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Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis. Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity. Methods: This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting. Results: The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0–4.6] to 3.6 [2.4–6.2] x10−5 pmol l−1 min−1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg−1 min−1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2. Conclusions/interpretation: The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Statins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ. [ABSTRACT FROM AUTHOR]

Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation. [ABSTRACT FROM AUTHOR]

We assessed differences in mitochondrial function in gluteal (gSAT) and abdominal subcutaneous adipose tissue (aSAT) at baseline and in response to 12-weeks of exercise training; and examined depot-specific associations with body fat distribution and insulin sensitivity (SI). Obese, black South African women (n = 45) were randomized into exercise (n = 23) or control (n = 22) groups. Exercise group completed 12-weeks of aerobic and resistance training (n = 20), while the control group (n = 15) continued usual behaviours. Mitochondrial function (high-resolution respirometry and fluorometry) in gSAT and aSAT, SI (frequently sampled intravenous glucose tolerance test), body composition (dual-energy X-ray absorptiometry), and ectopic fat (MRI) were assessed pre- and post-intervention. At baseline, gSAT had higher mitochondrial respiratory capacity and hydrogen peroxide (H2O2) production than aSAT (p < 0.05). Higher gSAT respiration was associated with higher gynoid fat (p < 0.05). Higher gSAT H2O2 production and lower aSAT mitochondrial respiration were independently associated with lower SI (p < 0.05). In response to training, SI improved and gynoid fat decreased (p < 0.05), while H2O2 production reduced in both depots, and mtDNA decreased in gSAT (p < 0.05). Mitochondrial respiration increased in aSAT and correlated with a decrease in body fat and an increase in soleus and hepatic fat content (p < 0.05). This study highlights the importance of understanding the differences in mitochondrial function in multiple SAT depots when investigating the pathophysiology of insulin resistance and associated risk factors such as body fat distribution and ectopic lipid deposition. Furthermore, we highlight the benefits of exercise training in stimulating positive adaptations in mitochondrial function in gluteal and abdominal SAT depots. [ABSTRACT FROM AUTHOR]

Background: Statins are used to lower cholesterol in plasma and are one of the most used drugs in the world. Many statin users experience muscle pain, but the mechanisms are unknown at the moment. Many studies have hypothesized that mitochondrial function could be involved in these side effects. Aim: The aim of the study was to investigate mitochondrial function after 2 weeks of treatment with simvastatin (S; n = 10) or pravastatin (P; n = 10) in healthy middle-aged participants. Methods: Mitochondrial respiratory capacity and substrate sensitivity were measured in permeabilized muscle fibers by high-resolution respirometry. Mitochondrial content (citrate synthase (CS) activity), antioxidant content, as well as coenzyme Q concentration (Q) were determined. Fasting plasma glucose and insulin concentrations were measured, and whole body maximal oxygen uptake (VO) was determined. Results: No differences were seen in mitochondrial respiratory capacity although a tendency was observed for a reduction when complex IV respiration was analyzed in both S (229 (169; 289 (95% confidence interval)) vs. 179 (146; 211) pmol/s/mg, respectively; P = 0.062) and P (214 (143; 285) vs. 162 (104; 220) pmol/s/mg, respectively; P = 0.053) after treatment. A tendency (1.64 (1.28; 2.00) vs. 1.28 (0.99; 1.58) mM, respectively; P = 0.092) for an increased mitochondrial substrate sensitivity (complex I-linked substrate; glutamate) was seen only in S after treatment. No differences were seen in Q, CS activity, or antioxidant content after treatment. Fasting glucose and insulin as well as VO were not changed after treatment. Conclusion: Two weeks of statin (S or P) treatment have no major effect on mitochondrial function. The tendency for an increased mitochondrial substrate sensitivity after simvastatin treatment could be an early indication of the negative effects linked to statin treatment. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine if the expression of the mitochondrial biogenesis-regulating proteins SIRT1, SIRT3 and PGC-1alpha in human skeletal muscle is influenced by adiposity.Method: Twenty-nine male subjects were recruited into three groups: control (n = 10), obese (n = 10) and post-obese (n = 9). Intentionally, groups were matched by age, aerobic capacity and in addition the control and post-obese groups also by BMI. Muscle biopsies were obtained from the m. deltoid and vastus lateralis. PGC-1alpha, SIRT1 and SIRT3 protein expression was analyzed by Western blot.Result: PGC-1alpha, SIRT1 and SIRT3 protein expression was similar regardless of the level of adiposity. Only a main effect of group on SIRT1 protein showed a trend toward higher expression in post-obese than control and obese (P = 0.09). Despite similar muscle fiber-type composition (previously reported), PGC-1alpha, SIRT1 and SIRT3 protein expression was higher in leg compared to arm muscle in all groups (P < 0.05).Conclusion: This study shows that PGC-1alpha, SIRT1 and SIRT3 protein expression in basal conditions was not altered in humans with different levels of adiposity but similar aerobic capacity. The expression of PGC-1alpha, SIRT1 and SIRT3 was higher in vastus lateralis than in deltoid muscle, indicating that local rather than systemic factors prevail in regulating the level of expression of these proteins. [ABSTRACT FROM AUTHOR]

This study investigated fiber-type-specific muscle ceramide content in obese subjects and type 2 diabetes patients. Two substudies, one which compared type 2 diabetes patients to both lean- and obese BMI-matched subjects and the other study which compared lean body-matched post-obese, obese, and control subjects, were performed. A fasting blood sample was obtained and plasma insulin and glucose determined. A muscle biopsy was obtained from deltoideus and vastus lateralis, and fiber-type ceramide content was determined by fluorescence immunohistochemistry. Insulin sensitivity estimated by Quicki index was higher in lean compared to type 2 diabetes patients and obese controls. Also in control and post-obese subjects, a higher insulin sensitivity was observed compared to obese subjects. Ceramide content was consistently higher in type I than in type II muscle fibers and higher in deltoideus than vastus lateralis across all groups. No significant differences between groups were observed in ceramide content in either of the two substudies. In human skeletal muscle, ceramide content was higher in type I than in type II fibers in patients with type 2 diabetes and in obese subjects, but overall ceramide muscle fiber content was not different compared to controls. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic adjustable gastric banding (LAGB) provides weight loss in obese individuals and is associated with improved glucose homeostasis and resolution of type 2 diabetes. However, in most available reports, potentially inappropriate methodology has been applied when measuring the impact of LAGB on glucose intolerance. In order to clarify the applicability of the diagnostic 75 g-oral glucose tolerance test (OGTT) to measure the effect of LAGB on glucose metabolism, we investigated the effect of LAGB on gastric emptying for liquids as well as pancreatic and incretin hormone responses. Methods: Eight obese patients (three with normal glucose tolerance, three with impaired glucose tolerance, and two with type 2 diabetes; age 47.5 ± 1.1 years (mean±SEM); body mass index 44 ± 1 kg/m; HbAc 6.2 ± 0.4%) underwent a 75 g-oral glucose tolerance test with 1 g acetaminophen before and ~6 weeks after LAGB. Results: A small weight reduction was seen after LAGB (125 ± 8 vs. 121 ± 8 kg, P = 0.014). No differences in determinants of gastric emptying were observed before and after LAGB (area under the serum acetaminophen curve 10.1 ± 0.6 vs. 9.8 ± 0.5 mM×4 h, P = 0.8; peak acetaminophen concentration 62 ± 3 vs. 61 ± 3 μM, P = 0.8; acetaminophen peak time 98 ± 6 vs. 100 ± 6 min, P = 0.9). No differences in plasma glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide, or glucagon-like peptide-1 responses to the OGTT were observed before as compared to after LAGB. Conclusions: OGTT can be used to evaluate glucose tolerance in obese patients before and after LAGB without bias from changes in gastric emptying. LAGB has no direct impact on incretin hormone secretion. [ABSTRACT FROM AUTHOR]

Adoption of the 10GbE Ethernet standard as a high performance interconnect has been impeded by two important performance-oriented considerations: (1) processing requirements of common protocol stacks and (2) end-to-end latency. The overheads of typical software based protocol stacks on CPU utilization and throughput have been well evaluated in several recent studies. We focus on end-to-end latency and present a detailed characterization across typical server system hardware and software stack components. We demonstrate that application level end-to-end one-way latency with a 10GbE connection can be as low as 10 μs for a single isolated request in a standard Linux network stack. The paper analyzes the components of the latency and discusses possible significant variations to the components under realistic conditions. We found that methods that optimize for throughput can significantly compromise Ethernet based latencies. Methods to pursue reducing the minimum latency and controlling the variations are presented. [ABSTRACT FROM AUTHOR]

Background. Abdominal pain is the dominant symptom in 50–75% of patients with chronic pancreatis, often requiring opioid analgesics. Fentanyl, a potent synthetic opioid, can be administered percutaneously at a constant dose and is claimed to have fewer systemic side effects. Aim. To evaluate transdermal fentanyl plaster versus sustained release morphine tablets as analgesic treatment of painful chronic pancreatitis. Methods. In an open randomized crossover trial, 18 patients were included. The treatment period was 4 wk for each drug. All patients had immediate-release morphine tablets as rescue medication. Results. The dosage of transdermal fentanyl had to be increased on average 50% over that indicated by the manufacturer. When this was done and rescue medication was secured, no difference between the two drugs in primary endpoint or patient preference was observed. There was also no difference in the secondary endpoints, pain control, and quality of life. However, skin side effects, mostly mild, occurred in 44% of the patients during treatment with transdermal fentanyl, and the mean daily dose of immediate release morphine was significantly higher during the transdermal fentanyl period than during the sustained-release morphine period (30.7 mg vs. 14.7 mg [ p<0.01]). Conclusion. When given in an appropriate dose, transdermal fentanyl might be useful for treatment of some patients with painful chronic pancreatitis, e.g., when tablet ingestion is difficult. However, the dosage often has to be increased above that recommended by the manufacturer. The need of rescue morphine is considerable and skin side effects often occur. Transdermal fentanyl is, therefore, not the ideal first-choice analgesic in patients with painful chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Investigates mechanisms affecting memory for the dates of events selected and recorded by subjects in diaries. Comparison of retention time for personal and public events; Day-of-the-week (DOW) accuracy; High DOW accuracy for events with personal context; Memory reconstruction based on a reference to a temporal week schema based on personal experiences.

Reading performance of 46 poor readers was compared with that of 20 normal control readers. All subjects were second grade children. In Experiment 1 two matching word lists were presented under two conditions: one version of the test was read in the upright position and the other inverted. In Experiment 2 the eye movements of all subjects were recorded during reading of two meaningful sentences in the normal and inverted position. While the controls were negatively influenced by inversion of the text, the poor readers showed a variety of responses. Overall, the poor readers showed a slight tendency to be better at reading in the inverted position when the text must be scanned from right to left. An individual analysis of the data revealed that in 28.3% of the poor readers inverted reading improved performance at least 15 %, a phenomenon found in none of the controls. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) may be one ofthe enterogastrone hormones of the ileal brakemechanism. We therefore studied its effects on gastriclipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. Theintestinal incretin hormone GLP-1 (glucagon-likepeptide-1, 7-36 amide) was investigated because of itsinhibitory effects on gastric acid secretion andmotility. GLP-1 infused intravenously in amountscorresponding to the postprandial release significantlyinhibited pentagastrinstimulated gastric lipasesecretion and lipolytic activity. The inhibitory effectof GLP-1 persisted in vagotomized patients,suggesting that fundic chief cells, from which gastriclipase is released, or neighboring inhibitory cellscould be equipped with GLP-1 receptors. Vagotomizedpatients had significantly higher plasma concentrationsof gastrin and secretin. No significant changes ofgastrin, secretin, and CCK secretion were seen duringGLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthyvolunteers. GLP-1 seems to be a naturally occurringinhibitor of gastric lipase secretion acting via anonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonalstimulatory as well as inhibitory mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Gastric lipase and gastric acid are secreted simultaneously. The aim of this study was to investigate weather the acid interferes with the lipase secretion. The secretion of human gastric lipase was studied during blockade of gastric acid secretion and modified sham feeding to estimate the impact of these conditions on both gastric lipase enzyme activity and immunoreactivity. Methods: Eight healthy volunteers were intubated with a nasogastric tube. We examined gastric aspirates for the amount and activity of lipase secretion during basal conditions, after blockade of acid secretion with a proton pump inhibitor (omeprazole i.v. infusion), and in response to sham feeding (chewing gum) during the blockade. Results: The amount of secreted gastric lipase was unaffected by blockade of acid secretion and increased significantly after sham feeding (169.9 ± 35.7 µg/15 min to 348.1 ± 79.2 µg/15 min; p < 001). Likewise, the output of enzyme activity increased after sham feeding (0.63 ± 0.09 kU/15 min to 1.52 ± 0.36 kU/15 min; p < 0.03). The concentration of enzyme activity remained unchanged by blockade of acid secretion, whereas the output of enzyme activity was decreased, probably because of reduced volume secretion or denaturation and conformational changes of the enzyme. Plasma concentrations of gastrin increased in response to blockade of acid secretion (basal 9.6 ± 1.4 pmol/L to 13.3 ± 2.9 pmol/L; p < 0.02). Conclusions: Gastric acid secretion is not a prerequisite for gastric lipase secretion. Lipase enzyme activity, though, is sensitive to anacidic conditions. [ABSTRACT FROM AUTHOR]

Statins are prescribed to treat hypercholesterolemia and to reduce the risk of cardiovascular disease. However, statin users frequently report myalgia, which can discourage physical activity or cause patients to discontinue statin use, negating the potential benefit of the treatment. Although a proposed mechanism responsible for Statin-Associated Myopathy (SAM) suggests a correlation with impairment of mitochondrial function, the relationship is still poorly understood. Here, we provide evidence that long-term treatment of hypercholesterolemic patients with Simvastatin at a therapeutic dose significantly display increased mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and platelets compared to untreated controls. Furthermore, the amount of superoxide is higher in mitochondria in PBMCs, and platelets from Simvastatin-treated patients than in untreated controls, and the abundance of mitochondrial superoxide, but not mitochondrial respiration trends with patient-reported myalgia. Ubiquinone (also known as coenzyme Q10) has been suggested as a potential treatment for SAM; however, an 8-week course of oral ubiquinone had no impact on mitochondrial functions or the abundance of superoxide in mitochondria from PBMCs, and platelets. These results demonstrate that long-term treatment with Simvastatin increases respiration and the production of superoxide in mitochondria of PBMCs and platelets. [ABSTRACT FROM AUTHOR]