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Biomedical subjects

B White

Publications and source records attributed to B White.

At least 109 records · Page 6Linked to original sources
PubMed1997

Recombinant human thyrotropin is a potent stimulator of thyroid function in normal subjects.

Recombinant human TSH (rhTSH) is known to stimulate 131I uptake and thyroglobulin (Tg) release from the postoperative remnant and metastases in thyroid cancer patients, but its effects on serum thyroid hormone and Tg concentrations in normal subjects have not been reported. Before using rhTSH in the management of thyroid disorders other than cancer, the thyroid response to rhTSH in normal subjects must be assessed. Six subjects, two men and four women, without evidence of thyroid disease, including normal serum free T4 index and TSH concentrations and negative tests for antithyroid peroxidase and Tg, were studied. Each received 0.1 mg rhTSH, im, 11% of the lowest dose that has been administered to thyroid cancer patients. Blood was obtained before; 2, 4, and 8 h after; and 1, 2, 3, 4, 7, and about 3 weeks after rhTSH administration. Serum TSH significantly increased at 2 h (mean +/- SE, 2.4 +/- 0.9 to 40.7 +/- 7.4 mU/mL), peaked at 4 h (50.9 +/- 9.3), remained significantly elevated for 1 day, and was significantly below baseline (0.8 +/- 0.5) 7 days after rhTSH administration. Serum T3 increased significantly at 4 h (115 +/- 4 to 190 +/- 14 ng/dL), peaked at 24 h (217 +/- 23 ng/dL), and remained significantly elevated for 3 days (151 +/- 12 ng/dL). Serum T4 increased significantly at 8 h (7.3 +/- 0.2 to 9.8 +/- 0.4 micrograms/dL), peaked at 24 h (11.2 +/- 0.5 micrograms/dL), and remained significantly elevated for 4 days (9.4 +/- 0.5 micrograms/dL). Serum Tg did not change for the first 8 h, increased significantly at 1 day (15.9 +/- 3.9 to 34.7 +/- 6.0 ng/mL), peaked at 2 days (44.2 +/- 7.0 ng/mL), and remained significantly elevated for 4 days (37.7 +/- 13.7 ng/mL). All values returned to baseline at 3 weeks. TSH antibodies were not detected at 3 weeks. A single dose of 0.1 mg rhTSH is a potent stimulator of thyroid function in normal subjects. rhTSH may be a useful agent to test thyroid reserve and for use in clinical settings that require direct thyroid stimulation.

Adult↗
PubMed1996

Identification and characterization of two alternative splice variants of human interleukin-2.

Our previous work showed that alternative splicing is used to make an inhibitory variant of human interleukin (IL)-4. Because of homology between IL-4 and IL-2 proteins and receptors, we tested whether alternative splicing is used to generate similar inhibitory variants of human IL-2. Messenger RNA from peripheral blood mononuclear cells was subjected to reverse transcription-polymerase chain reaction using IL-2 exon 1- and exon 4-specific primers. Two amplification products, named IL-2delta2 and IL-2delta3, were found in addition to the native IL-2 product. The IL-2delta2 cDNA sequence was identical to IL-2 cDNA throughout the entire coding region, except exon 2 was omitted by alternative splicing. In IL-2delta3 cDNA, the third exon of IL-2 was omitted by alternative splicing. Unlike IL-2, IL-2delta2 and IL-2delta3 did not stimulate T cell proliferation. However, both inhibited IL-2 costimulation of T cell proliferation, and both inhibited cellular binding of rhIL-2 to high affinity IL-2 receptors. Thus, IL-2 is the second cytokine that uses alternative splicing to generate variants that are competitive inhibitors.

Alternative Splicing↗
PubMed1996

Restricted T-cell antigen receptor repertoire in bronchoalveolar T cells from normal humans.

The repertoire of variable alpha (AV) and beta (BV) TCR genes was compared in the peripheral blood and BAL fluid of five healthy individuals. Rearranged TCR transcripts were amplified by a reverse transcription-polymerase chain reaction, using oligonucleotide primers specific for 22 AV and 24 BV gene families. Nearly all AV and BV gene families were expressed in BAL T cells at levels similar to those in blood T cells. The diversity of AV and BV gene repertoire was examined further, testing the distribution of nucleotide lengths of TCR junctional regions. Most V gene families had a normal distribution of junctional region lengths in both blood and BAL T cells. Some gene families, particularly AV21 and BV9 in BAL samples, had a skewed banding pattern, with fewer bands or predominance of several bands. The limited diversity in TCR junctional region lengths was more prominent in CD8+ T cells from BAL fluids than from blood. CD4+ T cells also contributed to the limited diversity in BAL T cells. The oligoclonal expansion of bronchoalveolar CD8+ T cells was confirmed by sequence analysis of AV21-constant alpha (AC) and BV9-BC junctional regions in the blood and BAL cells. The levels of V gene expression and the diversity of junctional region lengths were very similar in T cells obtained from three separate lobes of one donor. In general, skewed patterns of TCR junctional region lengths were not consistent over time two donors, over periods of 3 and 17 months. Together, these data show that the T-cell repertoire is diverse within the lungs of normal humans, except for an oligoclonal predominance of a few V gene families in both CD4+ and CD8+ T cells. The T-cell repertoire in the lungs changes over time, which may reflect environmental exposures.

Adolescent↗
PubMed1996

High phenotypic correlations among siblings with autism and pervasive developmental disorders.

The objective of this study was to examine familial factors influencing clinical variation in sibships that contained at least 2 children affected with autism or another form of pervasive developmental disorder (PDD). The sample included a total of 60 families, 23 with multiple cases of PDD and 37 with a single affected child. Measurements of IQ, adaptive behaviors in socialization and communication, and autistic symptoms were taken on all affected children. A high intraclass correlation, especially on IQ and an index of social behaviors, was observed between affected children from the same family. In contrast, low correlations were observed on measurements of IQ and adaptive behavior between affected and unaffected children from the same family. These data indicate that variation in severity of PDD is influenced by familial, and probably genetic, mechanisms. The results are discussed in relation to current theories on the genetics of autism and the heritable mechanisms underlying variations in clinical severity.

Autistic Disorder↗
PubMed1996

An alternative splice variant of human IL-4, IL-4 delta 2, inhibits IL-4-stimulated T cell proliferation.

Alternative splicing of mRNA can generate protein isoforms that are preferentially expressed in different tissues or during different states of cell differentiation or activation. Protein isoforms may have different functions. In this study, we cloned, expressed, and tested functional effects of a naturally occurring splice variant of human IL-4, called IL-4 delta 2. In IL-4 delta 2, the second exon of IL-4 is omitted by alternative splicing, with exons 1, 3, and 4 joined in an open reading frame. We found that IL-4 delta 2 RNA is expressed in the PBMC of all donors tested, usually in lower amounts than IL-4 RNA. In contrast, IL-4 delta 2 RNA is expressed in much higher levels than IL-4 RNA in thymocytes and bronchoalveolar lavage cells, suggesting tissue specificity of expression. IL-4 delta 2 cDNA was expressed in yeast. Recombinant human (rh) IL-4 delta 2 was partially purified and found to be glycosylated, with a protein core of 13 to 15 kDa. Unlike rhIL-4, rhIL-4 delta 2 did not act as a costimulator for T cell proliferation. However, rhIL-4 delta 2 inhibited the ability of rhIL-4 to act as a T cell costimulator. Inhibition was independent of glycosylation and was not mediated by toxicity. Iodinated IL-4 delta 2 was found to bind specifically to human PBMC and tumor lines known to express IL-4 receptors. Excess unlabeled IL-4 inhibited cellular binding of labeled IL-4 delta 2. Thus, rhIL-4 delta 2 is a naturally occurring splice variant of IL-4 that is preferentially expressed in the thymus and airways and inhibits function of complete IL-4. The balance between IL-4 and IL-4 delta 2 may be important in the regulation of IL-4 effects.

Amino Acid Sequence↗
PubMed1996

Depressive symptoms associated with scleroderma.

OBJECTIVE: To examine the prevalence and correlates of depressive symptoms among patients with systemic sclerosis (SSc; scleroderma). METHOD: Fifty-four outpatients with scleroderma were administered the Beck Depression Inventory, the Neuroticism-Extraversion-Openness Personality Inventory, the Health Assessment Questionnaire, and the Psychosocial Adjustment to Illness Scale. In addition, patients underwent a comprehensive clinical assessment, and pulmonary function tests were obtained. RESULTS: Nearly half of the patients had mild depressive symptoms, and an additional 17% had symptoms in the moderate-to-severe range. Younger patients, those with digital ulceration, and those with more self-rate functional impairment had more depressive symptoms, but there were few other relationships between depressive symptoms and either demographic or physician-rated medical variables. In contrast, there were highly significant relationships between depression and aspects of personality, psychosocial adjustment to illness, and social support. CONCLUSION: Depressive symptoms in patients with SSc are more strongly related to personality, self-rated disability, and adequacy of emotional support than to objective medical indices of illness severity. Depression in scleroderma is a debilitating comorbid condition that should be recognized and treated in its own right.

Age Factors↗
PubMed1996

Lack of association between augmentation mammoplasty and systemic sclerosis (scleroderma).

OBJECTIVE: To examine the possible association between augmentation mammoplasty and systemic sclerosis (SSc; scleroderma). METHODS: Eight hundred thirty-seven women with a clinical diagnosis of SSc, recruited as a volunteer sample from 3 university-based, tertiary care scleroderma clinical research centers, and 2,507 race-matched local control women, recruited by the technique of random-digit-dialing and frequency-matched on age, completed a questionnaire providing data on history of augmentation mammoplasty, including possible complications of the procedure. The odds ratio (OR) and 95 percent confidence interval (95% CI) for the association of augmentation mammoplasty with SSc were estimated by multivariate logistic regression analysis with adjustment for age, race and center, and by conditional logistic regression analysis with adjustment for age. RESULTS: Eleven (1.31%) of the 837 cases reported a history of augmentation mammoplasty prior to diagnosis of SSc, compared with 31 (1.24%) of the 2,507 controls. The adjusted OR from the unmatched analysis was 1.07 (95% CI 0.53-2.13), while that from the matched analysis was 1.11 (95% CI 0.55-2.24). CONCLUSION: These results fail to demonstrate a significant association between augmentation mammoplasty and SSc, and are consistent with those reported from other epidemiologic studies.

Adult↗
PubMed1996

Erythroid progenitor proliferation is stimulated by phenoxyacetic and phenylalkyl acids.

Short-chain fatty acids, such as butyrate and propionate, are under investigation as therapeutic stimulants of fetal hemoglobin production in the beta-hemoglobin disorders. Significant limitations to these fatty acids and derivatives as optimal therapeutics are their rapid metabolism in vivo and their induction of cell growth arrest in the G1 phase of the cell cycle. This antiproliferative activity is related to their inhibition of metabolic transport pumps which are essential for cell proliferation. Other small carbon compounds, the phenylalkyl acids, phenoxyacetic acids, and phenylacetic acids, which are structurally resistant to oxidative metabolism, are shown here to induce fetal globin production in human erythroid cultures at concentrations of 0.2 mM, lower than those required for most other fatty acids. Certain of these compounds were found not to inhibit cellular neutral amino acid transport function in erythroid cells, nor to inhibit erythroid colony (Bfu-e) growth. Certain of these compounds even stimulated human Bfu-e proliferation in vitro beyond that induced by optimal concentrations of hematopoietic growth factors. The combination of increased fetal globin chain production by these compounds and their stimulatory effects on erythropoiesis result in an increase in Hb F-expressing erythroid cells in culture several-fold greater than that achieved by the butyrates. These new compounds thus have the potential to provide superior therapy for the beta-hemoglobinopathies and other anemias.

Biological Transport↗
PubMed1996

Immunopathogenesis of systemic sclerosis.

The information outlined above can be used to generate a model of the immunopathogenesis of SSc (Fig. 3). This model includes a susceptible host, with age greater than 25 and female gender being risk factors. The model also includes exposure to exogenous agents, which could be different in different individuals and may include inhaled or ingested chemicals or infectious agents. An early event is T-cell activation, with infiltration in the skin and internal organs. Activation of the T cells is a selective process that appears to be influenced by antigen in SSc patients. The importance of a particular T-cell subpopulation may depend upon the organ involved and the stage of the disease. CD4+ T cells predominate in the skin. In contrast, CD8+ T cells are increased in the lungs of patients with alveolitis, where they are oligoclonal, showing evidence of antigen-driven selection. V delta 1+ gamma/delta T cells are increased in both the blood and lungs of SSc patients and also show evidence of selection by antigen. B cells are activated early, with polyclonal activation leading to hypergammaglobulinemia. SSc-specific autoantibodies target DNA topoisomerase I, centromeric proteins, and RNA polymerases I and III. Characteristics of autoantibodies in SSc suggest that the target antigens are presented to the immune system as native molecules or even part of a multiunit complex. There is some homology between viruses and autoantibody targets in SSc, which suggests that molecular mimicry may play a role in initiating the antibody response. Many nonspecific inflammatory cells infiltrate the tissues and show evidence of activation. These include macrophages and monocytes, mast cells, eosinophils, basophils, and natural killer cells. Soluble mediators made by these T cells, B cells, and nonspecific inflammatory cells can activate and damage fibroblasts, endothelial cells, and other vascular cells. The relative importance of the various candidate cytokines, the temporal sequence of their production, and their cellular sources remain largely to be defined. There may be some contribution of direct T-cell cytotoxicity or antibody-dependent cellular cytoxicity to the tissue damage that occurs.

Antibody Formation↗
PubMed1996

Simultaneous quantitation of cytokine mRNAs by reverse transcription-polymerase chain reaction using multiple internal standard cRNAs.

Cytokines produced in abnormal amounts or patterns contribute to many immunologically mediated human diseases. We describe a competitive reverse transcription-polymerase chain reaction (RT-PCR) assay to measure interleukin (IL)1-2, IL-4, and interferon-gamma (IFN-gamma) mRNAs within the sample. Internal standard cRNAs and native cytokine mRNAs are reverse transcribed and then amplified by PCR in the same reaction tubes to control for tube-to-tube variability in these reactions. In contrast to systems that use a single multigene internal standard cRNA, this method uses separate internal standard cRNAs for IL-2, IL-4, and IFN-gamma, allowing independent dosing of the internal standards, which reduces the number of tubes processed and the amount of starting mRNA required. Internal standards are produced from cytokine cDNAs by the insertion of short segments of DNA. The same oligonucleotide primers are used to amplify internal standard and native cytokine cDNAs. Each internal standard cDNA and its matching native cytokine cDNA are amplified with equal efficiency. The RT-PCR products of the internal standards and native cytokines are distinguished by size. This technique can detect a twofold difference in mRNA levels. Examples of using this technique to measure cytokine mRNAs in peripheral blood mononuclear cells and in bronchoalveolar lavage cells are given.

Bronchoalveolar Lavage Fluid↗
PubMed1996

Scalable and expressive medical terminologies.

The K-Rep system, based on description logic, is used to represent and reason with large and expressive controlled medical terminologies. Expressive concept descriptions incorporate semantically precise definitions composed using logical operators, together with important non-semantic information such as synonyms and codes. Examples are drawn from our experience with K-Rep in modeling the InterMed laboratory terminology and also developing a large clinical terminology now in production use at Kaiser-Permanente. System-level scalability of performance is achieved through an object-oriented database system which efficiently maps persistent memory to virtual memory. Equally important is conceptual scalability-the ability to support collaborative development, organization, and visualization of a substantial terminology as it evolves over time. K-Rep addresses this need by logically completing concept definitions and automatically classifying concepts in a taxonomy via subsumption inferences. The K-Rep system includes a general-purpose GUI environment for terminology development and browsing, a custom interface for formulary term maintenance, a C+2 application program interface, and a distributed client-server mode which provides lightweight clients with efficient run-time access to K-Rep by means of a scripting language.

Artificial Intelligence↗
PubMed1995

Oligoclonal expansion of V delta 1+ gamma/delta T-cells in systemic sclerosis patients.

Systemic sclerosis (SSc) is a multisystem disease characterized by T-cell infiltration of involved tissues, fibrosis, and small vessel vasculopathy. Using flow cytometric analyses, we found an increased percentage of gamma/delta T-cells expressing the T-cell antigen receptor variable (V) delta 1 gene segment in the peripheral blood and bronchoalveolar lavage fluid of patients with SSc. To estimate clonality of these V delta 1+ T-cells, the diversity of V delta 1 junctional regions (V-Diversity-Joining gene segments) was examined using a reverse transcriptase-polymerase chain reaction to amplify T-cell antigen receptor delta chain transcripts isolated from peripheral blood mononuclear cells, lung, esophagus, stomach, or skin of patients and controls. Limited diversity of V delta 1-J delta junctional regions in SSc patients was demonstrated by the finding of greater restriction in the nucleotide lengths of junctional region cDNAs in individual SSc patients than in controls. Sequence analyses confirmed that V delta 1-J delta junctional regions from the blood of SSc patients had less diversity than those from controls, in that a significantly higher proportion of sequences were repeated in patients (54.4% vs. 19.4% in controls). Evidence for selection of the V delta 1+ T-cells in tissues of individual SSc patients came from the findings that the same V delta 1-J delta junctional sequences could be isolated from the same tissue over time and that identical V delta 1-J delta junctional sequences could be isolated from multiple tissues. These data suggest that expansion of V delta 1+ gamma/delta T cells may be antigen driven in SSc patients.

Base Sequence↗