Search

Background & aims: To investigate the acute effects of intravenous vs enteral meal administration on circulating bile acid and gut hormone responses.Methods: In a randomized crossover design, we compared the effects of duodenal (via a nasoduodenal tube) vs parenteral (intravenous) administration over 180 min of identical mixed meals on circulating bile acid and gut hormone concentrations in eight healthy lean men. We analysed the bile acid and gut hormone responses in two periods: the intraprandial period from time point (T) 0 until T180 during meal administration and the postprandial period from T180 until T360, after discontinuation of meal administration.Results: Intravenous meal administration decreased the intraprandial (AUC (mmol/L*min) duodenal 1469 +/- 284 vs intravenous 240 +/- 39, p < 0.01) and postprandial bile acid response (985 +/- 240 vs 223 +/- 5, p < 0.05) and was accompanied by decreased gut hormone responses including glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon-like peptide 2 and fibroblast growth factor 19. Furthermore, intravenous meal administration elicited greater glucose concentrations, but similar insulin concentrations compared to enteral administration.Conclusions: Compared to enteral administration, parenteral nutrition results in lower postprandial bile acid and gut hormone responses in healthy lean men. This was accompanied by higher glucose concentrations in the face of similar insulin concentrations exposing a clear incretin effect of enteral mixed meal administration. The alterations in bile acid homeostasis were apparent after only one intravenous meal. (C) 2020 The Authors. Published by Elsevier Ltd.

Retinol‐binding protein‐4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity‐induced insulin resistance and correlates inversely with insulin‐stimulated glucose disposal. But its role in insulin‐mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux‐en‐Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin‐mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4‐activated macrophages markedly increased basal lipolysis and impaired insulin‐mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro‐inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4‐induced insulin resistance in humans.

Objective to investigate the effect of potentially inappropriate medications (PIMs) on inpatient falls and to identify whether PIMs as defined by STOPPFall or the designated section K for falls of STOPP v2 have a stronger association with inpatient falls when compared to the general tool STOPP v2. Methods a retrospective observational matching study using an electronic health records dataset of patients (≥70 years) admitted to an academic hospital (2015–19), including free text to identify inpatient falls. PIMs were identified using the STOPP v2, section K of STOPP v2 and STOPPFall. We first matched admissions with PIMs to those without PIMs on confounding factors. We then applied multinomial logistic regression analysis and Cox proportional hazards analysis on the matched datasets to identify effects of PIMs on inpatient falls. Results the dataset included 16,678 hospital admissions, with a mean age of 77.2 years. Inpatient falls occurred during 446 (2.7%) admissions. Adjusted odds ratio (OR) (95% confidence interval (CI)) for the association between PIM exposure and falls were 7.9 (6.1–10.3) for STOPP section K, 2.2 (2.0–2.5) for STOPP and 1.4 (1.3–1.5) for STOPPFall. Adjusted hazard ratio (HR) (95% CI) for the effect on time to first fall were 2.8 (2.3–3.5) for STOPP section K, 1.5 (1.3–1.6) for STOPP and 1.3 (1.2–1.5) for STOPPFall. Conclusions we identified an independent association of PIMs on inpatient falls for all applied (de)prescribing tools. The strongest effect was identified for STOPP section K, which is restricted to high-risk medication for falls. Our results suggest that decreasing PIM exposure during hospital stay might benefit fall prevention, but intervention studies are warranted.

The aim of this scoping review is to summarize approaches and outcomes of clinical validation studies of clinical decision support systems (CDSSs) to support (part of) a medication review. A literature search was conducted in Embase and Medline. In total, 30 articles validating a CDSS were ultimately included. Most of the studies focused on detection of adverse drug events, potentially inappropriate medications and drug-related problems. We categorized the included articles in three groups: studies subjectively reviewing the clinical relevance of CDSS's output (21/30 studies) resulting in a positive predictive value (PPV) for clinical relevance of 4–80%; studies determining the relationship between alerts and actual events (10/30 studies) resulting in a PPV for actual events of 5–80%; and studies comparing output of CDSSs to chart/medication reviews in the whole study population (10/30 studies) resulting in a sensitivity of 28–85% and specificity of 42–75%. We found heterogeneity in the methods used and in the outcome measures. The validation studies did not report the use of a published CDSS validation strategy. To improve the effectiveness and uptake of CDSSs supporting a medication review, future research would benefit from a more systematic and comprehensive validation strategy.

Background Falls and delirium are common complications in older inpatients. Implementation of fall and delirium guidelines is complex and may be facilitated by Clinical Decision Support Systems (CDSSs). Our study aimed to understand the differences between guidelines (work-as-imagined) and actual care (work-as-done) and how these can impact the design of a CDSS. Methods We used Functional Resonance Analysis Method (FRAM) as structured method to visualize work-as-imagined and work-as-done and to develop an initial CDSS design. As input for work-as-imagined, we used national guidelines. To identify work-as-done and CDSS preferences, we conducted semi-structured interviews in two rounds. We identified differences between guidelines and actual care by creating a FRAM model for work-as-imagined and one for work-as-done. CDSS preferences were coupled to activities in the FRAM models and to the identified barriers and facilitators for following guidelines. Results Eighteen clinicians participated in 24 individual and small-group interviews. For both falls and delirium, we found substantial differences between work-as-imagined and work-as-done. Several CDSS opportunities to improve fall and delirium care were identified including reminders for screening, an order set to facilitate risk assessment, automatically-generated advice with personalized preventive interventions and support to facilitate medication reviews. The required CDSSs addressed both barriers and facilitators. Conclusion In our study, work-as-done for falls and delirium differed substantially from work-as-imagined and the preferred CDSSs would address both barriers and facilitators. Furthermore, our study showed that FRAM is a suitable tool to identify differences between actual care and guidelines and to design CDSSs from a user-centred approach.

BackgroundClinical decision support systems (CDSSs) form an implementation strategy that can facilitate and support health care professionals in the care of older hospitalized patients.ObjectiveOur study aims to systematically review the effects of CDSS interventions in older hospitalized patients. As a secondary aim, we aim to summarize the implementation and design factors described in effective and ineffective interventions and identify gaps in the current literature.MethodsWe conducted a systematic review with a search strategy combining the categories older patients, geriatric topic, hospital, CDSS, and intervention in the databases MEDLINE, Embase, and SCOPUS. We included controlled studies, extracted data of all reported outcomes, and potentially beneficial design and implementation factors. We structured these factors using the Grol and Wensing Implementation of Change model, the GUIDES (Guideline Implementation with Decision Support) checklist, and the two-stream model. The risk of bias of the included studies was assessed using the Cochrane Collaboration’s Effective Practice and Organisation of Care risk of bias approach.ResultsOur systematic review included 18 interventions, of which 13 (72%) were effective in improving care. Among these interventions, 8 (6 effective) focused on medication review, 8 (6 effective) on delirium, 7 (4 effective) on falls, 5 (4 effective) on functional decline, 4 (3 effective) on discharge or aftercare, and 2 (0 effective) on pressure ulcers. In 77% (10/13) effective interventions, the effect was based on process-related outcomes, in 15% (2/13) interventions on both process- and patient-related outcomes, and in 8% (1/13) interventions on patient-related outcomes. The following implementation and design factors were potentially associated with effectiveness: a priori problem or performance analyses (described in 9/13, 69% effective vs 0/5, 0% ineffective interventions), multifaceted interventions (8/13, 62% vs 1/5, 20%), and consideration of the workflow (9/13, 69% vs 1/5, 20%).ConclusionsCDSS interventions can improve the hospital care of older patients, mostly on process-related outcomes. We identified 2 implementation factors and 1 design factor that were reported more frequently in articles on effective interventions. More studies with strong designs are needed to measure the effect of CDSS on relevant patient-related outcomes, investigate personalized (data-driven) interventions, and quantify the impact of implementation and design factors on CDSS effectiveness.Trial RegistrationPROSPERO (International Prospective Register of Systematic Reviews): CRD42019124470; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=124470.

Introduction: There is considerable variability in the rates and extent of drug metabolism between patients due to physiological, genetic, pharmacologic, environmental and nutritional factors such as fasting. This variability in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Preclinical studies have shown that fasting alters drug metabolism by modulating the activity of drug metabolizing enzymes involved. However, until recently little was known about the effects of fasting on drug metabolism in humans. Areas covered: This review describes the effects of fasting on drug metabolism based on both preclinical studies and studies performed in humans. Expert opinion: A better understanding of the effects of fasting may improve the efficacy and safety of pharmacotherapy for individual patients. Fasting contributes to variability in human drug metabolism by differentially affecting drug metabolizing enzymes. Although the effects of fasting on drug metabolism appear to be small (between 10-20%), fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism such as physiological, genetic or pharmacological factors. Therefore, additional research on this topic is warranted.

Background and Aims: Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile add levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement.Methods: We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement.Results: Both fasting and postprandial bile add levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile add species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandial plasma courses were unaffected.Conclusions: DJBL placement leads to profound increases in unconjugated bile add levels after 6 months, similar to the effects of bariatric surgery. The temporal dissociation between the changes in bile adds, GLP-1 and FGF19 and other gut hormone responses warrant caution about the beneficial role of bile acids after DJBL placement. This observational uncontrolled study emphasizes the need for future controlled studies. (C) 2019 Elsevier Inc. All rights reserved.

The assessment of gaze behaviour is essential for understanding the psychology of communication. Mobile eye-tracking glasses are useful to measure gaze behaviour during dynamic interactions. Eye-tracking data can be analysed by using manually annotated areas-of-interest. Computer vision algorithms may alternatively be used to reduce the amount of manual effort, but also the subjectivity and complexity of these analyses. Using additional re-identification (Re-ID) algorithms, different participants in the interaction can be distinguished. The aim of this study was to compare the results of manual annotation of mobile eye-tracking data with the results of a computer vision algorithm. We selected the first minute of seven randomly selected eye-tracking videos of consultations between physicians and patients in a Dutch Internal Medicine out-patient clinic. Three human annotators and a computer vision algorithm annotated mobile eye-tracking data, after which interrater reliability was assessed between the areas-of-interest annotated by the annotators and the computer vision algorithm. Additionally, we explored interrater reliability when using lengthy videos and different area-of-interest shapes. In total, we analysed more than 65 min of eye-tracking videos manually and with the algorithm. Overall, the absolute normalized difference between the manual and the algorithm annotations of face-gaze was less than 2%. Our results show high interrater agreements between human annotators and the algorithm with Cohen’s kappa ranging from 0.85 to 0.98. We conclude that computer vision algorithms produce comparable results to those of human annotators. Analyses by the algorithm are not subject to annotator fatigue or subjectivity and can therefore advance eye-tracking analyses.

OBJECTIVE Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. RESEARCH DESIGN AND METHODS We recruited obese subjects who met criteria for bariatric surgery with (n = 16) or without (n = 15) NAFLD and assessed 1) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, 2) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and 3) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery. RESULTS Compared with subjects without NAFLD, those with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated—not increased—glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: Signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor ChREBP was increased in subjects with NAFLD. CONCLUSIONS Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.

Background Glucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB). Objectives The objectives of this study were to elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes, and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB. Setting Clinical research facility in university hospital. Methods We recruited 35 patients scheduled for RYGB and assessed the plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a two-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Ten out of 35 subjects were studied both before surgery and at one-year follow-up. Results Plasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index (BMI). One year after RYGB, participants had lost 24±6% of body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted. Conclusions Postprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and one year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.

Animal studies indicate that hypothalamic dysfunction plays a major role in type 2 diabetes mellitus (T2DM) development, and that insulin resistance and inflammation are important mechanisms involved in this disorder. However, it remains unclear how T2DM and antidiabetic treatments affect the human hypothalamus. Here, we characterized the proopiomelanocortin (POMC) immunoreactive (-ir) neurons, the neuropeptide-Y–ir (NPY-ir) neurons, the ionized calcium-binding adapter molecule 1–ir (iba1-ir) microglia, and the transmembrane protein 119–ir (TMEM119-ir) microglia in the infundibular nucleus (IFN) of human postmortem hypothalamus of 32 T2DM subjects with different antidiabetic treatments and 17 matched nondiabetic control subjects. Compared with matched control subjects, T2DM subjects showed a decrease in the number of POMC-ir neurons, but no changes in NPY-ir neurons or microglia. Interestingly, T2DM subjects treated with the antidiabetic drug metformin had fewer NPY-ir neurons and microglia than T2DM subjects not treated with metformin. We found that the number of microglia correlated with the number of NPY-ir neurons, but only in T2DM subjects. These results indicate that different changes in POMC and NPY neurons and microglial cells in the IFN accompany T2DM. In addition, T2DM treatment modality is associated with highly selective changes in hypothalamic neurons and microglial cells., Type 2 diabetes impacts energy homeostasis-regulatory neurons and the surrounding microglia in the hypothalamus, and these effects are modulated by metformin.

Purpose To investigate prevalence, independent associations, and variation over time of potentially inappropriate prescriptions in a population of older hospitalized patients. Methods A longitudinal study using a large dataset of hospital admissions of older patients (≥ 70 years) based on an electronic health records cohort including data from 2015 to 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) prevalence during hospital stay were identified based on the Dutch STOPP/START criteria v2. Univariate and multivariate logistic regression were used for analyzing associations and trends over time. Results The data included 16,687 admissions. Of all admissions, 56% had ≥ 1 PIM and 58% had ≥ 1 PPO. Gender, age, number of medications, number of diagnoses, Charlson score, and length of stay were independently associated with both PIMs and PPOs. Additionally, number of departments and number of prescribing specialties were independently associated with PIMs. Over the years, the PIM prevalence did not change (OR = 1.00, p = .95), whereas PPO prevalence increased (OR = 1.08, p p Conclusion We found potentially inappropriate prescriptions in the majority of admissions of older patients. Prescribing relatively improved over time when considering complexity of the admissions. Nevertheless, the high prevalence shows a clear need to better address this issue in clinical practice. Studies seeking effective (re)prescribing interventions are warranted.

Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four-hour fasting increased liver Dio3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced Dio3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both Dio3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, Dio3 mRNA expression increased five-fold after 48-h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced Dio3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce Dio3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Background & aims: Bile acids (BAs) play a key role in lipid uptake and metabolic signalling in different organs including gut, liver, muscle and brown adipose tissue. Portal and peripheral plasma BA concentrations increase after a meal. However, the exact kinetics of postprandial BA metabolism have never been described in great detail. We used a conscious porcine model to investigate postprandial plasma concentrations and transorgan fluxes of BAs, glucose and insulin using the para-aminohippuric acid dilution method.Methods: Eleven pigs with intravascular catheters received a standard mixed-meal while blood was sampled from different veins such as the portal vein, abdominal aorta and hepatic vein. To translate the data to humans, fasted venous and portal blood was sampled from non-diabetic obese patients during gastric by-pass surgery.Results: The majority of the plasma bile acid pool and postprandial response consisted of glycine-conjugated forms of primary bile acids. Conjugated bile acids were more efficiently cleared by the liver than unconjugated forms. The timing and size of the postprandial response showed large interindividual variability for bile acids compared to glucose and insulin.Conclusions: The liver selectively extracts most BAs and BAs with highest affinity for the most important metabolic BA receptor, TGR5, are typically low in both porcine and human peripheral circulation. Our findings raise questions about the magnitude of a peripheral TGR5 signal and its ultimate clinical application. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Introduction: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure. Methods: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland–Altman method. Results: Short-term fasting increased acetaminophen exposure by 20% (ΔAUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (ΔAUC0–8 hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28–0.61), compared to 0.87 (0.81–0.92) and 0.87 (0.79–0.91) in the control and high-fat samples respectively. Conclusions: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed.

A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

Background & aims: Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity. In this study we used a 2-week very-low-calorie diet (VLCD) to investigate the effects of weight loss on BA pool composition and postprandial dynamics.Methods: We performed mixed meal tests in obese, insulin resistant subjects before and after the VLCD. We measured postprandial plasma levels of glucose, insulin, BA and the BA-induced enterokine fibroblast growth factor 19 (FGF19).Results: The VLCD decreased weight by 4.5 +/- 2.3 kg (p Conclusions: VLCD induced weight loss increased postprandial DCA peak levels and decreased resting energy expenditure in obese insulin resistant subjects. (C) 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

BACKGROUND/OBJECTIVES: Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. SUBJECTS/METHODS: We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3-H-2(5)] glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50 +/- 11 years; body mass index 38 +/- 7 kg m(-2)). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. RESULTS: Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r = 0.960, P = 0.801, P

Background and Objective Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. Methods In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM. Results Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p

SummaryWhile experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p

Ultimately, almost all patients who are appropriately treated for pituitary tumours enter a chronic phase with control or cure of hormonal excess, adequate treatment of pituitary insufficiency and relief of mass effects. This phase is associated with improvement of initial signs and symptoms, but also with the persistent consequences of the initial disease and associated treatments. Pituitary insufficiency is a common denominator in many of these patients, and is associated with a reduction in quality of life, despite adequate endocrine substitution. Hypothalamic dysfunction can be present in patients previously treated for visual impairments caused by large suprasellar adenomas, or craniopharyngiomas. In addition to hypopituitarism, these patients can have multisystem morbidities caused by altered hypothalamic function, including weight gain and disturbed regulation of sleep-wake cycles. Mortality can also be affected. Patients cured of Cushing disease or acromegaly have chronic multisystem morbidities (in the case of Cushing disease, also affecting mortality) caused by irreversible effects of the previous excesses of cortisol in Cushing disease and growth hormone and insulin-like growth factor 1 in acromegaly. In addition to early diagnosis and treatment of pituitary tumours, research should focus on the amenability of these chronic post-treatment syndromes to therapeutic intervention, to improve quality of life and clinical outcomes.

Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6- 2 H 2 ]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18 F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.

Background and Objectives: Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5′-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites. Methods: In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0.015 mg/kg midazolam after: (1) an overnight fast (control); (2) 36 h of fasting; and (3) an overnight fast after 3 days of a HFD consisting of 500 ml of cream supplemented to their regular diet. Pharmacokinetic parameters were analyzed simultaneously using non-linear mixed-effects modeling. Results: Short-term fasting increased CYP3A4-mediated midazolam clearance by 12% (p < 0.01) and decreased UGT-mediated metabolism apparent 1-OH-midazolam clearance by 13% (p < 0.01) by decreasing the ratio of clearance and the fraction metabolite formed (ΔCL1-OH-MDZ/f1-OH-MDZ). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL1-OH-MDZ-glucuronide/(f1-OH-MDZ-glucuronide × f1-OH-MDZ)) by 20% (p < 0.01). The HFD did not affect systemic clearance of midazolam or metabolites. Conclusions: Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam.

Background Patients with type 1 diabetes have altered sleep characteristics and are thought to have deficits in sustained attention. We compared the sustained attention to response task (SART) of patients with type 1 diabetes to that of healthy controls, and related results with sleep characteristics and disease-related factors. Methods SART was applied in 122 patients and 109 controls. Glucoregulation was assessed by HbA1c values and a questionnaire assessing glycaemic history. Clinical parameters were obtained from medical charts. Polyneuropathy was assessed by neurological examination and quantitative sensory testing. Sleep characteristics were assessed with sleep questionnaires. Anxiety and depression scores were assessed by the Hospital Anxiety and Depression Scale. Results The SART reaction time (RT) was significantly longer than in controls (327 ± 5 vs. 285 ± 3 ms, p

Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy,111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.

Background This retrospective analysis describes blood conservation strategies and overall consumption of red blood cells (RBCs), fresh-frozen plasma (FFP), and platelet (PLT) concentrates during nonaortic cardiac surgery with cardiopulmonary bypass (CPB) in a tertiary hospital over a 10-year period. Study Design and Methods Study variables of 6026 patients that underwent cardiac surgery between 2002 and 2011 were incorporated in the database and included hemoglobin (Hb), lowest temperature, CPB duration, 24-hour blood loss, fluid balance, and overall transfusion requirements. Results Between 2002 and 2011, the lowest intraoperative Hb levels and temperature increased from 8.5 ± 1.2 to 10.4 ± 1.4 g/dL and from 32 ± 2 to 34 ± 1°C, respectively. In addition to the steep decrease in the postoperative fluid balance over time, a reduction in 24-hour blood loss from 815 ± 588 mL (2002) to 590 ± 438 mL (2011) was observed. These changes were paralleled by a 28% reduction in overall RBC transfusion from 1443 units in 2002 to 1038 in 2011. While RBC transfusion decreased over time, there was no significant change in the use of FFP or PLT concentrate transfusion. The probability to receive RBC transfusion increased after cessation of aprotinin, but reduced after routine cell salvage in all operations. Conclusion This institutional report shows a large reduction in blood loss and transfusion requirements in cardiac surgery over a 10-year period. This reduction is most probably attributed to structural cell salvage, reduced intraoperative fluid volumes, and the increase in the lowest intraoperative body temperature.

ObjectivePatients with long-term remission of Cushing's disease (CD) have persistent psychological and cognitive impairments. It is unknown whether, and to what extent, these impairments are accompanied by structural abnormalities in the brain. We aim to investigate structural changes in the brain in patients with predominantly long-term remission of CD and to examine whether these changes are associated with psychological and cognitive dysfunction and clinical severity.DesignA cross-sectional, case–control study.MethodsIn 25 patients with predominantly long-term remission of CD and 25 matched healthy controls, grey matter volumes in the regions of interest (hippocampus, amygdala, and anterior cingulate cortex (ACC)) and in the whole brain were examined, using 3T magnetic resonance imaging and a voxel-based morphometry approach. Psychological and cognitive functioning were assessed using validated questionnaires and clinical severity was assessed using the Cushing's syndrome severity index.ResultsCompared with controls, patients had smaller grey matter volumes of areas in the ACC (on average 14%, PPP=0.005), more anxiety (P=0.003), more social phobia (P=0.034), more apathy (P=0.002), and more cognitive failure (P=0.023) compared with controls, but the differences in grey matter volumes were not associated with psychological or cognitive measures, nor with clinical severity.ConclusionPatients with predominantly long-term remission of CD showed specific structural brain abnormalities, in the presence of psychological dysfunction. Our data form a basis for future work aimed at elucidating the relation of the structural brain abnormalities and the sustained psychological deficits after long-term exposure to high cortisol levels.

Background and Purpose Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro. Experimental Approach Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells. Key results In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL-1) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[ 3H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells. Conclusion and Implications In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS. © 2013 The British Pharmacological Society.

PURPOSE: To assess the short-term effects of a standardized oral glucose load on regional aortic pulse wave velocity (PWV) using two-directional in-plane velocity encoded MRI. MATERIALS AND METHODS: A randomized, controlled intervention was performed in 16 male subjects (mean +/- standard deviation: age: 59+/-7 years, body mass index: 28+/-3 kg/m2) with impaired fasting glucose. The intervention consisted of an oral glucose load (75 grams of carbohydrates in 300 mL water) at 1 study day and water (300 mL) at the other study day. PWV was measured using multislice two-directional in-plane velocity-encoded MRI. RESULTS: PWV in the proximal aorta at 1 h post-glucose load decreased compared with PWV 1-h post-water (delta PWV: -1.0+/-2.6 m/s versus 0.6+/-2.0 m/s, P=0.02). Eight responding subjects showed a significant decrease in PWV of the proximal aorta after the glucose load and had a decreased waist circumference (P=0.037) compared with nonresponders, being one of the major criteria of the metabolic syndrome. There was no significant change in PWV of the distal aorta at 1 h post-load comparing both intervention groups. CONCLUSION: A standardized oral glucose load induces a decrease of the proximal, but not of the distal, aortic PWV. Regional response of aortic PWV may be associated with features of the metabolic syndrome.

Contains fulltext : 137607.pdf (Publisher’s version ) (Closed access) PURPOSE: Tumors in the carotid bodies may interfere with their function as peripheral chemoreceptors. An altered control of ventilation may predispose to sleep-disordered breathing. This study aimed to assess whether patients with unilateral or bilateral carotid body tumors (uCBT or bCBT, respectively) or bilateral CBT resection (bCBR) display sleep-disordered breathing and to evaluate the global contribution of the peripheral chemoreceptor to the hypercapnic ventilatory response. METHODS: Eight uCBT, eight bCBT, and nine bCBR patients and matched controls underwent polysomnography. The peripheral chemoreflex drive was assessed using euoxic and hyperoxic CO2 rebreathing tests. Daytime sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Multidimensional Fatigue Index. RESULTS: All patient groups reported significant fatigue-related complaints, but no differences in excessive daytime sleepiness (EDS) were found. The apnea/hypopnea index (AHI) did not differ significantly between patient groups and controls. Only in bCBT patients, a trend towards a higher AHI was observed, but this did not reach significance (p=0.06). No differences in the peripheral chemoreflex drive were found between patients and controls. CONCLUSIONS: Patients with (resection of) CBTs have more complaints of fatigue but are not at risk for EDS. The presence or resection of CBTs is neither associated with an altered peripheral chemoreflex drive nor with sleep-disordered breathing.

Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a ‘hungry bone syndrome’ in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25–90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0–6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.

Background This study investigated whether implementation of cell salvage of shed mediastinal and residual blood in all patients undergoing low-to-moderate-risk cardiac surgery reduces the need for allogeneic red blood cell (RBC) transfusion compared to patients not subjected to cell salvage. Study Design and Methods This retrospective cohort study included patients undergoing low-to-moderate-risk cardiac surgery with cardiopulmonary bypass without (control; n = 531) or with cell salvage (n = 433; Autolog, Medtronic). Study endpoints, including 24-hour blood loss and RBC requirements, were evaluated using adjusted logistic regression. Results Baseline characteristics were similar between groups. The cell saver group received 568 ± 267 mL of autologous blood. Median number of allogeneic RBC transfusions was higher in the control group (2 [1-5]) compared with the cell salvage group (1 [0-3]; p < 0.001). There were no clinically relevant differences in postoperative coagulation test results between groups. The relative risk (RR) for postoperative RBC transfusion was reduced to 0.76 (95% confidence interval [CI], 0.70-0.83; p < 0.0001) in the cell salvage group. Moreover, patients in the cell salvage group had a lower chance for myocardial infarction (RR, 0.26; 95% CI, 0.08-0.91; p = 0.035), whereas the cell salvage group was associated with a higher probability for intensive care discharge within 24 hours after surgery (RR, 1.08; 95% CI, 1.02-1.14; p = 0.009). Conclusion The use of cell salvage throughout the entire procedure reduces postoperative blood loss and allogeneic RBC transfusion. These findings advocate implementation of cell salvage in all patients undergoing on-pump cardiac surgery, irrespective of anticipated surgery-related blood loss. © 2013 American Association of Blood Banks.

Item does not contain fulltext Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism. 01 december 2013

Item does not contain fulltext BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma ANGPTL4 concentrations in humans. OBJECTIVE: The objective was to assess plasma ANGPTL4 concentrations after various nutritional interventions that increase NEFA concentrations in healthy subjects and in patients with type 2 diabetes mellitus. DESIGN: We studied 4 groups, both at baseline and after 3 d of either fasting (n = 22 healthy men), a very-low-calorie diet (VLCD; n = 10 healthy men and n = 10 patients with diabetes), or a high-fat, high-energy diet (HFED; n = 15 healthy men). Plasma ANGPTL4, NEFA, and triglyceride concentrations were measured. RESULTS: In healthy men, a VLCD increased ANGPTL4 from 13.2 (IQR: 8.1-24.2) at baseline to 18.2 (16.7-33.4) ng/mL (P < 0.05), fasting increased ANGPTL4 from 10.6 (7.6-17.6) to 28.0 (23.1-35.0) ng/mL (P < 0.05), and an HFED increased ANGPTL4 from 13.9 (8.2-22.0) to 17.2 (11.2-23.6) ng/mL (P < 0.05). In men with diabetes, a VLCD also increased ANGPTL4, from 10.9 +/- 2.4 to 19.2 +/- 3.2 ng/mL (P < 0.05). All interventions significantly increased plasma NEFAs in both healthy men and patients with diabetes. The change in ANGPTL4 positively correlated with the change in NEFA concentrations (beta = 0.048, P < 0.001) and negatively correlated with the change in plasma triglycerides (beta = -0.051, P = 0.01). CONCLUSIONS: Three days of either fasting, a VLCD, or an HFED increased plasma ANGPTL4 concentrations in healthy men, concomitantly with increased plasma NEFA concentrations. Similarly, a VLCD in patients with diabetes increased ANGPTL4 concentrations, concomitantly with increased NEFA concentrations.

Patients with pituitary diseases have decreased quality of life. Sleep disorders are prevalent among patients with pituitary diseases and contribute to decreased quality of life. Patients previously treated for compression of the optic chiasm by surgery, and in some cases postoperative radiotherapy, suffer from sleep disorders. These are characterized by decreased sleep quality, delayed onset of sleep, and daytime sleepiness. Circumstantial evidence suggests that this may be caused by hypothalamic dysfunction. A challenging speculation is that previous compression of the optic chiasm compromised the function of the retinohypothalamic tract. Through this tract the eyes convey information on day-night cycles to the hypothalamic nuclei. Patients with acromegaly, even despite biochemical control, suffer frequently from obstructive sleep apnea. Patients with Cushing's disease suffer from fragmented sleep, sleep apnea, and snoring. Prolactinomas do not seem to affect sleep characteristics. The association between appropriately substituted pituitary insufficiency and sleep disorders is less clear. The effects of recombinant human growth hormone on sleep characteristics in adults are inconsistent. Pituitary disorders are associated with different sleep disorders. Different studies point to irreversible changes in sleep-wake rhythmicity in patients treated previously for pituitary tumors with chiasm compression. VIDEO ABSTRACT

BACKGROUND High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects. OBJECTIVE We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity. DESIGN We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. RESULTS Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: -0.79 pmol/L; 95% CI: -6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: -0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (∼25% excess of energy compared with that of the weight-maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA-IR (MD: 0.18; 95% CI: -0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: -0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly

AIM: Elevated basal endogenous glucose production (EGP), impaired suppression of EGP by insulin and reduced insulin-stimulated glucose disposal are cornerstones of the pathogenesis of hyperglycemia in patients with type 2 diabetes. We aimed to determine the contribution of these processes to impaired fasting glucose (IFG) levels in obese non-diabetic adults.METHODS: We included 131 obese non-diabetic adults with normal fasting glucose levels (NFG; fasting glucose RESULTS: Compared to equally obese adults with NFG, individuals with IFG did not differ in basal EGP (9.1±0.2 vs 9.8±0.3μmolkg(-1)min(-1), p=0.082), insulin-mediated suppression of circulating free fatty acid levels (75±1 vs 72±3%, p=0.240) and insulin-stimulated glucose disposal (26.6±1.0 vs 25.2±1.5μmolkg(-1)min(-1), p=0.441). Insulin-mediated suppression of EGP (68±2 vs 55±3%, pCONCLUSIONS: Hepatic insulin resistance is a distinct metabolic feature of IFG in obesity. Insulin sensitivity of free fatty acid suppression and skeletal muscle does not differ between obese people with NFG and IFG. Hepatic insulin resistance may contribute to the onset of prediabetes in obese adults.

Item does not contain fulltext Pericardial fat accumulation has been associated with an increased cardiovascular risk. A very low calorie diet (VLCD) improves the cardiovascular risk profile in patients with type 2 diabetes mellitus (T2DM), by improving the metabolic profile, heart function, and triglyceride (TG) stores in (non)adipose tissues. However, long-term effects of a VLCD on pericardial fat volume and tissue-specific TG accumulation have not been documented. The aim of this study was therefore to assess the effects of a 16-week VLCD and of subsequent 14 months follow-up on a regular diet on pericardial fat in relation to other TG stores in obese T2DM patients. We included 14 obese patients with insulin-treated T2DM (mean +/- s.e.m.: age 53 +/- 2 years; BMI 35 +/- 1 kg/m(2)). Pericardial fat and other (non)adipose TG stores were measured using magnetic resonance (MR) imaging and proton spectroscopy before and after a 16-week VLCD and after a 14-month follow-up without dietary interventions. A 16-week VLCD reduced body weight, pericardial fat, hepatic TG content, visceral and subcutaneous abdominal fat volumes to 78, 83, 16, 40, and 53% of baseline values respectively, (all P < 0.05). After an additional 14 months of follow-up on a regular diet, the reduction in pericardial fat volume sustained, despite a substantial regain in body weight, visceral abdominal fat, and hepatic TG content (respectively 90, 83 and 73% of baseline values). In conclusion, VLCD-induced weight loss in obese T2DM patients is accompanied by a substantial decrease in pericardial fat volume, which is sustained even after subsequent weight regain. 01 augustus 2012

Psychological research has shown that people tend toward accepting rather than refuting hypotheses. Diagnostic suggestions may evoke such confirmatory tendencies in physicians, which may lead to diagnostic errors.This study investigated the influence of a suggested diagnosis on physicians' diagnostic decisions on written clinical cases. It was hypothesized that physicians would tend to go along with the suggestions and therefore would have more difficulty rejecting incorrect suggestions than accepting correct suggestions.Residents (N = 24) had to accept or reject suggested diagnoses on 6 cases. Three of those suggested diagnoses were correct, and 3 were incorrect.Results showed the mean correct evaluation score on cases with a correct suggested diagnosis (M = 2.21, SD = 0.88) was significantly higher than the score on cases with an incorrect suggested diagnosis (M = 1.42, SD = 0.97), meaning physicians indeed found it easier to accept correct diagnoses than to reject incorrect diagnoses, t(23) = 2.74, p.05, d = .85, despite equal experience with the diagnoses.These findings indicate that suggested diagnoses may evoke confirmatory tendencies and consequently may lead to diagnostic errors.

ObjectivePatients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs.MethodsWe measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls.ResultsCompared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, PP=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31).ConclusionsMen with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.

OBJECTIVE Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. DESIGN We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. RESULTS The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. CONCLUSION The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands.

Item does not contain fulltext Transsphenoidal surgery (TS) is the treatment of choice for many pituitary tumors. Because TS may cause pituitary insufficiency in some of these patients, early postoperative assessment of pituitary function is essential for appropriate endocrine management. The aim of our study was to evaluate the clinical relevance of the CRH-stimulation test in assessing postoperative pituitary-adrenal function. We performed a retrospective analysis of 144 patients treated by TS between January 1990 and November 2009, in whom a CRH-test and a second stimulation test was performed to assess adrenal function during follow-up. Patients with Cushing's disease were excluded. Hydrocortisone substitution was started if peak cortisol levels were

Summary Context The majority of patients with head and neck paragangliomas (HNPGL) have biochemically silent tumours. Chromogranin A (CgA) is a tumour marker for neuroendocrine tumours. Objective To assess the role of CgA as a tumour marker in patients with hereditary HNPGL. Patients and Methods We included 95 consecutive patients with hereditary HNPGL for screening of plasma CgA levels and catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)adrenaline, VMA, dopamine and 3-methoxytyramine. In all patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by 123I-MIBG scintigraphy, MRI and/or CT. Results Plasma CgA levels were increased in only 15 of 95 patients (16%). Thirty-three of the 95 patients (35%) had increased urinary excretion rates of catecholamines. Six of these 33 patients (18%) had increased plasma CgA levels. Nine of the 62 patients (15%) with a biochemically silent tumour, i.e. no increased urinary excretion of catecholamines or their metabolites, had increased CgA levels. Increased plasma CgA levels were positively correlated with urinary excretion rates of noradrenaline (r = 0·68, P = 0·005) and normetanephrine (r = 0·68, P = 0·005). There was a positive correlation between maximal HNPGL diameter and plasma CgA levels in the 57 patients with a single HNPGL (r = 0·57, P = 0·001). Conclusions Plasma CgA levels are increased in only a small portion of patients with hereditary HNPGL and have limited additional value to the combination of radiological and routine biochemical assessment of patients with HNPGL. Increased plasma CgA levels are associated with increased noradrenergic activity and tumour size in patients with a single HNPGL.

Introduction: Balanced colloidal priming solutions are supposed to further minimize the effects of cardiopulmonary bypass (CPB) on haemostasis as compared to gelatin-based preparations. This exploratory study investigated whether clot formation, in particular the fibrin part of the clot, is less altered by a modern balanced HES solution as compared to a gelatin-based priming solution. Methods: CPB priming solutions containing 60% gelatin (Gelofusin®) or balanced HES starch (100% or 60% Tetraspan®) were mixed with blood samples from healthy volunteers and compared with respect to their impact on clotting time (CT), alpha angle, maximum clot firmness (MCF), and fibrinogen, using thromboelastometry. Results: The 100% and 60% HES priming solutions significantly increased the EXTEM CT from 66 ± 9 s to 82 ± 19 and 83 ± 13, respectively (both P Conclusions: Ex vivo rotation thromboelastometry did not reveal the expected preservation of coagulation parameters, in particular the fibrin part of clot formation, by a balanced HES priming solution.