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Biomedical subjects

P C Wilson

Publications and source records attributed to P C Wilson.

At least 19 recordsLinked to original sources
PubMed2006

A genome-scale assessment of peripheral blood B-cell molecular homeostasis in patients with rheumatoid arthritis.

OBJECTIVE: While rheumatoid arthritis (RA) is considered a prototypical autoimmune disease, the specific roles of B-cells in RA pathogenesis is not fully delineated. METHODS: We performed microarray expression profiling of peripheral blood B-cells from RA patients and controls. Data were analysed using differential gene expression analysis and 'gene networking' analysis (characterizing clusters of functionally inter-relelated genes) to identify both regulatory genes and the pathways in which they participate. Results were confirmed by quantitative real-time polymerase chain reaction and by measuring the levels of 10 serum cytokines involved in the pathways identified. RESULTS: Genes regulating and effecting the cell-cycle, proliferation, apoptosis, autoimmunity, cytokine networks, angiogenesis and neuro-immune regulation were differentially expressed in RA B-cells. Moreover, the serum levels of several soluble factors that modulate these pathways, including IL-1beta, IL-5, IL-6, IL-10, IL-12p40, IL-17 and VEGF were significantly increased in this cohort of RA patients. CONCLUSIONS: These results outline aspects of the multifaceted role B-cells play in RA pathogenesis in which immune dysregulation in RA modulates B-cell biology and thereby contributes to the induction and perpetuation of a pathogenic humoral immune response.

Adult↗
PubMed2006

Diversity of the Ig repertoire is maintained with age in spite of reduced germinal centre cells in human tonsil lymphoid tissue.

Humans and almost all species studied to date exhibit a decreased responsiveness to immunization and increased autoimmunity with age. While this has been observed clinically for decades, only recently has an understanding of the molecular basis for these changes begun to be appreciated. Studies of the B-cell aspects of these changes in ageing mice and the very few reports in ageing humans have not been conclusive. Here we examine the nucleotide sequence of over 1250 VH transcripts from the tonsils of individuals of various ages for changes to the VH4 immunoglobulin repertoire. An exhaustive examination of VH, DH and JH gene segment utilization revealed a remarkable similarity of the repertoires. The extent of somatic hypermutation was fully maintained or even increased by some measures into the eighth decade of life. However, we found by middle age that the representation of naïve and germinal centre B-cell subpopulations changed relative to total B lymphocytes in the tonsil. While the percentage of naïve and germinal centre B-cell subpopulations changes during the second half of life, these findings suggest that even with advancing age, humans remain capable of generating an extremely diverse Ig repertoire while maintaining a similar spectrum of Ig rearrangements once the germinal centre reaction begins.

Adult↗
PubMed2004

The management of advanced thyroid cancer.

Although the prognosis of the majority of patients with thyroid cancer is excellent there are some patients with advanced thyroid cancer in whom the prognosis is poor. Such patients include: patients with locally invasive or recurrent differentiated thyroid cancer and medullary thyroid cancer, and all patients with anaplastic cancer. The management of patients with advanced thyroid cancer is reviewed with emphasis on the role of external beam radiotherapy.

Humans↗
PubMed2001

Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease.

It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3-6 months, and even then remains incomplete.

Adolescent↗
PubMed2000

Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes.

Contrary to the general precepts of the clonal selection theory, several recent studies have provided evidence for the secondary rearrangement of immunoglobulin (Ig) genes in peripheral lymphoid tissues. These analyses typically used transgenic mouse models and have only detected secondary recombination of Ig light chain genes. Although Ig heavy chain variable region (V(H)) genes encode a substantial element of antibody combining site specificity, there is scant evidence for V(H) gene rearrangement in the periphery, leaving the physiological importance of peripheral recombination questionable. The extensive somatic mutations and clonality of the IgD(+)Strictly-IgM(-)CD38(+) human tonsillar B cell subpopulation have now allowed detection of the first clear examples of receptor revision of human V(H) genes. The revised VDJ genes contain "hybrid" V(H) gene segments consisting of portions from two separate germline V(H) genes, a phenomenon previously only detected due to the pressures of a transgenic system.

Base Sequence↗
PubMed2000

Metalaxyl and simazine toxicity to and uptake by Typha latifolia.

This research focused on the potential use of common cattails (Typha latifolia) for removing metalaxyl and simazine residues from contaminated water. Specifically, it established toxicity thresholds to the herbicide simazine and characterized the uptake and distribution of simazine and metalaxyl by the plants. Simazine tolerance levels were determined by exposing plants to a series of six concentrations (0-3.0 mg L(-1)) in aqueous nutrient media for 7 days. Metalaxyl toxicity was not evaluated because other studies indicated it was relatively nontoxic to plants. Toxicity endpoints measured included fresh mass production after 7 days of exposure and 7 days postexposure. Pesticide uptake and distribution were determined by growing plants in nutrient media amended with (14)C-ring-labeled metalaxyl (0.909 mg L(-1)) or simazine (0.242 mg L(-1)) for 1, 3, 5, or 7 days. Plants were dissected, and tissues were combusted and analyzed by liquid scintillation spectroscopy. Cattail fresh mass production was reduced 84 and 117% at 1.0 and 3.0 mg L(-1) simazine, respectively, after 7 days of exposure. Metalaxyl and simazine activity in solution was reduced 34 and 65%, respectively, after 7 days. By day 7, activity from both pesticides was detected predominantly in the leaves. Uptake of each pesticide was correlated with water uptake throughout the 7 days. These results suggest that the common cattail may be a good candidate for incorporation into a phytoremediation scheme for metalaxyl and simazine.

Alanine↗
PubMed2000

Acquired immunodeficiency syndrome-related primary cerebral lymphoma: response to irradiation.

Acquired immunodeficiency syndrome-related primary cerebral lymphoma (AIDS-PCL) is uncommon. Fourteen cases of presumed AIDS-PCL between 1986 and 1995 were reviewed retrospectively in order to characterize the natural history, and the response to radiotherapy. The median age was 38 years (range 24-65). The median interval between seropositive diagnosis of HIV and AIDS-PCL was 28 months (range 5-113). The median duration of symptoms was 2 weeks (range 0.2-12). At presentation, the Eastern Cooperative Oncology Group performance status (PS) was PS1 (2/14 patients), PS2 (6/14) and PS3 (6/14). The symptoms and signs were non-specific and depended on the site and extent of cerebral involvement. There was no characteristic pattern of brain imaging in terms of size, number, location or pattern of contrast enhancement of the cerebral lesions. Nine patients received various fractionation-dose schedules (range 8-50 Gy). Complete and partial responses were seen in 2/9 and 3/9 cases, respectively. Clinical stabilization of neurological symptoms was noted in 3/9 cases and disease progression in 1/9. The median survival times (MST) from presentation for irradiated and non-irradiated patients were 9.3 and 2.1 weeks, respectively (range 0.9-43.1). Although patient selection introduced bias, there appears to be a modest improvement in MST for treated patients. The MST with radiotherapy alone remains poor, but radiotherapy may provide palliation. For some selected patients, a prolonged response is possible.

Adult↗
PubMed1998

Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes.

During a germinal center reaction, random mutations are introduced into immunoglobulin V genes to increase the affinity of antibody molecules and to further diversify the B cell repertoire. Antigen-directed selection of B cell clones that generate high affinity surface Ig results in the affinity maturation of the antibody response. The mutations of Ig genes are typically basepair substitutions, although DNA insertions and deletions have been reported to occur at a low frequency. In this study, we describe five insertion and four deletion events in otherwise somatically mutated VH gene cDNA molecules. Two of these insertions and all four deletions were obtained through the sequencing of 395 cDNA clones (approximately 110,000 nucleotides) from CD38+IgD- germinal center, and CD38-IgD- memory B cell populations from a single human tonsil. No germline genes that could have encoded these six cDNA clones were found after an extensive characterization of the genomic VH4 repertoire of the tonsil donor. These six insertions or deletions and three additional insertion events isolated from other sources occurred as triplets or multiples thereof, leaving the transcripts in frame. Additionally, 8 of 9 of these events occurred in the CDR1 or CDR2, following a pattern consistent with selection, and making it unlikely that these events were artifacts of the experimental system. The lack of similar instances in unmutated IgD+CD38- follicular mantle cDNA clones statistically associates these events to the somatic hypermutation process (P = 0.014). Close scrutiny of the 9 insertion/deletion events reported here, and of 25 additional insertions or deletions collected from the literature, suggest that secondary structural elements in the DNA sequences capable of producing loop intermediates may be a prerequisite in most instances. Furthermore, these events most frequently involve sequence motifs resembling known intrinsic hotspots of somatic hypermutation. These insertion/deletion events are consistent with models of somatic hypermutation involving an unstable polymerase enzyme complex lacking proofreading capabilities, and suggest a downregulation or alteration of DNA repair at the V locus during the hypermutation process.

Amino Acid Sequence↗
PubMed1991

Neuroblastoma stage IV-S: a heterogeneous disease.

Eighteen patients were diagnosed and treated for Stage IV-S neuroblastoma at The Hospital for Sick Children, Toronto between January 1971 and December 1988. All patients were 6 months of age or younger at diagnosis. Nine patients (50%) have remained disease free with a mean follow-up of 9.3 years. Of the seven patients under 6 weeks of age at presentation, four presented in the early neonatal period and died, three due to mechanical complications related to progressive disease, and one due to late recurrence. The remaining three patients under 6 weeks of age, two of whom had skin involvement at diagnosis, are alive and disease free. Six of the 11 patients over 6 weeks of age at presentation survived, combined modality therapy (CMT) being more effective than single modality treatment. N-myc was studied from tumor tissue at diagnosis in four patients and was amplified in three (25x, 25x, 100x), all of whom had late disease progression and died. The patient with a single gene copy has no evidence of disease 24 months following diagnosis. Our study confirms the heterogeneity described in this clinically defined group of patients. Because of it, management of Stage IV-S neuroblastoma cannot be uniform and until further development of a subclassification, or a reclassification based on molecular biologic markers is developed, pediatric oncologists will regularly be confronted with a decision whether or not to treat a newly presenting patient that fits into the clinical classification IV-S.

Adrenal Gland Neoplasms↗
PubMed1991

Extrarenal Wilms' tumor: staging, treatment, and prognosis.

Extrarenal Wilms' tumors are rare and have mainly been the subject of isolated case reports. This retrospective evaluation of 34 patients suggests a clinical course very similar to that of renal Wilms' tumor. While clinical presentation varies according to the extrarenal localization, investigations to determine the size of the primary tumor (T), regional lymph node involvement (N), and the occurrence of distant metastasis (M) are very similar, ie, chest x-ray, abdominal ultrasound (US), and computed axial tomographic (CAT) scan of the abdomen and chest. Stage grouping according to the pathologic TNM classification showed stage I in 30%, stage II in 10%, stage IIIa in 34%, stage IIIb in 23%, and stage IVa in 3%; four patients could not be staged. Evaluation of therapy and survival indicate the need for postoperative chemotherapy (CT) to all patients, while the same data suggest that the drugs used for renal Wilms' tumor are equally effective for extrarenal Wilms' tumor. Radiotherapy (RT) probably should be reserved for those patients with unresectable gross residual disease and for metastatic disease. The radiation dose used in the reviewed cases varied from 2,000 to 5,000 cGy. However, recent experience suggests that high doses are not justified in renal Wilms' tumor. The estimated overall 2-year survival of the 34 patients is 82% (95% confidence interval, 63% to 92%).

Adolescent↗
PubMed1989

Effects of misoprostol on histamine-related gastric secretion in man.

Misoprostol, a prostaglandin E1 analogue was administered orally to male volunteers in doses of 50, 100, 200 and 400 mcg and its effects on gastric secretion compared with those observed following placebo. All doses significantly inhibited basal acid secretion by up to 98% and also inhibited histamine-stimulated secretion during the first 60 minutes of stimulation. Only the 50 mcg dose did not cause a significant reduction in acid output over the entire 2 hour period of histamine stimulation. The effect on gastric secretory volume was much less than that on acid, and in general the reductions were not statistically significant. Pepsin concentration was reduced during basal secretion only. Misoprostol is a potent inhibitor of basal acid secretion and moderately inhibits histamine-stimulated acid secretion with a duration of action of at least three hours following drug ingestion.

Dose-Response Relationship, Drug↗
PubMed1986

Intestinal transport of zinc and folic acid: a mutual inhibitory effect.

Recent observations suggest an inverse relationship between folic acid intake and zinc nutriture and indicate an interaction between folic acid and zinc at the intestinal level. To define that interaction, we designed in vivo and in vitro transport studies in which folic acid transport in the presence of zinc, as well as zinc transport in the presence of folic acid was examined. These studies show that zinc transport is significantly decreased when folate is present in the intestinal lumen. Similarly folic acid transport is significantly decreased with the presence of zinc. To determine whether this intestinal inhibition is secondary to zinc and folate-forming complexes, charcoal-binding studies were performed. These studies indicate that zinc and folate from complexes at pH 2.0, but that at pH 6.0, these complexes dissolve. Therefore, our studies suggest that under normal physiological conditions a mutual inhibition between folate and zinc exists at the site of intestinal transport.

Animals↗
PubMed1984

Early evaluation of coronary artery bypass grafts: CT or selective angiography.

A prospective study was performed in 27 patients to compare the value of computed tomography and selective angiography in assessing coronary artery graft patency in the early post-operative period. The sensitivity of CT to graft patency was 85% with no falsely patent determinations. Dynamic CT was not found useful in predicting graft stenosis. There were no complications associated with CT studies, and two related to selective angiography. It is concluded that CT is the procedure of choice for graft evaluation in the early post-operative period; but that angiography is mandatory for the assessment of late symptom recurrence. A review is made of the results described in previous series.

Blood Vessel Prosthesis↗