT1) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGFbeta1, IL2, and IL4 upon exposure to viral antigens, whereas IFNgamma expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses.

Adenoviridae↗
PubMed1997

Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implications for early treatment of Alzheimer's disease.

Stearyl-Nle17-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE-deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide-treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase-activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design.

Alzheimer Disease↗
PubMed1997

Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat.

The host immune response limits the duration of expression of adenovirally transduced genes and precludes long-term gene expression upon re-administration of the virus. In this study we wished to evaluate whether short-term immunosuppression of the host, at the time of recombinant virus administration, would allow expression of the therapeutic gene product upon virus reinjection. Gunn rats were used as recipients of recombinant adenoviruses expressing human BUGT (Ad-hBUGT) or E. coli beta-galactosidase (Ad-LacZ). Rats were treated with FK506 (1-1.5 mg/kg, per OS daily) for three days beginning 24 hours before each virus injection. Control groups did not receive any immunosuppressant. The serum bilirubin level was reduced from 7.1 +/- 0.75 mg/dL to 2.0 +/- 0.7 mg/dL within two days of viral injection in both FK506 treated and control groups, and then gradually increased in 6 weeks. FK506-treated rats had low or undetectable antibody titers against the recombinant adenovirus and minimal or no cytotoxic T lymphocyte (CTL) response against adenovirus-infected cells. The tolerized rats received two subsequent injections 42 and 98 days after the first injection, which reduced the bilirubin levels again to 2.0 +/- 0.56 and 2.2 +/- 0.61 mg/dL, respectively. In contrast, control rats developed high titer neutralizing antibodies and a CTL response, and their serum bilirubin levels were not reduced following subsequent injections. We conclude that short-term FK506 treatment around the time of virus administration prevents the host immune response, permitting long-term gene therapy by repeated administration of the recombinant virus.

Adenoviridae↗
PubMed1997

Mechanisms of intrathymic tolerance induction to isolated rat hepatocyte allografts.

Intrathymic injection of alloantigen in young adult rats is capable of mediating long-lived transplantation tolerance. In this study, we use a well-defined model of isolated hepatocyte transplantation to define the mechanisms of intrathymic induced tolerance. The recipient rats are Nagase analbuminemic rats (NAR) that are deficient in albumin, to allow for following transplant acceptance using metabolic and genetic markers. Tolerance to allogeneic hepatocyte transplants could be mediated by intrathymic injection of live allogeneic splenocytes, lethally irradiated splenocytes, or isolated hepatocytes. Intrathymic injection of live allogeneic splenocytes, but not of hepatocytes or irradiated splenocytes, resulted in donor microchimerism in peripheral lymphoid organs, with preferential expansion of CD4-positive T cells in the recipient spleens. Tolerance could be adoptively transferred from tolerant animals to naive recipients, but only from those animals that had been inoculated with intrathymic donor splenocytes. We conclude that donor microchimerism is found after intrathymic inoculation of live splenocytes, but is not required for tolerance induction and that microchimerism is not an absolute requirement for the generation of regulatory cells.

Animals↗
PubMed1997

Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children's Cancer Study Group (UKCCSG).

We report a multicentre phase II study of orally administered prolonged schedule etoposide in children with refractory or relapsed malignancy. 83 children were entered into the study. The largest diagnostic groups were neuroblastoma (n = 20), rhabdomyosarcoma/soft tissue sarcoma (n = 16) and brain tumours (n = 16). Etoposide was administered twice daily at a dose of 50 mg/m2/day for 21 days using the intravenous preparation given orally. Disease reassessment was performed after the second course. Etoposide plasma concentrations were measured by HPLC, 2 and 6 h after administration of therapy on days 7 and 14 in 15 patients. 61 patients completed two courses and were evaluable for response. There was 1 complete response (CR), 5 partial responses (PR) 22 stable disease (SD) and 33 progressive disease (PD). Of the 6 with responses, 3 had a diagnosis of medulloblastoma/cerebral primitive neuroectodermal tumour. 24 of 26 patients with SD/PR/CR received further courses with excellent palliative effect. The main toxicity observed was myelosuppression, with 8% and 7% of evaluable courses complicated by grade III-IV neutropenia and thrombocytopenia, respectively. Severe infection (grade III-IV) was rare, complicating only 2/94 evaluable courses. Plasma etoposide median concentrations at 2 h after administration on day 7 of course 1 were 1.5 (range 0.6-2.4) micrograms/ml. Total course 1 area under the etoposide plasma concentration versus time curve (AUC) values were estimated using a limited sampling model. Grade > or = 2 leucopenia was only observed in patients with a day 72 h etoposide concentration of > 2 micrograms/ml or a course 1 AUC of > 35 mg/ml.min. It is concluded that given at a dose of 50 mg/m2/day in two doses for 21 day courses, oral etoposide is well tolerated in children. A correlation between drug concentrations and toxicity was observed. Overall, a low response rate was seen (approximately 10%), but disease stabilisation appears to occur, and useful palliative effect was frequently noted. The response in brain tumours was more encouraging (3/14 PR) and this group requires further evaluation.

Administration, Oral↗
PubMed1997

Preferential sequestration in vitro of BCR/ABL negative hematopoietic progenitor cells among cytokine nonresponsive CML marrow CD34+ cells.

It is believed that long-term cultures of CML marrow cells favor the outgrowth of BCR/ABL negative hematopoietic progenitor cells (HPC) and that this phenomenon may be enhanced with negative hematopoietic regulators which can maintain primitive HPC in a quiescent state. Proliferation of CML marrow CD34+ cells in primary short-term cultures, maintained in the presence or absence of macrophage inhibitory protein-1 alpha (MIP-1 alpha), was tracked with the membrane dye PKH2. After 7 to 10 days it was possible to distinguish between cytokine responsive (CR) CD34+ cells (cells which had divided thus becoming PKH2dim) and cytokine nonresponsive (CNR) CD34+ cells (cells which had not divided and had therefore remained PKH2bright). CR and CNR CD34+ cells were isolated by flow cytometric cell sorting, seeded in secondary long-term cultures, and their progeny cells assayed weekly for their clonogenic progenitor cell content and expression of BCR/ABL by reverse transcriptase polymerase chain reaction (RT-PCR). Whereas CNR cells isolated from control primary cultures (control/CNR) sustained in vitro hematopoiesis, similar cells from cultures treated with MIP-1 alpha (MIP-1 alpha/CNR) supported a higher and, in some patients, a more extended production of clonogenic HPC, indicating that MIP-1 alpha was able to maintain primitive HPC in a quiescent state. Predominance of BCR/ABL negative progenitors in vitro was more evident in secondary cultures initiated with CNR cells than in those initiated with CR cells, especially those established with MIP-1 alpha/CNR cells. Of interest is the observed decline in the percentage of BCR/ABL+ progenitors in these cultures with time. Whereas up to 100% of progenitors were BCR/ABL+ on day 0, by day 14, only 46% of progenitors in MIP-1 alpha/CNR secondary cultures were BCR/ABL+ and by day 28 and beyond, the percentage of BCR/ABL+ progenitors dropped to below 20%. These results suggest that the quiescent nature of normal HPC present in CML marrow may favor their identification via cell tracking and, subsequently, their isolation from the more actively cycling leukemic cells. These studies also confirm the feasibility of employing negative hematopoietic regulators to augment the sequestration of normal HPC among the cytokine nonresponsive fraction of CD34+ cells, an approach that may be clinically feasible for autotransplantation.

Adult↗
PubMed1997

The effectiveness of a needleless intravenous connection system: an assessment by injury rate and user satisfaction.

OBJECTIVE: To assess the impact of a needleless intravenous (i.v.) connection system on the rate of reported intravenous-connection-related (IVCR) percutaneous injuries, and to assess user satisfaction, frequency of use, and barriers to use. DESIGN: A pre-post intervention design, with injury incidence rates being compared 3 years before and 1 year after hospital wide device implementation; and a cross-sectional descriptive user satisfaction survey. SETTING: Two tertiary-care teaching hospitals, one general and one pediatric, located in a large metropolitan medical center. OUTCOME VARIABLE: All IVCR percutaneous injuries reported to the employee health services at both hospitals during the years from 1989 to 1991 and 1993. STUDY POPULATION: Survey participants were selected randomly from licensed nursing employees at both hospitals. INTERVENTION: i.v. connection system consisting of blunt plastic cannulas and compressed latex injection sites. RESULTS: After device implementation, the IVCR injury rate was reduced 62.4% (rate ratio [RR], 0.38; 95% confidence interval [CI95], 0.27-0.53) at the general hospital and 70.2% (RR, 0.30; CI95, 0.17-0.53) at the pediatric hospital. After adjusting for the reduction in injury rate due to factors other than device implementation, the IVCR injury rate was reduced 54.5% (adjusted RR, 0.46; CI95, 0.32-0.65) at the general hospital and 57.2% (adjusted RR, 0.43; CI95, 0.24-0.78) at the pediatric hospital. Approximately 94% of survey respondents (n = 478, response rate = 51%) were satisfied with the device and recommended continued use. However, needles still were being used for activities that could have been performed with the needleless system because of compatibility, accessibility, and other technical problems related to the device. CONCLUSIONS: The device was effective in reducing the rate of reported IVCR percutaneous injuries and users were satisfied with the device, but barriers to universal use were identified.

Cross-Sectional Studies↗
PubMed1997

Moclobemide in social phobia: a controlled dose-response trial.

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

Adult↗
PubMed1997

Comparison of the efficacy of paracetamol versus paracetamol, codeine and promethazine (Painstop) for premedication and analgesia for myringotomy in children.

This prospective double-blinded study compared the analgesic effectiveness and incidence of complications of a compound preparation Painstop (Paedpharm Pty Ltd) containing paracetamol 12 mg, codeine 0.5 mg and promethazine 0.65 mg per 1.0 ml, dosage 1.0 ml/kg, with paracetamol 20 mg/kg. Ninety-five children aged 1 to 12 years, ASA 1-2, scheduled for myringotomy and drain tuber insertion as a day procedure were randomized to receive Painstop or paracetamol 30 to 60 minutes prior to surgery. Preoperative drowsiness and complications on induction and postoperative sedation, pain and times to achieve goals were recorded. The groups were comparable for age, gender, weight, anaesthetic technique and duration of surgery. Times to eye opening (P = 0.05) and first oral intake (P = 0.006) were significantly longer in the Painstop group. There was, however, no difference in times to discharge. Late sedation was more common in the Painstop group (P = 0.03). Pain scores were low and similar in both groups and the need for additional analgesia was uncommon.

Acetaminophen↗
PubMed1997

Geographic analysis of pertussis infection in an urban area: a tool for health services planning.

OBJECTIVE: This study examined whether incident cases of pertussis cluster in urban census tracts and identified community characteristics that predict high-incidence areas. METHODS: An ecological study design was used. The study population included all persons diagnosed with pertussis from January 1, 1986, through December 31, 1994. Maps of rates were constructed via a geographic information system and clustering was statistically confirmed. Associations between pertussis rates and community characteristics were tested. RESULTS: Mapping and statistical analysis revealed spatial clustering of pertussis. Higher age-adjusted rates of pertussis infection were associated with higher proportions of residents below poverty level. CONCLUSIONS: In urban areas pertussis infection clusters in areas of poverty.

Age Distribution↗
PubMed1997

Prenatal diagnosis of the 22q11 deletion syndrome.

A 27 weeks gestation fetus, evaluated because of polyhydramnios, was found by echocardiography to have an interrupted aortic arch type B. Because of the known association between this malformation and DiGeorge syndrome, an amniocentesis was performed. Fluorescence in situ hybridization revealed a 22q11 deletion. This is, to our knowledge, the first report of prenatal detection of a fetus with 22q11 deletion in the absence of a family history.

Abnormalities, Multiple↗
PubMed1997

Diagnosing and Treating the Predominantly Female Problems of Systemic Autoimmune Diseases.

Autoimmune diseases with rheumatic manifestations are predominantly diseases of women. Any woman with new onset arthralgia or arthritis should have a thorough history and physical to rule out autoimmune connective-tissue disease. Screening serologic tests, however, are not necessarily recommended because of high false-positive rates. Serologic tests are most useful in confirming or ruling out the diagnosis; for example, systemic lupus erythematosus (SLE) is rarely present when antinuclear antibodies (ANAs) are absent; the absence of rheumatoid factor will not rule out rheumatoid arthritis (RA), but its presence confirms it. Most autoantibodies (RF [rheumatoid factor], ANA, ENA [extractable nuclear antigen], anti-Jo-1, etc) do not vary with disease flare-ups and remissions. Plain radiographs of the joints are not useful except as a baseline and in detecting erosion at end of long bones associated with RA. Polymyalgia rheumatica and RA, with an incidence of 1 in 2000 to 3000, are the most common autoimmune disorders. Other autoimmune diseases such as SLE, vasculitis, polymyositis, and dermatomyositis are seen infrequently in general practice. Pregnancy, menopause, or breast implantation may affect disease prognosis and treatment. For example, in pregnancy, RA symptoms generally improve, whereas those of SLE may worsen; both diseases may flare postpartum. Oral contraceptives have been associated with an increase in disease flare-ups, but there is little or no evidence that estrogen in the dose level used for replacement is harmful to SLE patients. Although relatively rare, autoimmune diseases can be devastating to the patient if not promptly recognized and properly treated.

Journal Article↗
PubMed1996

Induction of central tolerance by intrathymic inoculation of adenoviral antigens into the host thymus permits long-term gene therapy in Gunn rats.

Recombinant adenoviruses are highly efficient at transferring foreign genes in vivo. However, duration of gene expression is limited by the host antiviral immune response which precludes expression upon viral readministration. We tested the feasibility of prolonging gene expression by induction of central tolerance to adenoviral antigens in bilirubin-UDP-glucuronosyltransferase-1 (BUGT1)-deficient Gunn rats. Tolerance was induced by intraperitoneal injection of antilymphocyte serum, followed by intrathymic inoculation of one of the following: a recombinant adenovirus (Ad), adenovirus human UDP-glucuronosyltransferase (Ad-hBUGT1) carrying the hBUGT1 gene; a protein extract of the same virus; or viral infected hepatocytes. Controls received intrathymic injections of normal saline. After 12 d all groups were injected intravenously with 5 x 10(9) pfu of either Ad-hBUGT1 or adenovirus beta-galactosidase (Ad-LacZ) (expressing the Escherichia coli beta-galactosidase [LacZ] gene). In all three groups of tolerized rats, hBUGT1 was expressed in the liver after administration of Ad-hBUGT1, with glucuronidation of biliary bilirubin of above 95%. Serum bilirubin levels decreased from 7.2 to 1.8 mg/dl within 1 wk and remained low for 7 wk. Similar findings were observed following repeat injections given on days 45 and 112. In control rats serum bilirubin levels were reduced for only 4 wk, and viral readministration was ineffective. In all tolerized groups, but not in controls, there was a marked inhibition of appearance of neutralizing antibodies and cytotoxic lymphocytes against the recombinant adenovirus. Injection of wild type adenovirus-5 (Ad5) into the tolerized rats elicited a wild type-specific cytotoxic lymphocyte response. This is the first demonstration of Ad-directed long-term correction of an inherited metabolic disease following central tolerization with thymic antigen.

Adenoviridae↗
PubMed1996

An in vitro assay for detection of glomerular binding IgG autoantibodies in patients with systemic lupus erythematosus.

The deposition of anti-dsDNA antibodies in the glomerulus is believed to play a critical role in the pathogenesis of nephritis in SLE. However, an absolute correlation between serum levels of anti-dsDNA antibodies and renal disease has not been found. Recently a glomerular binding assay (GBA) has been developed to detect IgG binding to isolated rat glomeruli. We have used the GBA to study sera from four groups of SLE patients: (A) + anti-dsDNA antibodies, active nephritis; (B) - anti-dsDNA antibodies, active nephritis; (C) + anti-dsDNA antibodies, no nephritis; and (D) - anti-dsDNA antibodies, no nephritis. The serum anti-dsDNA antibodies in group A and group C patients could not be distinguished on the basis of isotype, charge, or cross-reactivity with histones. Nevertheless, the mean intensity of glomerular immunofluorescence was significantly higher in group A than in the three other patient groups and distinguished between patients with serum anti-dsDNA antibodies who had nephritis and those without clinically apparent nephritis. GBA reactivity was unaffected by DNase treatment of sera, but was partially inhibited by preincubation with dsDNA. These findings are consistent with the hypothesis that some anti-dsDNA antibodies cross-react with glomerular components and that the presence of this cross-reactivity is associated with, and may be responsible for, the development of nephritis. In addition, we have identified a group of SLE patients with renal disease and typical renal histopathology and immune deposits who do not have serum anti-dsDNA antibodies or antibodies that directly bind to glomeruli in the GBA. The mechanism of renal immune deposition in these patients remains to be determined.

Autoantibodies↗
PubMed1996

Retroviral gene transfer in autologous bone marrow transplantation for adult acute leukemia.

To evaluate whether marrow contributes to relapse after autologous bone marrow transplantation (AuBMT) for acute leukemia, transplanted marrow was marked with the G1N retroviral vector (Genetic Therapy Inc.) containing the neomycin phosphotransferase gene (neo). Between April 1992 and August 1993, 4 patients were transplanted for acute myeloid leukemia (AML) in second complete remission (CR) and 1 patient for acute lymphoid leukemia in first CR. An average of 12.4% (range 5-19%) of transplanted marrow mononuclear cells were exposed to G1N vector for 4 hr. In the vector-treated portion of the marrow, 4.9% of GM-CFU and 3.6% of erythroid burst-forming units (BFU-E) were resistant to G418 in vitro. In the 5 patients, the polymerase chain reaction (PCR) detected the neo sequence on only two occasions after AuBMT. Of 4 patients surviving 1 year after transplantation, only 1 had evidence of gene marked cells by PCR. Two AML patients have relapsed, one of whom had evidence of neo sequences in the bone marrow at day 100 but not at relapse 11 months after AuBMT. The second patient relapsed 18 months after AuBMT but never had PCR evidence of neo sequences before or after relapse. Our results indicate vector-transduced autologous bone marrow from heavily pretreated adults with acute leukemia mark with low efficiency, although vector sequences have been detected in bone marrow and peripheral blood up to 1 year after transplant. Of the 2 relapsed patients, no evidence of vector-marked leukemic blasts have been detected.

Acute Disease↗
PubMed1996

Rheumatoid factor idiotypic and antigenic specificity is strongly influenced by the light chain VJ junction.

The aim of this study was to define the structural basis for rheumatoid factor (RF) specificity and for the expression of the RF light chain-associated Ids, 4C9 and 6B6.6, by determining the reactivity of recombined heavy and light chains of Ig derived from monoclonal B cell lines of patients with rheumatoid arthritis and of light chains with site-directed mutations. We found that expression of the 4C9 and 6B6.6 Ids resulted from use of the VkIIIa genes Humkv 328 and Vg, but only in the presence of a permissive VJ junction. Expression of the Ids was independent of heavy chain use for the Humkv328-encoded light chains, but was highly dependent on the associated heavy chain for the Vg-encoded light chains. The RF specificity of the Abs was primarily heavy chain dependent, but the light chain VJ junction was critical in determining the relative avidity of the Abs for Fc. Our study points to the critical contribution of the somatically generated VJ junction to RF autoantibody specificity and to the expression of the two RF-associated Ids studied.

Amino Acid Sequence↗