iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

Technical note: Evaluation of an ear-attached movement sensor to record cow feeding behavior and activity.

The ability to monitor dairy cow feeding behavior and activity could improve dairy herd management. A 3-dimensional accelerometer (SensOor; Agis Automatisering BV, Harmelen, the Netherlands) has been developed that can be attached to ear identification tags. Based on the principle that behavior can be identified by ear movements, a proprietary model classifies sensor data as "ruminating," "eating," "resting," or "active." The objective of the study was to evaluate this sensor on accuracy and precision. First, a pilot evaluation of agreement between 2 independent observers, recording behavior from 3 cows for a period of approximately 9h each, was performed. Second, to evaluate the sensor, the behavior of 15 cows was monitored both visually (VIS) and with the sensor (SENS), with approximately 20 h of registration per cow, evenly distributed over a 24-h period, excluding milking. Cows were chosen from groups of animals in different lactation stages and parities. Each minute of SENS and VIS data was classified into 1 of 9 categories (8 behaviors and 1 transition behavior) and summarized into 4 behavioral groups, namely ruminating, eating, resting, or active, which were analyzed by calculating kappa (κ) values. For the pilot evaluation, a high level of agreement between observers was obtained, with κ values of ≥ 0.96 for all behavioral categories, indicating that visual observation provides a good standard. For the second trial, relationships between SENS and VIS were studied by κ values on a minute basis and Pearson correlation and concordance correlation coefficient analysis on behavior expressed as percentage of total registration time. Times spent ruminating, eating, resting, and active were 42.6, 15.9, 31.6, and 9.9% (SENS) respectively, and 42.1, 13.0, 30.0, and 14.9% (VIS), respectively. Overall κ for the comparison of SENS and VIS was substantial (0.78), with κ values of 0.85, 0.77, 0.86, and 0.47 for "ruminating," "eating," "resting," and "active," respectively. Pearson correlation and concordance correlation coefficients between SENS and VIS for "ruminating," "eating," "resting," and "active" were 0.93, 0.88, 0.98, and 0.73, and 0.93, 0.75, 0.97, and 0.35, respectively. In conclusion, the results provide strong evidence that the present ear sensor technology can be used to monitor ruminating and resting behavior of freestall-housed dairy cattle. Our results also suggest that this technology shows promise for monitoring eating behavior, whereas more work is needed to determine its suitability to monitor activity of dairy cattle.

Anti tumour necrosis factor as risk factor for free perforations in Crohn's disease? A case-control study.

AIM: Although the occurrence of intestinal perforation in Crohn's disease (CD) is rare, clinical observation has led to the question whether anti tumour necrosis factor (TNF) treatment is a risk factor for free perforation. The aim of this study was to investigate the possible relation between anti-TNF treatment and occurrence of free perforation, defined as intestinal perforations leading to emergency surgery. METHOD: In this case-control study, all emergency operation reports from the period 1999-2009 of patients diagnosed with CD were checked for the presence of free perforation. These cases were compared with a sixfold larger control group derived from our CD patient database. Cases and controls were matched for age, gender, Montreal classification and surgical stage to ensure equal disease severity. Cases and controls were then compared regarding previous or current exposure to anti-TNF treatment. RESULTS: Thirteen patients underwent emergency surgery for spontaneous free perforation. Eight (62%) had been treated with anti-TNF within 5 months before the perforation. In the 78 matched controls, 29 (37%) had been or were still treated with anti-TNF. The odds for a free perforation adjusted for known confounders in two separate regression analyses were significantly higher in anti-TNF treated CD patients, albeit with a large confidence interval (OR 4.1, 95% CI: 1.1-16.0; and OR 23.0, 95% CI 2.2-238.5). CONCLUSION: This study showed a higher occurrence of free perforations in CD patients with anti-TNF therapy compared with those without anti-TNF therapy. Patients with CD and anti-TNF treatment showing acute abdominal pain must be suspected of this complication.

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer.

Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7(-181A>G). In addition, the genotype distribution of MMP-7(-181A>G) was associated with Helicobacter pylori status (chi(2) 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2(303C>T) correlated significantly with the WHO classification (chi(2) 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2(-1306C>T) polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7(-181A>G) and TIMP-2(303C>T) polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7(-181A>G) and TIMP-2(303C>T), may be helpful in identifying gastric cancer patients with a poor clinical outcome.

What is the appropriate screening protocol in Lynch syndrome?

INTRODUCTION: Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. METHODS: All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. RESULTS: A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. CONCLUSION: The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate.

Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer.

In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n = 81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer.

Ileum resection is the most predictive factor for osteoporosis in patients with Crohn's disease.

INTRODUCTION: Crohn's disease is associated with a host of factors potentially increasing the risk for osteoporosis and fractures. The aim of our study was to identify the most predictive factors for skeletal pathology in this patients. METHODS: Using a cross-sectional study design, 146 randomly selected patients with Crohn's disease of variable disease activity who were given standard therapy to control disease activity, including glucocorticoids, and who attended the outpatient clinic of the Gastroenterology Unit on regular follow-up visits were studied. Bone mineral density (BMD) measurements and lateral X-rays of the spine were performed, and biochemical parameters of bone turnover, gonadal hormones and C-reactive protein (CRP) as markers of disease activity were measured in all patients. RESULTS: There were 61 men and 85 women, with a mean age of 43 years and mean disease duration of 20 years. The majority of patients (86%) had been treated with glucocorticoids at some stage during their illness at a median dose of 7.5 mg/day, 43% were currently using these agents and 66% had undergone an intestinal resection. Twenty-one percent of patients had below-normal 25-hydroxy vitamin D levels. Osteoporosis was documented in 26% of patients, predominantly at the femoral neck, but also at the lumbar spine or at both sites; osteopenia was documented in 45% of patients. Prevalence of vertebral and non-vertebral fractures was, respectively, 6% and 12%. Ileum resection was the most predictive factor for osteoporosis: RR 3.84 (CI 1.24-9.77, p=0.018), followed by age: RR 1.05 (CI 1.02-1.08, p<0.001) and current or past glucocorticoid use: RR 1.94 (CI 0.92-4.10, p=0.08). CONCLUSION: Our data suggest that in patients with Crohn's disease, the risk of osteoporosis is best predicted by a history of ileum resection.

Endoscopic treatment of Barrett's oesophagus.

Barrett's oesophagus develops as a consequence of severe gastro-oesophageal reflux. The importance of Barrett's oesophagus lies in the small risk of developing high-grade dysplasia and subsequent adenocarcinoma. Because of poor treatment results in patients with advanced adenocarcinoma, surveillance of patients with Barrett's oesophagus for the development of dysplasia, although not uncontroversial, is widely practised in the gastroenterological community. The aim of surveillance is to detect adenocarcinoma in an early stadium where surgical cure is possible. In recent years several endoscopic treatments for both high-grade dysplasia and intramucosal adenocarcinoma have been developed. In this review some basic aspects of Barrett's oesophagus are discussed together with endoscopic treatments such as endoscopic mucosal resection, local thermal treatments and photodynamic therapy. Although surgical resection is probably the treatment of choice in fit patients, local endoscopic treatments should be considered in patients with high-grade dysplasia or intramucosal carcinoma who are unfit or unwilling to have surgery.

Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect.

BACKGROUND: In view of the high risk of developing a new primary colorectal carcinoma (CRC), subtotal colectomy rather than segmental resection or hemicolectomy is the preferred treatment in hereditary non-polyposis colorectal cancer (HNPCC) patients. Subtotal colectomy however implies a substantial decrease in quality of life. To date, colonoscopic surveillance has been shown to reduce CRC occurrence. AIMS: To compare the potential health effects in terms of life expectancy (LE) for patients undergoing subtotal colectomy or hemicolectomy for CRC. METHODS: A decision analysis (Markov) model was created. Information on the 10 year risk of CRC after subtotal colectomy (4%) and hemicolectomy (16%) and stages of CRCs detected within a two year surveillance interval (32% Dukes' A, 54% Dukes' B, and 14% Dukes' C) were derived from two cohort studies. Five year survival rates used for the different Dukes stages (A, B, and C) were 98%, 80%, and 60%, respectively. Remaining LE values were calculated for hypothetical cohorts with an age at CRC diagnosis of 27, 47, and 67 years, respectively. Remaining LE values were also calculated for patients with CRC of Dukes' stage A. RESULTS: The overall LE gain of subtotal colectomy compared with hemicolectomy at ages 27, 47, and 67 was 2.3, 1, and 0.3 years, respectively. Specifically for Dukes' stage A, this would be 3.4, 1.5, and 0.4 years. CONCLUSIONS: Unless surveillance results improve, subtotal colectomy still seems the preferred treatment for CRC in HNPCC in view of the difference in LE. For older patients, hemicolectomy may be an option as there is no appreciable difference in LE.

Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5 per cent. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial. The aim of this study was to determine the effectiveness of various surgical treatments for cancer and severe duodenal adenomatosis. METHODS: A questionnaire was mailed to the members of the Leeds Castle Polyposis Group to obtain data on patients with FAP, treated for duodenal cancer or severe duodenal adenomatosis after 1990. RESULTS: Sixty-nine patients were included. The indication for surgery was invasive cancer in 13 patients, of whom six died from metastatic disease. Fifty-six patients were initially treated for severe duodenal adenomatosis, five (9 per cent) of whom died from metastatic disease (P = 0.002). In surviving patients, adenomas recurred after ampullectomy (six of eight, at mean follow-up of 11 months), after duodenotomy with polypectomy (17 of 21, at mean 29 months) and after pancreatoduodenectomy (six of 25, at mean 47 months). None of six patients who underwent a pancreas-sparing duodenectomy had recurrence of adenoma (mean follow-up 11 months). CONCLUSION: Surgery for duodenal adenomatosis should take place before endoscopic biopsy reveals invasive cancer. Even after extensive surgical procedures, small bowel adenomas may occur, emphasizing the need for chemoprevention.

[Desmoid tumors in patients with familial adenomatous polyposis]. / Desmoïdtumoren bij patiënten met familiaire adenomateuze polyposis.

Desmoid tumours (DT) are slow-growing tumours that consist of proliferations of well-differentiated fibroblasts. Although the typical characteristics of malignant tumours, such as distant metastases, are absent, the tumours are locally aggressive and grow into neighbouring structures. The prevalence of desmoid tumours in patients with FAP is 7-12%. The lifetime risk of developing desmoid tumours is about 20%. In FAP, most tumours are intra-abdominal or located in the abdominal wall. Next to colorectal cancer, desmoid tumours are the most frequent cause of death in FAP. Possible risk factors for the development of desmoid tumours are previous surgical procedures, pregnancy, female sex, a family history of desmoid tumours, and specific mutations in the APC-gene. Both CT scanning and MRI can be used to detect the tumours. An excision biopsy is needed to establish the diagnosis. Medicinal treatment with NSAIDs is the treatment of first choice, followed by hormonal treatment (e.g., tamoxifen) in combination with NSAIDs. Both forms of treatment lead to a response in about 30-50% of the patients. Surgery is the preferred treatment for extra-abdominal tumours or tumours located in the abdominal wall. Surgical treatment of intra-abdominal tumours is only indicated in patients with obstruction of the bowel or ureter. Chemotherapy is indicated in patients with progressive desmoid tumours when non-cytotoxic treatment has failed. Radiotherapy may play a role in the treatment of irresectable extra-abdominal or abdominal wall tumours, or as adjuvant treatment of tumours with positive margins.

Ileoanal pouch function is related to postprandial pouch tone.

BACKGROUND: Functional impairments are frequently observed in patients with an ileoanal pouch. Meal ingestion increases pouch tone and motility. Little is known, however, about the influence of meal-stimulated pouch characteristics on pouch function. The aim was to characterize basal and postprandial pouch motor and sensory characteristics in relation to clinical pouch function in patients with an ileoanal pouch. METHODS: Nineteen patients with an ileoanal pouch, without faecal incontinence but with either a high stool frequency (n = 8) or an adequate stool frequency (n = 11), underwent pressure distension of the pouch, by which pouch compliance and sensitivity characteristics were assessed using an electronic barostat. A set pressure procedure was performed to assess the influence of a meal on pouch tone and motility. RESULTS: Mean(s.d.) compliance was 10(6) and 11(4) ml/mmHg in the groups with poor and adequate pouch function respectively (P not significant). Mean(s.d.) visual analogue scale scores (0-10 cm) for urge at the highest pressure of 28 mmHg were 2.3(1.0) versus 2.3(2.4) cm respectively (P not significant); those for pain were 0.8(1.0) versus 0.5(0.7) (P not significant). Postprandially mean(s.d.) pouch volume decreased by 70(24) per cent in the group with poor pouch function and 29(25) per cent in the group with adequate pouch function (P < 0.01). The frequency and amplitude of phasic pouch contractions increased significantly postprandially, but no differences in motility characteristics were observed between the two groups. CONCLUSION: In patients with uniform pouch design and follow-up after pouch construction, pouch compliance and sensitivity were no different between patients with normal and high stool frequency; however, postprandial pouch tone was increased significantly in patients with a high stool frequency.

MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

Barium enema and endoscopy for the detection of colorectal neoplasia: sensitivity, specificity, complications and its determinants.

AIM: To analyse sensitivity, specificity and complication rate of endoscopy, and barium enema for the detection of colorectal neoplasia. MATERIALS AND METHODS: A MEDLINE search was performed (1980-2000) directed at the endoscopic and radiologic literature on barium enema. Articles were selected based on the type of study, availability of sensitivity and specificity values in sizeable patient groups, and reports on complications. Sixty articles were included in the analysis. RESULTS: Endoscopy proved to have superior sensitivity for polyps in patients at high-risk for colorectal neoplasia. The role of endoscopy and radiology in average-risk screening populations is not known. Sensitivity and specificity rates ranged widely, probably due to bias. For the detection of small polyps endoscopy has superior performance, whereas sensitivity is similar for endoscopy and barium enema for the detection of larger (>1 cm) polyps and tumours. Overall, endoscopy is associated with a higher complication rate. CONCLUSION: Endoscopy is the preferred detection method in high-risk patients. The role of endoscopy and radiology in a screening setting requires evaluation. This review provides the test characteristics of endoscopy and radiology which are relevant for a cost-effectiveness analysis. Double-contrast barium enema may play an important role for screening purposes, owing to its good sensitivity for detecting larger (>1 cm) polyps and its lack of major complications. de Zwart, I. M.et al. (2001). Clinical Radiology56, 401-409.

Comparison of ileoanal pouch and rectal function measured by barostat.

The aim of this study was to compare pouch and rectal sensory and motor characteristics and to assess the influence of a meal on pouch tone and motility. Fifteen patients with an ileoanal J-pouch, with adequate pouch function and 12 healthy controls were studied. Visceral compliance was assessed using an electronic barostat by a pressure distension procedure, during which also sensitivity was scored by visual analog scales (VAS). The response to a meal was assessed during set pressure. Pouch and rectal compliance were not significantly different (9.3+/-0.7 vs 10.6+/-1.1 ml/mm Hg). VAS score for urge at 28 mm Hg was reduced in patients: 2.4+/-0.5 cm vs 4.7+/-0.9 cm in controls (P < 0.05). The postprandial decrease in intra-bag volume was more pronounced in patients (44+/-11%) than in controls (9+/-6%, P < 0.01). Postprandial phasic contractions were also more pronounced in patients. In conclusion, compliance is not significantly different between ileoanal pouch and rectum; differences in sensitivity reach significance only at high pressure. Significant differences were especially observed in the postprandial state with an increase in tone and frequency of phasic contractions in pouch patients.

How effective is extensive nonsurgical treatment of patients with clinically active Crohn's disease of the terminal ileum in preventing surgery?

BACKGROUND/AIMS: The purpose of this study is to determine the effectiveness of extensive nonsurgical management of patients with clinically active Crohn's disease of the terminal ileum and to identify parameters that could predict failure of this nonsurgical approach. METHODS: All consecutive patients hospitalized for the first time because of active Crohn's disease of the terminal ileum between 1985 and 1994 were included. Two groups of patients were defined. Patients who responded favorably to the extensive treatment protocol (group I), and patients in whom an ileocolic resection had been performed (group II). Treatment and patient characteristics were related to outcome. RESULTS: Twenty-nine (38%) of the 76 patients were treated successfully by nonsurgical management (group I) and did not have surgery until the end of follow-up (mean 8.0 years, range 3-12 years). In total, 47 patients (62%) had ileocolic resection (group II). Logistic regression analysis revealed that a longer time between onset and exacerbation of this disease, the presence of stenosis and extraintestinal manifestations were independent predictors of failure of nonsurgical treatment. CONCLUSION: Prolonged medical treatment is effective in only one third of the clinically admitted patients. It should be applied with caution particularly in patients exhibiting stenosis, extraintestinal manifestations or a known history of Crohn's disease of more than 5 years.

Nucleocytoplasmic distribution of budding yeast protein kinase A regulatory subunit Bcy1 requires Zds1 and is regulated by Yak1-dependent phosphorylation of its targeting domain.

In Saccharomyces cerevisiae the subcellular distribution of Bcy1 is carbon source dependent. In glucose-grown cells, Bcy1 is almost exclusively nuclear, while it appears more evenly distributed between nucleus and cytoplasm in carbon source-derepressed cells. Here we show that phosphorylation of its N-terminal domain directs Bcy1 to the cytoplasm. Biochemical fractionation revealed that the cytoplasmic fraction contains mostly phosphorylated Bcy1, whereas unmodified Bcy1 is predominantly present in the nuclear fraction. Site-directed mutagenesis of two clusters (I and II) of serines near the N terminus to alanine resulted in an enhanced nuclear accumulation of Bcy1 in ethanol-grown cells. In contrast, substitutions to Asp led to a dramatic increase of cytoplasmic localization in glucose-grown cells. Bcy1 modification was found to be dependent on Yak1 kinase and, consequently, in ethanol-grown yak1 cells the Bcy1 remained nuclear. A two-hybrid screen aimed to isolate genes encoding proteins that interact with the Bcy1 N-terminal domain identified Zds1. In ethanol-grown zds1 cells, cytoplasmic localization of Bcy1 was largely absent, while overexpression of ZDS1 led to increased cytoplasmic Bcy1 localization. Zds1 does not regulate Bcy1 modification since this was found to be unaffected in zds1 cells. However, in zds1 cells cluster II-mediated, but not cluster I-mediated, cytoplasmic localization of Bcy1 was found to be absent. Altogether, these results suggest that Zds1-mediated cytoplasmic localization of Bcy1 is regulated by carbon source-dependent phosphorylation of cluster II serines, while cluster I acts in a Zds1-independent manner.

Metallothionein in human gastrointestinal cancer.

Metallothionein (MT) is a small thiol-rich metalloprotein with antioxidant properties, involved in tumour pathophysiology and therapy resistance. In order to assess the contribution of MT in gastrointestinal carcinogenesis, this study examined both the MT content by radioimmunoassay and the MT localization by immunohistochemistry in pairs of neoplastic and normal-appearing human gastrointestinal tissues. In addition, the relationship between MT expression and major clinicopathological parameters was assessed. The MT concentration of gastric carcinomas and of colorectal adenomas, carcinomas, and liver metastases was found to be significantly lower than that of corresponding normal-appearing tissue. A relatively high MT content, however, was found to be associated with the villous character of colorectal adenomas and with the Dukes' stage of colorectal carcinomas, indicating a relationship between MT level and malignant potential. Immunohistochemical evaluation showed a fairly good correlation with these quantitative data. MT was found to be expressed at a low level and in a patchy pattern in the gastrointestinal neoplastic and metastatic tissues, whereas in normal-appearing gastrointestinal mucosa MT was uniformly distributed in the cytoplasm and/or nucleus of apical cells. Although in the gastric cancer patients no association was found between the MT concentration and the clinicopathological parameters, the strong MT expression in areas with intestinal metaplasia, known to have neoplastic potential, further points to a relationship between this antioxidant metalloprotein and the malignant character of cells. Gastrointestinal neoplasms are apparently accompanied by a low level and decreased expression of MT, but those with a relatively high level seem to have an increased malignant potential. Further studies will be required to determine the clinical relevance of these observations.

Laparoscopic-assisted vs. open ileocolic resection for Crohn's disease. A comparative study.

BACKGROUND: The objective of this study was to compare laparoscopic-assisted ileocolic resection for Crohn's disease of the distal ileum with open surgery in two consecutive groups of patients. METHODS: From 1995 until 1998, 48 patients underwent open ileocolic resection at the Academic Medical Center (AMC) in Amsterdam, while 30 patients had laparoscopic-assisted ileocolic resection at the Leiden University Medical Center (LUMC). Patient characteristics, perioperative course, and recovery were compared. Differences between the groups were tested using Student's t-test for independent groups and chi-square tests when appropriate. RESULTS: The open and the laparoscopic patient groups were comparable for age, gender, body mass index (BMI), prior abdominal surgery, and length of resected bowel. The conversion rate was 6.6%. Laparoscopic operating times (138+/-SD 36 min) were significantly longer than those observed in the open group (104+/-SD 34 min). Discharge was significantly earlier in the laparoscopic group than the open group (5.7 vs 10.2 postoperative days, p<0.007). Postoperative morbidity did not differ significantly between the patients treated traditionally (14.6%) and laparoscopically (10%). CONCLUSION: Compared to open surgery, laparoscopic ileocolic resection for Crohn's disease is associated with similar morbidity rates, a shorter hospital stay, and improved cosmetic results, justifying the laparoscopic approach as the procedure of choice.