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F Shanahan

Publications and source records attributed to F Shanahan.

At least 163 records · Page 9Linked to original sources
PubMed1994

Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis?

The recommended approach to the increased risk of colorectal carcinoma in ulcerative colitis has been colonoscopic surveillance rather than prophylactic colectomy. This strategy is based on the assumption that dysplastic lesions can be detected before invasive cancer has developed. We have analysed published reports on dysplasia surveillance to find out whether this assumption is valid. Ten prospective studies (1225 patients) satisfied our criteria. Of 40 patients with dysplasia-associated mass or lesion (DALM) detected, 17 (43%) already had cancer at immediate colectomy. The risks of cancer at immediate colectomy were 42% (10 of 24 patients) for high-grade and 19% (3 of 16) for low-grade dysplasia. Of 47 patients found to have high-grade dysplasia after the initial colonoscopy, 15 (32%) had cancer. 16-29% of patients with untreated low-grade dysplasia progressed to DALM, high-grade dysplasia, or cancer. Of patients with indefinite results, 28% progressed to high-grade dysplasia and 9% to cancer, so continued surveillance is essential. The risk of progression to dysplasia was only 2.4% for patients whose initial result was negative, so surveillance could perhaps be less frequent for these patients. Immediate colectomy is essential for all patients diagnosed with high-grade or low-grade dysplasia. A diagnosis of dysplasia does not preclude the presence of invasive cancer. We believe that patients should be informed about the limitations of colonoscopic surveillance so that they can take part rationally in decision-making about their management.

Colitis, Ulcerative↗
PubMed1994

Reduced signal transduction through glucocorticoid receptor in Burkitt's lymphoma cell lines.

Signal transduction through the glucocorticoid receptor (GR) was shown to be significantly reduced in Epstein-Barr virus (EBV)-positive group I Burkitt's lymphoma (BL) cell lines compared to human B-lymphocytes immortalized by EBV (LCLs). On the basis of hormone binding assays, nuclear DNA binding activity, and transactivation assays the response was reduced 5- to 10-fold. Direct sequence analysis of the expressed glucocorticoid receptor mRNA in two BL cell lines indicated that the phenotype did not result from mutation of the GR gene. By preparing a high-titer polyclonal antiserum against the t-1 region of the human GR, we further showed that the deficient GR response in BLs is largely reflected in reduced GR steady-state protein levels in BL cells compared to LCLs. However, the level of GR mRNA varies less between the BL cell lines and the LCLs. The Cp promoter of EBV which normally drives expression of the EBNA gene family in EBV-immortalized LCLs contains a functional glucocorticoid response element. Transfection of GR expression constructs to group I BL cells converted the GR response to approximately LCL levels both with respect to hormone binding and glucocorticoid-dependent transcription of a glucocorticoid-dependent promoter. A modest activation of EBNA-2 expression was seen in some such cell lines, suggesting that the lower GR response contributes to the down-regulation of EBNA expression observed in BL.

Antigens, Viral↗
PubMed1994

Low-dose 6-mercaptopurine in inflammatory bowel disease is associated with minimal hematologic toxicity.

A feared complication of therapy with 6-mercaptopurine (6-MP) is myelosuppression. To evaluate whether rigorous blood count monitoring is necessary, we prospectively followed the hematologic profiles of 57 patients with inflammatory bowel disease who were treated with low-dose 6-MP. Most patients (97%) were treated initially with a single dose of 50 mg/day and 79% never used more than 50 mg/day. Blood counts were obtained at weekly intervals over the first month, every two weeks for the second month, and monthly thereafter in the first year. Sixteen (28%) developed mild leukopenia (white blood count < 4.5 x 10(3)/mm3). No patient had a white blood cell count < 2.8 x 10(3)/mm3 and no patient developed leukopenia prior to three months of treatment. In only five patients did the leukopenia prompt a change in 6-mercaptopurine dose. Very mild thrombocytopenia (platelet count of < 145 x 10(3)/mm3) developed in three (5%) and macrocytosis (mean cell volume > 101 fl) was seen in nine (16%). In conclusion, leukopenia was not uncommon in patients treated with low-dose 6-MP, but was not clinically significant. Leukopenia occurred no earlier than three months and as late as 42 months into therapy. Thrombocytopenia was uncommon, mild, and was not associated with apparent bleeding. Macrocytosis may occur in the absence of vitamin B12 and folate deficiencies. Patients can be spared from weekly blood count monitoring when using low-dose 6-mercaptopurine treatment.

Anemia, Macrocytic↗
PubMed1994

Current concepts of the pathogenesis of inflammatory bowel disease.

Although the cause of inflammatory bowel disease is not known, the pathogenesis involves an immune-mediated tissue damage that is the result of an interaction among genetic predisposing factors, exogenous triggers and endogenous modifying influences. Multiple genes are involved and operate at the level of the immune response and at the target organ. Exogenous triggers include the enteric microflora which might stimulate the mucosal immune system in genetically predisposed individuals. Endogenous modifying factors such as the psychoneuroendocrine system have regulatory effects on the immune system and the inflammatory response, and may influence the course of the disease. While autoimmune phenomena do occur, particularly in ulcerative colitis, there is no evidence that they are directly responsible for the tissue damage. It appears more likely, particularly in Crohn's disease, that tissue injury may occur as an indirect or "bystander" effect of mucosal T-cell hyperactivation, perhaps in response to a normal enteric microbial antigen. Most of the immunologic and histologic features of Crohn's disease can be explained by the effects of T-cell derived and other cytokines on the epithelium, the local immune system, the microvasculature, and the recruitment of auxiliary effector cells such as neutrophils.

Autoimmunity↗
PubMed1994

Neurotransmitters and cytokines in CNS pathology.

In summary, we have demonstrated an in vitro model for oligodendrocyte cell death that may be relevant to events in formation of lesions in MS. It involves cell contact to oligodendrocytes with activated, viable microglia (or inflammatory macrophages), surface TNF-alpha, surface adhesion molecules, and production of NO. Precise mechanisms of TNF-alpha and ICAM-1/LFA-1 participation and the nature of the susceptibility of the oligodendrocyte are currently being studied.

AIDS Dementia Complex↗
PubMed1994

Milk tolerance in adults with ulcerative colitis.

OBJECTIVES: There has been concern in the literature and among physicians and patients that milk intolerance may contribute to disease activity in ulcerative colitis. We sought to define whether patients with ulcerative colitis have problems with milk tolerance. METHODS: 1) A questionnaire was administered to a group of gastroenterologists. 2) Consecutive unselected ulcerative colitis patients were administered a questionnaire regarding issues concerning their ingestion and tolerance of milk products. 3) Patients, and age- and ethnically matched controls, underwent lactose hydrogen breath testing at a 50-g dose, and if intolerant, returned for testing at a 12.5-g dose. RESULTS: Eighty percent of responding physicians stated that they recommend avoidance of milk products at some time to their patients. Thirteen of 29 (44%) ulcerative colitis patients were lactose intolerant compared with five of 14 (36%) controls (p = 0.57). Of 11 subjects returning for the 12.5-g test dose, only three (28%) were intolerant. Of 10 ulcerative colitis patients tested during a flare, only two (20%) were intolerant. Nineteen of 28 (66%) patients reduced or eliminated milk products from their diet, but only 10 (45%) of these patients were lactose intolerant. The discordance rate for predicting lactose tolerance status among patients was 35%. By logistic regression analysis, age (p = 0.04) and ethnicity (p = 0.006) were the only variables that were predictive of an abnormal lactose hydrogen breath test. CONCLUSIONS: There are common misperceptions among physicians and patients about lactose intolerance in ulcerative colitis. Lactose intolerance in patients with ulcerative colitis is dependent on their age and ethnicity and not any particular aspects of their disease. The proscription of milk products during flares of disease by many physicians is not supported by this study.

Adult↗
PubMed1993

Distinct associations of HLA class II genes with inflammatory bowel disease.

BACKGROUND: There are relatively few studies of HLA class II association either with Crohn's disease (CD) or ulcerative colitis (UC). The few available association studies have been carried out by serological techniques, and the results from these studies are inconclusive. METHODS: The association between HLA class II genes was studied using molecular genotyping in combination with allele-specific oligonucleotide hybridization by polymerase chain reactions. RESULTS: In UC (n = 74), we observed a positive association with the HLA DR2 allele (P = 0.008) and negative associations with the DR4 (P = 0.018) and DRw6 (P = 0.028) when compared with ethnically matched controls (n = 77). No associations were observed with any DQ alleles. In contrast, in CD (n = 95) we observed a positive association with the combination of DR1 and DQw5 alleles (P = 0.021). Furthermore, stratifying DR1 and DQw5 alleles indicated that neither allele was independently associated with CD, suggesting that the association was with the haplotype rather than either of the alleles individually. A suballele of DQw5, DQB1*0501, contributed this haplotypic association (P = 0.012). CONCLUSIONS: DR and DQ molecules firmly separate UC and CD on genetic grounds, suggesting that the contribution of the HLA class II genes to the disease susceptibility is quite different for the two disorders.

Alleles↗
PubMed1993

Production of interleukin-1 by microglia in response to substance P: role for a non-classical NK-1 receptor.

Substance P (SP) is a central and peripheral neurotransmitter which has been found in multiple sclerosis plaques. SP stimulates peripheral immune cells and may play a role in some chronic inflammatory diseases. Human peripheral monocyte/macrophages have been shown to produce the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) in response to SP. Therefore, in this study we examined rat brain microglia for the presence of SP receptors and production of IL-1 and TNF alpha in response to SP. Microglia had 4900 +/- 950 (mean +/- SE) receptors per cell fitting a two-site model. Four percent of these were high-affinity receptors with a Kd of 8.2 x 10(-8) M +/- 3.6 x 10(-8) M (mean +/- SE), and 96% of them were low-affinity receptors with a Kd of 2.1 x 10(-6) M +/- 5.2 x 10(-7) M (mean +/- SE). Competitive studies with CP 96,345 and other SP analogs demonstrate these to be non-classical NK-1 receptors. SP alone did not stimulate IL-1 or TNF alpha production. However, SP in synergy with lipopolysaccharide (LPS) quadrupled IL-1 production compared to LPS alone, but did not affect TNF alpha production. These results have implications for certain inflammatory conditions in the central nervous system.

Animals↗