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Background/objectives: There is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.Patients and methods: We retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.Results: We included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20-1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31-0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15-1.80), p = 0.002 and 1.54 (1.02-2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92-3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09-2.00), p = 0.02) and underweight (2.05 (OR 1.40-3.02), p < 0.001) were all associated with presence of EPI.Conclusions: Smoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC.

BACKGROUND: Chronic pancreatitis (CP) may cause intermittent or continuous pain and complications requiring invasive interventions. No specific recommendations for surgical interventions have been presented. Our aim was to determine the surgical treatment strategies for the treatment of CP in the Scandinavian and Baltic countries.METHODS: This multi-centre cross sectional study included 1327 CP patients from eight centres. The data was gathered from the Scandinavian Baltic Pancreatic Club (SBPC) database. Patients who underwent pancreatic surgery were analysed. The baseline CP population from the eight centres was used as a reference. The information registered included comorbidities, pancreatic function, previous interventions, time and type of surgery and the EORTC-30 quality of life (QOL) questionnaire.RESULTS: Overall, 95/1327 (7%) patients underwent pancreatic surgery. Fifty-one (54%) of these underwent pancreatic surgery for chronic pain (PSCP) and formed the final study group. Median follow-up time was two (range 0-8) years after surgery and seven (1-46) years after diagnosis. The most common surgical procedures were pancreatic resection combined with drainage (54%) followed by pancreatic resections (32%) and drainage procedures (14%). Postoperatively, 47% of the patients were pain free with or without pain medication while 16% had chronic pain episodes, this did not differ from the base CP population. In QOL questionnaires, PSCP patients reported the same QOL but worse social functioning and more symptoms compared to the CP population.CONCLUSIONS: Pancreatic surgery for CP is rare: surgical procedures were performed on only 7% of the CP patients in the SBPC database. In half of the patients the indication was pain. Most of these patients underwent endoscopic procedures before surgery. Half of the patients reported being pain-free after surgery.

Background: Diabetic constipation is traditionally attributed to slow colonic transit, despite limited evidence. More than half of patients find treatment unsatisfactory. To improve treatment, there is a need for better diagnostic understanding of the condition. Objective: In this wireless motility capsule study, we aimed to investigate gastrointestinal transit and contractility in diabetes patients with and without constipation, and in healthy controls. Methods: We prospectively included type 1 or type 2 diabetes patients with gastrointestinal symptoms. Based on the Gastrointestinal Symptom Rating Scale we distinguished into two groups: with constipation and without constipation. Non-diabetic controls were asymptomatic. All were examined with wireless motility capsule, determining transit times and contractility parameters. Results: 57 patients (42 women, 46 with type 1 diabetes) and 26 healthy controls (14 women) were included. We found no difference in transit times between diabetes patients with and without constipation. Compared to healthy controls (35:55, h:min), whole-gut transit was slower in both diabetes patients with constipation (66:15, p = 0.03) and without constipation (71:16, p < 0.001). Small bowel motility index correlated rs = −0.32 (p = 0.01) with constipation symptoms. Conclusions: Diabetes patients with constipation had similar transit times as those without constipation. Both groups had slower whole-gut transit than healthy controls. Constipation was associated with reduced small bowel, but not colonic contractility. Our results imply that other mechanisms than slow colonic transit may be more important in the pathogenesis of diabetic constipation. publishedVersion

Objectives: Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence-based guidelines treatment of CP. Patients and methods: Patients with definitive or probable CP according to M-ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase

Objectives Computed tomography (CT) is the most commonly used imaging modality when diagnosing chronic pancreatitis (CP). We aimed to evaluate the diagnostic accuracy of CT scores for diagnosing CP. Methods One hundred eighteen patients were retrospectively included from an observational cohort study that comprised patients referred because of suspected CP. Patients were categorized as CP or non-CP using a modified Mayo score based on biochemistry, clinical presentation, and findings on endoscopic ultrasound and/or transabdominal ultrasound. The CT scans were scored according to the modified Cambridge classification and the unweighted CT score. Diagnostic performance indices were calculated using the modified Mayo score as reference standard. Results Seventy-six of the 118 patients fulfilled the CP diagnostic criteria (Mayo score ≥4). The modified Cambridge classification and the unweighted CT score yielded sensitivities of 63% and 67% and specificities of 91% and 91%, respectively, and similar areas under the receiver operating characteristic curves (95% confidence interval) of 0.79 (0.71-0.88)/0.81 (0.73-0.89), respectively (P, not significant). Conclusions Both CT scores had similar, moderate accuracies for diagnosing CP. The limitation in diagnostic accuracy makes CT ineligible as a single method to diagnose CP, supporting that the diagnostic process for CP needs to incorporate other imaging methods and/or markers for better diagnostics.

Background: Gastroparesis is a severe diabetes complication characterized by delayed gastric emptying. We examined patients with symptoms of diabetic gastroparesis using gastric emptying scintigraphy and ultrasound drink test. The primary aim was to investigate how ultrasound could provide information about gastric motility features in diabetic gastroparesis. Material and methods: We prospectively included 58 patients with diabetes (48 type 1) with symptoms of gastroparesis and 30 healthy controls. Patients were examined with ultrasound of the stomach in a seated position after drinking 500 ml low-caloric meat soup, at the same time recording dyspeptic symptoms. The following day, they were examined with gastric emptying scintigraphy, defining gastroparesis as >10% retention after 4 h. Key Results: We found motility disturbances in the proximal stomach measured by ultrasound in patients with diabetic gastroparesis. A linear mixed effects model including repeated ultrasound measurements revealed a slower decrease of the proximal stomach size in gastroparesis compared to healthy controls (p < 0.01), and the proximal diameter at 20 min was correlated to scintigraphy at 4 h (r = 0.510, p = 0.001). The antrum in patients with diabetic gastroparesis was twice as large compared to healthy controls (p = 0.009), and fasting antral size was correlated to gastric emptying scintigraphy (r = 0.329, p = 0.013). Both diabetes patients with and without gastroparesis had impaired accommodation (p = 0.011). Conclusions and Inferences: On ultrasound, we found delayed reduction of proximal stomach size and impaired accommodation after a liquid meal in patients with gastroparesis, emphasizing the role of the proximal stomach. Furthermore, we found antral distention in gastroparesis patients. publishedVersion

Background Chronic diarrhoea is a common, but poorly investigated diabetes complication. Autonomic neuropathy is a leading pathophysiological theory founded on old, small studies. Studies of gastrointestinal motility and pH levels are lacking. Objectives Using new diagnostic methods, we aimed to find out if diabetic diarrhoea was associated with alterations in gastrointestinal motility, pH levels and autonomic function. Methods Fifty-seven patients (42 women, 46 type 1 diabetes) were prospectively included. Symptoms were evaluated with the gastrointestinal symptom rating scale, defining ≥ 4 points as cases with diarrhoea. Patients scoring < 4 were used as controls. We used the wireless motility capsule to measure gastrointestinal transit times, pH levels and contractility parameters. Autonomic function was assessed by measuring heart rate variability, baroreflex sensitivity and orthostatic hypotension. Results Seventeen patients (30%) had diarrhoea. Compared with controls, cases had slower gastric emptying (21:46 vs. 4:14, h:min, p = 0.03) and faster colonic transit (18:37 vs. 54:25, p < 0.001). Cases had increased intraluminal pH in the antrum (2.4 vs. 1.2, p = 0.009), caecum (7.3 vs. 6.4, p = 0.008) and entire colon (7.1 vs. 6.7, p = 0.05). They also had a decreased pH difference across the pylorus (3.3 vs. 4.9, p = 0.004) and ileocaecal junction (0.6 vs 1.0, p = 0.009). The groups did not differ in autonomic function, but diastolic blood pressure drop correlated rs = −0.34 (p = 0.04) with colonic transit time. Conclusions Patients with diabetic diarrhoea had altered gastrointestinal transit and intraluminal pH levels, but minimal changes in autonomic function. Our results suggest that tests of gastrointestinal function are clinically useful in diabetic diarrhoea. publishedVersion

Objectives The relation between aetiology and structural changes of the pancreas in patients with chronic pancreatitis (CP) is not fully understood. Earlier studies are limited by focusing on selected factors in studies of limited sample size. We aimed to use a large dataset to explore associations between aetiology and pancreatic morphology in CP. Methods Subjects with definite or probable CP according to the M-ANNHEIM diagnostic criteria were included in this multicentre cross-sectional observational study and assessed using a standardized and validated CP imaging system. We performed multivariate logistic regression to analyse if aetiological factors adjusted for covariates were independently associated with morphological pancreatic features. Results We included 959 patients (66% males). Mean (SD) age was 55 (14) years. Pancreatic structural changes were found in 94% of the subjects: 67% had calcifications, 59% main pancreatic duct dilatation, 33% pseudo-cysts and 22% pancreatic atrophy. Alcohol abuse was independently associated with pancreatic calcifications (odds ratio (OR, [95% CI]); 1.61, [1.09, 2.37]) and focal acute pancreatitis (OR; 2.13, [1.27, 3.56]), whereas smoking was independently associated with more severe calcifications (OR; 2.09, [1.34, 3.27]) and involvement of the whole gland (OR; 2.29, [1.61, 3.28]). Disease duration was positively associated with calcifications (OR; (per year) 1.05 [1.02, 1.08]) and pancreatic atrophy (OR; 1.05 [1.02, 1.08]) and negatively associated with focal acute pancreatitis (OR 0.91, [0.87, 0.95] and pseudo cysts (OR; 0.96, [0.93, 0.98]). Conclusion In this large-scale study, etiological risk factors and disease duration in CP were independently associated with specific structural pancreatic imaging changes.

Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies.

OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic exocrine secretion. In this prospective observational study, we compare the diagnostic accuracy of s-MRI for exocrine pancreatic failure due to different pancreatic diseases and healthy controls.METHODS: We performed s-MRI in 21 cystic fibrosis (CF) patients, 78 patients with chronic pancreatitis (CP) and 20 healthy controls. Exocrine failure was defined by fecal elastase-1 of less than 200 μg/g or bicarbonate concentration from endoscopic secretin test of less than 80 mmol/L.RESULTS: Eleven CF and 61 CP patients were exocrine insufficient. Insufficient CF patients had lower s-MRI volume output compared with all other groups (P < 0.05). Insufficient CP patients had reduced volume output compared with controls and sufficient CF (P < 0.05). Secretin-stimulated MRI yielded overall accuracy of 0.78 (95% confidence interval [CI], 0.70-0.86) for exocrine failure. When divided according to etiology, the test yielded accuracy of 0.95 (95% CI, 0.90-1) in CF and 0.73 (95% CI, 0.64-0.82) in CP.CONCLUSIONS: The accuracy of s-MRI volume output measures to diagnose exocrine failure was higher in CF than in CP. Differences in s-MRI volume output in patients with exocrine failure may be due to different etiological and pathogenic mechanisms in CF and CP.

BACKGROUND AND AIM: Pain is the primary symptom of chronic pancreatitis (CP) and associates with a number of patient and disease characteristics. However, the complex interrelations of these parameters are incompletely understood, and pain treatment remains unsatisfactory in a large proportion of patients. The aim of this study is to investigate multiple pain risk factors in a large population of CP patients, with a special emphasis on patients' patterns of smoking and alcohol use.METHODS: This was a multicenter, cross-sectional study including 1384 patients with CP. Patient demographics and disease characteristics, as well as current patterns of smoking and alcohol use, were compared for patients with pain (n = 801) versus without pain (n = 583). Multivariate logistic regression models were performed to assess the variables associated with the presence and type of pain (constant vs intermittent pain).RESULTS: The mean age of participants was 52.1 ± 14.6 years, and 914 (66%) were men. Active smoking (odds ratio 1.6 [95% confidence interval 1.1-2.2], P = 0.005) and alcohol consumption (odds ratio 1.8 [95% confidence interval 1.1-3.0], P = 0.03) were independently associated with the presence of pain. In addition, patients' age at diagnosis, pancreatic duct pathology, and the presence of pseudocysts, duodenal stenosis, and exocrine pancreatic insufficiency were confirmed as pain risk factors (all P ≤ 0.01). Constant pain, as opposed to intermittent pain, was more frequently reported by smokers (P = 0.03), while alcohol consumption was associated with intermittent pain (P = 0.006).CONCLUSION: Multiple patient and disease characteristics, including patterns of smoking and alcohol consumption, associate with the presence and type of pain in patients with CP.

Background/objectives: Smoking and alcohol abuse are established risk factors for chronic pancreatitis (CP). Few studies have examined how exposure to smoking and alcohol abuse act as risk factors for complications in CP. Our aim was to examine associations between patient reported exposure to smoking and alcohol abuse and complications in CP in a large cohort of patients from the Scandinavian and Baltic countries. Methods: We retrieved data on demographics, CP related complications and patients’ histories of exposure to smoking and alcohol abuse from the Scandinavian Baltic Pancreatic Club database. Associations were investigated by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. Results: A complete history of smoking and alcohol exposure was available for 932 patients. In multivariate regression analyses, the presence of pain and exocrine pancreatic insufficiency were both significantly associated with history of smoking (OR 1.94 (1.40–2.68), p < 0.001 and OR 1.89 (1.36–2.62), p < 0.001, respectively) and alcohol abuse (OR 1.66 (1.21–2.26), p = 0.001 and 1.55 (1.14–2.11), p = 0.005, respectively). Smoking was associated with calcifications (OR 2.89 (2.09–3.96), p < 0.001), moderate to severe ductal changes (OR 1.42 (1.05–1.92), p = 0.02), and underweight (OR 4.73 (2.23–10.02), p < 0.001). History of alcohol abuse was associated with pseudocysts (OR 1.38 (1.00–1.90) p = 0.05) and diabetes mellitus (OR 1.44 (1.03–2.01), p = 0.03). There were significantly increased odds-ratios for several complications with increasing exposure to smoking and alcohol abuse. Conclusion: Smoking and alcohol abuse are both independently associated with development of complications in patients with CP. There seems to be a dose-dependent relationship between smoking and alcohol abuse and complications in CP.

We aimed to evaluate the agreement of single criteria and dedicated scores from transabdominal ultrasound of the pancreas (US) compared to standards by endoscopic ultrasound (EUS) and computed tomography (CT). In this observational cohort study performed in a tertiary care center, US and EUS were performed in 110 patients referred for suspected CP. Based on the Mayo score, 52 patients were diagnosed with CP. The sonographic findings obtained by both methods were registered. The number of criteria was counted and scored according to the Rosemont score. Agreement between the number of detected US and EUS criteria was substantial (ICC = 0.74 [0.61-0.83]. Adding Rosemont weighting improved the agreement (ICC = 0.88 [0.81-0.92]). Regarding individual criteria, the agreement was substantial for the detection of calcifications (κ = 0.86) and moderate for cysts and irregular or dilated pancreatic duct (κ = 0.42-0.58). Agreement for the other criteria was poorer (κ≤ 0.40). The diagnostic performance indices [95 % CI] of US for diagnosing CP (using Mayo score as reference standard) were for the unweighted score: Sensitivity: 0.65 [0.51-0.78], specificity: 0.97 [0.87-1.00]; and for Rosemont score: Sensitivity: 0.75 [0.61-0.86], specificity: 0.95 [0.83-0.99]. The agreement between US and EUS for the unweighted and weighted scores was substantial. For the features calcifications, cysts and main pancreatic duct (MPD) changes, agreement was moderate to substantial. For the other detected US criteria, the agreement with EUS was too poor to be clinically relevant.ZIEL: Das Ziel bestand darin, die Übereinstimmung von Einzelkriterien und dedizierten Scores des transabdominalen Ultraschalls der Bauchspeicheldrüse (US) im Vergleich zu den Standards des endoskopischen Ultraschalls (EUS) und der Computertomografie (CT) zu bewerten. In dieser Beobachtungsstudie, die in einem tertiären Versorgungszentrum durchgeführt wurde, wurde bei 110 Patienten mit Verdacht auf chronische Pankreatitis (CP) US und EUS durchgeführt. Basierend auf dem Mayo-Score wurde bei 52 Patienten eine CP diagnostiziert. Die mit beiden Methoden erhobenen sonografischen Befunde wurden erfasst. Die Anzahl der Kriterien wurde bestimmt und mittels Rosemont-Score bewertet. Die Übereinstimmung zwischen der Anzahl der festgestellten US- und EUS- Kriterien war beträchtlich (ICC = 0,74 [0,61–0,83]. Durch die zusätzliche Rosemont-Gewichtung verbesserte sich die Übereinstimmung (ICC = 0,88 [0,81–0,92]). In Bezug auf die Einzelkriterien war die Übereinstimmung für den Nachweis von Verkalkungen beträchtlich (κ = 0,86) und von Zysten und eines irregulären oder dilatierten Pankreasgangs moderat (κ = 0,42–0,58). Die Übereinstimmung bezüglich der übrigen Kriterien war schlechter (κ ≤ 0,40). Die diagnostischen Leistungsindizes [95 % CI] des US für die Diagnose einer CP (mit Mayo-Score als Referenzstandard) betrugen für den ungewichteten Score: Sensitivität: 0,65 [0,51–0,78], Spezifität: 0,97 [0,87–1,00] und für den Rosemont-Score: Sensitivität: 0,75 [0,61–0,86], Spezifität: 0.95 [0.83–0.99]. Die Übereinstimmung zwischen US und EUS bei den ungewichteten und gewichteten Scores war erheblich. Für die Merkmale Verkalkungen, Zysten und Veränderungen des Pankreashauptganges (MPD) war die Übereinstimmung moderat bis beträchtlich. Für die anderen festgestellten US-Kriterien, war die Übereinstimmung zu schlecht, um klinisch relevant zu sein.

Aims To examine patient reported outcomes (PRO) in patients previously assessed for diabetic gastroparesis, and to investigate how symptoms of gastroparesis evolve over time. In addition, to further evaluate outcomes in those with versus without diabetic gastroparesis at baseline. Methods Thirty-four patients with diabetes and gastrointestinal (GI) symptoms, diagnosed with or without diabetic gastroparesis in 2011–2013, were included in this follow-up study. PRO were measured with the Patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM), 36-Item Short Form Survey (SF-36), Patient assessment of upper gastrointestinal disorders-quality of life (PAGI-QOL) and Hospital Anxiety and Depression Scale (HADS). Demographic factors and clinical variables were also recorded. Results Participants diagnosed with gastroparesis had improved glycemic control ( p =0.04) and less GI symptoms ( p =0.001), after a follow-up time of 3.2years (mean). Both groups reported severely impaired quality of life (QoL). In total 47% reported symptoms of anxiety, 38% symptoms of depression (scores≥8). GI symptom severity or other PRO could not differentiate between the two groups. Conclusions Patients diagnosed with diabetic gastroparesis, as well as those with gastroparesis symptoms - but normal gastric emptying, suffer from severely impaired QoL and a high burden of anxiety and depressive symptoms.

Background: The prevalence of pancreatic exocrine insufficiency (PEI) in diabetes mellitus (DM) varies widely between studies, which may be explained by methodological problems. We aimed to establish the prevalence of PEI in DM using the faecal elastase-1 (FE-1) assay as a screening test, and to further investigate these patients by the mixed 13C-triglyceride ( 13C-MTG) breath test. Methods: One hundred and thirty-three consecutive type 1 or type 2 DM patients without known exocrine pancreatic disorders were recruited. Demographic parameters, stool consistency, stool frequency, routine laboratory tests, and the presence of DM complications were registered. An FE-1 value 13C-MTG breath test. Results: One hundred and two patients returned faecal samples. The prevalence of PEI as measured by low FE-1 was 13%. Insulin usage, type 1 DM, and DM duration were associated with low FE-1. Stool habits were unaffected by low FE-1. Twelve out of 13 patients with low FE-1 performed the breath test, which was normal in all cases. Conclusions: The prevalence of PEI defined by FE-1 was low in our mixed cohort of type 1 and 2 DM patients. Furthermore, there was a discrepancy between FE-1 and the breath test. Hence, the role of FE-1 in evaluating pancreatic exocrine function in DM should be evaluated in larger studies in order to clarify the association between low FE-1 and clinically relevant PEI.

Background: Gastroparesis is a potentially severe late complication of diabetes mellitus. Today, delayed gastric emptying (GE) is mandatory for establishing the diagnosis. In this study, we compared wireless motility capsule (WMC) with gastric emptying scintigraphy (GES). Methods: Seventy‐two patients (49 women) with diabetes mellitus (59 type 1) and symptoms compatible with gastroparesis were prospectively included between 2014 and 2018. Patients were simultaneously examined with GES and WMC. Symptoms were assessed with the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI‐SYM) questionnaire. All patients were on intravenous glucose‐insulin infusion during testing. Key Results: WMC and GES correlated r = .74, P < .001. Compared to GES, WMC at ordinary cutoff for delayed GE (300 minutes) had a sensitivity of 0.92, specificity 0.73, accuracy 0.80, and Cohen's kappa κ = 0.61 (P < .001). By receiver operating characteristics (ROC), the area under the curve was 0.95 (P < .001). A cutoff value for delayed GE of 385 minutes produced sensitivity 0.92, specificity 0.83, accuracy 0.86, and Cohen's kappa κ = 0.72 (P < .001). Inter‐rater reliability for GE time with WMC was r = .996, κ = 0.97, both P < .001. There was no difference in symptom severity between patients with normal and delayed GE. Conclusions & Inferences: Our findings demonstrate the applicability of WMC as a reliable test to assess gastric emptying in diabetic gastroparesis showing very high inter‐observer correlation. By elevating the cutoff value for delayed emptying from 300 to 385 minutes, we found higher specificity without reducing sensitivity. publishedVersion

Direct pancreas function testing (DPFT) has been regarded as gold standard for assessment of exocrine pancreas function. One of the outcomes from DPFT is pancreatic lipase activity in duodenal juice, but no standard assay for measuring pancreas lipase activity in duodenal juice exists.To optimize and evaluate an autoanalyzer assay for measuring lipase activity in duodenal juice.We used samples of duodenal juice from our biobank, collected through a short endoscopic secretin test in patients with suspected exocrine pancreas insufficiency. Samples were analyzed on a Cobas autoanalyzer (Roche Diagnostics), using a colorimetric, kinetic enzyme activity assay. We compared stability of samples diluted in saline to samples diluted in 3-(N-morpholino) propane sulfonic acid (MOPS) buffer added bovine serum albumin (BSA). Results from the Cobas assay were compared to Confluolip method, a fluorometric, kinetic enzyme assay, modified to fit into a microplate setting.We tested the stability of 54 samples from 21 patients. Diluting samples with MOPS buffer added BSA gave stable results, and was superior to diluting samples in saline. We compared the two assays in 50 samples from 20 patients and found a good correlation between the two assays (r = 0.91, p .001). There was a significant proportional bias between the two assays, but no significant systematic bias.Pancreatic lipase activity in duodenal juice samples diluted in MOPS buffer added BSA is stable for one hour at room temperature. Quantification of lipase activity in duodenal juice using a standard automated activity assay has comparable accuracy to a manual fluorometric method.

Background: Chronic pancreatitis (CP) can lead to severe pancreatic exocrine insufficiency (PEI). Pancreatic enzyme replacement therapy (PERT) is well established, but knowledge of the physiological response to increasing doses on fecal fat- and energy loss is scarce. Methods: We included 10 patients with CP and established PEI and 12 healthy controls for a prospective interventional study. Subjects received no PERT in the first week followed by four weeks PERT incrementally increasing doses every week. For each week, three-day stool collection followed three days registration of nutritional intake. We measured the fecal output of fat and energy by van de Kamer titration and decomposition vessel calorimetry, respectively. We calculated fecal fat- and energy loss per day, the coefficient of fat absorption (CFA) and coefficient of energy absorption (CEA). Results: Without PERT treatment, CP patients with PEI had significantly higher daily fecal fat and energy loss (p = .022; p = .035) compared to HC. In CP patients, there was a significant reduction of fecal fat and energy loss (p = .045; p = .037) when PERT doses reached maximum intake of 75,000 units per meal. In CP patients, there was a strong positive correlation between fecal loss of energy and fat (r = 0.99), and between fecal loss of energy and daily stool weight (r = 0.97). CFA and CEA correlated negatively with daily fecal fat loss (r = −0.72) and fecal energy loss (r = −0.65). Conclusions: PERT reduces fecal energy and fat loss in patients with CP and PEI. Fecal energy loss in CP patients is strongly dependent on fecal fat loss, and on fecal weight.

OBJECTIVE: Fatty infiltration of the pancreas is a dominating feature in cystic fibrosis (CF). We evaluate the association between pancreatic fat content assessed by Dixon magnetic resonance imaging (MRI), pancreatic echogenicity at ultrasonography (US) and exocrine function in CF patients and healthy controls (HC).MATERIAL AND METHODS: Transabdominal US, pancreatic Dixon-MRI and diffusion-weighted imaging (DWI) were performed in 21 CF patients and 15 HCs. Exocrine function was assessed by endoscopic secretin test and fecal elastase.RESULTS: CF patients were grouped according to exocrine pancreatic function as subjects with normal (CFS: n = 11) or reduced (CFI: n = 10) function. Among CFI 90% (9/10) had visual hyperechogenicity. CFI also had increased echo-level values (pCONCLUSION: Pancreas insufficient CF patients exhibit severe pancreatic fatty-infiltration at MRI and hyperechoic pancreas at US. Pancreas hyperechogenicity in pancreatic sufficient subjects does not co-exist with fatty infiltration at MRI. MRI evaluates pancreatic fatty infiltration more accurately than US and fat infiltration estimated by MRI outperforms sonographic hyper-echogenicity as a marker for exocrine pancreatic failure in CF.

Background Perfusion assessment of the pancreas is challenging and poorly evaluated. Pancreatic affection is a prevalent feature of cystic fibrosis (CF). Little is known about pancreatic perfusion in CF. We aimed to assess pancreatic perfusion by contrast-enhanced ultrasound (CEUS) analysed in the bolus-and-burst model and software. Methods We performed contrast enhanced ultrasound of the pancreas in 25 CF patients and 20 healthy controls. Perfusion data was analysed using a dedicated perfusion model providing the mean capillary transit-time (MTT), blood flow (BF) and blood-volume (BV). CF patients were divided according to exocrine function. Results The pancreas insufficient CF patients had longer MTT (p ≤ 0.002), lower BF (p

Item does not contain fulltext BACKGROUND: In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed European guidelines for the management of chronic pancreatitis using an evidence-based approach. METHODS: Recommendations of multidisciplinary review groups based on systematic literature reviews to answer predefined clinical questions are summarised. Recommendations are graded using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Recommendations covered topics related to the clinical management of chronic pancreatitis: aetiology, diagnosis of chronic pancreatitis with imaging, diagnosis of pancreatic exocrine insufficiency, surgical therapy, medical therapy, endoscopic therapy, treatment of pancreatic pseudocysts, pancreatic pain, nutrition and malnutrition, diabetes mellitus and the natural course of the disease and quality of life. CONCLUSIONS: The HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. This article summarises the HaPanEU recommendations and statements.

This paper presents a system for correcting motion influences in time-dependent 2D contrast-enhanced ultrasound (CEUS) images to assess tissue perfusion characteristics. The system consists of a semi-automatic frame selection method to find images with out-of-plane motion as well as a method for automatic motion compensation. Translational and non-rigid motion compensation is applied by introducing a temporal continuity assumption. A study consisting of 40 clinical datasets was conducted to compare the perfusion with simulated perfusion using pharmacokinetic modeling. Overall, the proposed approach decreased the mean average difference between the measured perfusion and the pharmacokinetic model estimation. It was non-inferior for three out of four patient cohorts to a manual approach and reduced the analysis time by 41% compared to manual processing. HighlightsThis paper proposes a semi-automatic system to motion compensated CEUS perfusion data.Evaluation showed equal or improved performance compared to manual processing.It saves 41% of the time required for manual processing of the datasets.

OBJECTIVES: Chronic pancreatitis (CP) is a multifaceted disease associated with several risk factors and a complex clinical presentation. We established the Scandinavian Baltic Pancreatic Club (SBPC) Database to characterise and study the natural history of CP in a Northern European cohort. Here, we describe the design of the database and characteristics of the study cohort.METHODS: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report forms were used to collect several assessment variables including disease aetiology, duration of CP, preceding acute pancreatitis, as well as symptoms, complications, and treatments. The clinical stage of CP was characterised according to M-ANNNHEIM. Yearly follow-up is planned for all patients.RESULTS: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48-67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients had undergone pancreatic surgery.CONCLUSION: The SBPC database provides a mean for future prospective, observational studies of CP in the Northern European continent.

The performance of transabdominal ultrasound (US) in chronic pancreatitis (CP) following the advances in US technology made during recent decades has not been explored. Our aim in this prospective study was to evaluate the diagnostic accuracy of modern abdominal US compared with the Mayo score in CP. One hundred thirty-four patients referred for suspected CP were included in the study. Fifty-four patients were assigned the diagnosis CP. After inclusion, transabdominal US was performed. Ductal features (calculi, dilations and caliber variations, side-branch dilations and hyper-echoic duct wall margins) and parenchymal features (calcifications, cysts, hyper-echoic foci, stranding, lobulation and honeycombing) were recorded. Features were counted and scored according to a weighting system defined at the international consensus meeting in Rosemont, Illinois (Rosemont score). Diagnostic performance indices (95% confidence interval) of US were calculated: The unweighted count of features had a sensitivity of 0.69 (0.54–0.80) and specificity of 0.97 (0.90–1). The Rosemont score had a sensitivity of 0.81 (0.69–0.91) and specificity of 0.97 (0.90–1). Exocrine pancreatic failure was most pronounced in Rosemont groups I and II (p < 0.001). We conclude that using both unweighted and weighted scores, the diagnostic accuracy of modern transabdominal US is good. The extent of pancreatic changes detected by the method is correlated with exocrine pancreatic function. publishedVersion

Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic secretion. The purpose of this study was to compare volume output measures from secretin-stimulated transabdominal ultrasonography (s-US) to s-MRI for the diagnosis of exocrine pancreatic failure in cystic fibrosis (CF). We performed transabdominal ultrasonography and MRI before and at timed intervals during 15 minutes after secretin stimulation in 21 CF patients and 13 healthy controls. To clearly identify the subjects with reduced exocrine pancreatic function, we classified CF patients as pancreas-sufficient or -insufficient by secretin-stimulated endoscopic short test and faecal elastase. Pancreas-insufficient CF patients had reduced pancreatic secretions compared to pancreas-sufficient subjects based on both imaging modalities (p < 0.001). Volume output estimates assessed by s-US correlated to that of s-MRI (r = 0.56–0.62; p < 0.001). Both s-US (AUC: 0.88) and s-MRI (AUC: 0.99) demonstrated good diagnostic accuracy for exocrine pancreatic failure. Pancreatic volume-output estimated by s-US corresponds well to exocrine pancreatic function in CF patients and yields comparable results to that of s-MRI. s-US provides a simple and feasible tool in the assessment of pancreatic secretion. • Cystic fibrosis patients with affected pancreas have reduced pancreatic secretions. • Secretin-stimulated sonography is a simple and feasible method to assess pancreatic output. • Secretin-simulated MRI is a more precise method to assess pancreatic secretions. • The sonographic and MRI methods yielded comparable pancreatic secretory output estimates.

Secretin-stimulated magnetic resonance imaging (s-MRI) and pancreatic diffusion weighted imaging (DWI) are novel non-invasive imaging techniques for assessment of exocrine pancreatic insufficiency (EPI). The aim was to validate s-MRI assessed pancreatic secreted volume using novel semi-automatic quantification software, and to assess the ability of s-MRI with DWI to diagnose EPI in patients with cystic fibrosis (CF). s-MRI and DWI was performed in 19 patients with CF (median age 21 years; range 16–56; eight men) and in 10 healthy controls (HC) (median age 46 years; range 20–65; four men). Sequential coronal T2-weighted images covering the duodenum and small bowel and axial DWI were acquired before and 1, 5, 9, and 13 min after secretin stimulation. A short endoscopic secretin test was used as reference method for EPI. CF patients with EPI had lower apparent diffusion coefficient before secretin in the pancreatic head (P

Introduction Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility. Aim To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC). Subjects and methods Bristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points. Results The FGDS patients had 4 (range 1–10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response. Conclusion Despite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.

Objective Quantitative determination of fecal fat still is the gold standard for measuring malabsorption. We evaluated the importance of standardized food intake before and under the collection of feces. Material and Methods In a project, evaluating patients with suspected chronic pancreatitis (CP) and healthy volunteers (HC), stools were collected for 72 hours coupled to registration of nutritional intake over five consecutive days. Patient groups were created by a modified Layer score, which includes imaging findings, clinical parameters and pancreas function testing. Results We found 12 patients with CP, 11 patients without CP and 13 healthy individuals in our database. Median fecal fat in CP patients was 12 g/day, in non-CP patients 5 g/day and in healthy controls 5 g/day. Median fat absorption coefficient was 81% in those with chronic pancreatitis, 92% in those without CP and 92% in healthy controls. Corresponding median fat intake was 65 g/day, 68 g/day and 81 g/day in the respective groups. Spearman Rank Order Correlation between fecal fat (g/d) and fat absorption coefficient in all study subjects (n = 36) was good (-0.88 (p

BACKGROUND Gastroparesis is a motility disorder of the stomach. The symptoms are non-specific: nausea and vomiting are most common. Stomach pains, early satiety, postprandial fullness and bloating are also frequent symptoms. Current diagnostic criteria require delayed gastric emptying in the absence of any detectable mechanical obstruction. In this review article we elucidate the causes, assessment and treatment options.MATERIAL AND METHOD Structured article search in Embase and PubMed.RESULTS A number of conditions can lead to gastroparesis. The most frequent somatic cause is diabetes mellitus. Gastroparesis may also be iatrogenically inflicted by means of surgery or drugs. It may be difficult to discriminate between functional dyspepsia and idiopathic gastroparesis. Examination is based on patient history, gastroscopy and measurement of the rate of gastric emptying. Biochemical tests are also relevant for differential diagnosis. The treatment is primarily symptomatic, and consists of dietary measures, fluid therapy, drugs, gastric electrical stimulation, or endoscopic or surgical intervention in the form of insertion of a feeding tube for nutrition and abdominal relief, pyloroplasty or gastrectomy.INTERPRETATION Gastroparesis is a serious motility disorder. The condition may have significant consequences for patients, entailing reduced quality of life, reduced workforce participation and a considerable need for health assistance.

The over-the-scope clip (OTSC; Ovesco Endoscopy AG, Tubingen, Germany) has recently proven to be of great benefit for the closure of gastrointestinal defects, especially fistula following bariatric surgery [1]. Until recently, there were no good methods of removing the OTSC after unintended placement, but a newly developed dedicated cutter has proven to be efficient [2]. A 42-year-old manwho underwent sleeve gastrectomy developed a 13-mm chronic fistula at the angle of His, and an abscess into the left mediastinum. The fistula was initially unsuccessfully treated by placement of a fully covered stent. Closure with an OTSC-gc was then attempted after de-epithelialization of the edges of the fistula with argon plasma coagulation (APC2; Erbe Elektromedizin, Tubingen, Germany). After the edges of the fistula had been anchored with the Ovesco Twin grasper and pulled, suction was applied before the release of the clip.The result was total closure of the esophageal lumen, as a result of too much mucosal tissue being sucked into the cap.The total occlusion was confirmed by contrast examination (●" Fig.1). Attempts to cut the clip with APC at the maximum setting were unsuccessful and resulted in severe thermal damage to the surrounding tissue (●" Video 1). The patient fasted for 24 hours while a newly developed and commercialized DC ClipCutter (Ovesco Endoscopy AG) was acquired. By using this cutting device, it was possible to cut the OTSC into four sections (●" Fig.2) and remove it (●" Fig.3, ●" Video 1). Following removal of the clip, the surrounding tissuewasswollenand inflamed, rendering the area temporarily inaccessible for further evaluation and intervention. A covered stent was placed to bypass the fistula for a few weeks, prior to a new attempt to close the fistula. To our knowledge, this is the first description of an iatrogenic total closure of the esophagus with an OTSC. Such emergencies require adedicated cuttingdevice.Another lesson learned was to avoid suction when using the OTSC in the esophagus. Endoscopy_UCTN_Code_CPL_1AH_2AG

Udgivelsesdato: 2008-Nov Pain mechanisms in patients with chronic pancreatitis are incompletely understood and probably multifactorial. Recently, evidence from experimental human pain research has indicated that in many of these patients pain processing in the central nervous system is abnormal and mimics that seen in neuropathic pain disorders. The current review focuses on several lines of evidence supporting this hypothesis. Hence, the spontaneous and postprandial pain in chronic pancreatitis may reflect the characteristic pain features seen in patients with neuropathic pain. Biochemical and histopathological findings in tissues from patients with chronic pancreatitis are similar to those observed in patients with other nerve fibre lesions. Experimental studies have shown that patients with chronic pancreatitis show signs of spinal hyper-excitability counter-balanced by segmental and descending inhibition. Changes in the brain with cortical reorganisation to gut stimulation and increased activity in specific electroencephalographic features characteristic for neuropathic pain are also seen in patients with chronic pancreatitis. Finally, principles involved in the treatment of pancreatic pain have many similarities with those recommended in neuropathic pain disorders. In conclusion, a mechanism-based understanding of pain in chronic pancreatitis may have important implications for the treatment.

Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis.Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration.In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F=12.4, p0.001, muscle: F=11.0, p0.001) and thermally (skin: F=8.5, p0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F=9.5, p0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F=8.6, p0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied.Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.

Objectives We have recently evaluated a short endoscopic secretin test for exocrine pancreatic function. Bicarbonate concentration in duodenal juice is an important parameter in this test. Measurement of bicarbonate by back titration as the gold standard method is time consuming, expensive and technically difficult, thus a simplified method is warranted. We aimed to evaluate an automated spectrophotometric method in samples spanning the effective range of bicarbonate concentrations in duodenal juice. We also evaluated if freezing of samples before analyses would affect its results. Methods Patients routinely examined with short endoscopic secretin test suspected to have decreased pancreatic function of various reasons were included. Bicarbonate in duodenal juice was quantified by back titration and automatic spectrophotometry. Both fresh and thawed samples were analysed spectrophotometrically. Results 177 samples from 71 patients were analysed. Correlation coefficient of all measurements was r = 0.98 (p < 0.001). Correlation coefficient of fresh versus frozen samples conducted with automatic spectrophotometry (n = 25): r = 0.96 (p < 0.001) Conclusions The measurement of bicarbonate in fresh and thawed samples by automatic spectrophotometrical analysis correlates excellent with the back titration gold standard. This is a major simplification of direct pancreas function testing, and allows a wider distribution of bicarbonate testing in duodenal juice. Extreme values for Bicarbonate concentration achieved by the autoanalyser method have to be interpreted with caution. publishedVersion

The present cross-sectional study of 46 adult Danish white men and women aimed to evaluate association between intra-abdominal obesity, 4 anthropometric measurements of obesity, and combinations of 3 nonobese metabolic risk factors: systolic blood pressure of 130 mm Hg or higher, serum triglyceride concentration of more than 1.7 mmol/L, and fasting capillary blood glucose concentration of 5.6 mmol/L or more. For 80% of the subjects, intra-abdominal fat on a computed tomography scan of the abdomen using a cutoff limit of more than 144 cm(2) gave a correct classification of combinations of at least 2 of the 3 metabolic risk factors. Body mass index and waist circumference were better markers of intra-abdominal obesity than waist-to-hip ratio in receiver operating characteristic analyses (P = .0035). Body mass index of more than 26 kg/m(2) and waist circumference of more than 0.92 m classified 76% and 74% of the subjects correctly regarding combinations of the 3 nonobese metabolic risk factors. Intra-abdominal obesity was significantly stronger associated with the combinations than a raised waist-to-hip ratio (P = .016). Both body mass index and waist circumference may be used as markers of intra-abdominal obesity, whereas waist-to-hip ratio was significantly inferior. Correspondingly, both body mass index and waist circumference were better than waist-to-hip ratio to indicate combinations of the 3 nonobese metabolic risk factors.

The association between plasma fibrinogen concentration and other coronary risk factors diverged in previous studies, and the impact from complex lipoprotein patterns has not been studied. Our research involved 24 healthy subjects without coronary heart disease (control) and 22 patients who had survived having acute myocardial infarction before the age of 41 years (cases), overall 40 men and 6 women with age range of 34 to 54 years. In multiple linear regression analyses concerning control subjects, family disposition, social class, a score based on serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations, and fasting capillary blood glucose concentration were significantly associated with plasma fibrinogen concentration (P < .00005, R2 = 0.81). For case subjects, the ratio between serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentrations was significantly associated with plasma fibrinogen concentration (P = .0018, R2 = 0.39). Thus, for healthy subjects, 4 coronary risk factors explained three quarters of the variation of plasma fibrinogen concentration, and for patients with a previous acute myocardial infarction, another coronary risk factor explained one third of the variation. In conclusion, the pattern of coronary risk factors associated with plasma fibrinogen concentration differed between those without coronary heart disease and those with a previous acute myocardial infarction.

OBJECTIVE: To assess the relative importance of the extent and regional distribution of fat for metabolic risk factors in young adults. DESIGN: Cross-sectional study of findings from a hospital-based case–control study. SUBJECTS: A total of 46 adult Danish Caucasian patients (40 men and six women, aged 34–54 y). Of these, 22 had had non fatal acute myocardial infarction before 41 y of age and 24 were age- and gender-matched controls without coronary heart disease. MEASUREMENTS: Four measurements of fat: body mass index (BMI, kg/m2), body fat percentage measured using a dual energy X-ray absorptiometry (DEXA) scanner, waist/hip circumference ratio (WHR), and intra-abdominal adipose tissue area measured using computed tomography (CT) scanning, and eight metabolic risk factors: systolic and diastolic blood pressure, HbA1c percentage, fasting concentrations of capillary whole blood glucose, high-density lipoprotein (HDL) cholesterol, serum triglyceride, plasma plasminogen activator inhibitor 1 (PAI-1), and urinary albumin:creatinine excretion ratio. RESULTS: Of 46 participants, 10 were obese (BMI >30 kg/m2), 12 were abdominally obese (WHR >0.90 for men and >0.85 for women), and 20 were intra-abdominally obese (intra-abdominal adipose tissue area >135 cm2). Men had a higher intra-abdominal adipose tissue area than women (P=0.0053, Mann–Whitney U-test). In multiple regression analyses of the four fat variables, only intra-abdominal adipose tissue area significantly predicted the levels of six metabolic risk factors: systolic blood pressure, diastolic blood pressure, fasting concentrations of capillary whole blood glucose, serum HDL cholesterol, serum triglyceride, and PAI-1. The intra-abdominal adipose tissue area had a linear relation with the six metabolic risk factors. CONCLUSIONS: For young individuals, intra-abdominal fat is the important component of the body fat for six of the eight metabolic risk factors. Intra-abdominal fat might contribute to that most patients with acute myocardial infarction at a young age are men.

A new multimodal pain assessment model was developed integrating electrical, mechanical, cold, and warmth stimuli into the same device. The device, with a bag and electrodes for electrical stimulation, was positioned in the lower part of the esophagus in 11 healthy subjects. Mechanical stimuli were delivered with an impedance planimetric system. Thermal stimuli were performed by circulating water of different temperatures (5–50°C) inside the bag. All subjects reported both nonpainful and painful local and referred sensations to all stimuli. Temporal summation to repeated electrical stimuli could be studied. For all stimuli, there was a relationship between stimulus intensity and pain intensity. The referred pain area increased with increasing intensity of the electrical and mechanical stimuli. There were several differences between the sensations evoked by the four stimulus modalities, indicating activation of different visceral nerve pathways. This model offers the possibility for controlled multimodal stimuli activating the superficial and deeper layers of the human gut and should be used in basic, clinical, and pharmacological pain studies.

International audience; PURPOSE:Adenocarcinoma of the pancreas remains one of the most lethal human cancers. The high mortality rates associated with this form of cancer are subsequent to late-stage clinical presentation and diagnosis, when surgery is rarely possible and of modest chemotherapeutic impact. Survival rates following diagnosis with advanced pancreatic cancer are very low; typical mortality rates of 50% are expected within 3 months of diagnosis. However, adjuvant chemotherapy improves the prognosis of patients even after palliative surgery, and successful newer neoadjuvant chemotherapeutical modalities have recently been reported. For patients whose tumours appear unresectable, chemotherapy remains the only option. During the past two decades, the nucleoside analogue gemcitabine has become the first-line chemotherapy for pancreatic adenocarcinoma. In this study, we aim to increase the delivery of gemcitabine to pancreatic tumours by exploring the effect of sonoporation for localised drug delivery of gemcitabine in an orthotopic xenograft mouse model of pancreatic cancer.EXPERIMENTAL DESIGN:An orthotopic xenograft mouse model of luciferase expressing MIA PaCa-2 cells was developed, exhibiting disease development similar to human pancreatic adenocarcinoma. Subsequently, two groups of mice were treated with gemcitabine alone and gemcitabine combined with sonoporation; saline-treated mice were used as a control group. A custom-made focused ultrasound transducer using clinically safe acoustic conditions in combination with SonoVue® ultrasound contrast agent was used to induce sonoporation in the localised region of the primary tumour only. Whole-body disease development was measured using bioluminescence imaging, and primary tumour development was measured using 3D ultrasound.RESULTS:Following just two treatments combining sonoporation and gemcitabine, primary tumour volumes were significantly lower than control groups. Additional therapy dramatically inhibited primary tumour growth throughout the course of the disease, with median survival increases of up to 10% demonstrated in comparison to the control groups.CONCLUSION:Combined sonoporation and gemcitabine therapy significantly impedes primary tumour development in an orthotopic xenograft model of human pancreatic cancer, suggesting additional clinical benefits for patients treated with gemcitabine in combination with sonoporation.

Background Increasing evidence points to association between long-term diabetes mellitus and abnormal brain processing. The aim of this study was to investigate central changes due to electrical stimulation in esophagus in patients with upper gastrointestinal (GI) symptoms due to diabetic neuropathy. Methods Twenty-three diabetes patients with upper GI symptoms and 27 healthy controls were included. A standard ambulatory 24-h electrocardiography was carried out. 122-channel esophageal evoked brain potentials to electrical stimulation were acquired. Brain source/network analysis was performed. Gastroparesis Cardinal Symptom Index was used to evaluate upper GI symptoms and SF-36 questionnaire was utilized to assess patients' quality of life (QOL). Key Results Diabetes patients with GI symptoms showed modifications in three brain networks: (i) brainstem/operculum/frontal cortex, (ii) operculum/cingulate, and (iii) mid-cingulate/anterior-cingulate/operculum/deep limbic structures. Operculum brain source in patients was localized deeper and more anterior in all three networks. The shift of operculum source was correlated with the severity of upper GI symptoms, decreased heart beat-to-beat interval, and decreased SD of the intervals. The activation of the first network was delayed in patients. Operculum source had higher activity than cingulate in the second network in patients, and this was correlated with decreased physical QOL. Deep limbic source was localized deeper in patients, which also correlated with decreased physical QOL. Conclusions & Inferences This study indicates involvement of central nervous system in diabetes. Reorganization within opercular cortex was correlated with GI symptoms suggesting that operculo-cingulate cortex could contribute to development and maintenance of GI symptoms in diabetes patients.

The course and outcome is poor for most patients with pancreatic diseases. Advances in pancreatic imaging are important in the detection of pancreatic diseases at early stages. Ultrasonography as a diagnostic tool has made, virtually speaking a technical revolution in medical imaging in the new millennium. It has not only become the preferred method for first line imaging, but also, increasingly to clarify the interpretation of other imaging modalities to obtain efficient clinical decision. We review ultrasonography modalities, focusing on advanced pancreatic imaging and its potential to substantially improve diagnosis of pancreatic diseases at earlier stages. In the first section, we describe scanning techniques and examination protocols. Their consequences for image quality and the ability to obtain complete and detailed visualization of the pancreas are discussed. In the second section we outline ultrasonographic characteristics of pancreatic diseases with emphasis on chronic pancreatitis. Finally, new developments in ultrasonography of the pancreas such as contrast enhanced ultrasound and elastography are enlightened.

Carboxyl-ester lipase (CEL) maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes and pancreatic exocrine dysfunction due to mutations in the CEL gene encoding CEL. The pathogenic mechanism for diabetes development is unknown. Since CEL is expressed mainly in pancreatic acinar cells, we asked whether we could find structural pancreatic changes in CEL-MODY subjects during the course of diabetes development. Furthermore, we hypothesized that the diseased pancreas releases proteins that are detectable in pancreatic fluid and potentially reflect activation or inactivation of disease-specific pathways. We therefore investigated nondiabetic and diabetic CEL-mutation carriers by pancreatic imaging studies and secretin-stimulated duodenal juice sampling. The secretin-stimulated duodenal juice was studied using cytokine assays, mass spectrometry (MS) proteomics, and multiplexed MS-based measurement of kinase activities. We identified multiple pancreatic cysts in all eight diabetic mutation carriers but not in any of the four nondiabetic mutation carriers or the six healthy controls. Furthermore, we identified upregulated mitogen-activated protein kinase (MAPK) target proteins and MAPK-driven cytokines and increased MAPK activity in the secretin-stimulated duodenal juice. These findings show that subjects with CEL-MODY develop multiple pancreatic cysts by the time they develop diabetes and that upregulated MAPK signaling in the pancreatic secretome may reflect the pathophysiological development of pancreatic cysts and diabetes.

OBJECTIVELong-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms.RESEARCH DESIGN AND METHODSFifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (per short-form health survey with 36 questions) were collected.RESULTSDiabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2-P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). Cingulate source shift was correlated negatively with physical health (P = 0.005) and positively with postprandial fullness (P ≤ 0.001).CONCLUSIONSThis study provides evidence for interaction between autonomic neuropathy and peripheral nervous degeneration, as well as changes in dipole sources in diabetic patients with gastrointestinal symptoms. The findings may lead to improved treatment modalities targeting pharmacological neuroprotection or neuromodulation. OBJECTIVELong-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms.RESEARCH DESIGN AND METHODSFifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (per short-form health survey with 36 questions) were collected.RESULTSDiabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2-P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P

Clinical and morphological criteria are not precise enough to diagnose early chronic pancreatitis (CP). We investigated if short endoscopic pancreas function testing as a part of routine upper endoscopy could improve clinical diagnostics.Patients with suspected CP underwent modified secretin-stimulated upper endoscopy (short endoscopic secretin test, or EST). Duodenal juice was collected during 15 minutes starting 30 minutes after stimulation. A modified scoring system for CP after Layer with bicarbonate and fecal elastase 1 (FE1) was used. We tested with receiver operating characteristic curves the diagnostic accuracy of bicarbonate and FE1 and with analysis of variance how precise the 2 parameters can discriminate the groups.Fifty-two patients aged 19 to 67 years and 25 healthy controls aged 19 to 64 years were included. Twenty-four patients fulfilled the modified Layer Score for CP or non-CP. The overall accuracy of the EST versus FE1 test was 85%/71%, with positive and negative predictive values of 100%/79% and 80%/69%, respectively.Short EST is rapid and easy to perform and can be incorporated in daily routines. We demonstrate that EST is superior to FE1 in the assessment of pancreatic insufficiency and may prove to be useful in diagnosing early or mild CP.

Aims: Gastrointestinal complaints are common in diabetes mellitus. However, its association to peripheral sensorimotor and autonomic neuropathies is not well investigated. The aim was to assess skin, muscle, bone and visceral sensitivity in diabetes patients with sensorimotor neuropathy, and correlate these with gastrointestinal symptoms and degree of cardiac autonomic neuropathy. Methods: Twenty patients with sensorimotor neuropathy (65% type 2 diabetes, aged 58.3 ± 12.0 years, diabetes duration 15.8 ± 10.0 years) and 16 healthy controls were recruited. Cutaneous sensitivity to von Frey filaments, mechanical allodynia, muscle/bone/rectosigmoid sensitivities, and heart rate variability were examined. Gastrointestinal symptom scores (PAGI-SYM) and health-related quality of life (SF-36) were also recorded. Results: Patients displayed hypesthesia to von Frey filaments (p = 0.028), but no difference to muscle and bone pain sensitivities. Also, patients were hyposensitive to multimodal rectal stimulations (all p < 0.05), although they suffered more gastrointestinal complaints. Heart rate variability was reduced in the patient cohort. Rectal mechanical and cutaneous sensitivities correlated (p < 0.001), and both were associated with heart rate variability as well as PAGI-SYM and SF-36 scores (p < 0.01). Conclusions: In diabetic sensorimotor neuropathy there is substantial evidence of concomitant cutaneous, cardiac and visceral autonomic neuropathies. The neuropathy may reduce quality of life and explain the higher prevalence of gastrointestinal complaints. publishedVersion

The purpose of this study was to investigate the ability and efficacy of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients' quality of life and extend the low Eastern Cooperative Oncology Group performance grade; as a result increasing the overall survival in patients with pancreatic adenocarcinoma.Patients were treated using a customized configuration of a commercial clinical ultrasound scanner over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue(®) ultrasound contrast agent was injected intravascularly during the treatment with the aim to induce sonoporation.Using the authors' custom acoustic settings, the authors' patients were able to undergo an increased number of treatment cycles; from an average of 9 cycles, to an average of 16 cycles when comparing to a historical control group of 80 patients. In two out of five patients treated, the maximum tumor diameter was temporally decreased to 80 ± 5% and permanently to 70 ± 5% of their original size, while the other patients showed reduced growth. The authors also explain and characterize the settings and acoustic output obtained from a commercial clinical scanner used for combined ultrasound microbubble and chemotherapy treatment.It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles, prolonging the quality of life in patients with pancreatic adenocarcinoma compared to chemotherapy alone.

The impact of pancreatic dysfunction in several diseases of the pancreas, including chronic pancreatitis and cystic fibrosis, is obscured by concomitant extra-pancreatic disease. Carboxyl-ester lipase-maturity-onset diabetes in the young (CEL-MODY) is a monogenic, highly penetrant and progressive pancreatic disease with no known primary extrapancreatic manifestations. It is characterized by low fecal elastase, steatorrhea, and development of diabetes mellitus. We sought to determine the nature of the exocrine dysfunction in CEL-MODY and relate the findings to clinical parameters of malnutrition.We examined CEL-MODY patients and control subjects by rapid, endoscopic secretin test and dynamic magnetic resonance imaging of the pancreas. The findings were related to the subjects' clinical status.The CEL-MODY patients displayed severely reduced acinar function and moderately reduced ductal function of the pancreas compared with control subjects. Surprisingly, CEL-MODY patients did not have clinical or biochemical signs of malnutrition, except for subnormal levels of vitamin E. Vitamin E levels seemed to be directly related to pancreatic acinar function.Pancreatic exocrine dysfunction in CEL-MODY is associated with severely reduced acinar and moderately reduced ductal dysfunction. Despite severely reduced exocrine pancreatic function, CEL-MODY patients revealed only minor signs of malnutrition.

Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0.03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0.03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies.

To examine the exocrine pancreatic function in carriers of the hepatocyte nuclear factor 1β gene (HNF1B) mutation by direct testing.Patients with HNF1B mutations and control subjects were assessed using rapid endoscopic secretin tests and secretin-stimulated magnetic resonance imaging. Seven patients and 25 controls underwent endoscopy, while eight patients and 20 controls had magnetic resonance imaging. Ductal function was assessed according to peak bicarbonate concentrations and acinar function was assessed according to peak digestive enzyme activities in secretin-stimulated duodenal juice. The association of pancreatic exocrine function and diabetes status with pancreatic gland volume was examined.The mean increase in secretin-stimulated duodenal fluid was smaller in patients than controls (4.0 vs 6.4 ml/min; P = 0.003). We found lower ductal function in patients than controls (median peak bicarbonate concentration: 73 vs 116 mEq/L; P0.001) and lower acinar function (median peak lipase activity: 6.4 vs 33.5 kU/ml; P = 0.01; median peak elastase activity: 0.056 vs 0.130 U/ml; P = 0.01). Pancreatic fluid volume outputs correlated significantly with pancreatic gland volumes (r² = 0.71, P = 0.008) in patients. The total fluid output to pancreatic gland volume ratios were higher in patients than controls (4.5 vs 1.3 ml/cm³; P = 0.03), suggesting compensatory hypersecretion in the remaining gland.Carriers of the HNF1B mutation have lower exocrine pancreatic function involving both ductal and acinar cells. Compensatory hypersecretion suggests that the small pancreas of HNF1B mutation carriers is attributable to hypoplasia, not atrophy.