A rare cause of hemosuccus pancreaticus diagnosed with endoscopic ultrasound.

INTRODUCTION: Hemosuccus pancreaticus (HP), hemorrhage from the papilla of Vater through the pancreatic duct (PD), is a rare cause of upper gastrointestinal bleeding. It may be caused by chronic pancreatitis, pseudoaneurism and pancreatic tumors. Only 2% of HP involves the hepatic arteries. Endoscopic ultrasound (EUS) may not only visualize the presence of HP, previously seen on computed tomography/magnetic resonance imaging (CT/MRI), but also reveal additional pathology. CASE REPORT: A 62-year-old man was admitted with severe intermittent gastrointestinal bleeding. He underwent gastroscopy, colonoscopy and capsule endoscopy without sign of bleeding. The patient had no previous history of pancreatitis or infection. On CT and MRI scan with angiography, an aneurism of the common hepatic artery (CHA) was found, with a dilatation of the main PD toward the tail of the pancreas, but no apparent source of bleeding. EUS was then performed, and could show a partial thrombosed aneurysm of a hepatica with a diameter of 5 cm. In addition, a narrow fistula between the hepatic artery and PD could be identified using power Doppler. The patient was subsequently operated, which revealed a thrombosed arteriosclerotic aneurysm in the CHA with fistula to the PD. CONCLUSION: To the best of our knowledge, this is the second reported case of a severe gastrointestinal bleeding due to a fistula between the CHA and PD. The use of EUS in diagnosing this rare condition has not been reported before, but seems feasible.

The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy.

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.

Central response to painful electrical esophageal stimulation in well-defined patients suffering from functional chest pain.

BACKGROUND: Functional chest pain (FCP) of presumed esophageal origin is considered a common cause for chest pain in which central nervous system hyperexcitability is thought to play an important role. We aimed to compare cerebral responses with painful esophageal stimuli between FCP patients and healthy subjects (HS). METHODS: Thirteen patients with FCP (seven females, mean age 50.4 ± 7.5 years) and 15 HS (eight females, mean age 49.1 ± 12.9 years) were enrolled. Inclusion criteria consisted of typical chest pain, normal coronary angiogram, and normal upper gastrointestinal evaluation. Electrical stimulations evoking the pain threshold were applied in the distal esophagus, while cortical evoked potentials were recorded from the scalp. Pain scores, resting electroencephalogram (EEG), evoked potential characteristics and brain electrical sources to pain stimulation were compared between groups. KEY RESULTS: No differences were seen between patients and HS regarding (i) pain thresholds (patients: 20.1 ± 7.4 mA vs HS: 22.4 ± 8.3 mA, all P > 0.05), (ii) resting-EEG (P > 0.05), (iii) evoked brain potential latencies (N2: patients 181.7 ± 25.7 mS vs HS 182.2 ± 25.8 mS, all P > 0.05) and amplitudes (N2P2: patients 8.2 ± 7.2 µV vs HS: 10.1 ± 3.4 µV, all P > 0.05), (iv) topography (P > 0.05), and (v) brain source location (P > 0.05). CONCLUSIONS & INFERENCES: No differences in activation of brain areas to painful esophageal stimulation were seen in this group of well characterized patients with FCP compared with sex- and age-matched HS. The mechanism of pain in FCP and whether it originates in the esophagus remains unsolved.

Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study.

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.

Exocrine pancreatic function in hepatocyte nuclear factor 1ß-maturity-onset diabetes of the young (HNF1B-MODY) is only moderately reduced: compensatory hypersecretion from a hypoplastic pancreas.

OBJECTIVES: To examine the exocrine pancreatic function in carriers of the hepatocyte nuclear factor 1ß gene (HNF1B) mutation by direct testing. METHODS: 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. RESULTS: 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; P < 0.001) 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. CONCLUSION: 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.

A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis.

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 (T(½)) utilizing (13)C-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.

Esophageal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients.

BACKGROUND: Gastrointestinal (GI) symptoms, such as nausea, vomiting, bloating, postprandial fullness, and abdominal pain, are frequent in patients with diabetes mellitus (DM). The pathogenesis is complex and multi-factorial. To determine easy accessible and valid biomarkers for disordered GI function in DM patients, we aimed to study esophageal mechanical parameters and their relation to symptoms typically arising from the digestive tract. METHODS: Seventeen patients with longstanding DM and GI symptoms and 13 healthy controls were studied using ultrasound monitored esophageal distension. The sensory response was recorded and their symptoms registered. Biomechanical parameters, such as compliance and stiffness were computed from luminal diameters during distension based on the ultrasound images and from pressure data. Biomechanical and sensory parameters were correlated with the clinical data. KEY RESULTS: Diabetes patients had reduced esophageal sensitivity compared with controls (P = 0.046). The esophageal compliance was reduced (P = 0.004) and the esophageal stiffness was increased (P = 0.004) in the diabetes patients. Among patients, both postprandial fullness/early satiety and bloating correlated negatively to the esophageal compliance parameters (all P < 0.05). CONCLUSIONS & INFERENCES: Patients with long-standing DM and GI symptoms had reduced esophageal sensitivity together with reduced compliance and increased stiffness, which were correlated to the patients' GI symptoms. Biomechanical parameters obtained during distension may serve as biomarker for similar pathophysiologic effects of diabetes in the stomach and small bowel. They may contribute to our understanding of the pathophysiology underlying GI dysfunction and symptoms in patients with longstanding DM.

Effects of isolated hyperinsulinaemia on sensory function in healthy adults.

AIMS: Gastrointestinal symptoms such as pain, bloating, nausea and vomiting are more frequent in pre-diabetic states as well as established diabetes, compared to healthy individuals. The mechanisms behind these symptoms are multi-factorial and complex. Furthermore, the effect of isolated hyperinsulinaemia on visceral and peripheral sensory function is poorly understood. Thus, the current study aimed to evaluate effects of acute hyperinsulinaemia on sensory function in healthy adults. METHODS: The sensitivity to electrical oesophageal and median nerve stimulation was assessed in 15 healthy volunteers together with recording of evoked brain potentials. All subjects were studied both fasting and using a euglycaemic hyperinsulinaemic clamp. RESULTS: There was on average a 15% increased sensitivity to oesophageal electrical stimulation during hyperinsulinaemia compared to fasting state (P<0.05), but the sensation after median nerve stimulation remained stable (P=0.58). No significant changes in latencies and amplitudes of evoked brain potentials were observed after oesophageal or median nerve stimulation (all P>0.05). CONCLUSIONS: This study suggests that acute isolated hyperinsulinaemia increases visceral sensitivity, but does not influence the somatic sensory function. The lack of changes in the evoked brain potentials may indicate that hyperinsulinaemia affects the visceral sensory system at a peripheral level. Our result suggests distinct functions of insulin in the various parts of the nervous system, and yields further clues to the significance of insulin as a satiety signal.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Pain in chronic pancreatitis: the role of neuropathic pain mechanisms.

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.

Geometric and mechanosensory properties of the sigmoid colon evaluated with magnetic resonance imaging.

The aim of this study was to use magnetic resonance imaging (MRI) to evaluate the three-dimensional geometry and mechanosensory properties of the sigmoid colon. The sigmoid colon was stepwise distended by a water-filled bag in eight subjects. Simultaneous MRI, bag pressure recording and sensory assessment were performed before and after smooth muscle relaxation with butylscopolamine. The surface distributions of principal curvature radii, wall thickness, tension, stress and circumferential strain were calculated. The geometry of the distended sigmoid colon was complex and the spatial distributions of the biomechanical parameters were non-homogeneous. The circumferential length, strain, pressure and wall stress increased as a function of bag volume (all P < 0.001). In response to butylscopolamine, the pressure and wall stress were reduced (P < 0.05) and the stress-strain curves were shifted to the right. The sensory response was a linear function of the biomechanical parameters (all P < 0.001) and decreased in response to butylscopolamine as a function of volume (P = 0.02). The stimulus-response data indicate that the mechanosensitive afferents are affected by smooth muscle tone. The present study provides a method for characterizing the complex geometry and mechanical properties of the sigmoid colon, including the role of smooth muscle tone. This may be valuable in understanding of the biomechanical and mechanosensory functions in colonic diseases.

Cortical changes to experimental sensitization of the human esophagus.

Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.

Cerebral processing of painful oesophageal stimulation: a study based on independent component analysis of the EEG.

BACKGROUND AND AIMS: Independent component analysis (ICA) of the electroencephalogram (EEG) overcomes many of the classical problems in EEG analysis. We used ICA to determine the brain responses to painful stimulation of the oesophagus. METHODS: Twelve subjects with a median age of 41 years were included. With a nasal endoscope, two series of 35 electrical stimuli at the pain threshold were given to the distal oesophagus and the EEG was subjected to ICA. The sessions were separated by 30 minutes. For each component head models, event related images, spectral perturbation, coherence analysis, and dipoles were extracted. The most valid components were found according to time/frequency information and reliability in both experiments. RESULTS: Reliable components with the most valid dipoles were found in the thalamus, insula, cingulate gyrus, and sensory cortex. Time locked activities were consistent with upstream activation of these areas, and cross coherence analysis of the sources demonstrated dynamic links in the beta(14-25 Hz) and gamma(25-50 Hz) bands between the suggested networks of neurones. The thalamic components were time and phase locked intermittently, starting around 50 ms. In the cingulate gyrus, the posterior areas were always firstly activated, followed by the middle and anterior regions. Components with dipoles in the sensory cortex were localised in several regions of the somatosensory area. CONCLUSIONS: The method gives new information relating to the localisation and dynamics between neuronal networks in the brain to pain evoked from the human oesophagus, and should be used to increase our understanding of clinical pain.

Intra-abdominal obesity and metabolic risk factors: a study of young adults.

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/m(2)), 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, HbA(1c) 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/m(2)), 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 cm(2)). 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.

Recurrence of urogenital Chlamydia trachomatis infection evaluated by mailed samples obtained at home: 24 weeks' prospective follow up study.

OBJECTIVES: To evaluate the rate of recurrence of genital Chlamydia trachomatis infection after antibiotic therapy in a population of patients drawn from general practice, and to evaluate whether retesting after antibiotic therapy was advisable and, if so, whether it could be based on a strategy involving samples obtained at home and mailed to the laboratory for analysis. METHODS: Prospective follow up study of 42 patients with genital C trachomatis infection drawn from general practice. Patients at or above the age of 18, with a positive urogenital swab sample obtained by a general practitioner were invited to participate. Follow up testing was based on LCR testing (LCx, Abbott diagnostics) of first void urinary and vaginal flush samples taken by the patients at home and mailed to the laboratory at weeks 2, 4, 8, 12, and 24 after antibiotic therapy. RESULTS: Cumulated incidence of recurrent infection was calculated to 29% (95% CI: 12%-46%) during the 24 weeks of follow up. Previous or present sexually transmitted diseases other than C trachomatis were significantly associated with recurrence (OR 6.1, p = 0.03). 89% of patients tested negative at week 2, and all patients tested negative at some point during the first 4-8 weeks. 84% of the test kits mailed to the patients were returned to the laboratory for analysis. CONCLUSIONS: Recurrence of C trachomatis after antibiotic treatment is a substantial problem. Retesting should be carried out, but not sooner than 12-24 weeks after treatment. Requiring patients to take tests at home appears to be a promising method for retesting.