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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

Purpose Computed tomography (CT) is the most used imaging modality for diagnosing chronic pancreatitis (CP), but advances in transabdominal ultrasound (US) technology have given US a position as a viable alternative. We aimed to evaluate the diagnostic accuracy of abdominal CT and pancreatic US compared to the reference standard, a modified Mayo score. Materials and Methods CT, US, and endoscopic ultrasound (EUS) were performed in patients referred due to suspected CP. The modified Mayo score included EUS results, clinical presentation, and results from exocrine and endocrine pancreatic function tests. We scored CT findings according to the modified Cambridge classification and US findings according to the Rosemont classification. Results In total, 73 patients were included. 53 patients (73%) were categorized as CP and 20 (27%) as non-CP. CT and US yielded similar sensitivities (68% and 64%, respectively) and specificities (75 and 85%, respectively) and similar areas under the receiver operating characteristic curves for diagnosing CP. We found no significant differences between the areas under the receiver operating characteristic curves (AUROCs) for CT (AUROC 0.75, 95% CI 0.63–0.87) and US (AUROC 0.81, 95% CI 0.71–0.91). Conclusion We conclude that CT and US had comparable, moderate accuracy in diagnosing CP. Neither modality had high enough sensitivity to exclude the diagnosis as a standalone method.

Purpose: Determining gastric emptying is mandatory in the diagnosis of diabetic gastroparesis. Several methods of investigation exist, but none has proven reliable, inexpensive and accessible. In this study, we aimed to compare gastric emptying of radiopaque markers (ROM) and 13carbon-labelled gastric emptying breath tests for solids (GEBT). We also aimed to determine any association between gastric emptying and patient-reported symptoms, glycemic control and the patients' age, diabetes duration and occurrence of other late complications. Patients and methods: Forty-five patients (30 women, 15 men) with diabetes mellitus types 1 or 2 (40, 5) and symptoms of gastroparesis were examined with ROM and GEBT. All were interviewed, filled out symptom questionnaires and had HbA1c levels measured. Results: Forty percent of patients had delayed gastric emptying of ROM, while 55% had delayed gastric emptying of GEBT. Correlation between ROM and GEBT was not significant. Compared to GEBT, sensitivity for a positive ROM test was 0.52, while specificity was 0.74. In women, we found a higher specificity of 0.92, sensitivity 0.47. Difference in HbA1c between patients with positive and negative results was of borderline significance for both tests. GEBT (r=0.41, P=0.008) correlated with HbA1c. Patients with any late complications of diabetes had higher gastric retention of ROM (P=0.028), while patients with polyneuropathy (P=0.014) and diabetic wounds (P=0.004) had slower emptying with GEBT. None of the methods identified significant associations between gastric emptying and symptom scores, age or diabetes duration. Conclusions: As a measure of gastric emptying, the ROM test has benefits of being affordable and available. Compared to GEBT, the method has low diagnostic reliability. Before continued use, we recommend additional studies validating the test in diabetes patients.

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.

Mattis Bekkelund,1,2 Dag A Sangnes,2– 4 Eirik Søfteland,3– 5 Lars Aabakken,1,6 Martin Biermann,4,7 Elisabeth K Steinsvik,2,4,8 Trygve Hausken,2,8 Georg Dimcevski,4,8 Jan Gunnar Hatlebakk2– 4 1Department of Clinical Medicine, University of Oslo, Oslo, Norway; 2Norwegian Competence Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, Norway; 3Department of Medicine, Haukeland University Hospital, Bergen, Norway; 4Department of Clinical Medicine, University of Bergen, Bergen, Norway; 5Hormone Laboratory, Haukeland University Hospital, Bergen, Norway; 6Department of Transplantation Medicine, Section for Gastroenterology, Oslo University Hospital, Oslo, Norway; 7Centre for Nuclear Medicine and PET, Department of Radiology, Haukeland University Hospital, Bergen, Norway; 8National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, NorwayCorrespondence: Mattis BekkelundNorwegian Competence Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, 5021, NorwayTel +47 48 18 68 97Email mattis.bekkelund@hotmail.comObjective: Gastric emptying measurements are mandatory in gastroparesis diagnostics, but the association between delayed emptying and symptoms is questionable. It is imperative to find biomarkers better correlated to symptom generation. Hence, we examined the association between symptom severity and gastrointestinal motility measured by wireless motility capsule.Patients and Methods: In this prospective single-centre study, patients with gastroparesis symptoms were simultaneously investigated with gastric emptying scintigraphy and wireless motility capsule, measuring regional transit times and contractility parameters. Symptom severity was assessed with the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM), including the Gastroparesis Cardinal Symptom Index (GCSI).Results: We included 107 patients (70% women). In the whole patient group, nausea correlated with the gastric (rs = − 0.31, p = 0.007), small bowel (rs = − 0.41, p < 0.001) and colonic (rs = − 0.33, p = 0.012) motility indices. In patients with idiopathic etiology, nausea correlated with small bowel motility index (rs = − 0.81, p < 0.001) and mean stomach pressure (rs = − 0.64, p = 0.013). We also found negative correlations between total GCSI score and maximum pressure of the small bowel (rs = − 0.77, p < 0.001) and colon (rs = − 0.74, p = 0.002). In diabetes patients, total PAGI-SYM score correlated with colonic motility index (rs = − 0.34, p = 0.012), and mean pressure of the colon correlated with upper abdominal pain (rs = − 0.37, p = 0.007). We found no association between symptoms, gastric emptying nor any other transit times.Conclusion: In patients with gastroparesis symptoms, we found that symptom severity was associated with intestinal hypomotility. Based on these results, gastroparesis diagnostics should also include an evaluation of the small bowel and colon.Keywords: gastric emptying, gastrointestinal motility, gastroparesis, gastroparesis-like syndrome, small bowel, wireless motility capsule, scintigraphy

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

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.

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.

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

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 causes significant morbidity and treatment options are limited. TZP-102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double-blind, placebo-controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once-daily administrations of 10-mg (n = 22), 20-mg (n = 21), 40-mg (n = 23) TZP-102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half-emptying time (T½) utilizing 13C-breath test methodology and secondary endpoints included symptom improvement using patient-reported gastroparesis symptom scores (PAGI-SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T½ changes were not statistically significant between TZP-102 and placebo after 28 days of treatment at any dose. Clinical improvements (−1.0 to −1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI-SYM, which was significant vs placebo for all TZP-102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP-102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP-102 doses were well-tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions & Inferences TZP-102 for 28 days, at doses of 10–40 mg once daily, was well-tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient-defined outcomes in determining therapeutic benefit.

International audience; Background: Pancreatic Adenocarcinoma (PDAC)represents one of the most lethal human cancers. Surgery is often unfeasible, and the tumors respond poorly to radiation or chemotherapeutic drugs. Consequently, pancreatic cancer represents a huge burden to society and the need for new therapeutic options is evident. Experimental research using ultrasound to improve therapeutic delivery has soared in the past decade. We aimed toevaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary goal was to develop a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance grade, and prolongation of survival. Methods: Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of enhancing therapeutic efficacy. Results: The combined therapeutic regimen did not induce any additional toxicity or increase side effect frequency when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls (n = 63 patients; average of 8.3±6.0 cycles, versus 13.8±5.6 cycles). In five patients, the maximum tumor diameter was decreased during treatment. The median survival in our patients was also increased from 7.0 months to 17.6 months (p = 0.0044). Conclusions: We perform the first-in-human study evaluating the toxicity and efficacy of ultrasound and microbubble enhanced chemotherapy. It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting with no additional toxicity. This combined treatment may improve the clinical efficacy of chemotherapeutic agents, prolong the quality of life, and extend survival in patients with PDAC. Clinical trial information: NCT01674556.

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

International audience; Experimental research of ultrasound to induce or improve delivery has snowballed in the past decade. In our work, we investigate the use of low-intensity ultrasound in combination with clinically approved microbubbles to enhance the therapeutic efficacy of chemotherapy. Ten voluntary patients with locally advanced or metastatic pancreatic adenocarcinoma were consecutively recruited. Following standard chemotherapy protocol (intravenous infusion of gemcitabine over 30 min), a clinical ultrasound scanner was targeted at the largest slice of the tumour using modified non-linear contrast imaging settings (1.9 MHz center frequency, 0.27 MPa peak-negative pressure), and SonoVue® was injected intravenously. Ultrasound and microbubble treatment duration was 31.5 min. The combined therapy did not induce any additional toxicity or increase side effect frequency when compared to chemotherapy alone. Combination treated patients were able to tolerate an increased amount treatment cycles when compare historical controls (n = 63); average of 8.3±6.0 cycles, versus 13.8±5.6 cycles. The median survival also increased from 7.0 months to 17.6 months (p = 0.0044). In addition, five patients showed a primary tumor diameter decrease. Combined treatment of ultrasound, microbubbles, and gemcitabine does not increase side effects and may have the potential to increase the therapeutic efficacy of chemotherapy in patients with pancreatic adenocarcinoma.

Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system (CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal (GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testing mainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes, especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.

Eur J Clin Invest 2010; 40 (10): 883–886 Abstract Background Acute hyperglycaemia is known to increase gastrointestinal (GI) sensitivity in healthy subjects and may contribute to the increased prevalence of GI symptoms in diabetes patients. The aim of this study was to evaluate the effect of acute hyperglycaemia on perception and brain responses to painful visceral and somatic stimuli in diabetic patients. Materials and methods The sensitivity and evoked brain potentials (EPs) to electrical oesophageal and median nerve stimulations were assessed in 14 type-1 diabetes patients with autonomic neuropathy and GI symptoms using a hyperinsulinaemic clamp at 6 and 15 mM. Results No differences between the normo- and hyperglycaemic conditions were found in sensitivity to both oesophageal (P = 0·72) and median nerve (P = 0·66) stimulations. The latencies and amplitudes of EPs did not differ between the normo- and hyperglycaemic conditions following oesophageal (P = 0·53 and 0·57) and median nerve (P = 0·78 and 0·52) stimulations. Conclusions Acute hyperglycaemia itself does not contribute to the sensations in patients with longstanding diabetes and autonomic neuropathy. Any potential sensory effects of acute hyperglycaemia can likely be blurred by the neuropathic-like changes in the sensory nervous system.

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.

International audience; ObjectivesThe objectives of this Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and to possibly increase the overall survival in patients with pancreatic adenocarcinoma.Methods10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner (GE LOGIQ 9) over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T = 30.0, 33.5, 37.0, 40.5, 44.0, 47.5, 51.0, 54.5, and 58.0min. A single vial (4.5 ml) was used throughout each treatment. Treatment was stopped at T=61.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min.ResultsUsing the authors’ custom acoustic settings, the 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated (published data, ref below), 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. Compared to historical data, there was increased survival with 60% of patients surviving 12 months (versus 10% in literature).ConclusionsIt 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. Our study also indicates increased survival in patients with inoperable pancreatic adenocarcinoma. Ref: Medical Physics, Vol. 40, No. 7, July 2013.

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.