Whipple's disease - a rare and challenging complication in a patient with Crohn's disease.

INTRODUCTION: Whipple's disease (WD) is a rare and infectious condition leading to multi-organ impairment caused by Tropheryma whipplei (TW), a ubiquitously occurring bacterium. TW can be detected in tissues by histological detection of PAS ("periodic acid-ship reaction")-positive macrophages and by polymerase-chain-reaction (PCR). Clinically, WD is often characterized by diarrhea, abdominal pain, and weight loss. These symptoms are also typical for a flare in Crohn's disease (CD) and, therefore, can lead to fatal misdiagnosis and wrong treatment by using biologics (e.g., anti-TNF-α). CASE REPORT: We here report a young male patient with pre-existing CD. The patient's symptoms were misinterpreted as a flare of CD and illustrate the multifaceted nature of WD. After intensifying immunosuppressive therapy, the patient developed therapy-refractory diarrhea with several opportunistic infections with a final, fatal outcome. CONCLUSION: Patients with inflammatory bowel disease (IBD) are not only at risk from infectious complications known with clostridium difficile or cytomegalovirus (CMV); infection with WD should also be ruled out by endoscopy and biopsy before the escalation of the immunosuppressive regime.

Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials.

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.

P wave dispersion and QT dispersion in adult Turkish migrants with familial mediterranean fever living in Germany.

BACKGROUND: Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease associated with subclinical inflammation, which includes atherosclerosis arising from endothelial inflammation, which in turn increases the risk of atrial or ventricular arrhythmias. Conduction abnormalities can be detected using the electrocardiographic (ECG) indices P and QT dispersion (Pdisp and QTdisp). Currently, it is unknown whether patients with FMF are more likely to have abnormalities of these ECG indices. Moreover, existing studies were conducted in countries with higher FMF prevalence. We therefore perform the first prospective study assessing Pdisp and QTdisp in adult FMF patients in Germany, where prevalence of FMF is low. METHOD: Asymptomatic FMF patients (n=30) of Turkish ancestry living in Germany and age-matched healthy controls (n=37) were prospectively assessed using 12-lead ECG. RESULTS: Patients and controls were comparable in gender and body mass index, and patients had higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) compared to controls (ESR: 23.7±14.3 vs. 16.1±13,3 mm/1(st)h, p=0.03, CRP: 0.73±0.9 vs. 0.26±0.4 g/dl, p=0.01, SAA: 3.14±4,8 vs. 0.37±0.3 mg/dl, p<0.01). No statistically significant difference between patients and controls respectively, for Pdisp (43.7±11.9 vs. 47.1±11.2ms, p=0.23), QTdisp (65.9±12.3 vs. 67.6±12.7 ms, p=0.58) or corrected QTdisp (cQTdisp: 73.9±15.0 vs. 76.0±13.3 ms, p=0.55) was found. No correlation could be found between Pdisp or QTdisp or cQTdisp and any of the biochemical markers of inflammation. CONCLUSION: FMF patients living in Germany show a Pdisp and QTdisp comparable to healthy controls, with no increased risk of atrial or ventricular arrhythmias indicated.

Sonographic assessment of spleen size in Turkish migrants with Familial Mediterranean fever in Germany.

OBJECTIVES: Familial Mediterranean fever (FMF) can be associated with splenomegaly. Prospective quantitative data are lacking. We performed a sonographic assessment of spleen size in patients with FMF and healthy control participants to assess its diagnostic value. METHODS: Patients with FMF according to the criteria of Livneh et al (Arthritis Rheum 1997; 40:1879-1885) who were in an asymptomatic interval and control participants were prospectively included in this study in Germany and underwent sonographic measurement of the spleen as well as a structured interview and a physical examination. Patients and controls were Turkish migrants. RESULTS: Thirty-six patients and 27 controls were included. Patients and controls did not differ significantly in age (mean ± SD, 34.8 ± 9.7 versus 33.3 ± 10.0 years, respectively; P = .56), sex, height, weight, or body mass index (26.7 ± 4.7 versus 26.1 ± 4.3 kg/m(2); P = .63). Spleen size was greater in patients than controls in width (4.3 ± 1.0 versus 3.7 ± 0.7 cm; P = .008) and also length (12.1 ± 1.9 versus 10.5 ± 1.4 cm; P = .001). Twenty-six of 36 patients (72.2%) had a history of appendectomy compared to 3 of 27 controls (11.1%; P < .001). The combination of an enlarged spleen (length >11 cm and/or width >4 cm) gave specificity of 100% (95% confidence interval, 87%-100%) and a positive predictive value of 100% (95% confidence interval, 78%-100%) for the diagnosis of FMF in our study. CONCLUSIONS: Spleen size as evaluated by sonography is larger in patients with FMF compared to healthy controls. Most patients with FMF included in this study had undergone appendectomy. Familial Mediterranean fever should be considered as a differential diagnosis in Turkish migrants in Germany if the spleen is enlarged and a history of appendectomy is reported.

Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.

INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

Oxidative stress and inflammation distinctly drive molecular mechanisms of diastolic dysfunction and remodeling in female and male heart failure with preserved ejection fraction rats.

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular insufficiency syndrome presenting with an ejection fraction (EF) of greater than 50% along with different proinflammatory and metabolic co-morbidities. Despite previous work provided key insights into our understanding of HFpEF, effective treatments are still limited. In the current study we attempted to unravel the molecular basis of sex-dependent differences in HFpEF pathology. We analyzed left ventricular samples from 1-year-old female and male transgenic (TG) rats homozygous for the rat Ren-2 renin gene (mRen2) characterized with hypertension and diastolic dysfunction and compared it to age-matched female and male wild type rats (WT) served as control. Cardiomyocytes from female and male TG rats exhibited an elevated titin-based stiffness (Fpassive), which was corrected to control level upon treatment with reduced glutathione indicating titin oxidation. This was accompanied with high levels of oxidative stress in TG rats with more prominent effects in female group. In vitro supplementation with heat shock proteins (HSPs) reversed the elevated Fpassive indicating restoration of their cytoprotective function. Furthermore, the TG group exhibited high levels of proinflammatory cytokines with significant alterations in apoptotic and autophagy pathways in both sexes. Distinct alterations in the expression of several proteins between both sexes suggest their differential impact on disease development and necessitate distinct treatment options. Hence, our data suggested that oxidative stress and inflammation distinctly drive diastolic dysfunction and remodeling in female and male rats with HFpEF and that the sex-dependent mechanisms contribute to HF pathology.

Bacteribilia with resistant microorganisms after preoperative biliary drainage--the influence of bacteria on postoperative outcome.

BACKGROUND: In pancreatic surgery, preoperative biliary drainage (PBD) leads to bacteribilia. Whether positive bile duct cultures are associated with a higher postoperative morbidity might be related to the resistance of the species isolated from bile. STUDY: Intraoperative bile duct cultures were collected from all patients who underwent pancreatic surgery. Postoperative morbidity was analyzed according to the species and the resistance found on bile duct cultures. RESULTS: Fifty-five percent (166/301) of patients had PBD, while 45% (135/301) underwent primary operation. PBD was associated with a positive bile duct culture in 87% (144/166) versus 21% (28/135) in patients without PBD (p = 0.001) and polymicrobial infections in 53% (88/166) versus 6% (8/135) (p = 0.001). Postoperative morbidity was 40% (121/301); mortality was 3% (9/301). PBD was not associated with morbidity and mortality, but resistant species on bile duct cultures lead to significantly more postoperative complications, 54% (25/46) versus 38% (96/255) (p = 0.033), with significantly more antibiotic therapies. CONCLUSION: PBD is associated with polymicrobial infections with resistant microorganisms, resulting in more postoperative complications. Since PBD cannot always be avoided, surgeons and gastroenterologists must be aware of their institutional surveillance data to identify patients at risk for postoperative complications.

Low Serological Prevalence of SARS-CoV-2 Antibodies in Cancer Patients at a German University Oncology Center.

BACKGROUND: Coronavirus disease 2019 (COVID-19) cases in Germany, as in most other places in Europe or worldwide, are still highly prevalent. Vaccination rates currently remain low, putting cancer patients at a continued risk of infection with SARS-CoV-2, while prevalence of SARS-CoV-2 antibodies among cancer patients in Germany remains essentially unknown. METHODS: Between August 2020 and February 2021, patients admitted to our hospital were prospectively enrolled in our COVID-19 biobank. Collected sera were analyzed for SARS-CoV-2-IgM/IgG using Elecsys Anti-SARS-CoV-2 assay. RESULTS: One hundred and ten patients with cancer were included in this study. With 71 (65%) patients, most had active cancer treatment, mainly chemotherapy (56%). The most frequent diagnosis was gastrointestinal cancer (54%) with pancreatic cancer being the most common cancer type (24%). Hematologic malignancies were present in 21 patients (17%). Among the cancer patients first diagnosed during the pandemic, the rate of palliative treatment situations tended to be higher (76% vs. 67%, p = 0.17). A history of SARS-CoV-2 infection was documented in 15 (14%) patients; however, SARS-CoV-2 antibodies were detected in 10 (67%) patients only. Of the patients without a history of SARS-CoV-2 infection, none displayed SARS-CoV-2 antibodies. CONCLUSION: In the present single-center experience, a low serological prevalence of SARS-CoV-2 antibodies among cancer patients even after SARS-CoV-2 infection was found. The results support continued strict preventive measures as well as efforts toward faster vaccination, due to a low immunity level in the population.

Cell cycle control of ß-cell replication in the prenatal and postnatal human pancreas.

ß-Cell regeneration declines with aging, but the molecular mechanisms controlling ß-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins in prenatal and adult tissue and examined the association of these proteins with ß-cell replication. Pancreatic tissue from a total of 20 human fetuses and adults was stained for Ki67, cyclin D3, p16 and p27, and insulin. The ß-cellular expression of these cell cycle proteins was determined. The frequency of ß-cell replication was lower in adult compared with prenatal ß-cells (<0.5 vs. 3.4 ± 0.5%, respectively; P < 0.0001). p16 was sporadically expressed in prenatal ß-cells (8.0 ± 1.1%) but highly enriched in adult ß-cells (63.1 ± 5.2%, P < 0.0001). Likewise, the expression of p27 was much lower in prenatal ß-cells (1.7 ± 0.4 vs. 44.1 ± 5.4%, respectively, P < 0.0001), and cyclin D3 expression increased from 24.2 ± 4.1 to 47.25 ± 5.0%, respectively (P < 0.001), with aging. The expression of all three proteins was significantly correlated with each other (P < 0.01 and r > 0.75, respectively). The strong expression of cyclin D3 in adult human ß-cells and its correlation to p27 and p16 suggest a positive role in human ß-cell cycle regulation. p16 and p27 appear to restrict ß-cell replication with aging. The age dependency of cell cycle regulation in human ß-cells might explain the reduced ß-cell regeneration in adult humans.

Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo.

Pituitary adenylate cyclase-activating peptide (PACAP) is an important neuropeptide and immunomodulator in various tissues. Although this peptide and its receptors (ie, VPAC1R, VPAC2R, and PAC1R) are expressed in human skin, their biological roles are unknown. Therefore, we tested whether PACAP regulates vascular responses in human skin in vivo. When injected intravenously, PACAP induced a significant, concentration-dependent vascular response (ie, flush, erythema, edema) and mediated a significant and concentration-dependent increase in intrarectal body temperature that peaked at 2.7°C. Topical application of PACAP induced marked concentration-dependent edema. Immunohistochemistry revealed a close association of PACAP-immunoreactive nerve fibers with mast cells and dermal blood vessels. VPAC1R was expressed by dermal endothelial cells, CD4+ and CD8+ T cells, mast cells, and keratinocytes, whereas VPAC2R was expressed only in keratinocytes. VPAC1R protein and mRNA were also detected in human dermal microvascular endothelial cells. The PACAP-induced change in cAMP production in these cells demonstrated VPAC1R to be functional. PACAP treatment of organ-cultured human skin strongly increased the number of CD31+ vessel cross-sections. Taken together, these results suggest that PACAP directly induces vascular responses that may be associated with neurogenic inflammation, indicating for the first time that PACAP may be a crucial vascular regulator in human skin in vivo. Antagonists to PACAP function may be beneficial for the treatment of inflammatory skin diseases with a neurogenic component.

Histomorphological features of the pancreatic remnant as independent risk factors for postoperative pancreatic fistula: a matched-pairs analysis.

BACKGROUND/AIMS: Postoperative pancreatic fistula (POPF) is a major complication after resective pancreatic surgery. This study aimed to identify histomorphological features of the pancreatic remnant as independent determinants for the development of POPF. METHODS: Twenty-five patients, 3.6% of 696 resections over a period of 5 years, who developed POPF were matched for age, gender, diagnosis, comorbidities, surgeon and procedure with 25 controls without POPF. Pancreatic duct size and index, fibrosis grade, fat content, edema, and signs of chronic and acute inflammation were measured in frozen sections of the resection margin and were then compared. RESULTS: The POPF rate was 12.2 and 2.6% after distal pancreatectomy and pancreatoduodenectomy, respectively. The POPF group was characterized by a longer ICU and total postoperative stay, higher rate of reoperations and complications. Their pancreata were softer at palpation (88 vs. 56%). Their pancreatic duct was smaller (2.5 vs. 3.2 mm) and their pancreatic fat content higher (16 vs. 8%). High inter- and intralobular fat content, small duct size, low interlobular fibrosis grade and lack of signs of chronic pancreatitis were predictors of POPF development. A score including these parameters identified high-risk patients with a sensitivity of 92% and a specificity of 84%. CONCLUSION: Histomorphological features of the pancreatic remnant play an independent role as risk factors for the development of POPF. A simple histological score based on the frozen sections may already intraoperatively predict the risk of POPF development.

Hepatic mitochondrial dysfunction in Friedreich ataxia.

BACKGROUND: Mitochondrial dysfunction due to respiratory chain impairment is a key feature in pathogenesis of Friedreich ataxia. Friedreich ataxia affects the nervous system, heart and pancreas. METHODS: We assessed hepatic mitochondrial function by (13)C-methionine-breath-test in 16 Friedreich ataxia patients and matched healthy controls. RESULTS: Patients exhaled significantly smaller amounts of (13)CO(2) over 90 minutes. Maximal exhaled percentage dose of (13)CO(2) recovery was reduced compared to controls. CONCLUSIONS: (13)C-methionine-breath-test indicates subclinical hepatic mitochondrial dysfunction in Friedreich ataxia but did not correlate with GAA repeat lengths, disease duration or disease severity.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6).

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. FUNDING: Novo Nordisk A/S.

Reduced pancreatic volume and beta-cell area in patients with chronic pancreatitis.

BACKGROUND & AIMS: Chronic pancreatitis (CP) often leads to the development of diabetes. To understand better this pathogenic mechanism, we investigated whether islet cell area and pancreatic volume are reduced in CP patients, islet cell turnover increases in CP patients, and islet cells are less vulnerable to apoptosis than acinar cells. METHODS: Pancreatic tissues from 43 patients with CP and 27 controls were examined by immunohistochemistry and quantitative morphometry. Pancreas volume was determined using abdominal computed tomography data. RESULTS: The pancreatic volumes were 64.9 +/- 4.3 cm(3) in CP patients and 82.3 +/- 6.7 cm(3) in controls (P = .035). beta-cell areas were 0.69% +/- 0.08% in CP patients and 0.97% +/- 0.08% in controls (P = .017), whereas alpha-cell areas did not differ between the groups (P = .47). There were no differences in the frequencies of replication among groups of alpha-cells, beta-cells, duct cells, or acinar cells nor were there differences in numbers of apoptotic alpha-cells or beta-cells between CP patients and controls. However, CP patients had an approximately 10-fold increase in numbers of apoptotic acinar cells compared with controls (P < .0001). CONCLUSIONS: Pancreatic volume was reduced by 21%, and the area comprising beta-cells was reduced by 29% in patients with CP. The lack of increased beta-cells turnover in CP patients, despite an approximately 10-fold increase in the number of apoptotic acinar cells, suggests that the damage to the pancreas is highly specific for the exocrine compartment and affects the endocrine islets to a lesser extent.

Assessment of pancreatic hardness-surgeon versus durometer.

BACKGROUND: This study reports the first results of durometrically measured hardness of human pancreas and investigates its correlation to palpatory determined hardness, grade of pancreatic fibrosis, and preoperatively determined radiodensity. METHODS: Fifty-two patients with pancreatic resections were prospectively recruited. Hardness of samples from pancreatic cancer, chronic pancreatitis, and normal pancreas was measured using a durometer on a 0-100 Shore units (SU) scale. Three pancreatic surgeons palpated the pancreas and reported their assessment of hardness on a subjective 0-100 "Bochum units" (BU) scale. Radiodensity and fibrosis of pancreatic tissue were used for comparison. RESULTS: Pancreatic hardness differed significantly in normal pancreas, chronic pancreatitis, and pancreatic cancer; 30 SU, 51 SU, and 65.8 SU, respectively. Palpatory hardness of normal pancreas was 20 BU and of pancreatitis 60 BU. It correlated well to durometric readings: r(2)=0.56, P<0.00001. Fibrosis grade and radiodensity correlated neither to durometry nor to palpation. Pancreatic leak developed 4/20 (20%) patients with normal pancreas vs. 1/32 (3.1%) with chronic pancreatitis in the resection margin, P<0.05. CONCLUSIONS: Palpatory assessment of pancreatic hardness performed by experienced surgeons correlated well to durometric measurements and remains the method of choice for intraoperative decision making. Durometry was more precise and should be considered in studies on pancreatic texture and for teaching purposes. Hardness and fibrosis grade appeared to be independent characteristics of pancreatic texture.

Carbachol induces TGF-alpha expression and colonic epithelial cell proliferation in sensory-desensitised rats.

OBJECTIVE/BACKGROUND: Signals for the expression of the peptide growth factors epidermal growth factor and transforming growth factor-alpha (TGFalpha) in the gastrointestinal mucosa are largely unknown. We have shown earlier that extrinsic afferents in the gastrointestinal tract induce TGFalpha expression in colonic mucosa via the deliberation of neurotransmitters substance P and calcitonin gene-related peptide. The aim of our present study was to determine the effects of carbachol on mucosal TGFalpha expression and epithelial cell proliferation in vivo. DESIGN/METHODS: Rats were divided in three groups. Group 1 was treated with vehicle only, group 2 received one single subcutaneous injection of 250 microg/kg of carbachol and animals in group 3 were sensory-desensitised prior to the injection of 250 microg/kg carbachol. TGFalpha expression and epithelial cell proliferation was evaluated by polymerase chain reaction, Western blot analysis and bromodeoxyuridine staining. RESULTS: Carbachol induced a significant increase in mucosal epithelial cell proliferation and TGFalpha expression. Sensory desensitisation did neither abolish the increased TGFalpha expression nor the increase in epithelial cell proliferation. CONCLUSION: Parasympathetic pathways are involved in the control of TGFalpha expression in gastrointestinal mucosa as well as in epithelial cell proliferation.

Sustained partial remission of metastatic pancreatic cancer following systemic chemotherapy with gemcitabine and oxaliplatin plus adjunctive treatment with mistletoe extract.

BACKGROUND: The clinical prognosis of metastatic pancreatic cancer is very poor, with a median survival time of such patients ranging from 3 to 6 months. Current chemotherapy regimens include the combination of oxaliplatin and gemcitabine. CASE REPORT: A 43-year-old woman was diagnosed with pancreatic adenocarcinoma spreading into the regional lymph nodes and into multiple liver segments (pT3, pN1, pM1). Upon diagnosis, she underwent a pylorus-preserving pancreatic head resection, including dissection of regional lymph nodes and atypical resection of a single liver segment, followed by 9 cycles of palliative chemotherapy with gemcitabine and oxaliplatin. 37 weeks after surgery, the patient demonstrated a sustained partial remission, and the chemotherapy was stopped. Surprisingly, 10 months later, she still showed no evidence of tumor progression. Since the time of pancreatic surgery, the patient had taken mistletoe extracts and this adjunctive treatment has been continued until now. CONCLUSIONS: Cases of sustained long-term remission of metastatic pancreatic cancer are extremely rare. Although this single case observation does not allow for firm conclusions regarding potential mechanisms, the adjunctive therapy with mistletoe extracts might have played a role. Therefore, the clinical effects of such treatment in patients with pancreatic cancer warrant further investigation.

Probiotics regulate the expression of COX-2 in intestinal epithelial cells.

Cyclooxygenase-2 (COX) 2 promotes intestinal wound healing but elicits also proinflammatory effects and has been implicated in colorectal carcinogenesis. Thus, a balanced expression of COX-2 is essential for intestinal homeostasis. This study was designed to evaluate the regulation of COX-2 by probiotic organisms and to characterize ligands and receptors involved. Colo320 and SW480 intestinal epithelial cells (IEC) were stimulated with gastrin or TNF-alpha and pre- or coincubated with commensales, bacterial supernatants, or distinct toll-like receptor (TLR) ligands. COX-2 promoter activity was determined by luciferase assays, protein expression by Western blotting, and secretion of prostaglandin E(2) (PGE(2)) by ELISA. Commensales differentially regulated COX-2 expression in IEC. E. coli Nissle 1917, the probiotic mixture VSL#3, and media conditioned by these organisms ameliorated induced COX-2 expression and PGE(2) secretion. Heat inactivation and DNase treatment significantly decreased these regulatory capacities. Lactobacillus acidophilus, however, significantly increased COX-2 expression and PGE(2) secretion. TLR agonists differentially ameliorated basal or induced COX-2 expression. Distinct probiotics specifically and significantly decrease induced COX-2 expression in IEC, most likely mediated by released factors and in part by bacterial DNA. A significant involvement of TLRs in these regulatory processes remains to be established.

Bacteribilia after preoperative bile duct stenting: a prospective study.

STUDY DESIGN: A prospective analysis of intraoperative bile duct cultures in patients undergoing surgery for both, malignant or benign periampullary diseases at the Department of Surgery, St Josef Hospital, Bochum, Germany, during a period of 18 months, between January 2004 and June 2005. GOALS: The goals of the presented study were to investigate the effects of preoperative bile duct stenting on intraoperative bile duct cultures and postoperative outcome in patients undergoing pancreatic surgery. BACKGROUND: In pancreatic surgery, bile duct stenting is often aimed at improving postoperative outcome. As implantation of xenograft material in the main bile duct facilitates bacterial contamination and cholangitis, a critical evaluation of stenting is mandatory. STUDY: In all patients with a hepaticojejunostomy (n=80), a bile duct culture was collected during the operation. All patients received antibiotic prophylaxis perioperatively and a retrograde flushing of bile ducts with warm saline after bile duct resection. Fifty-one percent (41/80) patients had biliary drainage before surgery, whereas 49% (39/80) were operated without preoperative draining procedures. RESULTS: After bile duct stenting, 98% of patients had a positive bile culture, whereas only 21% of infected bile was seen in patients without drainage (P<0.001). Despite infected bile, only 2% stented patients developed acute cholangitis postoperatively, versus 13% patients in the group without stent (P=0.231). After stenting, major complications occurred in 12%, versus 8% in patients without stent (P=0.817). CONCLUSIONS: Preoperative biliary drainage leads to an almost 100% bacterial contamination of bile ducts. With hospital-adjusted antibiotic prophylaxis and retrograde flushing of bile ducts, the postoperative rate of acute cholangitis and morbidity is not elevated. A critical evaluation of benefits from preoperative biliary drainage for each patient is necessary.