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Biomedical subjects

C B Williams

Publications and source records attributed to C B Williams.

At least 55 records · Page 3Linked to original sources
PubMed1998

In vivo antagonism of a T cell response by an endogenously expressed ligand.

3.L2 T cell receptor transgenic T cells are activated by the 64-76 peptide of the mouse hemoglobin d beta chain [Hb(64-76)], and their response is antagonized by the position 72 alanine substitution of this peptide (A72). To test the effect of this altered peptide ligand (APL) on 3.L2 T cell function in vivo, a transgene expressing A72 in major histocompatibility complex II positive cells (A72tg) has been introduced into mice. We demonstrate that 3.L2 T cells, when transferred to A72tg+ mice show a dramatically reduced proliferative response to Hb(64-76). Identical decreased responses were observed using T cells that developed in either A72tg+ or A72tg- hosts. This affect was not attributable to diminished precursor frequency, anergy, or competition for binding to I-Ek molecules. These results unequivocally demonstrate in vivo antagonism by an endogenous APL and characterize a class of self-peptides that, although inefficient in causing deletion in the thymus, effectively modulate T cell responses in the periphery.

Alleles↗
PubMed1998

The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history.

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.

Adult↗
PubMed1998

In vivo expression of a TCR antagonist: T cells escape central tolerance but are antagonized in the periphery.

Transgenic 3.L2 T cells are stimulated by Hb(64-76)/I-Ek and are positively selected on I-Ek plus self-peptides. To this pool of self-peptides we have added a single, well-defined 3.L2 TCR antagonist (A72) in vivo. We find that mice expressing both the 3.L2 TCR and A72 have a minimal loss of T cells expressing the clonotypic TCR in the thymus and spleen. Importantly, the proliferative response of 3.L2 x A72 splenocytes is significantly reduced compared with splenocytes from 3.L2 mice. This reduced response can be attributed to peripheral antagonism. Thus we have identified a new class of self-ligands whose predominant effect is constitutive peripheral antagonism rather than negative selection. The net effect of these ligands is to avoid potential self-reactivity while maintaining as large a repertoire as possible.

Animals↗
PubMed1998

The study of self-tolerance using murine haemoglobin as a model self antigen.

T cell tolerance to self proteins involves both thymic and peripheral mechanisms. We have used allotypic differences in murine haemoglobin (Hb) to study the development of tolerance to the abundantly expressed self-protein. In Hb beta s/H-2k mice, the response to Hb beta d is directed against Hb beta d (64-76) presented by I-Ek molecules. Using T cell hybridomas and clones specific for this epitope, we have demonstrated that Hb(64-76)/I-Ek complexes and present on antigen-presenting cells in all lymphoid organs including dendritic cells, B cells and macrophages. In the thymus, the presence of these complexes results in negative selection of transgenic T cells with high levels of Hb(64-76)/I-Ek-specific receptor. However, cells with intermediate levels of specific receptor escape negative selection and can be found in the periphery. Under normal circumstances these cells remain tolerant, but can be activated by mechanisms which increase the number of Hb(64-76)/I-Ek complexes.

Animals↗
PubMed1998

An analysis of interferon gamma, IL-4, IL-5 and IL-10 production by ELISPOT and quantitative reverse transcriptase-PCR in human Peyer's patches.

The cytokine profiles of mononuclear cells freshly isolated from Peyer's patch (PPMC), adjacent ileal lamina propria lymphocytes (LPMC) and peripheral blood (PBMC) in children without histological evidence of gastrointestinal disease has been investigated by single-cell enzyme-linked immunoabsorbent spot forming assay (ELISPOT) and reverse transcriptase (RT)-PCR. In the blood, interferon gamma and IL-4 ELISPOTs were regularly detected albeit at low frequency (< 50/10(5) cells). IL-5 and IL-10 ELISPOTs were not seen in most patients. In Peyer's patches and lamina propria there was a dramatic increase in cytokine secreting cells of all types compared to blood, reaching a very high frequency for interferon gamma in the lamina propria (1000-3000/10(5) cells). IL-4 and IL-5 ELISPOTs were 20-100-fold less common in both PP and LPL. At all sites, cytokine secretion depended on protein synthesis and enrichment for CD4+ cells in PP increased the frequency of all cytokine-secreting cells. Quantification of messenger RNA for cytokines using RT-PCR demonstrated that IL-4 and IL-10 transcripts were significantly greater than interferon gamma transcripts in PP and in lamina propria, IL-4, IL-10 and interferon gamma transcripts were equivalent. IL-5 transcripts were not detected in most samples of PP and lamina propria. These results clearly show that cells secreting interferon gamma predominate in human PP and LPL. However the high mRNA concentrations for IL-4 and IL-10 shows that although these cells are quantitatively few, they are highly transcriptionally active.

Adolescent↗
PubMed1998

Relationship between facilitation at threshold and suprathreshold contour integration.

We reevaluate the facilitation at threshold previously reported between aligned micropatterns and assess the role of such lateral spatial interactions in suprathreshold contour integration tasks. Contrary to previous claims, we show that these interactions are phase dependent. Furthermore, they are clearly evident only for foveal viewing, are not evident for curved alignments (> 20 degrees), and do not produce any suprathreshold consequence for contrast perception. Such findings question their usefulness for contour integration of smoothly curved suprathreshold paths.

Form Perception↗
PubMed1998

A computer model to predict composition of empty body weight changes in cattle at all stages of maturity.

We developed methods to integrate two published models that partitioned gains in empty body weight (EBW) to fat and fat-free matter. These models were based on separate mathematical formulations for growing and mature cattle. We assumed that as cattle grow from birth to maturity a transition would occur at some point in the life cycle from the growing to the mature mathematical formulation. This transition point and the rate at which the transition occurs between the two mechanisms were estimated from published data. Evaluation results with data on steers that were full-fed to grow from birth to 815 kg EBW showed that the methods used to integrate the two models provided an accurate prediction of empty body composition at final slaughter. Evaluation results with full-fed growing cattle that were slaughtered at market weights suggest that partitioning of EBW gains can be fully described by the mathematical formulation used for growing cattle. However, for cattle that were restricted in growth, then realimented, the results showed that a model with a transition to the mathematical formulation for mature cattle, during the realimentation phase, accurately predicted the observed final composition. These results suggest that the integrated model would accurately predict the changes in body composition of cattle of all ages, under different systems of nutritional management.

Animals↗
PubMed1997

Immediate recovery of psychomotor function after patient-administered nitrous oxide/oxygen inhalation for colonoscopy.

BACKGROUND AND STUDY AIMS: Previous studies have shown that patients inhaling-self-administered nitrous oxide/oxygen as a sedative/analgesic medication for colonoscopy were ready to leave the endoscopy unit on average sooner than those given conventional intravenous premedication. The aim of this study was to define the time course of recovery after nitrous oxide/oxygen sedation or intravenous opiate/benzodiazepine premedication for colonoscopy. PATIENTS AND METHODS: Consecutive colonoscopy patients were randomized to receive either a 50% nitrous oxide/oxygen mixture (n = 12), or pethidine 25-50 mg and midazolam 2.5 mg (n = 15), or no sedation (n = 10). Psychomotor function was assessed by multiple-choice reaction time, hand-eye co-ordination, and letter deletion tests before and at 15-minute intervals after colonoscopy, with the assessment carried out by an observer blinded to the sedation regime. RESULTS: The mean duration and tolerance of the procedure were similar in the three study groups. Patients receiving nitrous oxide/oxygen mixture were judged (by clinical observation) to recover more quickly than those given conventional sedation (median 8 min, range 3- 25 min, vs. median 16 min, range 3-50 min). Recovery, as judged by a return to baseline in psychomotor function tests, was complete within 30 minutes in all patients receiving the nitrous oxide/oxygen mixture, compared to 50 minutes in those given conventional intravenous sedation. CONCLUSIONS: The rapid recovery observed with nitrous oxide/oxygen sedation for colonoscopy suggests that it is safe for patients to travel unescorted after the procedure. Driving may also be safe soon after nitrous oxide/oxygen sedation, but this requires further clarification.

Analgesia, Patient-Controlled↗
PubMed1997

Real-time magnetic three-dimensional imaging of flexible endoscopy.

Because of the variability of the colonic anatomy from patient to patient, colonoscopy may be technically difficult to perform and teach, and lesions may be localized inaccurately by the endoscopist. Endoscopists understandably have abandoned fluoroscopy as an adjunct because of its expense, complexity, and potential hazard. The authors have developed a novel method of magnetic imaging that gives real-time views in simulated three dimensions of the endoscope configuration and the location of its tip in the abdomen. The system is inherently safe and easy to use, although it currently requires a catheter to be inserted into the instrumentation channel. Preliminary experience suggests that this approach will be a significant help to endoscopists performing colonoscopy, particularly to those who are currently learning or less experienced.

Clinical Competence↗
PubMed1996

Endogenous altered peptide ligands can affect peripheral T cell responses.

T cells potentially encounter a large number of endogenous self-peptide/MHC ligands in the thymus and the periphery. These endogenous ligands are critical to both positive and negative selection in the thymus; however, their effect on peripheral T cells has not been directly ascertained. Using the murine allelic Hbd (64-76)/I-Ek self-antigen model, we have previously identified altered peptide ligands (APLs) which are able to stimulate some but not all TCR-mediated effector functions. To determine directly the effect of endogenously synthesized APL/MHC complexes on peripheral T cells, we used a TCR transgenic mouse which had reversed our normal antigen system, with Ser69 peptide now being the agonist and Hbd(64-76) being the APL. In this report, we show that the constitutive level of endogenous Hbd(64-76)/I-Ek complexes presented by APCs in vivo is too low to affect the response of Ser69 reactive T cells. However, by increasing the number of Hbd(64-76)/I-Ek complexes expressed by the APCs, TCR antagonism is observed for both primary T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells and T cell hybridomas. In addition, the level of the CD4 coreceptor expressed on T cells changes the response pattern to endogenously presented Hbd(64-76)/I-Ek ligand. These findings demonstrate that T cells are selected to ignore the constitutive levels of endogenous complexes they encounter in the periphery. T cell responses can be affected by endogenous APLs in the periphery under limited but attainable circumstances which change the efficacy of the TCR/ligand interaction. Thus, endogenous APLs play a role in both the selection of T cells in the thymus and the responses of peripheral T cells.

Animals↗
PubMed1996

Why is colonoscopy more difficult in women?

BACKGROUND: In our experience colonoscopy in women is more difficult than in men. A retrospective review of 2194 colonoscopies performed by a single experienced endoscopist (CBW) showed that 31% of examinations in women were considered technically difficult compared with 16% in men. METHODS: To investigate a possible anatomic basis for this finding, normal barium enema series from 183 female and 162 male patients were identified. From these barium enemas, measurements of colonic length and mobility were independently taken by two physicians who were unaware of each patient's gender. RESULTS: Total colonic length was greater in women (median, 155 cm) compared to men (median, 145 cm), p = 0.005, despite women's smaller stature (p < 0.0001). Although there were no significant differences in rectum plus sigmoid, descending, or ascending plus cecum segmental lengths, women had longer transverse colons (female median length, 48 cm; male median length, 40 cm), p < 0.0001. There were no differences in mobility of the descending colon and transverse colon between the sexes, but the transverse colon reached the true pelvis more often in women (62%) than in men (26%), p < 0.001. CONCLUSIONS: Colonoscopy appears to be a technically more difficult procedure in women. The reason for this may be due in part to an inherently longer colon.

Adolescent↗
PubMed1996

Premedication with intravenous antispasmodic speeds colonoscope insertion.

BACKGROUND: Use of antispasmodic medication prior to colonoscopy is controversial but may improve visualization of colonic mucosa and ease colonoscope insertion. METHOD: The effects on the performance of colonoscopy by premedication with the antispasmodic hyoscine n-butyl bromide were studied in a prospective, double-blind, placebo-controlled trial. Fifty-six consecutive patients were randomly assigned to receive intravenous hyoscine 20 mg (n = 29) or placebo (n = 27) in conjunction with our standard initial medications (meperidine 0.7 mg/kg and midazolam 0.03 mg/kg). Insertion and withdrawal of the colonoscope were timed, and 100 mm visual analogue scales were used to assess procedure difficulty, colonic motility, and the degree of discomfort experienced by the patients. RESULTS: In those patients receiving hyoscine, intubation time was quicker (median hyoscine, 13 minutes; median placebo, 17.5 minutes, p = 0.045) and colonic spasm less (median hyoscine, 19 mm; median placebo, 53.5 mm, p = 0.01). The procedure was considered significantly less difficult in the hyoscine group (median, 23.5 mm) compared to the placebo group (median, 50), p <0.05. No significant differences in withdrawal time or patient pain scores were found. CONCLUSIONS: Premedication with intravenous hyoscine n-butyl bromide reduces colonic spasm and in this study made colonoscope insertion significantly quicker and easier.

Adult↗
PubMed1996

Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis.

Twenty children with active ulcerative colitis were assessed before and after 8 weeks of medical therapy with 5-aminosalicylic acid (5-ASA) derivatives and corticosteroids. Local therapy was given for distal disease (seven cases); other disease was treated with oral prednisolone (1-2 mg/kg/day, maximum 40 mg). Eighteen of the children showed a clinical improvement on therapy, and complete remission of clinical disease activity by 8 weeks was seen in 17 (85%). C-reactive protein was elevated initially in 10 of 20 children and returned to normal posttreatment in all but one. Reassessment of the colon after treatment showed an improved endoscopic appearance in 15 and complete remission in eight (40%). Histological improvement was seen in 13, with full remission in only three (15%). In conclusion, remission of clinical disease activity by corticosteroid therapy in ulcerative colitis may not be accompanied by endoscopic remission and uncommonly by mucosal healing. This finding may be important prognostically because of the risk of dysplasia in long-standing persistent mucosal inflammation.

Adolescent↗
PubMed1996

A modifying locus for familial adenomatous polyposis may be present on chromosome 1p35-p36.

Mutations of the APC gene cause familial adenomatous polyposis (FAP) in humans and multiple intestinal neoplasia (Min) in laboratory mouse strains. A dominant modifying gene (Mom1), which partially suppresses the min phenotype, has been mapped to mouse chromosome 4. This region is syntenic with human chromosome 1p35-p36. The phospholipase A2 (Pla2s) locus is an excellent candidate for Mom1 and the equivalent human locus PLA2G2A is found on chromosome 1p35. It does not necessarily follow, however, than any modifier of mouse polyposis also influences human disease. In order to test whether a locus on 1p modifies FAP, subjects from 28 FAP families have been typed at microsatellite loci on this chromosome arm. The severity of their duodenal polyposis has also been assessed by endoscopy. Pedigree (lod score) linkage analysis found no evidence of a simple, dominant modifying gene, comparable with the action of Mom1 in inbred mouse strains. Given the more complex genetic and environmental interactions likely to exist in outbred human populations, it is probably more appropriate to use tests which do not specify a mode of inheritance. Using these methods of analysis, the data suggest that a locus on chromosome 1p35-p36 may influence the severity of duodenal FAP.

Adenomatous Polyposis Coli↗