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Biomedical subjects

C Stevens

Publications and source records attributed to C Stevens.

At least 37 records · Page 2Linked to original sources
PubMed1995

Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clinical review with six additional families.

X-linked hydrocephalus (HSAS) (MIM *307000), MASA syndrome (MIM *303350), and complicated spastic paraplegia (SPG1) (MIM *312900) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previous reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1.

Agenesis of Corpus Callosum↗
PubMed1995

Composition of TCR-CD3 complex in human intestinal intraepithelial lymphocytes: lack of Fc epsilon RI gamma chain.

Human intestinal intraepithelial lymphocytes (iIEL) are a unique population of predominantly CD8 alpha beta+, TCR alpha beta+ lymphocytes and, to a lesser extent, TCP gamma delta+ lymphocytes that proliferate poorly to anti-CD3 mitogenic signals but display significant cytolytic activity. Studies in mouse model systems have shown that the gamma chain of the high-affinity receptor for IgE (Fc epsilon RI gamma) may substitute for the zeta chain in the TCR-CD3 complex of iIEL. This has suggested that the functional properties of these cells may be associated with an altered composition of the TCR-CD3 complex. We therefore analyzed the TCR-CD3 complex of normal human iIEL. One- and two-dimensional non-reducing/reducing SDS-PAGE analysis of CD3 gamma, CD3 delta, CD3 epsilon, zeta and Fc epsilon RI gamma chain immunoprecipitates of cell surface radiolabeled proteins with subunit-specific antibodies revealed a TCR-CD3 complex without associated Fc epsilon RI gamma chains. Thus, normal human iIEL contain a TCR-CD3 complex that consists predominantly of zeta homodimers in association with the alpha beta TCR and CD3 gamma, delta and epsilon, similar to the majority of peripheral lymphocytes. This indicates that the distinct properties of human iIEL are not associated with substitutions of the Fc epsilon RI gamma chain in the TCR-CD3 complex.

Animals↗
PubMed1995

5-Aminosalicylic acid abrogates T-cell proliferation by blocking interleukin-2 production in peripheral blood mononuclear cells.

The antiinflammatory agent sulfasalazine (SS) is prescribed to treat Crohn's disease, ulcerative colitis and rheumatoid arthritis. Activated T cells are present within diseased mucosal and synovial sites. We tested whether SS or its metabolites 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) inhibited the T-cell activation products interleukin 2 (IL-2) and interleukin 2 receptor alpha-chain (IL-2R alpha). Experiments were performed in phytohemaglutinin- and phorbol ester-stimulated peripheral blood mononuclear cells. Radioactive thymidine and leucine incorporation assayed DNA and protein synthesis, respectively. Enzyme-linked immunosorbent assay and Northern blot analysis measured IL-2 and IL-2R alpha. Lactate dehydrogenase release determined cell viability, and intracellular free calcium was measured by an indole fluorescent indicator. SS and 5-ASA, but not SP, inhibited T-cell proliferation and protein synthesis in phytohemaglutinin- and phorbol ester-stimulated peripheral blood monomuclear cells. 5-ASA (625 microM) markedly reduced culture supernatant IL-2 protein levels by 92% and steady-state IL-2 messenger RNA levels 4.4-fold at 24 and 18 hr, respectively. The supplementation of IL-2 restored T-cell proliferation only in 5-ASA-treated cultures. SS, 5-ASA and SP did not alter intracellular calcium accumulation after mitogenic stimulation. SS and 5-ASA (625 microM) caused 71% and 37% cytotoxicity, respectively, in 72-hr cultures. 5-ASA inhibits T-cell proliferation in part by blocking IL-2 messenger RNA accumulation and protein production downstream of the rise in cytosolic calcium. Inhibition of IL-2 production is an additional mechanism of action for 5-ASA.

Aminosalicylic Acids↗
PubMed1994

Structure and mechanism of galactose oxidase. The free radical site.

Crystallographic and spectroscopic studies on galactose oxidase have shown that the active site involves a free radical on tyrosine 272, one of the ligands coordinated to the Cu2+ cofactor. A novel thioether bond between tyrosine 272 and cysteine 228, and a stacking tryptophan 290, over this bond, are features of the crystal structure. The present study describes the development of a high level heterologous expression system for galactose oxidase and the construction of mutational variants at these key active site residues. The expressed wild-type enzyme and mutational variants (W290H and C228G) have been characterized by x-ray crystallography, visible spectroscopy, and catalytic activity measurements. A further variant protein, Y272F, could not be purified. The data establish that the thioether bond and stacking tryptophan are essential for activity and further support a role for tryptophan 290 as a component of the free radical site.

Base Sequence↗
PubMed1994

Distribution of dominant T cell receptor beta chains in human intestinal mucosa.

The majority of human intestinal intraepithelial lymphocytes (iIELs) are CD8+ T cells that use the T cell receptor (TCR)-alpha/beta. Previous studies have shown that iIELs isolated from segments of small intestine or colon contain one or several dominant alpha/beta T cell clones. It is not known whether these clones expand only locally in response to a particular antigen or whether they are widely distributed throughout the intestine. To address this question, iIELs were purified from near the proximal and distal margins in a series of intestinal resections for noninflammatory diseases. TCR-beta expression was then assessed by semiquantitative polymerase chain reaction amplification, analysis of N-region length, and DNA sequencing. The previously described oligoclonal expansion of iIELs was confirmed in each sample. Identical dominant clones were identified in the proximal and distal samples from most cases, including samples taken from sites as distant as the transverse and sigmoid colon or rectum. Distinct clones were found in only one case with samples from the terminal ileum and transverse colon. These results demonstrate that a relatively small number of widely dispersed T cell clones comprise the majority of cells in the human intestinal mucosa.

Adult↗
PubMed1994

Human immunodeficiency virus type 1 mRNA expression in peripheral blood cells predicts disease progression independently of the numbers of CD4+ lymphocytes.

To address the significance of human immunodeficiency virus (HIV) replication in peripheral blood mononuclear cells (PBMCs), we have used reverse transcriptase-initiated PCR to measure HIV-1 mRNA expression in PBMC specimens collected from a cohort of HIV-infected individuals during a long-term prospective study. We found dramatic differences in HIV mRNA expression among individuals with very similar clinical and laboratory indices, and this variation strongly correlated with the future course of the disease. No evidence of viral replication was detected in PBMCs from asymptomatic individuals who, thereafter, had normal levels of CD4+ cells for at least 5 years. Irrespective of whether the CD4+ cell numbers were normal at the time of sampling, abundant expression of HIV-1 mRNA in PBMCs predicted accelerated disease progression within the next 2 years. Thus, independently of what may be the rate of HIV replication in other viral reservoirs, such as lymphatic tissue, the amount of HIV mRNA in PBMCs appears to reflect the subsequent development of HIV disease. We have also used the reverse transcriptase-initiated PCR assay to demonstrate a transient response to 3'-azido-3'-deoxythymidine treatment. Determination of HIV-1 mRNA expression in the PBMCs of infected individuals could, therefore, have significant clinical utility as a prognostic indicator and as a means to guiding and monitoring antiviral therapies.

CD4-Positive T-Lymphocytes↗
PubMed1994

Modelling symmetry detection with back-propagation networks.

This paper reports experimental data and results of network simulations in a project on symmetry detection in small 6 x 6 binary patterns. Patterns were symmetrical about the vertical, horizontal, positive-oblique, or negative-oblique axis, and were viewed on a computer screen. Encouraged to react quickly and accurately, subjects indicated axis of symmetry by pressing one of four designated keys. Detection times and errors were recorded. Back-propagation networks were trained to categorize the patterns on the basis of axis of symmetry, and, by employing cascaded activation functions on their output units, it was possible to compare network performance with subjects' detection times. Best correspondence between simulated and human detection-time functions was observed after the networks had been given significantly more training on patterns symmetrical about the vertical and the horizontal axes. In comparison with no pre-training and pre-training with asymmetric patterns, pre-training networks with sets of single vertical, horizontal, positive-oblique or negative-oblique bars speeded subsequent learning of symmetrical patterns. Results are discussed within the context of theories suggesting that faster detection of symmetries about the vertical and horizontal axes may be due to significantly more early experience with stimuli oriented on these axes.

Computer Simulation↗
PubMed1994

The spectrum of "complicated spastic paraplegia, MASA syndrome and X-linked hydrocephalus". Contribution of DNA linkage analysis in genetic counseling of individual families.

X-linked hydrocephalus and the X-linked MASA syndrome (Mental retardation. Adducted thumbs, Shuffling gait and Aphasia) both have a variable clinical spectrum with great overlap. Data from DNA linkage analysis placed the locus for both conditions at Xq28. On clinical and molecular grounds it has been hypothesized that both MASA syndrome and X-linked hydrocephalus are caused by a mutation in the same gene at Xq28. There is no significant clinical marker in the obligate female carriers and prenatal diagnosis by ultrasound is not reliable; DNA analysis can offer an improved genetic counseling for the families and more reliable prenatal diagnosis. In the gene encoding for Ll, a neural cell adhesion molecule and located at Xq28, several different mutations have been reported in X-linked hydrocephalus families and in a MASA family. We report data on DNA linkage analysis in 6 families with X-linked hydrocephalus/MASA syndrome. These data illustrate the importance of DNA linkage analysis in the individual family; they also show, however, the problem of studying small families. Genetic heterogeneity cannot be excluded.

Abortion, Eugenic↗
PubMed1994

Ganciclovir: treatment of cytomegalovirus in immunocompromised individuals.

Ganciclovir is synthetic antiviral agent that interferes with the CMV DNA synthesis. Administered intravenously, the antiviral drug can effectively stop the CMV herpes virus from replicating in adolescents and adults. CMV does pose a serious threat to immunocompromised individuals. Nursing care of patients receiving ganciclovir should include a complete assessment, predosing laboratory work and a complete drug and allergy history. Proper administration of ganciclovir, observation of side effects, and documentation are the responsibility of the nephrology nurse.

Cytomegalovirus Infections↗
PubMed1993

Validity and reliability of three methods used in the diagnosis of Raynaud's phenomenon. The UK Scleroderma Study Group.

Three different assessment methods for the classification of Raynaud's phenomenon (RP) were compared. These were (i) a previously validated method using colour charts supplemented with a short questionnaire, (ii) answers to a questionnaire based on criteria derived from the consensus opinion of a group of clinicians, and (iii) individual clinician's assessment using standard descriptions based upon the same consensus view. We report the results of a study involving six clinicians and 30 subjects investigating the level of repeatability between the three methods and also the reliability between the six clinicians. There did not exist any overall systematic bias between the six clinicians. Further, agreement between them, as assessed by the kappa statistic, ranged from moderate to good. However, there did exist systematic bias between the results from all three of the classification approaches with agreement between them ranging from only poor to moderate. We conclude that the previously validated colour chart assessment is too insensitive to detect RP. Further, a structured questionnaire based on perceived clinician's opinion could not reproduce clinicians' classification in practice. By contrast, supplying clinicians with standard descriptions did yield a reliable classification system for RP.

Humans↗