PubMed Health⌕ Search

Biomedical subjects

L Simms

Publications and source records attributed to L Simms.

14 recordsLinked to original sources
PubMed2003

Lipid-induced colonic hypersensitivity in irritable bowel syndrome: the role of 5-HT3 receptors.

BACKGROUND: Irritable bowel syndrome patients demonstrate colonic hypersensitivity after duodenal lipid infusion. AIM: To investigate the role of 5-hydroxytryptamine-3 (5-HT3) receptors in this sensory component of the gastrocolonic response in irritable bowel syndrome. METHODS: Fifteen female patients with diarrhoea-predominant irritable bowel syndrome completed a trial with the 5-HT3 receptor antagonist alosetron (1 mg b.d.) or placebo (b.d.) over 15 days, followed by the alternative treatment. Each treatment period was followed by a colonic distension trial before and after duodenal lipids. Changes in colonic thresholds, tone and compliance and viscerosomatic referral pattern after lipids were compared between treatments. RESULTS: With placebo, the colonic thresholds after lipids were significantly reduced for all studied sensations, whereas, with alosetron, the thresholds were significantly reduced only for first sensation and discomfort, but not for gas and pain. The reductions in thresholds did not differ significantly between treatments, but the pain threshold after alosetron tended to be less reduced compared with placebo (P = 0.10). The effects of lipids on tone, compliance and viscerosomatic referral pattern were unaffected by alosetron relative to placebo. CONCLUSIONS: 5-HT3 receptor antagonism reduces the lipid-induced colonic hypersensitivity in irritable bowel syndrome. However, 5-HT3 receptors do not seem to be the principal mediator, but may be a cofactor for the exaggerated sensory component of the gastrocolonic response in irritable bowel syndrome.

Adult↗
PubMed2001

Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.

Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.

3' Untranslated Regions↗
PubMed2001

Budesonide for maintenance of remission in Crohn's disease.

OBJECTIVES: The primary objective was to precisely derive an estimate of the efficacy of oral budesonide for the maintenance of remission in Crohn's disease. SEARCH STRATEGY: Medline 1966-September 2000 was searched using the text and key words "oral budesonide", "Crohn's disease", "Crohn disease", and "inflammatory bowel disease". Proceedings from the American Gastroenterology Association conference (1980-1998) were hand searched. Additionally, the Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Registers were also searched. The manufacturer of oral budesonide was also contacted, as were some of the local trialists involved in the oral budesonide trials. Relevant articles were retrieved, and their reference lists were also reviewed. SELECTION CRITERIA: Randomized controlled trials of oral budesonide in which patients at entry were in remission with a Crohn's Disease Activity Index (CDAI) <= 150, and had disease restricted to the ileum and colon. DATA COLLECTION AND ANALYSIS: The primary outcome was the relative risk (RR) of relapse (and 95% confidence interval [CI]) during the 12 months of treatment, as defined by the number of patients who relapsed, and the number of patients who entered the trial. The numbers needed to treat were also derived. MAIN RESULTS: Three randomized controlled trials of oral budesonide (controlled ileal release preparation) 6 mg/day, 3mg/day and placebo for a one year period were included in the analysis. Budesonide 6 mg/day was not effective at preventing relapse of Crohn's disease over the 12 months of treatment. The relative risk of relapse was 0.89 (95% CI: 0.71-1.13) comparing budesonide 6 mg/day and placebo. Similar results were also observed in the comparison of budesonide 6 mg/day with budesonide 3 mg/day; the relative risk of relapse was 0.89 (95% CI: 0.70-1.11). The 3 mg/day dose was similarly found to be ineffective at preventing relapse during the 12 months of treatment; the relative risk of relapse was 1.00 (95% CI: 0.80-1.24). The results of the analysis of relative risk of relapse were supported by the analysis of withdrawal due to treatment failure. The relative risks for withdrawal due to treatment failure for budesonide 6 mg/day compared with placebo was 0.85 (95% CI: 0.65-1.10), for budesonide 3 mg/day compared with placebo was 0.94 (95% CI: 0.73-1.20), and for budesonide 6 mg/day compared with budesonide 3 mg/day was 0.89 (95% CI: 0.68-1.17). REVIEWER'S CONCLUSIONS: Oral budesonide therapy at 6 mg/day is not effective in preventing relapses of Crohn's disease.

Administration, Oral↗
PubMed2001

Effect of alosetron on the pharmacokinetics of alprazolam.

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP 2C9 and 3A4. Alprazolam is a short-acting benzodiazepine commonly prescribed for the treatment of anxiety disorders and a potential comedication in patients with IBS. Alprazolam is extensively metabolized by CYP3A4. This clinical study was conducted to assess the potential for a metabolic drug interaction between these two CYP3A4 substrates. This was an open-label, randomized, two-period, crossover study in 12 healthy female and male volunteers to determine the effect of concomitant administration of alosetron at the recommended dose of 1 mg p.o. bid on the pharmacokinetics of alprazolam following a single oral 1 mg dose. The results showed no effect of alosetron on the pharmacokinetics of alprazolam. Mean alprazolam AUC was 210 and 202 ng.h/mL in the absence and the presence of alosetron, respectively. Therefore, alprazolam may be safely coadministered with alosetron without the need for dosage adjustment.

Administration, Oral↗
PubMed2001

Effect of alosetron on the pharmacokinetics of fluoxetine.

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP3A4. Fluoxetine is an antidepressant that is administered as a racemic mixture of equipotent R- and S-enantiomers. Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine. This metabolite is also present as two enantiomers, of which only the S-enantiomer exhibits comparable antidepressant activity. This study was conducted to assess the potential for an effect of alosetron on the pharmacokinetics of fluoxetine. This was an open-label, two-period, nonrandomized, crossover study in 12 healthy female and male volunteers. The pharmacokinetics for both enantiomers of fluoxetine and norfluoxetine were examined following single oral doses of 20 mg fluoxetine, given alone and in combination with alosetron 1 mg twice daily for 15 days. The results showed small delays in peak concentration but no clinically significant effect of alosetron on the pharmacokinetics of S- and R-fluoxetine or S- and R-norfluoxetine. Coadministration of alosetron and fluoxetine was well tolerated by all subjects.

Administration, Oral↗
PubMed2000

Anti-tuberculous therapy for maintaining remission of Crohn's disease.

OBJECTIVES: To evaluate the effects of anti-tuberculous therapy for the maintenance of remission in patients with Crohn's disease. SEARCH STRATEGY: We searched the Inflammatory Bowel Disease Trials Register, the Cochrane Controlled Trials Register and MEDLINE from 1966 to 1998 (supplemented by a manual search of Index Medicus from 1966 to 1994). We also searched for abstracts in Gut, Gastroenterology, and The American Journal of Gastroenterology from 1990 to 1996. Date of most recent search: August 1998. SELECTION CRITERIA: Randomized trials of anti-tuberculous therapy in patients with Crohn's disease. DATA COLLECTION AND ANALYSIS: Data on the number of patients maintaining remission for each treatment group were abstracted. These data were pooled to yield Mantel-Haenszel odds ratios and numbers needed to treat for maintenance of remission in treated versus control groups. MAIN RESULTS: A total of seven randomized trials which included 355 patients were identified. Two trials used anti-tuberculous therapy (clofazimine or clofazimine, rafmpin, ethambutol, and dapsone) in combination with corticosteroids to induce remission. Maintenance therapy consisted of the anti-tuberculous agents without corticosteroids. Control patients received corticosteroids to induce remission but no anti-tuberculous therapy. The analysis of all seven trials yielded an odds ratio for maintenance of remission of 1.36 (95% CI 0.87-2. 13). Removing the two studies that were published as abstracts did not significantly affect this result: the pooled odds ratio was 1.14 (95% CI 0.71-1.83). The two trials reported as abstracts were excluded from subgroup analyses because they did not include any information on adjunct therapy. Subgroup analysis of the two trials which used steroids to induce remission yielded an odds ratio for maintenance of remission of 3.37 (95% CI 1.38-8.24). The number needed to treat was three. However, these two trials included only 89 patients, and the results should be interpreted with caution. The remaining three trials compared the combination of anti-tuberculous therapy and 'standard therapy' with 'standard therapy alone'. The pooled odds ratio was 0.70 (95% CI 0.39-1.25). REVIEWER'S CONCLUSIONS: Anti-tuberculous therapy may be effective in maintaining remission in patients with Crohn's disease when remission has been induced with corticosteroids combined with anti-tuberculous therapy. However, the results which support this conclusion come from a subgroup of only two trials with small numbers of patients and should be interpreted with caution. Use of this therapy cannot be recommended on the basis of this evidence.

Antitubercular Agents↗
PubMed2000

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer.

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.

Adenoma↗
PubMed1997

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.

Adenocarcinoma↗
PubMed1997

A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms.

BACKGROUND & AIMS: Numerous gastrointestinal tumors, notably sporadic and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias, gastric cancers, and esophageal carcinomas, manifest microsatellite instability. Recently, a transforming growth factor beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in colorectal carcinomas showing instability. One hundred thirty-eight human neoplasms (61 UC-associated, 35 gastric, 26 esophageal, and 16 sporadic colorectal) were evaluated for this TGF-beta 1RII mutation. METHODS: Whether instability was present at other chromosomal loci in these lesions was determined. In lesions manifesting or lacking instability, the TGF-beta 1RII coding region polydeoxyadenine (poly A) microsatellite tract was polymerase chain reaction amplified with 32P-labeled deoxycytidine triphosphate. Polymerase chain reaction products were electrophoresed on denaturing gels and exposed to radiographic film. RESULTS: Three of 18 UC specimens with instability at other chromosomal loci (17%) showed TGF-beta 1RII poly A tract mutation, including 2 cancers and 1 dysplasia; moreover, 2% of UC specimens without instability (1 of 43) (1 cancer), 81% of unstable sporadic colorectal cancers (13 of 16), and none of the 61 stable or unstable gastric or esophageal cancers contained TGF-beta 1RII mutations. CONCLUSIONS: Mutational inactivation of the poly A microsatellite tract within TGF-beta 1RII occurs early and in a subset of unstable UC neoplasms and commonly in sporadic colorectal cancers but may be rare in unstable gastric and esophageal tumors.

Activin Receptors, Type I↗
PubMed1996

Alterations of transforming growth factor-beta 1 receptor type II occur in ulcerative colitis-associated carcinomas, sporadic colorectal neoplasms, and esophageal carcinomas, but not in gastric neoplasms.

BACKGROUND & AIMS: Gastric cancers, sporadic colorectal cancers, and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias manifest microsatellite instability (MI); however, esophageal carcinomas rarely exhibit MI. Recently, a transforming growth factor-beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in primary colorectal carcinomas demonstrating MI. No previous studies of TGF-beta 1RII have addressed mechanisms of inactivation other than MI in human tumors; furthermore, MI-negative tumors have not been examined for TGF-beta 1RII mutation. We evaluated 138 primary human neoplasms for mutation in the poly-A microsatellite tract of TGF-beta 1RII. Additionally, a group of esophageal tumors was evaluated for the expression of TGF-beta 1RII messenger RNA (mRNA). METHODS: First, we determined whether MI was present at other chromosomal loci in these lesions. The poly-deoxyadenine (poly-A) microsatellite tract within the TGF-beta 1RII coding region was then PCR-amplified. In a group of MI-negative esophageal tumors, RT-PCR was performed to determine the expression of TGF-beta 1RII mRNA. RESULTS: Among 17 MI+ UC specimens, 3 (18%) demonstrated TGF-beta 1RII poly-A tract mutation (2 cancers and 1 dysplasia), while 2 (4%) of 44 MI-negative UC specimens (1 dysplasia and 1 tumor), and 13 (81%) of 16 MI+ sporadic colorectal cancers, contained TGF-beta 1RII poly-A mutation. No gastric or esophageal tumors contained TGF-beta 1RII mutation. Among 21 MI-negative esophageal carcinomas. 6 cases (28.5%) had TGF-beta 1RII transcripts that were low or undetectable by RT-PCR. CONCLUSIONS: Mutation within the poly-A microsatellite tract of TGF-beta 1RII occurs early in a subset of UC-neoplasms and commonly in sporadic colorectal cancers, but may be rare in MI+ gastric tumors. Diminished expression of TGF-beta 1RII mRNA in esophageal tumors suggests that mechanisms of inactivation in this gene other than MI play a role in esophageal carcinogenesis.

Colitis, Ulcerative↗
PubMed1987

A simple method for preparing prometaphase chromosomes from amniotic fluid cell cultures.

A simple method for preparing prometaphase chromosomes from amniotic fluid cell cultures is described. The technique is based upon several key steps including: (1) reduced colcemid concentration, (2) reduced exposure to trypsin-EDTA, and (3) maintaining cells in single suspension by adjusting cell concentration appropriately. Chromosomes with banding resolution up to 800 bands per haploid set can be routinely produced. The described methodology is particularly useful in defining and establishing the clinical significance of subtle structural aberrations.

Amniotic Fluid↗
PubMedDate not supplied

Learning environment: the catalyst for work excitement.

A recent study investigated the relationship between learning environment and work excitement among a group of nurses. In a secondary analysis of the original survey of 268 nurses, approximately 20% were very excited about their work. The learning environment variables (availability of learning opportunities; stimulating, motivating, challenging environment; and opportunity to work with other professionals) were found to be related to the level of work excitement among nurses. Results of this study suggest that enhancement of the learning environment can lead to higher levels of work excitement. Nurses in staff development can use the knowledge obtained in this study to assist nurses to find excitement in their work through new learning and work behaviors. The results suggest the importance of unit-based learning opportunities and flexible work groups that include other health professionals.

Adult↗