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

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

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

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

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

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

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

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

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

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

Importance of localization of insulinomas: a systematic analysis.

BACKGROUND: Procedures suitable for preoperative localization of insulinomas are widely used but it is unclear whether they determine surgical success. We wanted to clarify whether preoperative localization or intraoperative ultrasound determines the success of surgically identifying and removing insulinomas. METHODS: We performed a systematic literature search (PubMed) yielding 100 publications with patient-level data on preoperative localization procedures, intraoperative ultrasound, success of surgical identification and removal or single, benign insulinomas (published until 31 December 2016). The consequences of successful preoperative localization and intraoperative ultrasound for surgical identification and removal of an insulinoma could be analyzed for 863 and 529 patients with single benign insulinomas, respectively. Sensitivities of commonly employed methods to localize biochemically proven insulinomas were calculated for single benign (1,153 patients), multiple benign, and malignant insulinomas, also in relation to diameter and intra-pancreatic location. RESULTS: The success of surgery (identification and removal of single benign insulinomas) in patients with a biochemically proven insulinoma was high (approximately 98%) even in the absence of preoperative localization. However, successful preoperative localization or intraoperative ultrasonography slightly, but significantly, increased the probability of surgically identifying/removing single benign insulinomas (by 1.4% and 2.0%, P = 0.012 and 0.0032, respectively). Diagnostic sensitivities of localization procedures varied widely, with GLP-1 receptor scintigraphy achieving the highest sensitivity despite its non-invasive nature. CONCLUSION: The probability of surgically identifying and removing a single, benign insulinoma is high even in the absence of successful preoperative localization or intraoperative ultrasound. However, both approaches slightly, but significantly, improve the outcome to near 100%.

Sarcoidosis of the Intra- and Extrahepatic Bile Ducts with Concomitant Cholangitis in a Patient with Ulcerative Colitis.

Cholangitis in patients with ulcerative colitis (UC) can lead to misdiagnosis of primary sclerosing cholangitis (PSC). Furthermore, it can mimic cholangiocellular carcinoma, which also can lead to inappropriate and potentially harmful treatment of the patient. An 18-year-old male patient with known UC presented with pain in his right upper abdomen and elevation of the cholestatic liver enzymes (alkaline phosphatase: 197 U/L, γ-glutamyltransferase: 229 U/L) and increased inflammatory parameters (leukocytosis and CrP of 13.6 mg/L). Magnetic resonance cholangiopancreatography revealed unclear stenosis in the bifurcation of the main hepatic bile duct as well as in the prepapillary bile duct. Ultrasound (US) examination and endoscopic retrograde cholangiopancreatography showed dilatation of the intra -and extrahepatic bile ducts, which raised the suspicion of PSC. US image with dilated intra- and extrahepatic dilatation of the bile duct was also suggestive for autoimmune cholangitis. However, serum analysis revealed an elevated soluble interleukin-II receptor (1,305 U/mL), while immunoglobulin G4 was within normal ranges. Liver biopsy demonstrated hepatic inflammation and presence of granulomatous cells within the portal fields - convenient to sarcoidosis. After starting treatment with steroids, we observed a rapid clinical response with improvement of the dilated bile ducts and decrease of the initially elevated cholestatic liver enzymes. Sarcoidosis within the bile duct is a rare condition. Steroids are the treatment of choice and - along with the histology - are furthermore helpful to differentiate between several potential differential diagnoses like IgG4 cholangitis, primary biliary cholangitis, or PSC.

Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans.

INTRODUCTION: Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans. PATIENTS AND METHODS: Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35). RESULTS: Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63). CONCLUSIONS: These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.

Noninvasive estimation of disease activity and liver fibrosis in nonalcoholic fatty liver disease using anthropometric and biochemical characteristics, including insulin, insulin resistance, and 13C-methionine breath test.

OBJECTIVE: The purpose of this study was to noninvasively estimate disease activity and liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) using anthropometric and biochemical characteristics and the C-methionine breath test (MeBT). METHODS: A total of 164 patients with histologically proven NAFLD and 56 healthy controls were included in the study. Anthropometric and biochemical analyses and the MeBT were performed on all patients and controls. RESULTS: BMI; waist circumference; waist-hip ratio; transaminase, lipid, γ-glutamyl transpeptidase (GGT), glucose, and insulin levels; and insulin resistance were significantly higher in patients with NAFLD than in controls. The GGT level and the MeBT were independent predictors of nonalcoholic steatohepatitis (NASH). Fibrosis was correlated with GGT, bilirubin, cholesterol, and insulin levels, and the MeBT, but the test was the only independent predictor of significant fibrosis. Patients with simple steatosis had similar MeBT values as controls. The MeBT values were significantly lower in NASH and NASH-cirrhosis patients (P<0.001) compared with simple steatosis patients and controls. Patients with advanced fibrosis (F2-3) had significantly lower MeBT values than patients with mild fibrosis (F0-1; P<0.001). The area under the receiving operating characteristic curve for NASH and advanced fibrosis was estimated to be 0.95 in the total cohort. CONCLUSION: This study indicates that anthropometric and biochemical parameters are insufficient for estimating the presence of NASH or the fibrosis stage. However, the MeBT is a suitable noninvasive method for accurately predicting which patients suffer from simple steatosis, NASH, or NASH-cirrhosis.

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

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

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

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

Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease.

OBJECTIVE: In this cross-sectional study, we investigated whether there is evidence for hepatic mitochondrial dysfunction in manifest and/or premanifest Huntington disease (HD) by using the ¹³C-methionine breath test. METHODS: The ¹³C-methionine breath test was performed within a group of 21 patients with early manifest HD without medication, 30 premanifest mutation carriers, as well as 36 healthy controls. Premanifest mutation carriers were stratified into the 2 groups preHD-A (further from predicted onset) and preHD-B (nearer) based on a calculation of the probability of estimated disease onset within 5 years. The ¹³C-methionine breath test was performed after an overnight fasting, breath samples were analyzed by nondispersive isotope-selective infrared spectroscopy, and results expressed as percentage dose recovered after 90 minutes of testing time. Statistical analyses comprised analysis of covariance and post hoc t tests. RESULTS: Patients with manifest HD and mutation carriers from our preHD-B group revealed a lower amount of exhaled ¹³CO2 compared with healthy controls (p < 0.001 and p = 0.017, respectively). In a stepwise linear regression model, breath test results correlate to functional and cognitive scores of the Unified Huntington's Disease Rating Scale in manifest and also in premanifest HD. For all mutation carriers together, there was a weak but significant correlation of breath test results to ratio caudate volume/total intracranial volume. CONCLUSION: This study demonstrates for the first time in vivo a subclinical, hepatic involvement in manifest and premanifest HD.

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

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

Impaired crosstalk between pulsatile insulin and glucagon secretion in prediabetic individuals.

INTRODUCTION: Postprandial hyperglucagonemia is frequently found in patients with diabetes. Recently, a loss of the inverse relationship between pulsatile insulin and glucagon secretion has been reported in patients with type 2 diabetes. The crosstalk between pulsatile islet hormone secretion in prediabetic individuals has not yet been examined. PATIENTS AND METHODS: Eleven individuals with impaired glucose tolerance and/or impaired fasting glucose and 13 nondiabetic controls were examined after mixed meal ingestion. Glucose, insulin, and glucagon levels were determined frequently and analyzed by deconvolution and cross-correlation methods. RESULTS: Postprandial glucose levels were higher in prediabetic individuals (P = 0.017). Insulin concentrations were not different between the groups (P = 0.29). Postprandial glucagon levels were higher in the impaired glucose tolerance/impaired fasting glucose individuals (P = 0.039). Pulsatile insulin and glucagon secretion was apparent in both groups, but there were no differences in the frequency or mass of insulin and glucagon pulses between the groups. An inverse relationship between the insulin and glucagon concentration time curves was found in the control subjects (P < 0.05). This association was not detectable in the prediabetic individuals. CONCLUSIONS: Increased postprandial glucagon concentrations in prediabetic individuals are accompanied by a loss of the pulsatile insulin-glucagon crosstalk. This suggests that disturbances in islet hormone pulsatility precede the actual manifestation of hyperglycemia.

Long-term recovery of ß-cell function after partial pancreatectomy in humans.

Glucose homeostasis is significantly altered immediately after partial pancreatectomy. The present study examined the long-term consequences of a hemipancreatectomy in 10 patients with chronic pancreatitis and 10 patients with benign pancreatic and extrapancreatic tumors. A 240-minute oral glucose challenge was performed before and shortly after pancreatic surgery, as well as after a follow-up of 3.1 ± 0.5 years. Plasma concentrations of glucose, insulin, and C-peptide were determined; and indices of insulin sensitivity and insulin secretion were calculated. In both groups of patients, fasting and postchallenge glucose concentrations were significantly altered immediately after surgery, but returned to preoperative levels at the time of follow-up (P < .0001). Postchallenge insulin and C-peptide concentrations were reduced immediately after surgery (P < .0001), but were partly normalized at the time of follow-up (P < .0001). These changes were not accompanied by improvements in insulin sensitivity (Matsuda index). However, the oral disposition index revealed a significant recovery of ß-cell function at the time of follow-up (P < .05). These findings demonstrate a capacity for recovery of glucose control after partial pancreatectomy and suggest that ß-cell function can improve significantly over time even in adult humans.

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

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

Hepatic mitochondrial dysfunction in Friedreich ataxia.

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

Chronic reduction of fasting glycemia with insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes.

OBJECTIVE: Insulin secretion is often diminished in hyperglycemic patients with type 2 diabetes. We examined whether chronic basal insulin treatment with insulin glargine improves glucose-induced insulin secretion. RESEARCH DESIGN AND METHODS: Fourteen patients with type 2 diabetes on metformin monotherapy received an add-on therapy with insulin glargine over 8 weeks. Intravenous glucose tolerance tests (IVGTTs) were performed before and after the intervention, with and without previous adjustment of fasting glucose levels using a 3-h intravenous insulin infusion. RESULTS: Fasting glycemia was lowered from 179.6 ± 7.5 to 117.6 ± 6.5 mg/dL (P < 0.001), and HbA(1c) levels declined from 8.4 ± 0.5 to 7.1 ± 0.2% (P = 0.0046). The final insulin dose was 59.3 ± 10.2 IU. Acute normalization of fasting glycemia by intravenous insulin reduced C-peptide levels during the IVGTT (P < 0.0001). In contrast, insulin and C-peptide responses to intravenous glucose administration were significantly greater after the glargine treatment period (P < 0.0001, respectively). Both first- and second-phase insulin secretion increased significantly after the glargine treatment period (P < 0.05, respectively). These improvements in insulin secretion were observed during both the experiments with and without acute adjustment of fasting glycemia. CONCLUSIONS: Chronic supplementation of long-acting basal insulin improves glucose-induced insulin secretion in hyperglycemic patients with type 2 diabetes, whereas acute exogenous insulin administration reduces the ß-cell response to glucose administration. These data provide a rationale for basal insulin treatment regiments to improve postprandial endogenous insulin secretion in hyperglycemic patients with type 2 diabetes.

Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes.

OBJECTIVE: In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known. RESEARCH DESIGN AND METHODS: Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals. RESULTS: Both insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes. CONCLUSIONS: Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin-glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.