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Biomedical subjects

C Stewart

Publications and source records attributed to C Stewart.

At least 109 records · Page 6Linked to original sources
PubMed1994

Phase I study of topotecan for pediatric patients with malignant solid tumors.

PURPOSE: To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS: In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS: Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION: Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.

Adolescent↗
PubMed1994

Characterization of the synthesis and secretion of transforming growth factor-alpha from salivary glands and saliva.

Whole saliva collected from rat, mouse, and human sources was found to contain high concentrations of transforming growth factor-alpha (TGF alpha) when analyzed by RIA. The concentrations of TGF alpha in unstimulated human saliva (age, 30-45 yr; n = 10; 1.5 +/- 3.1 nM) was reduced with age (age, 55-70 yr; n = 10; 0.4 +/- 0.1 nM), but increased in oral pathologies manifested in xerostomia (age, 57-70; n = 6; 0.8 +/- 0.2 nM) and Paget's disease (age, 58-76; n = 8; 2.0 +/- 0.6 nM). Immunohistochemical localization of TGF alpha in the salivary glands of rats and mice revealed specific immunostaining of the granular ductal cells of the parotid and submandibular glands. Reverse transcription followed by polymerase chain reaction amplification of total RNA from the parotid and submandibular glands of rats and mice demonstrated the presence of TGF alpha mRNA, suggesting endogenous synthesis by the salivary glands. Thus, salivary glands appear to be an exocrine source for a second member of the epidermal growth factor-like growth factor family in the oral cavity.

Adult↗
PubMed1994

Laryngeal botulinum toxin injections for disabling stuttering in adults.

Stuttering is an action-induced speech disorder with involuntary, audible, or silent repetitions or prolongations in the utterance of short speech elements (sounds, syllables) and words. Symptomatic treatment programs frequently have initial success; persistent benefit is variable and many patients remain disabled. Stuttering has many characteristics similar to spasmodic dysphonia (laryngeal dystonia), often including the presence of adductor laryngeal spasms that obstruct airflow (glottal block). We hypothesized that relief of the spasmodic dysphonic glottal blocks in stutterers would modify the stuttering phenomenon and increase fluency. We therefore studied the effects of bilateral vocal fold injections of botulinum toxin type A (BTX) on dysfluency and speech characteristics in stuttering. We treated 14 adult patients (12 men, 2 women) with persistent stuttering and glottal block who previously failed standard speech therapy with 1.25 U BTX into each thyroarytenoid (vocalis) muscle. Fluency evaluations included the Stuttering Severity Instrument, the Perceptions of Stuttering Inventory, and a global rating scale (percent of normal function). Patients were evaluated at baseline and at 2-, 6-, and 12-week follow-up visits. Improvement in fluency documented by each rating instrument occurred at 2 and 6 weeks, with functional relapse by 12 weeks in most patients. We conclude that therapeutic laryngeal injections of botulinum toxin are useful in the management of stuttering with glottal block and result in a moderate improvement in fluency. When an adult patient with developmental stuttering with glottal blocks has failed speech interventional therapy and presents for treatment, a trial of BTX can be considered early.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin-releasing pituitary cells as a model for somatic cell gene therapy in diabetes mellitus.

Insulin delivery by somatic cell gene therapy was evaluated using murine pituitary AtT20MtIns-1.4 cells. These cells have been stably transfected to release human insulin by the introduction of a recombinant plasmid bearing a human preproinsulin cDNA under the control of a zinc-sensitive metallothionein promoter. 6 x 10(7) AtT20MtIns-1.4 cells were implanted subcutaneously into streptozotocin-diabetic mice immunosuppressed with cyclosporin A. Release of human insulin was assessed using a specific plasma human C-peptide assay. On days 1 and 2 after implantation human C-peptide concentrations were about 0.02 pmol/ml. Consumption of zinc sulphate solution (500 mg/l) as drinking fluid for days 3-5 increased plasma human C-peptide concentrations to 0.11 +/- 0.01 pmol/ml (mean +/- S.E.M.), n = 11, P < 0.01, and concentrations declined when zinc was discontinued. The extent of hyperglycaemia was slightly lower (P < 0.05) than in a group implanted with non-transfected AtT20 cells. The study was terminated after 9 days, and tumour-like aggregations of implanted cells were identified at autopsy. These comprised a large necrotic core with insulin-containing cells at the periphery. The study provides support for the view that somatic cell gene therapy offers a potential approach to insulin delivery in diabetes mellitus.

Animals↗
PubMed1994

Assessment of cartilage volume in the femorotibial joint with magnetic resonance imaging and 3D computer reconstruction.

OBJECTIVE: Our goal was the development of an accurate and objective technique to depict and quantitate articular cartilage using magnetic resonance imaging (MRI) and 3D data processing. METHODS: A method of 3D image analysis has been developed that provides a noninvasive technique of measuring cartilage volume from standard diagnostic MR images. RESULTS: Using a computer workstation, cartilage from Fast Field Echo (FFE) MR images was reconstructed into 3 dimensions (3D). The accuracy and reproducibility of both thickness and volume measurements obtained from the existing computer software was tested using calibration test objects. We describe the sources of error we encountered when attempting to quantitate cartilage using the existing computer software, the methods developed to reduce these errors, and a preliminary cartilage volume study using healthy human volunteers. CONCLUSION: We have identified errors involved in attempting cartilage volume estimations using the existing 3D computer software and have developed a data processing technique that minimizes these errors. With these objective data processing techniques we have improved the reproducibility of the technique to +/- 10-15% error. This modified technique provides a promising new method for viewing and quantifying cartilage volume from standard diagnostic MR images.

Animals↗
PubMed1994

Localization of the gene for the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant multisystem disorder characterized by multiple basal cell carcinomas, jaw cysts, pits of the palms and/or soles, ectopic calcification, and skeletal malformations. The NBCC gene has recently been mapped to chromosome 9q22.3-9q31. In order to further define the region containing the NBCC gene, we have analyzed 137 individuals from eight families for linkage, using 11 markers from the region. Eight markers showed statistically significant evidence for linkage to NBCC. Three markers (D9S180, ALDOB, and D9S173) showed no definite recombination with the disease locus. All families showed some evidence for linkage to markers in this region. On the basis of the inspection of individual recombinants and previously published information about map location, we suggest the following order for the markers: D9S119-D9S12-D9S197-D9S196-(NBCC,D9S180 -D9S173,ALDOB)-D9S109- D9S127-(D9S53,D9S29). We are currently developing YAC contigs for the most closely linked markers, to further refine the location of the NBCC gene.

Alleles↗
PubMed1994

Polymorphic admixture typing in human ethnic populations.

A panel of 257 RFLP loci was selected on the basis of high heterozygosity in Caucasian DNA surveys and equivalent spacing throughout the human genome. Probes from each locus were used in a Southern blot survey of allele frequency distribution for four human ethnic groups: Caucasian, African American, Asian (Chinese), and American Indian (Cheyenne). Nearly all RFLP loci were polymorphic in each group, albeit with a broad range of differing allele frequencies (delta). The distribution of frequency differences (delta values) was used for three purposes: (1) to provide estimates for genetic distance (differentiation) among these ethnic groups, (2) to revisit with a large data set the proportion of human genetic variation attributable to differentiation within ethnic groups, and (3) to identify loci with high delta values between recently admixed populations of use in mapping by admixture linkage disequilibrium (MALD). Although most markers display significant allele frequency differences between ethnic groups, the overall genetic distances between ethnic groups were small (.066-.098), and < 10% of the measured overall molecular genetic diversity in these human samples can be attributed to "racial" differentiation. The median delta values for pairwise comparisons between groups fell between .15 and .20, permitting identification of highly informative RFLP loci for MALD disease association studies.

Alleles↗
PubMed1994

Use of private duty nurses for daily CCPD and family relief in pediatric PD patients.

STUDY OBJECTIVE: To evaluate the role of trained home nurses in the care of end-stage renal disease (ESRD) pediatric patients on continuous cycling peritoneal dialysis (CCPD) and/or for family relief. DESIGN: The study was designed to investigate trained home nurses in the care of pediatric ESRD patients receiving peritoneal dialysis (PD) who entered the home program between February 1991 and October 1993. SETTING: Tertiary-referral university hospital. PATIENTS AND METHODS: We trained the nursing staff of nursing agencies to perform PD with a special emphasis on pediatric care. A weekly nursing summary including daily vital signs, PD flow sheet, medications, and progress notes was sent to the home program. The trained nurses were also utilized for family relief to prevent burn-out. RESULTS: Five children (4 female, 1 male) with ages ranging from 3-14 years were studied. The total number of patient-months was 81 with a range of 4-33 patient-months. During this time, there was only one hospital admission for hyperkalemia and hypertension. Five episodes of peritonitis occurred over 81 patient-months, and all were treated at home. The clinic visit compliance was 100% in patients having nursing help. The administration of erythropoietin at home in these patients was consistent, resulting in higher hematocrit (Hct) levels. The added support to patients and family resulted in a low incidence of complications and infrequent need for hospital admissions. CONCLUSIONS: Our experience suggests that the use of private duty nurses for performing CCPD or for family relief in ESRD children has a favorable outcome and would benefit most pediatric home dialysis programs.

Adolescent↗
PubMed1993

Electroconvulsive stimulation and synaptic plasticity in the rat.

The effects of repeated, spaced, electroconvulsive stimulation (ECS) on rodent hippocampal synaptic plasticity was investigated in vivo. Long-term potentiation (LTP) was induced in intact rats using high-frequency perforant path stimulation, and measured by recording extracellular excitatory field potentials and population spikes evoked in the dentate gyrus by low-frequency stimulation before and after LTP induction. LTP induction appeared to be inhibited in animals which had received ECS. However, inspection and analysis of absolute excitatory postsynaptic potential and population spike size before LTP induction in ECS treated animals suggested that LTP may have already been induced as a consequence of seizure activity, reducing the degree to which further potentiation could be elicited experimentally.

Analysis of Variance↗
PubMed1993

Analysis of Mdr50: a Drosophila P-glycoprotein/multidrug resistance gene homolog.

Using degenerate oligonucleotides from conserved portions of the ATP-binding domain of the active transporter genes, a new member of this gene superfamily has been cloned from Drosophila DNA. The gene contains two sets of transmembrane domains and two ATP-binding domains and shows a high degree of similarity to the mammalian P-glycoprotein/multidrug resistance (MDR) genes. The gene is adjacent to Hsc5, a locus mapped to chromosome 2, band 50, and is named Mdr50. Mdr50 represents the third MDR homolog identified in Drosophila. Conservation in the position of intervening sequences between Mdr50 and the human MDR genes provides further evidence for their common origin.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1993

Circulating CD3+ CD4+ CD8+ T lymphocytes in multiple sclerosis.

Triple-antibody flow cytometry was used to search for distinctive populations of peripheral blood lymphocyte immunophenotypes in multiple sclerosis (MS). Using monoclonal antibodies to the cell surface markers CD3, CD4, and CD8, T cell subsets were quantified on a cohort of 31 MS patients (not treated with corticosteroids for at least 6 months), 30 healthy donors, and 14 patients with other autoimmune diseases (also corticosteroid treatment-free for at least 6 months). Untreated MS patients displayed a significantly greater population of CD3+CD4+CD8+ circulating T cells than healthy donors (P = 0.023). Patients with other autoimmune diseases displayed mean populations of CD3+CD4+CD8+ cells greater than normal donors and less than MS, but not significantly different from either. An additional 45 MS patients who had received corticosteroid therapy within the previous 6 months were phenotyped. Treatment of symptomatic MS with corticosteroids was associated with a smaller population of circulating CD3+CD4+CD8+ cells. Some MS patients have significantly greater numbers of peripheral blood T lymphocytes simultaneously expressing CD3, CD4, and CD8 surface markers than healthy donors and this population of cells may be reduced by corticosteroids treatment. This triple positive phenotype may be a manifestation of a systemic immune abnormality in MS.

Antigens, CD↗
PubMed1993

Targeted disruption of the MHC class II Aa gene in C57BL/6 mice.

The MHC class II gene Aa was disrupted by targeted mutation in embryonic stem (ES) cells derived from C57BL/6 mice to prevent expression of MHC class II molecules. Contrary to previous reports, the effect of the null-mutation on T cell development was investigated in C57BL/6 mice, which provide a defined genetic background. The complete lack of cell surface expression of MHC class II molecules in B6-Aa0/Aa0 homozygous mutant mice was directly demonstrated by cytofluorometric analysis using anti-Ab and anti-Ia specific mAbs. Development of CD4+CD8- T cells in the thymus was largely absent except for a small population of thymocytes expressing high levels of CD4 together with low amounts of CD8. The majority of these cells express the TCR at high density. Although mature CD4+CD8- T cells were undetectable in the thymus, some T cells with a CD4+CD8-TCRhigh phenotype were found in lymph nodes and spleen. Peripheral T cells from the mutant mice can be polyclonally activated in vitro with the mitogen concanavalin A. However, they could not be stimulated with staphylococcal enterotoxin B in autologous lymphocyte reactions, thereby demonstrating the absence of MHC class II expression in these mice. Peripheral B cells in B6-Aa0/Aa0 mutants were functional and responded to the T cell independent antigen levan by the production of antigen-specific IgM antibodies similar to wild-type cells. The B6-Aa0/Aa0 mutant mice described in this study represent an important tool to investigate the involvement of MHC class II molecules in lymphocyte maturation and the immune response.

Animals↗
PubMed1993

Insulin delivery by somatic cell gene therapy.

The feasibility of somatic cell gene therapy as a method of insulin delivery has been studied in mice. Murine pituitary AtT20 cells were transfected with a human preproinsulin DNA in a plasmid containing a metallothionein promoter and a gene conferring resistance to the antibiotic G418. The AtT20MtIns-1.4 clone of cells was selected because of its higher insulin-releasing activity compared with other clones. After culturing for 24 h in Dulbecco's medium containing 10 mM glucose, the AtT20MtIns-1.4 cells released human insulin at about 5 ng/10(6) cells per 24 h. Insulin release was not significantly altered by raised concentrations of glucose, potassium or calcium, but insulin release was increased by 20 mM arginine, 5 mM isomethylbutylxanthine and 90 microM zinc. AtT20MtIns-1.4 cells (2 x 10(6)) were implanted intraperitoneally into non-diabetic athymic nude (nu/nu) mice, and the mice were made diabetic by injection of streptozotocin after 7 days. Release of human insulin in vivo was assessed using a specific plasma human C-peptide assay. Human C-peptide concentrations were maintained at about 0.1 pmol/ml throughout the 29 days of the study. The development of streptozotocin-induced hyperglycaemia was delayed in recipients of the cells releasing human insulin, compared with a control group receiving an implant of non-transfected cells. At autopsy the implanted AtT20MtIns-1.4 cells in each recipient had formed a tumour-like aggregation, with an outer region of insulin-containing cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Identification of P-glycoprotein/multidrug resistance genes from model organisms.

Using degenerate oligonucleotides from conserved portions of the ATP-binding domain of the active transporter genes, several new members of this gene superfamily have been cloned from Drosophila, Saccharomyces cerevisiae, and E. coli DNA. The Drosophila and E. coli genes contain two sets of transmembrane domains and two ATP-binding domains, whereas the yeast gene contains single transmembrane and ATP-binding domains. All three genes show a high degree of similarity to the mammalian P-glycoprotein/multidrug resistance (MDR) genes. The E. coli sequence is the only known transporter gene containing both ATP and transmembrane domains in a single open reading frame. While the function of these sequences has not been determined, they may prove to be useful for developing a model to study the function of P-glycoproteins.

Adenosine Triphosphate↗