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There is evidence that vitamin D receptor (VDR)-mediated action of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) could limit colon cancer cell growth particularly when induced by activation of the epidermal growth factor receptor (EGFR). We therefore wanted to ascertain the relevance of this observation for human colon cancerogenesis. Utilizing in situ mRNA hybridization and immunocytochemical techniques, we analyzed cell-specific expression of VDR and EGFR in normal and malignant human colonic mucosa. In normal mucosa, VDR positivity is weak and observed only in a small number of luminal surface colonocytes. In contrast, EGFR expression at a relatively high level is also found in cells at the crypt base. The number of VDR-positive colonocytes increases remarkably during tumor progression. It reaches its maximum in low grade adenocarcinomas and returns to lower levels in highly malignant cancers. In both low- and high grade carcinomas, the great majority of tumor cells contain the EGFR message. The relative abundance of EGFR over VDR in normal mucosa and in high grade carcinomas would create a situation in which mitogenic effects from EGFR activation are only ineffectively counteracted by signaling from 1 alpha,25-(OH)2D3/VDR. In contrast, in well to moderately differentiated tumors, upregulation of VDR could retard further tumor progression. [ABSTRACT FROM AUTHOR]

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.

Whatman FTA® cards provide the most reliable method for DNA storage and extraction, however, the literature lacks reports on the epigenetic analysis of FTA card-derived tumor DNA. Therefore, this study aimed at demonstrating that punches from colonic adenoma samples preserved on FTA filter cards are suitable for methylation analysis by real-time methylation-specific PCR (MSP). Genomic DNA was isolated from a total of 40 sporadic colorectal adenoma samples stored on FTA cards for a median of 59.60 (range 48-72) months. After bisulfite treatment, deaminated DNA was analyzed by SYBR Green real-time MSP using primers specific for methylated and unmethylated promotor sequences of the secreted frizzled-related protein 1 (SFRP1) gene. Amplifiable DNA could be isolated from all FTA card punches while SFRP1 promotor methylation was present in 34/40 (85.0%) colorectal adenomas. Our results indicate that genomic DNA isolated from colonic tumor samples preserved on FTA cards is suitable for downstream methylation detection methodologies such as MSP even after prolonged storage periods., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The abundance of OATP4A1 in colorectal cancer (CRC) might be related to tumor progression. This was studied by immunohistochemistry on paraffin-embedded samples obtained from 178 patients (43 patients with a relapse within 5 y) with early-stage CRC. Positivity for OATP4A1 in tumor cells and noncancerous mucosal cells was proved by double-immunofluorescence staining with antibodies against OATP4A1 and keratin 8, whereas antibodies against appropriate CD markers were used to identify immune cells. Automated microscopic image analysis was used to measure the percentage of OATP4A1-positive cells and OATP4A1 staining intensity in tumor, immune, and adjacent normal-looking mucosal cells separately, as well as in the mucosal and immune cells of 14 nonmalignant tissue samples. In CRC the percentage of OATP4A1-positive cells, but not staining intensity, was significantly higher in tumor and mucosal cells adjacent to the tumor compared to the mucosa of nonmalignant samples (P<0.001 each). No difference was registered between immune cells in malignant and nonmalignant samples. Importantly, high levels of OATP4A1 in immune (odds ratio, 0.73; confidence interval, 0.63-0.85; P<0.001), and tumor cells (odds ratio, 0.79; confidence interval, 0.69-0.91; P<0.001) are significantly associated with a low risk of recurrence and also significantly enhance the discriminative power of other clinical parameters [such as International Union Against Cancer (UICC), adjuvant therapy, localization of the primary tumor] of the risk of relapse (receiver operating characteristics analysis; P=0.002). Using an advanced digital microscopic quantification procedure, we showed that OATP4A1 abundance is negatively associated with tumor recurrence in early-stage CRC. This digital scoring procedure may serve as a novel tool for the assessment of potential prognostic markers in early-stage CRC.

Background: During the last 30 years a threefold increase in the number of overweight children has been reported in Western countries. More than 15% of adolescents have a body mass index (BMI) higher than the 95th percentile. The use of surgical strategies in adolescent patients is still controversial due to the impact on the continuing maturing process. Laparoscopic adjustable gastric banding (LAGB) is considered a minimal invasive procedure that does not alter the physiological behavior of the bowel and has already shown promising results in short-term studies., Methods: Between 1998 and 2004, 50 adolescent patients above the 99.5th age- and gender-adjusted growing percentile were treated with LAGB. The surgical procedure was performed at three highly experienced centers for bariatric surgery. Mean age was 17.1 ± 2.2 years (range = 9-19 years) at the time of surgery. Follow-up investigations were performed in the outpatient clinic of the treating hospitals. Psychological changes were analyzed using the BAROS questionnaire., Results: The mean BMI decreased from 45.2 ± 7.6 kg/m(2) at the time of surgery to 38.3 ± 6.2 kg/m(2) 1 year after surgery, 31.5 ± 6.6 kg/m(2) after 3 years, and 27.3 ± 5.3 kg/m(2) after 5 years. Mean excessive weight loss was 49.7 ± 29.2, 76.8 ± 27.5, and 92.6 ± 24.5% at 1, 3, and 5 years after surgery. Quality of life showed a further significant improvement between 3 and 5 years after surgery (BAROS: 5.5 ± 1.9 increased to 6.3 ± 2.2, p = 0.01). All preoperative comorbidities resolved in patients with a functional band after 5 years of follow-up., Conclusion: LAGB shows promising results in the long-term follow-up with continuous weight loss in patients with a functional band. Nevertheless, most of the weight loss is within the first 3 years after surgery. Thereafter, further weight reduction is about 10% over the following 2 years. Perioperative comorbidities resolve within the first 5 years after treatment.

Aim: To assess long-term efficacy of initially successful endo-sponge assisted therapy., Methods: Between 2006 and 2009, consecutive patients who had undergone primary successful endo-sponge treatment of anastomotic leakage following rectal cancer surgery were enrolled in the study. Patients were recruited from 6 surgical departments in Vienna. Clinical and oncologic outcomes were assessed through routine endoscopic and radiologic follow-up examination., Results: Twenty patients (7 female, 13 male) were included. The indications for endo-sponge treatment were anastomotic leakage (n = 17) and insufficiency of a rectal stump after Hartmann's procedure (n = 3). All patients were primarily operated for rectal cancer. The overall mortality rate was 25%. The median follow-up duration was 17 mo (range 1.5-29.8 mo). Five patients (25%) developed a recurrent abscess. Median time between last day of endo-sponge therapy and occurrence of recurrent abscess was 255 d (range 21-733 d). One of these patients was treated by computed tomography-guided drainage and in 3 patients Hartmann's procedure had to be performed. Two patients (10%) developed a local tumor recurrence and subsequently died., Conclusion: Despite successful primary outcome, patients who receive endo-sponge therapy should be closely monitored in the first 2 years, since recurrence might occur.

Background: A cross-sectional study was performed on a cohort of colorectal cancer (CRC) patients to reveal any influence of age, gender, and subsite on grades of malignancy., Patients and Methods: Data from histopathological grading according to WHO criteria were pooled into groups of low-grade (well and moderately differentiated) and high-grade (poorly and undifferentiated) cancer and analyzed for associations., Results: In general, women with CRC were significantly older than men (p<0.05). In particular, women with high-grade cancer in the proximal and distal colon had a median age of 75 years and were thus 10-15 years older (p<0.01 and p<0.05, respectively) than their male counterparts. In contrast, high-grade rectal cancer developed in both genders around the early age of 60 years., Conclusion: Women are protected from more aggressive cancer in the colon though not in the rectum until well after menopause. This likely reflects the differential sensitivity of the mucosa at these sites against the anticancer effects triggered by activation of estrogen receptor-beta.

There is a growing body of evidence that disturbed circadian clock gene expression is associated with tumor development and tumor progression. Based on our initial experiments demonstrating decreased period 1 (Per1) expression in colon cancer, we evaluated clock gene and estrogen receptor (ER) alpha/beta expression in colon cancer cells of primary colorectal tumors and adjacent normal colon mucosa (NM) by real-time RT-PCR. Analysis of gene expression in G(2) and G(3) colorectal tumors revealed a decrease of Per1 mRNA compared with paired NM (G(2): 0.52-fold; P = n.s. and G(3): 0.48-fold; P = 0.03). A significant gender specific difference of Per1 expression was observed in G(2) tumors as compared with NM (female: 0.38-fold; P = 0.004 vs. male: 0.73-fold; P = n.s.). Expression of CLOCK was significantly elevated in G(2) tumors of male patients (1.63-fold, P = 0.01). The expression of ER-beta was significantly decreased in G(2) and G(3) tumors (G(2): 0.32-fold; P = 0.003 and 0.27; P = 0.001). No significant gender specific differences of ER-beta reduction in tumors were observed. A significant correlation between the decrease of Per1 and ER-beta in colorectal tumors (r = 0.61; P < 0.001) was found. No changes in gene expression were detected for ER-alpha and Per2. Our data demonstrate a correlated decrease of Per1 and ER-beta in colorectal tumors, mediated probably by epigenetic mechanisms. The observed gender differences in the expression of CLOCK and Per1 in G(2) tumors might suggest a gender-specific, distinctive role of the cellular clock in colorectal tumorigenesis.

Background: Osteopontin (OPN) is a multifunctional matrix glycoprotein associated with bone metabolism and has been linked to chronic inflammation, insulin resistance, and atherosclerosis. Diet-induced weight loss decreases elevated OPN concentrations in obese patients. The aim of the current study was to investigate the role of OPN after bariatric surgery, where not only improvements of chronic inflammation, insulin resistance and comorbidities, but also malabsorption and altered bone metabolism have been reported., Methods: OPN plasma concentrations were determined in 31 morbidly obese patients (5 men, 26 women, BMI 46.2+/-7.1 kg/m2, age 41+/-11 years; mean+/-SD) before and 18 months after bariatric surgery, together with parameters of bone metabolism and inflammation., Results: OPN concentrations increased by +20.3+/-26.6 ng/ml (mean+/-SD, p<0.01), concomitant to a weight loss of -38+/-22 kg, and a decrease in BMI by -13.1+/-7.7 kg/m2 (both p<0.01). HOMA-index improved from 5.2+/-3.4 to 1.5+/-1.0 (p<0.01). Calcium concentrations slightly decreased, and phosphate increased (-0.06+/-0.13 mmol/l and +0.08+/-0.16 mmol/l, respectively; both p<0.05), while 25-OH-Vitamin D3 remained unchanged and PTH tended to increase (+5.1+/-14.0 pg/ml, p=0.054). Monocyte chemoattractant protein 1 and interleukin 18 were significantly decreased and associated with HOMA both before and after bariatric surgery. DeltaOPN was correlated with DeltaPTH, but not with other parameters., Conclusions: OPN plasma concentrations increased concomitant to weight loss after bariatric surgery, which was independent from an improvement of insulin sensitivity and a decrease of inflammatory markers. Further studies are needed to differentiate whether these changes in bone metabolism after bariatric surgery are secondary to calcium deficiency or an adaptation to weight loss.

Background: Ghrelin and obestatin are derived from the same gene but have different effects: Ghrelin stimulates appetite, and previous-albeit inconsistent-data show that obestatin may be involved in satiety. The present study was designed to test the hypothesis that Roux-en-Y gastric bypass (RYGB) surgery and/or the weight loss that reliably results from this procedure would alter levels of ghrelin and obestatin and ghrelin/obestatin ratios in a cohort of morbidly obese women., Methods: This is a longitudinal follow-up study in 18 morbidly obese women (mean weight 131.2 kg, mean body mass index [BMI] 47.4). Clinical parameters and fasting serum concentrations of ghrelin, obestatin, triglycerides, low-density lipoprotein cholesterol, glucose, and insulin were measured before and 2 years after RYGB surgery, which was associated with body weight reductions of 41.5 +/- 11.6 kg (mean 62.5% excess weight loss)., Results: Ghrelin concentrations (-12%, p = 0.022) and ghrelin/obestatin ratios (-14%, p = 0.017) were lower after surgery than before, while obestatin levels did not change. Changes in ghrelin concentrations correlated with changes in insulin levels (r = 0.45, p = 0.011). Most cardiovascular risk factors studied improved postsurgically (p < 0.01)., Conclusion: In contrast to previous weight loss studies involving gastric banding, ghrelin levels decreased and obestatin levels remained stable after massive weight loss in long-term follow-up. The favorable gastrointestinal hormone profiles observed are likely to contribute to the long-term weight loss success rate attributed to RYGB.

Background: Gastric sleeve resection was initially planned as the first step of bilio-pancreatic diversion with duodenal switch but it continues to emerge as a restrictive bariatric procedure on its own. We describe intermediate results in a series of 126 laparoscopic sleeve gastrectomies (LSG) compiled from three bariatric centers in eastern Austria., Methods: The stomach was laparoscopically reduced to a "sleeve" along the lesser curvature over a 48-Fr bougie. Special attention was placed on complete resection of the gastric fundus., Results: After a mean follow-up of 19.1 months, patients had lost between 2.3 and 27 kg/m(2) or between 6.7% and 130% of their excessive weight. Sixty four percent of the patients lost >50% of their excess weight within an average of 20 months. Seven percent of the patients had an excess weight loss <25% and were therefore considered as failures. The only major surgical complication was leakage of the staple-line needing revision (three times). There were no operative mortalities., Conclusion: The final place of LSG in bariatric surgery is still unclear, but our results and those of others show that LSG can be a viable alternative to established procedures.

Background: Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are cosecreted in the same enteroendocrine L-cells of the gut and reported to inhibit food intake additively. However, findings in human studies regarding these peptides are controversial. The aim of this study was to analyze the relationships between fasting PYY, GLP-1, and weight status in morbidly obese patients before and after surgically induced weight loss., Methods: Fasting GLP-1, PYY, glucose, and insulin concentrations; blood pressure; and body-mass index (BMI) were determined in 30 morbidly obese adults (mean BMI 45.8, mean age 40 years) before bariatric surgery [Roux-en-Y gastric bypass (RYGB): n = 19; gastric banding (GB): n = 11] and after weight loss (mean 50% excess weight loss) in the course of mean 2 years., Results: GLP-1 concentrations decreased (mean -20 pg/ml; mean -38%; p = 0.001) and PYY concentrations increased (mean +19 pg/ml; mean +19%, p = 0.036) after bariatric surgery. The weight loss and changes of GLP-1 were significantly (p < 0.05) more pronounced after RYGB as compared to GB, whereas the changes of PYY did not differ significantly between the patients who had undergone RYGB or GB., Conclusions: In morbidly obese adults reducing their weight by bariatric surgery, fasting PYY levels increased and GLP-1 concentrations decreased independently of each other. Therefore, the relationship between PYY and GLP-1 seems more complicated than might be anticipated from animal and in vitro studies.

Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells.

Leakage and fistulization of the gastro-jejunostomy have been the major drawback of Roux-en-Y gastric bypass (RYGBP) surgery. Most authors agree that operative treatment is the mainstay of therapy in patients with signs of sepsis. However, intestinal contents causing localized infection may impede healing of sutured leaks in some patients, and fistulas develop. Because the anastomosis cannot be disconnected or exteriorized for anatomical reasons, other forms of treatment have to be applied. The following case-reports describe a technique with implantation of coated self-expanding stents. Leakage of the gastro-jejunostomy occurred in one patient 3 days after RYGBP and resulted in formation of a fistula. A fistula developed in a second patient 63 days after RYGBP. Coated self-extending stents were implanted endoscopically in both patients on postoperative days 19 and 67. Enteral nutrition could be started 6 days later. Stents were removed 2 months after implantation without problems. Weight loss and quality of life 7 and 21 months after stent removal have been excellent in both patients. Implantation of coated self-expanding stents was an effective and minimally invasive option for gastro-jejunal anastomotic fistulas after RYGBP where surgical repair was not possible. In these cases, application of stents allows septic source control without any other intervention.

Background: Morbid obesity is associated with insulin resistance (IR), type 2 diabetes, lipid abnormalities, and hypertension. The association of obesity with increased androgen production and low concentrations of sex hormone-binding globulin (SHBG) in women has been demonstrated as well as a strong association of androgens with markers of inflammation such as high-sensitive C-reactive protein (hsCRP). Because weight loss results in a significant decrease in cardiovascular risk factors, IR and inflammation, we questioned a possible interrelationship between androgens, IR and inflammation in a prospective study with 43 morbidly obese female patients undergoing bariatric surgery., Methods: SHBG, dehydroepiandrosterone-sulfate (DHEA-S), and insulin were measured by ELISA, cortisol by fluorescence polarization immunoassay, androstendione by RIA, and testosterone by electrochemiluminescence immunoassay. The free androgen index (FAI) was calculated as the total testosterone/SHBG ratio. High sensitivity assays were used to obtain concentrations of fasting hsCRP, Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha)., Results: Weight loss resulted in a significant increase in SHBG (17+/-12 vs 70+/-30 nmol/l, P<0.0001). Serum concentrations of androstendione, total testosterone, DHEA-S and the FAI decreased significantly (2.05+/-0.78 vs 1.40+/-0.54 ng/ml, P<0.0001; 1.88+/-0.84 vs 1.16+/-0.57 nmol/L, P<0.0001; 1.72+/-0.86 vs 1.49+/-0.78 microg/ml, P<0.01; 0.15+/-0.10 vs 0.02+/-0.01, P<0.0001; respectively). Preoperatively and postoperatively, no association between androgens and IR, chronic subclinical inflammation and lipid parameters could be observed., Conclusion: Massive weight loss induced by bariatric surgery is associated with a significant reduction of androgen concentrations but not related to the concomitant decline of chronic inflammation, IR, glucose and lipid abnormalities in premenopausal morbidly obese women.

Background: Morbid obesity is a rising problem in adolescents in the industrial nations. Up to 25% of children have a body mass index (BMI) higher than the 85th age- and sex-adjusted percentile. Obesity in youth is associated with increased risk for morbidity and mortality in adulthood. In addition, these patients suffer from psychological problems and decreased quality of life. Bariatric procedures have shown effective long-term results in adults, but they are still discussed controversially in adolescent patients., Methods: Between 1998 and 2004, 50 adolescent patients with a mean age of 17.1+/-2.2 years (range 9-19 years) underwent laparoscopic adjustable gastric banding (LAGB) in Austria. The psychological changes were analyzed by using Moorehead-Ardelt/BAROS questionnaire., Results: The mean BMI decreased from 45.2+/-7.6 kg/m2 at time of surgery to 32.6+/-6.8 kg/m2 after a mean follow-up of 34.7+/-17.5 months. The mean excess weight loss was 61.4+/-35.5%. Most of the adolescents showed remarkable improvements in their quality of life. The outcome was regarded as "excellent or very good" in 32 patients, "good" in 12 patients and "fair" in 5 patients. Only one patient noticed no alterations after surgery. Two-thirds of the preoperative co-morbidities resolved, and one-third improved during follow-up. Except for one port dislocation, no peri- or postoperative complications arose., Conclusion: LAGB is an effective and attractive treatment option in very carefully selected obese adolescents, because of its adjustability and the preservation of the gastrointestinal passage. The majority of patients showed a remarkable improvement in their quality of life.

Background: Morbid obesity is associated with insulin resistance (IR), chronic inflammation and premature atherosclerosis. Since vascular inflammation may contribute to the increased risk of cardiovascular morbidity and mortality of these patients, we studied circulating Interleukin-18 (L-18) and monocyte-chemoattractant-protein-1 (MCP-1) levels in 37 patients with morbid obesity before and after significant weight loss induced by bariatric surgery and their preoperative and postoperative associations with C-reactive protein (CRP) and IR-associated factors., Methods: High sensitivity assays were used to measure concentrations of fasting CRP, IL-18 and MCP-1. Differences between patients before and after bariatric surgery were analyzed by Student's paired t-test. To investigate the associations of the observed reductions of values, delta of parameters were calculated and preoperative, postoperative and delta data were tested by univariate and multivariate linear regression., Results: After a mean follow-up period of 26.5 months and a massive weight loss of 35 kg induced by bariatric surgery, circulating IL-18 levels decreased by 37% (P<0.001) and circulating MCP-1 levels by 47% (P<0.001). Multiple linear regression of delta values of IL-18 showed that only 2-hour glucose (P=0.008) remained independently and significantly associated with IL-18, whereas multiple linear regression analysis of delta values of MCP-1 revealed that only delta of HOMA-IR (P<0.001) remained independently and significantly associated with MCP-1, respectively., Conclusions: Because both biomarkers have been shown to play an important role in the development and progression of atherosclerosis, the observations presented in this study could be of clinical relevance for morbidly obese patients undergoing bariatric surgery.

Background: Although gastric bands are safe and effective devices, severe late complications may develop in rare cases., Patients: 3 patients were treated for complete dysphagia after slippage of gastric bands. 2 of the patients were admitted for severe dehydration, 1 of whom developed cerebral venous infarction. Ischemia of the gastric pouch occurred in 1 patient., Results: All 3 patients survived after successful medical therapy and surgical removal of the bands. Bariatric reoperations were performed in 2 patients (gastric sleeve resection, gastric bypass)., Conclusion: Complete dysphagia on the basis of band slippage represents a life-threatening acute event, which may occur even years after implantation. Patients and doctors should be informed about this long-term risk of gastric banding.

1,25-dihydroxyvitamin D(3) has anti-mitotic, pro-differentiating, and pro-apoptotic activity in tumor cells. We demonstrated that the secosteroid can be synthesized and degraded not only in the kidney but also extrarenally in intestinal cells. Evaluation of 1,25-dihydroxyvitamin D(3)-synthesizing CYP27B1 hydroxylase mRNA (real-time PCR) and protein (immunoblotting, immunofluorescence) showed enhanced expression in high- to medium-differentiated human colon tumors compared with tumor-adjacent normal mucosa or with colon mucosa from non-cancer patients. In high-grade undifferentiated tumor areas expression was lost. Many cells co-expressed CYP27B1 and the vitamin D receptor. We suggest that autocrine/paracrine antimitotic activity of 1,25-dihydroxyvitamin D(3) could prevent intestinal tumor formation and progression.

Objective: To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome., Research Methods and Procedures: Thirty-seven morbidly obese patients (4 men; BMI, 48 +/- 7 kg/m(2); range, 42 to 53 kg/m(2)), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 +/- 5 months postoperatively., Results: Weight loss significantly reduced circulating plasma TF (314 +/- 181 vs. 235 +/- 113 pg/mL, p = 0.04), coagulation factor VII (130 +/- 22% vs. 113 +/- 19%, p = 0.023), and prothrombin fragment F1.2 (2.4 +/- 3.4 vs. 1.14 +/- 1.1 nM, p = 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r = 0.56; p = 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 +/- 141.6 vs. 176.2 +/- 58.2, p < 0.001) and TF decrease after gastroplasty (DeltaTF: 164.7 +/- 51.4 vs. -81 +/- 31 pg/mL, p = 0.02) were significantly higher in obese patients with impaired glucose tolerance than in patients with normal glucose tolerance., Discussion: Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity.

In patients operated on for severe acute pancreatitis (SAP), the factors determining outcome remain unclear. From 1986 to 1998 a total of 340 patients with a diagnosis of SAP and in need of operative treatment were admitted to the intensive care unit (ICU) of a university hospital and a secondary care hospital. The mean APACHE II score on the day of admission was 16.1 (range 8-35). All patients required operative therapy. Among the 340 patients, 270 (79.4%) had to be reoperated: 196 patients (72.6%) underwent operative revisions on demand, and 74 (27.4%) patients had preplanned reoperation. The overall mortality was 39.1% (133 patients). Septic organ failure in 126 patients (37.1%) and myocardial infarction or pulmonary embolism in 7 patients (2%) were the causes of death. The patient's age (p < 0.0002), APACHE II scores at admission (p < 0.0001), presence or development of (single or multiple) organ failure (p < 0.002), infection (p < 0.02) and extent (p < 0.04) of pancreatic necrosis, and surgical control of local necrosis (p < 0.0001) significantly determined survival. SAP that requires surgical treatment is associated with high in-hospital mortality. Surgical control of local necrosis is the precondition for survival. Advanced age of the patient, high APACHE II score at admission, development of organ failure, and the extent and infection of pancreatic necrosis influence the outcome.

Background and Aims: Most colorectal carcinomas develop from preformed adenomas, but only a minority of adenomas undergo malignant transformation. The clinical significance of polyps of size < 0.5 cm is controversial. The primary goal of this study was to assess the independent risk factors of adenoma and patient characteristics associated with advanced pathological features (APF; i.e. high-grade dysplasia or invasive carcinoma) in colorectal adenomas. A secondary goal was to assess the malignant potential of adenomas with a diameter of < 0.5 cm., Patients and Methods: Patients who underwent total colonoscopy at our Medical Department between 1978 and 1996 and had at least one colorectal adenoma were considered for this study. Patients with a history of colorectal cancer, prior polypectomy or colorectal surgery were excluded. A total of 7590 adenomas removed from 4216 patients were included in this analysis. Logistic regression analysis was used to study the impact of different adenoma and patient characteristics on the risk of APF., Results: Size proved to be the most important risk factor for APF. The percentage of adenomas with APF was 3.4%, 13.5% and 38.5% for adenomas of diameter < 0.5 cm, 0.5-1 cm and > 1 cm, respectively. Villous or tubulovillous histology, left-sided location and age >or= 60 years were also associated with APF, whereas sex and number of adenomas had no significant impact. Logistic regression analysis revealed that the risk of an adenoma containing APF was best described by a model incorporating the factors size, location, age, and the age by histology interaction. In the class of adenomas with diameter < 0.5 cm, no invasive carcinoma was found, but 3.4% of adenomas had high-grade dysplasia., Conclusions: The risk of a colorectal adenoma containing APF can be estimated only by a complex model taking into account several adenoma and patient characteristics. Size, histological type, location and age are independent risk factors for APF in colorectal adenomas. As a considerable percentage of adenomas with diameter < 0.5 cm contain high-grade dysplasia, the clinical conclusion from our study is that all adenomas, including those with diameter < 0.5 cm, should be removed whenever possible.

Human colorectal cancer cells not only express the nuclear vitamin D receptor (VDR) but are also endowed with 25-hydroxy-vitamin D(3)-1alpha-hydroxylase activity and therefore are able to produce the specific ligand for the VDR, the hormonally active steroid 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)). In the present study we show by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) as well as by Western blotting and immunohistochemical methods, that in human large intestinal carcinomas expression of the genes encoding the 25-(OH)D(3)-1alpha-hydroxylase as well as the VDR increases in parallel with ongoing dedifferentiation in the early phase of cancerogenesis, whereas in poorly differentiated late stage carcinomas only low levels of the respective mRNAs can be detected. This indicates that, through up-regulation of this intrinsic 1alpha,25(OH)(2)D(3)/VDR system which mediates the anti-mitotic effects of the steroid hormone, colorectal cancer cells are apparently able to increase their potential for an autocrine counter-regulatory response to neoplastic cell growth, particularly in the early stages of malignancy.

There is evidence that vitamin D receptor (VDR)-mediated action of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) could limit colon cancer cell growth particularly when induced by activation of the epidermal growth factor receptor (EGFR). We therefore wanted to ascertain the relevance of this observation for human colon cancerogenesis. Utilizing in situ mRNA hybridization and immunocytochemical techniques, we analyzed cell-specific expression of VDR and EGFR in normal and malignant human colonic mucosa. In normal mucosa, VDR positivity is weak and observed only in a small number of luminal surface colonocytes. In contrast, EGFR expression at a relatively high level is also found in cells at the crypt base. The number of VDR-positive colonocytes increases remarkably during tumor progression. It reaches its maximum in low grade adenocarcinomas and returns to lower levels in highly malignant cancers. In both low- and high grade carcinomas, the great majority of tumor cells contain the EGFR message. The relative abundance of EGFR over VDR in normal mucosa and in high grade carcinomas would create a situation in which mitogenic effects from EGFR activation are only ineffectively counteracted by signaling from 1 alpha,25-(OH)2D3/VDR. In contrast, in well to moderately differentiated tumors, upregulation of VDR could retard further tumor progression.

Background: In order to evaluate natural history, clinical features, and socioeconomic aspects in HIV-infected women, a prospective study comprising 695 HIV-infected patients was performed at our department., Methods: Demographic data, CD4+ T-lymphocyte counts, human immunodeficiency virus-1 (HIV-1) plasma loads, AIDS indicator diseases and socioeconomic variables were recorded. Prognostic factors for survival were evaluated by univariate and multivariate analysis. Data of men and women were compared., Results: The mean age of the 150 women (29.4 +/- 9.4 years) was significantly lower than that of men (32.6 +/- 9.7 years, p = 0.0002). CD4+ T-lymphocyte counts, HIV1-plasma loads, and AIDS indicator diseases did not significantly differ between men and women; the same was true for all socioeconomic variables (family status, education, professional training, employment status) except family status. No significant difference in median overall and AIDS-free survival was observed between females (2033 and 1593 days) and males (1554.5 and 1235 days, respectively, p = 0.36 and p = 0.098). Overall survival compared by age groups (< 30, 31-50, > 50 years), by risk categories (homosexuals, i.v. drug users, heterosexual contacts) and by CD4+ T-lymphocyte count (< 200, 200-500, > 500 cells/mm3), differed significantly (p < 0.001) as did AIDS-free survival. Lower age and a high CD4+ T-lymphocyte count were independently associated with the outcome in the multivariate analysis. (Overall survival/relative risk: 0.49 for age < 30 years and 2.3 for CD4+ T-lymphocyte count < 200 cells/mm3, AIDS-free survival/relative risk: 0.65 for age < 30 years and 3.3 for CD4+ T-lymphocyte count < 200 cells/mm3). HIV-1 plasma loads as a prognostic factor could not be evaluated due to the small number of patients who died or developed AIDS (2/375 and 10/375 patients, respectively)., Conclusion: Our results showed no difference in the natural history and clinical features of HIV infection between men and women. However, pulmonary tuberculosis was associated with a significantly longer survival compared to other AIDS-defining diseases. Lower age and high CD4+ T-lymphocyte count are independent predictors for survival. With the exception of family status, socioeconomic variables showed no differences between male and female patients.

Open management (OM) of severe intraabdominal infection often is complicated by fistula formation and the need for complex reconstructive procedures. From 1988 to 1998 a series of 145 patients were treated by OM. Of these patients, 24 developed intestinal fistulas and 42 had to be treated by discontinuity resections prior to OM for intestinal perforations or anastomotic insufficiency. Of the patients with fistulas or enterostomies, 61% survived. Reconstructive surgery was performed after infections had completely subsided. Patients were examined on follow-up, and the quality of life was assessed by 36-item short-form health survey questionnaires. Restorative surgery was performed in 32 of 40 patients 102 days (median) after beginning OM. All patients survived. Anastomotic leakage developed in six patients (18%). Thirty patients (94%) were followed up; 70% indicated their quality of life to be good. Despite a higher rate of anastomotic problems than with elective visceral operations, reconstructive intestinal surgery after OM may be performed without mortality and satisfying long-term outcome.

We identified the parathyroid type Ca(2+)-sensing receptor (CaR) in normal human colon mucosa and in cancerous lesions at the mRNA and protein level. Polymerase chain reaction produced an amplification product from reverse-transcribed large intestinal RNA which corresponded in size and length to a 537-bp sequence from exon 7 of the CaR gene. With a specific antiserum against its extracellular domain, the CaR could be detected by immunostaining in normal human colon mucosa in cells preferentially located at the crypt base. The CaR protein was also expressed in tumors of the large bowel in all 20 patients examined. However, the great majority of CaR-positive cells in the adenocarcinomas inspected were confined to more differentiated areas exhibiting glandular-tubular structures. Poorly or undifferentiated regions were either devoid of specific immunoreactivity or contained only isolated CaR-positive cells. In the normal mucosa and in glandular-tubular structures of cancerous lesions, the CaR was exclusively expressed in chromogranin A-positive enteroendocrine cells and in only a small fraction of PCNA-positive cells.

Background: Gastric restriction surgery relies on obstruction to oral intake by formation of a gastric pouch. Therefore, the therapeutic effect is closely related to intolerance for different types of food, and an ingestion of an unbalanced diet. We investigated dietary changes after VBG and their associations with therapeutic success., Methods: 70 patients (4 men, 66 women, median age 32) with a median preoperative BMI of 44.6 were examined > or =3 years after VBG. Weight reduction, nutritional changes (type of diet, number of daily meals, amount of food that could be ingested, intolerance for different types of food, frequency of vomiting), satisfaction with results, and willingness to undergo the operation once again were investigated., Results: The average reduction of the BMI was 13, with sufficient weight loss in 80%. 36% were eating a solid, 43% a soft, and 21% a liquid diet. Weight reduction did not depend on the type of diet eaten but on the ingestion of sweets. 93% indicated they could take only small amounts of food. The average number of daily meals was 3.76% reported an intolerance for some type of food (most often meat, fruit, or vegetable). Vomiting was the most common problem and occurred in 71%. 71% indicated a high level of satisfaction with the results of the operation, and 96% said they would undergo the operation again., Conclusions: The investigation demonstrated successful weight reduction despite dietary changes in 80% of patients after VBG. Weight reduction was not influenced by type of, diet but depended on consumption of sweets.

Using the human colon adenocarcinoma-derived cell line Caco-2, we investigated the possible role of the Ca2+-sensing receptor (CaR) in mediating effects of extracellular Ca2+ on cellular proliferation. Caco-2 cells respond to low ambient [Ca2+]o by activation of the protein kinase C-signaling pathway, leading to upregulation of c-myc mRNA expression and thereby, finally, to alleviation from the G1/S phase control of the cell cycle. This proliferative response can be reverted by activation of the CaR either through raising [Ca2+]o or, respectively, by using the CaR agonist Gd3+ as a substitute for Ca2+. The inhibitory effect of [Ca2+]o on cell replication exhibits saturation kinetics (IC50 = 0.045 mM), indicating the existence of a highly sensitive CaR operating at low ambient [Ca2+]o. Specific immunostaining revealed the presence of CaR-positive cells in the crypt epithelium of normal human colonic mucosa as well as in glandular (i.e., differentiated structures) of carcinomatous lesions. This could provide a rationale for use of calcium supplements for intervention in early phases of colon tumorigenesis.

Objective: To evaluate risk factors, results of treatment, and prognostic influence of complications on survival from acute necrotising pancreatitis., Design: Retrospective study of prospectively collected data., Setting: Tertiary referral centre, Austria., Subjects: 100 consecutive patients operated on for necrotising pancreatitis confirmed by dynamic angio-computed tomography from 1988-1997., Interventions: 77 patients were operated on acutely followed by open management, and in 23 the operations were delayed., Main Outcome Measures: Morbidity, mortality, factors predisposing to complications, prognostic effect of complications on survival., Results: Acute operations, alcoholic origin, APACHE II scores of > or = 10 on admission, and organ dysfunction on admission were independent factors that predisposed patients to complications. Colonic necrosis (n = 17) bleeding (n = 12) and intestinal fistulisation (n = 10) predominated. The overall mortality of complicated pancreatic necrosis was higher among patients admitted with surgical complications than in those who were not, but not significantly so (12/33 compared with 7/44 p = 0.06). Colonic necrosis (mortality 53%, relative risk: 2.45, p = 0.01), however, seemed to be of prognostic relevance., Conclusions: Complications are common in severe necrotising pancreatitis leading to organ dysfunction and need for acute operations. Colonic necrosis is an independent prognostic factor for survival.

Background/aims: The pathogenesis of thrombocytopenia associated with advanced liver disease is still controversial. To study the impact of portal decompression on this hematologic complication, we conducted a prospective, controlled study to compare the course of platelet counts in patients after implantation of a transjugular intrahepatic portosystemic shunt (TIPS) with matched controls without shunts., Methods: Fifty-five TIPS patients and 110 controls matched for age, sex, Child-Pugh class, etiology of liver disease and baseline platelet count were included, and followed for 1 year. Follow-up visits were scheduled after 1 month, after 3 months, and at 3-month intervals thereafter., Results: Nonparametric Mann-Whitney U-tests revealed significantly higher platelet counts for TIPS patients as compared to controls from the 1st through the 12th month (p<0.01). During the study period, the median platelet count of TIPS patients increased by 19.7%, from 104.0/nl (IR: 68.0) to 124.5/nl (IR: 41.0). In contrast, during the same period the median platelet count of controls decreased by 17.1%, from 102.5/nl (IR: 66.0) to 85.0/nl (IR: 67.5). In the group of cases with baseline platelet counts < or =100/nl, platelet counts had increased by at least 25% at month 12 in 65% of TIPS patients, but in only 5% of controls (p<0.001). However, normalization of platelet counts, i.e. > or =150/nl, was not achieved in any case. Neither the portosystemic pressure gradient after TIPS implantation, nor the percentage of portosystemic pressure gradient reduction during the procedure was predictive of platelet response., Conclusions: TIPS implantation increases platelet counts significantly. However, portal hypertension is clearly not the only mechanism contributing to thrombocytopenia in advanced liver disease.

Background: Based on the changing disease pattern of human immunodeficiency virus (HIV) associated pulmonary complications we conducted a prospective study in order to compare the value of laboratory tests in patients with Pneumocystis (P.) carinii pneumonia (PCP) and other pulmonary complications and of different identification methods of P. carinii in bronchoalveolar lavage fluid (BALF) in PCP patients., Patients and Methods: In 217 HIV-1-infected patients we evaluated the following parameters: platelets, serum lactat dehydrogenase (LDH), total serum protein (TP), hemoglobin (Hb), and CD4+ and CD8+ T-lymphocyte count. P. carinii was identified in BALF by May Grünwald Giemsa stain (MGG), direct immunofluorescence test (DIFT), and polymerase chain reaction (PCR). We correlated these parameters in patients with a presumptive diagnosis of PCP and compared them with those of patients suffering from other pulmonary complications., Results: All patients underwent bronchoscopy. 55 patients (25.3%) had a presumptive diagnosis of PCP. The sensitivity values of MGG stain, DIFT, and PCR differed considerably (79.1%, 56.1%, and 65.9%, respectively), but specificity values did not (99.2%, 97.3%, and 98.2%, respectively) as well as accuracy values (93.8%, 86.2%, and 89.7%, respectively). The mean values of platelets, of LDH, and of total serum protein of PCP patients and those of patients with other pulmonary diseases differed statistically significant as well as the mean values of these parameters of PCP patients and those of patients with bacterial pneumonia. Logistic-regression analysis revealed the number of platelets and the amount of total serum protein as independent, significant prognostic factors. Moreover, each PCP patient had a CD4+ T-lymphocyte count of less than 200 cells/mm3 blood. The CD4/CD8 ratio of PCP patients was statistically significant lower than that of patients with bacterial pneumonia., Conclusions: A detection of P. carinii in BALF is inevitable for a definitive diagnosis of a PCP. The most efficient identification method in this case is the MGG stain. Platelets, total serum protein, and CD4+ T-lymphocyte count should be included into the criteria for the presumptive diagnosis of PCP.

Background: Outcome assessment after surgical treatment of intra-abdominal infections and pancreatic necrosis has concentrated on postoperative complications and survival, while long-term results have received little attention., Objectives: To evaluate hospital costs and long-term outcome for patients undergoing open treatment of intra-abdominal infection or pancreatic necrosis and to determine whether results justify costs., Design: Cohort study and cost-effectiveness analysis., Setting: Referral center., Patients: From January 1, 1988, through June 30, 1996, we used open treatment for 147 patients with pancreatic necrosis (n=75; group 1), severe intra-abdominal infections due to benign diseases (n=50; group 2), and infections due to malignant neoplasm (n=22; group 3). All surviving patients (n=92) were followed up. Fifty-seven patients in group 1, 25 patients in group 2, and 10 patients in group 3 survived., Interventions: The effective costs of treatment per surviving patient (including restorative surgery) were calculated. The patients were interviewed, and the residence location, medical treatment, degree of recovery, functional state, and employment status were assessed. We assessed the quality of life by using the short general health survey (SF-36)., Main Outcome Measures: Costs, survival, and long-term outcome., Results: The effective costs per survivor studied were $175000 (group 1) and $232400 (groups 2 and 3). Most patients experienced good long-term results, ie, employment status was unchanged for 69 (75%) of the patients, and the functional state was unchanged for 81 (88%) of the patients. Readmission to a hospital was necessary for 14 (15%) of the patients, and 5 (6%) required care in nursing homes. Of the patients studied, 75% described their quality of life as good. Patients in group 3 had significantly worse results for survival, functional status, and quality of life (P<.01, log-rank test)., Conclusions: Our study demonstrated that open treatment of severe intra-abdominal infection and pancreatic necrosis is a cost-effective treatment with good long-term results for most patients. However, patients with malignant neoplasms did not benefit from this therapy and, therefore, should not be treated by laparostomy.

Neurological complications occur in 40% of "human immunodeficiency virus type 1" (HIV-1)-infected patients. Aim of the study was to evaluate the diagnostic yield of stereotactic brain biopsy and non invasive diagnostic procedures (CT, antitoxoplasma antibodies) and to calculate the benefit of the brain biopsy for the patient and the costs of both methods. From October 1989 through September 1995 we biopsied 44 of 2749 (2%) HIV-1-infected patients after non invasive diagnostic procedures had been performed. In 93% of the patients an unambiguous diagnosis was possible based on the biopsy and lead in 73% of the patients to a change of therapy. No complications occurred after biopsy. 40 CTs and 15 MRIs were done. The radiological appearance of toxoplasmosis and non Hodgkin lymphoma (NHL) differed from that of progressive multifocal leucencephalopathy (PML) in respect to enhancement (PML). CT showed a sensitivity of 55% (toxoplasmosis, NHL) and 78% (PML) and a specificity of 83% (PML), 84% (NHL) and 96% (toxoplasmosis), respectively. Antitoxoplasma antibodies showed a sensitivity of 45%, only. The stereotactic brain biopsy was more expensive (20.166,- ATS) than CT, MRI and antitoxoplasma antibodies (4109,- ATS up to 6959,- ATS). We conclude that stereotactic brain biopsy is an efficient and safe and for the patients important diagnostic procedure. In selected patients even expensive investigations should be undertaken considering specific therapy and cost effective homecare.

Severely obese patients are vitally endangered by their overweight. Non operative therapies achieve less than 10% of persistent weight reductions in this high-risk group of patients. On condition of correct indications and adequate preoperative information gastric bypass, vertical banded gastroplasty or implantation of the adjustable gastric band represent effective surgical procedures enabling persistent reductions of at least 50% of overweight in 85% of patients.