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Biomedical subjects

A Davidson

Publications and source records attributed to A Davidson.

At least 19 recordsLinked to original sources
PubMed1995

Aberrant expression of the myeloid zinc finger gene, MZF-1, is oncogenic.

The zinc finger gene MZF-1 is preferentially expressed in primitive hematopoietic cells and plays an important role in regulating myelopoiesis. Regulators of development are potential targets for neoplastic transformation. This study investigated whether unregulated expression of MZF-1 could function as an oncogene. Retroviral transduction and subsequent overexpression of MZF-1 resulted in loss of contact inhibition, loss of substrate dependence, and more rapid cell cycling in NIH 3T3 cells. The MZF-1-transformed 3T3 cells formed aggressive tumors in athymic mice. Disruption of the tight lineage- and stage-specific regulation of MZF-1 can result in neoplastic transformation of embryonic fibroblasts. Therefore, MZF-1 represents a novel oncogene.

3T3 Cells↗
PubMed1995

Molecular characterization of monoclonal IgM derived from human B cell lines expressing the 4C9 rheumatoid factor associated idiotype.

Ten human monoclonal B cell lines that express the RF associated Id 4C9 were analyzed using an immunogenetic approach. Five of eight tested lines were also strongly positive for the 6B6.6 Id. We found that all the 4C9/6B6.6 positive lines expressed VkIIIa light chain genes. In contrast, 4C9 reactivity was also found on a cell line expressing a VkIIIb light chain gene and on a line expressing a V light chain gene. The two anti-Ids recognized a linear light chain determinant on Humkv328 encoded light chains but also a conformational determinant on Vg encoded light chains that appeared to be dependent on the presence of a heavy chain. Idiotypic reactivity occurred on both RF positive and RF negative antibodies. Within this idiotypic system, the basis for idiotypic reactivity and RF reactivity is complex, subject to both heavy and light chain gene usage and sensitive to small numbers of somatic mutations.

Amino Acid Sequence↗
PubMed1995

Superactive lipophilic peptides discriminate multiple vasoactive intestinal peptide receptors.

To distinguish vasoactive intestinal peptide (VIP) receptors in the brain-mediating neurotransmission and neurotrophism, potent VIP analogues were designed. Using a single amino acid substitution and the addition of a fatty acyl moiety, an analogue was devised that exhibited both a 100-fold greater potency than VIP and specificity for a VIP receptor associated with neuronal survival. This VIP agonist increased neuronal survival via a cAMP-independent mechanism. Identical chemical modification of a prototype VIP antagonist (Met-Hybrid, Neurotensin6-11-VIP7-28) also resulted in a 100-fold greater potency in blocking VIP-mediated increases in neuronal survival. Blockade of circadian activity rhythms was limited to VIP antagonists that could inhibit VIP-mediated increases in cAMP. These lipophilic peptides provide novel tools in receptor discrimination and drug design.

Amino Acid Sequence↗
PubMed1995

Managing constipation using a research-based protocol.

Constipation, a common health problem particularly for elderly and hospitalized patients, can cause abdominal pain, discomfort, gas, headaches, nausea, anorexia, a bad taste in the mouth, and potentially adds to functional loss and length of stay. As part of a quality improvement initiative, a research-based interdisciplinary protocol was developed to prevent constipation in hospitalized immobile vascular surgery patients. Using a combination of dietary fiber, increased fluid, and hygiene measures over a 3-year period, incidence of constipation was reduced from 59% to about 9%. The incidence of impaction was eliminated and requests for laxatives and enemas were reduced from 59% to about 8%.

Clinical Nursing Research↗
PubMed1994

Functional neurological outcome in leukaemic children receiving repeated cranial irradiation.

Long-term outcome defined by educational or employment history has been recorded in a group of children with acute lymphoblastic leukaemia (ALL) who received cranial radiotherapy at some stage prior to TBI conditioned bone marrow transplant (BMT). Median follow-up in 24 survivors of 69 consecutive patients was 4 years and 2 months. Individual risk factors for poor functional outcome were considered, including calculations of biological effective radiation doses. There was no incidence of CNS treatment-related mortality. All survivors are in normal school or employment, although three who had CNS relapse are receiving remedial teaching. No individual risk factors could be identified but the worst outcome was seen in children who were of young age at the time of initial treatment, who suffered CNS relapse and who had received the highest total dose of cranial irradiation.

Adolescent↗
PubMed1994

Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated.

We report the DNA sequences of the heavy and light chain immunoglobulin genes of 11 monoclonal rheumatoid factor (RF)-secreting lines derived from the peripheral blood of two patients with rheumatoid arthritis (RA). It is evident from immunogenetic analysis of these lines that RA-associated RF activity can arise from a wide variety of heavy and light chain genes and gene combinations. Although the RF response from our two patients shows a bias in gene usage toward those genes used to encode monoclonal RF, particularly VkIII, relatively few of these RFs are reactive with the monoclonal antiidiotypes 6B6.6 and 17.109 that define VkIII germline-encoded light chains and the loss of this idiotypic reactivity is clearly related to somatic mutation. Finally, RFs derived from peripheral blood of RA patients show a similar heterogeneity of epitope binding to Fc as that seen for synovium-derived RF and some are clearly different in binding specificity from the restricted RF population found in patients with B cell malignancies. Somatic mutations as well as different VH/VL combinations contribute to the heterogeneity in the binding patterns of these RA-derived RF.

Amino Acid Sequence↗
PubMed1994

Expression of rheumatoid factor idiotypes 17.109, 6B6.6 and 4C9 in the sera of Pima Indians.

This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rheumatoid factor (RF) idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease. Serial sera were obtained from 25 subjects who developed RA and 25 RF-positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies. Expression of the three RF-associated idiotypes was found in both the subjects who developed RA and those who did not. The amount of idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiidiotypes overlapped, with 4C9 appearing to mark a broader spectrum of RF than 6B6.6. Thus, even in an inbred and genetically predisposed population, the RF-associated antiidiotypes studied here did not identify a dominant idiotypic response and were no better markers for the development of RA than was RF itself.

Adult↗
PubMed1993

Mapping studies reveal unique epitopes on IgG recognized by rheumatoid arthritis-derived monoclonal rheumatoid factors.

We have used chimeric IgG antibodies and their genetically engineered variants prepared by a combination of site-directed mutagenesis and exon exchange to define the structure(s) on IgG recognized by monoclonal rheumatoid factor (RF) autoantibodies from rheumatoid arthritis (RA) patients. Nineteen RF produced by EBV-transformed cell lines from the synovium or blood of RA patients were analyzed. Their binding patterns differ significantly from those seen with RF obtained from patients with Waldenstrom's macroglobulinemia (WMac). Half of the RA-derived RF bound IgG1, 2, and 4, but not 3 (Ga specificity), the common pattern in WMac. However, heterogeneity in fine specificity within the Ga reactivity pattern was observed. Moreover, seven others bound all four IgG subclasses, a pattern observed for only one WMac-derived RF from a patient who also had RA. Three RF had subclass specificities unlike any observed with WMac-derived RF. Most RA-derived RF bound IgG at a discontinuous epitope comprised of residues from both the CH2 and CH3 H chain constant regions. However, unlike any WMac-derived RF, one RA-derived RF bound IgG in CH2, another in CH3, and a third at an undetermined site outside of the CH2-CH3 interface. Some RA-derived RF bound aglycosylated IgG4 less well than glycosylated IgG4, suggesting that the carbohydrate moiety was important in establishing their binding epitope in CH2. These studies demonstrate that the repertoire of RF expressed by RA patients contains some unique binding specificities for IgG epitopes not found among our panel of WMac-derived RF. Our results therefore call into question whether WMac-derived RF with their limited diversity are appropriate models for disease-related RF. In addition, RF with their multiple specificities can serve as probes of antibody structure.

Animals↗
PubMed1993

A vasoactive intestinal peptide antagonist inhibits non-small cell lung cancer growth.

The most prevalent lung cancer, non-small cell lung cancer (NSCLC) has receptors for vasoactive intestinal peptide (VIP). Here the effects of a VIP antagonist (VIP-hyb) on NSCLC growth were investigated. In vivo, when VIPhyb (10 micrograms, s.c.) was daily injected into nude mice, xenograft formation was significantly inhibited by approximately 80%. In vitro, VIP (100 nM) stimulated colony formation approximately 2-fold, whereas 1 microM VIPhyb inhibited colony formation by approximately 50% when adenocarcinoma cell line NCI-H838 was used. The attenuation of tumor proliferation is receptor mediated, as VIPhyb inhibited specific 125I-labeled VIP binding to cell lines NCI-H157 and NCI-H838 with an IC50 of 0.7 microM. VIP (10 nM) increased the cAMP levels 5-fold when cell line NCI-H838 was used, and 10 microM VIPhyb inhibited the increase in cAMP caused by VIP. Northern blot analysis and radioimmunoassays have shown VIP mRNA and VIP-like immunoreactivity in NSCLC cells. These data suggest that VIP may be a regulatory peptide in NSCLC and that VIPhyb is a VIP receptor antagonist that inhibits proliferation.

Amino Acid Sequence↗
PubMed1993

A cDNA clone for a pathogenesis-related protein 1 from barley.

A barley cDNA clone (PRb-1) corresponding to an mRNA differentially induced in resistant compared to susceptible barley cultivars by powdery mildew infection was isolated and characterised. The deduced amino acid sequence revealed 24 amino acids comprising the signal peptide and 140 amino acids of the mature peptide (15 kDa). This showed close homology to PR-1-like proteins, which have been isolated from maize, tobacco, tomato and Arabidopsis thaliana. Northern blot analysis showed accumulation of the corresponding mRNA 12 h after inoculation of resistant barley cultivars with Erysiphe graminis. Increased expression of the PRb-1 gene was also observed in resistant compared with near-isogenic susceptible barley plants following treatment with ethylene, salicylic acid, methyl jasmonate and 2,6-dichloro-isonicotinic acid.

Amino Acid Sequence↗
PubMed1993

21-day schedule oral etoposide in children--a feasibility study.

To determine the feasibility and toxicity of prolonged oral etoposide in children, 22 patients with relapsed or refractory disease were commenced on etoposide 50-100 mgs/m2 per day for 21 days. A second course was administered after full blood count recovery, followed by disease reassessment. In total, 72 courses were evaluable for toxicity, with 10% of completed courses complicated by febrile neutropenia. 15 patients were evaluable for response, with 1 partial response, 10 stable disease and 4 progressive disease. This schedule was well tolerated with acceptable toxicity when doses of less than 80 mg/m2/day were administered and warrants further evaluation.

Administration, Oral↗
PubMed1993

Evaluation of 50 consecutive segmental hepatic resections.

The development of increasingly sensitive imaging techniques along with improved follow-up and screening of high-risk patients has led to hepatic tumors, both primary and secondary, being detected while still at an early stage. Improved understanding of hepatic anatomy along with advances in surgical technique has led to the ability to undertake hepatic resections based on the segmental hepatic anatomy as described by Couinaud. The purpose of this paper is to assess the safety, technique, and oncologic efficacy of segmental hepatic resection. Fifty consecutive patients undergoing segmental hepatic resection during a 3-year time period ending in January 1992 were reviewed. Parametric statistical analysis was undertaken using Student's t-tests. Overall mortality was 2% with a morbidity rate of 8%. Transfusion requirements were 1 +/- 1.5 U; however, cirrhotic patients showed a significantly increased transfusion requirement of 2.0 +/- 1.3 U versus 0.7 +/- 1.3 U (p = 0.03). Sixty percent of patients required no transfusion at all. The mean duration of inflow occlusion was 42 +/- 17 minutes. Resection margins were clear of tumor by greater than 1 cm in 48 of 50 patients. Segmental hepatic resection is a safe and effective technique that occasionally may offer advantages over formal resection. Some aspects of the technique are reviewed.

Adolescent↗
PubMed1992

A monoclonal anti-idiotype specific for human polyclonal IgM rheumatoid factor.

One of the hallmarks of rheumatoid arthritis (RA) is the production of high titers of rheumatoid factor (RF) antibody directed against the Fc portion of IgG. Anti-Id that recognize the majority of monoclonal RF from patients with B cell dyscrasias are reactive with only 1 to 2% of these polyclonal RF from RA patients. We describe a new monoclonal anti-Id, 4C9, that recognizes a L chain determinant on polyclonal IgM RF from patients with RA but does not recognize a panel of monoclonal RF from patients with B cell malignancies. 4C9 reactivity is found in the serum of 34/43 RF-positive RA patients and in 12/12 RF-positive synovial fluids, but in only 1/14 RF-negative sera from RA patients and 1/22 sera containing monoclonal IgM RF. 4C9 reactivity is highly enriched in purified IgM RF from nine RA patients and represents a variable percentage of total IgM RF up to a maximum of 23%. Furthermore, 4C9 reactivity is enriched in the synovial fluid of three of five RA patients compared with serum, suggesting that 4C9-reactive IgM RF are synthesized within the joint. IgG RF from RA synovial fluids are not 4C9 reactive, indicating either that different genes are used to encode IgM and IgG RF in RA patients, or that IgG RF have somatically mutated away from idiotypic reactivity.

Antibodies, Anti-Idiotypic↗