Remote Ischemic Conditioning on Recipients of Deceased Renal Transplants Does Not Improve Early Graft Function: A Multicenter Randomized, Controlled Clinical Trial.

Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia-reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham-RIC. RIC consisted of 4 × 5-min thigh occlusion by an inflatable tourniquet each followed by 5-min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham-RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham-RIC-treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98-151] vs. 112 h [95% CI 91-139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719.

Soluble CD163: a biomarker linking macrophages and insulin resistance.

AIMS/HYPOTHESIS: Soluble CD163 (sCD163) was recently identified as a strong risk marker for developing type 2 diabetes. We hypothesised that sCD163 independently associates with insulin resistance. METHODS: This cross-sectional study includes 234 participants: 96 with type 2 diabetes, 34 with impaired glucose tolerance (IGT) and 104 with normal glucose tolerance (NGT), matched for sex and BMI. Glucose-lowering medication was paused for 1 week before plasma samples were obtained for determination of sCD163 and other inflammatory and metabolic variables. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Concentrations of sCD163 were 1.95 mg/l (0.63-6.97) in individuals with type 2 diabetes, 1.64 mg/l (0.58-4.19) in those with IGT, and 1.48 mg/l (0.48-4.11) (median [range]) in those with NGT (p < 0.0001). In univariate analyses, sCD163 correlated significantly with HOMA-IR (R = 0.44), insulin (R = 0.41), glucose (R = 0.30), triacylglycerol (R = 0.29) and HDL-cholesterol (R = -0.34) (all p < 0.0001). All but glucose remained significant when adjusting for age, sex, BMI and glycaemic group. In univariate regression analyses, HOMA-IR was associated with sCD163, C-reactive protein (CRP), TNF-α and IL-6 (all p ≤ 0.0001). An increase of 50% in sCD163 resulted in an estimated increase in HOMA-IR of 36% (95% CI 26, 48; p < 0.0001). In multiple linear regression analyses, sCD163 (p = 0.001) and CRP (p = 0.01) remained independent predictors of HOMA-IR, whereas TNF-α and IL-6 did not. CONCLUSIONS/INTERPRETATION: Macrophage-specific sCD163 was strongly associated with insulin resistance independently of TNF-α and other predictors. Moreover, sCD163 was associated with well-known variables of the metabolic syndrome.

Is the impact of fatigue related to walking capacity and perceived ability in persons with multiple sclerosis? A multicenter study.

BACKGROUND: The relationship between fatigue impact and walking capacity and perceived ability in patients with multiple sclerosis (MS) is inconclusive in the existing literature. A better understanding might guide new treatment avenues for fatigue and/or walking capacity in patients with MS. OBJECTIVE: To investigate the relationship between the subjective impact of fatigue and objective walking capacity as well as subjective walking ability in MS patients. METHODS: A cross-sectional multicenter study design was applied. Ambulatory MS patients (n = 189, age: 47.6 ±â€¯10.5 years; gender: 115/74 women/men; Expanded Disability Status Scale (EDSS): 4.1 ±â€¯1.8 [range: 0-6.5]) were tested at 11 sites. Objective tests of walking capacity included short walking tests (Timed 25-Foot Walk (T25FW), 10-Metre Walk Test (10mWT) at usual and fastest speed and the timed up and go (TUG)), and long walking tests (2- and 6-Minute Walk Tests (MWT). Subjective walking ability was tested applying the Multiple Sclerosis Walking Scale-12 (MSWS-12). Fatigue impact was measured by the self-reported modified fatigue impact scale (MFIS) consisting of a total score (MFIStotal) and three subscales (MFISphysical, MFIScognitive and MFISpsychosocial). Uni- and multivariate regression analysis were performed to evaluate the relation between walking and fatigue impact. RESULTS: MFIStotal was negatively related with long (6MWT, r = -0.14, p = 0.05) and short composite (TUG, r = -0.22, p = 0.003) walking measures. MFISphysical showed a significant albeit weak relationship to walking speed in all walking capacity tests (r = -0.22 to -0.33, p < .0001), which persisted in the multivariate linear regression analysis. Subjective walking ability (MSWS-12) was related to MFIStotal (r = 0.49, p < 0.0001), as well as to all other subscales of MFIS (r = 0.24-0.63, p < 0.001), showing stronger relationships than objective measures of walking. CONCLUSIONS: The physical impact of fatigue is weakly related to objective walking capacity, while general, physical, cognitive and psychosocial fatigue impact are weakly to moderately related to subjective walking ability, when analysed in a large heterogeneous sample of MS patients.

Bayesian mixture models for within-herd prevalence estimates of bovine paratuberculosis based on a continuous ELISA response.

Diagnostic inference by use of assays such as ELISA is usually done by dichotomizing the optical density (OD)-values based on a predetermined cut-off. For paratuberculosis, a slowly developing infection in cattle and other ruminants, it is known that laboratory factors as well as animal specific covariates influence the OD-value, but while laboratory factors are adjusted for, the animal specific covariates are seldom utilized when establishing cut-offs. Furthermore, when dichotomizing an OD-value, information is lost. Considering the poor diagnostic performance of ELISAs for diagnosis of paratuberculosis, a framework for utilizing the continuous OD-values as well as known coavariates could be useful in addition to the traditional approaches, e.g. for estimating within-herd prevalences. The objective of this study was to develop a Bayesian mixture model with two components describing the continuous OD response of infected and non-infected cows, while adjusting for known covariates. Based on this model, four different within-herd prevalence indicators were considered: the mean prevalence in the herd; the age adjusted prevalence of the herd for better between-herd comparisons; the rank of the age adjusted prevalence to better compare across time; and a threshold-based prevalence to describe differences between herds. For comparison, the within-herd prevalence and associated rank using a traditional dichotomization approach based on a single cut-off for an OD corrected for laboratory variation was estimated in a Bayesian model with priors for sensitivity and specificity. The models were applied to the OD-values of a milk ELISA using samples from all lactating cows in 100 Danish dairy herds in three sampling rounds 13 months apart. The results of the comparison showed that including covariates in the mixture model reduced the uncertainty of the prevalence estimates compared to the cut-off based estimates. This allowed a more informative ranking of the herds where low ranking and high ranking herds were easier to identify.

High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex.

Several studies link increasing body mass index (BMI) to cognitive decline both as a consequence of obesity per se and as a sequela of obesity-induced type 2 diabetes. Obese individuals are prone to a chronic low-grade inflammation as the metabolically active visceral fat produces proinflammatory cytokines. Animal studies indicate that these cytokines can cross the blood-brain barrier. Such crossover could potentially affect the immune system in the brain by inducing gene expression of proinflammatory genes. The relationship between obesity and neuroinflammation in the human brain is currently unknown. Therefore we aim to examine the relationship between BMI and gene expression of central inflammatory markers in the human frontal cortex. Microarray data of 141 neurologically and psychiatrically healthy individuals were obtained through the BrainCloud database. A simple linear regression analysis was performed with BMI as variable on data on IL10, IL1ß, IL6, PTGS2 (COX2) and NOS2 (iNOS). Increasing BMI is associated with a decrease in the mRNA expression of IL10 (P=0.014) and an increase in the expression of NOS2 (iNOS; P=0.040). Expressions of IL10 and NOS2 (iNOS) were negatively correlated (P<0.001). The expression of IL10 was mostly affected by individuals with BMI ⩾40. Multiple linear regression analyses with BMI, age, sex and race as variables were performed in order to identify potential confounders. In conclusion, increasing BMI could affect the IL10-mediated anti-inflammatory defense in the brain and induce iNOS-mediated inflammatory activity.

Walking capacity and ability are more impaired in progressive compared to relapsing type of multiple sclerosis.

BACKGROUND: Patients with progressive multiple sclerosis (MS) have been attributed greater walking disability than relapsing-remitting MS (RRMS) patients but quantitative data on walking speed and ability are lacking. AIM: To investigate the impact of type of MS on severity of reduced walking ability and capacity taking into account age, sex, height and disease duration. DESIGN: Cross-sectional observational multi-center study SETTING: European MS centers providing either in- or out-patient services, or both. POPULATION: This study included 502 patients: 259, 162 and 81 patients showed RRMS, secondary and primary progressive MS respectively. METHODS: Walking was evaluated by T25FW, six minute walk test and MS-Walking Scale-12. Patient characteristics were compared using a one-way ANOVA, and simple and multivariate regression analysis were applied with the walking measures. RESULTS: In adjusted (sex, age, weight, height and disease duration) analyses, walking impairments were more than 20% greater in progressive types of MS compared to RRMS. There were also indications of greater walking impairment in primary compared to secondary progressive MS patients. CONCLUSION: Clinical walking impairment was larger in progressive compared to relapsing-remitting type of MS. The biological disease mechanism, being degeneration or inflammation, impacts on disability. CLINICAL REHABILITATION IMPACT: Health care professionals must be aware of different severity of walking impairment in progressive compared to relapsing type of MS, and need for intensive treatment. Also, studies must report rehabiltiation effects according to MS type.

D-tagatose, a stereoisomer of D-fructose, increases blood uric acid concentration.

D-Fructose has been found to increase uric acid production by accelerating the degradation of purine nucleotides, probably due to hepatocellular depletion of inorganic phosphate (Pi) by an accumulation of ketohexose-1-phosphate. The hyperuricemic effect of D-tagatose, a stereoisomer of D-fructose, may be greater than that of D-fructose, as the subsequent degradation of D-tagatose-1-phosphate is slower than the degradation of D-fructose-1-phosphate. We tested the effect of 30 g oral D-tagatose versus D-fructose on plasma uric acid and other metabolic parameters in 8 male subjects by a double-blind crossover design. Both the peak concentration and 4-hour area under the curve (AUC) of serum uric acid were significantly higher after D-tagatose compared with either 30 g D-fructose or plain water. The decline in serum Pi concentration was greater at 50 minutes after D-tagatose versus D-fructose. The thermogenic and lactacidemic responses to D-tagatose were blunted compared with D-fructose. D-Tagatose attenuated the glycemic and insulinemic responses to a meal that was consumed 255 minutes after its administration. Moreover, both fructose and D-tagatose increased plasma concentrations of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). The metabolic effects of D-tagatose occurred despite its putative poor absorption.

Messengers of renal graft quality during warm and cold ischemia: a porcine microdialysis study.

INTRODUCTION: Little is known about local graft metabolism during warm and cold ischemia before renal transplantation. We sought to characterize local metabolic changes in renal grafts during storage to understand acceptable ischemia time. METHODS: Kidneys from 60- or 15-kg pigs were randomized to cold (4°C) or warm (37°C) storage. Local renal graft metabolism was monitored for 24 hours by use of microdialysis and measurements of glycerol, glutamate glucose and lactate. RESULTS: For all metabolites, there was a significant interaction between time, storage temperature, and kidney size (all P < .0001). For local glycerol and glutamate, a significant increase was observed initially during warm storage, reaching a high steady state level. Glycerol remained low in cold kidneys for 80 minutes, but after 100 minutes there was an ongoing increase (P = .003) with no steady-state maximum level reached during the first 24 hours. The curves in the 2 size groups were parallel (P = .384) with 74% higher glycerol content in large kidneys (P = .005). Glutamate increased in cold kidneys in a similar manner in the 2 size groups (P = .924). Warm storage caused a rapid glucose decline within 60-100 minutes. In cold storage, glucose remained at a steady level until 480 minutes. CONCLUSIONS: Reducing cold ischemia time is of great importance, because concentrations of ischemic metabolites continuously increase in renal grafts. Furthermore, small kidney grafts from growing individuals are more resistant to cold ischemia but more susceptible to warm ischemia. In the setting of donation after circulatory death with prolonged warm ischemia, ongoing catabolism in the potential renal graft may be measured by microdialysis to achieve optimal timing of transplantation.

Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes.

CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists provide beneficial cardiovascular effects by protecting against ischemia and reperfusion injury. Type 2 diabetes mellitus patients have reduced glycolysis in the heart. OBJECTIVE: We hypothesized that cardioprotection by GLP-1 is achieved through increased glucose availability and utilization and aimed to assess the effect of exenatide, a synthetic GLP-1 receptor agonist, on myocardial glucose uptake (MGU), myocardial glucose transport, and myocardial blood flow (MBF). DESIGN AND METHODS: We conducted a randomized, double-blinded, placebo-controlled crossover study in eight male, insulin-naive, type 2 diabetes mellitus patients without coronary artery disease. Positron emission tomography was used to determine the effect of exenatide on MGU and MBF during a pituitary-pancreatic hyperglycemic clamp with (18)F-fluorodeoxyglucose and (13)N-ammonia as tracers. RESULTS: Overall, exenatide did not alter MGU. However, regression analysis revealed that exenatide altered initial clearance of glucose over the membrane of cardiomyocytes and MGU, depending on the level of insulin resistance (P = 0.017 and 0.010, respectively). Exenatide increased MBF from 0.73 ± 0.094 to 0.85 ± 0.091 ml/g · min (P = 0.0056). Except for an increase in C-peptide levels, no differences in circulating hormones or metabolites were found. CONCLUSIONS: The action of exenatide as an activator or inhibitor of the glucose transport and glucose uptake in cardiomyocytes is dependent on baseline activity of glucose transport and insulin resistance. Exenatide increases MBF without changing MGU.

Effect of remote ischemic conditioning on dendritic cell number in blood after renal transplantation--flow cytometry in a porcine model.

Delayed graft function after transplantation increases the risk of rejection. Remote ischemic conditioning (rIC) consists of repetitive, brief, non-damaging periods of ischemia in a limb. For reasons not fully understood, rIC protects the target organ against subsequent ischemia-reperfusion injury. Because ischemic endothelium attracts dendritic cells (DCs), we hypothesised that rIC protects the organ by "trapping" circulating DCs in the limb exposed to rIC. With fewer DCs thus available to infiltrate the graft, a strong T-cell mediated immune response toward the graft is less likely. To test this hypothesis, we measured the number of circulating DCs in a porcine model of renal transplantation with and without rIC. Brain death was induced in eight 65-kg donor pigs. After 22 h of cold ischemia, the kidneys were transplanted into sixteen 15-kg recipient pigs. The recipients were randomised to either non-rIC or rIC before reperfusion of the graft and observed 10 h after reperfusion. The number of DCs was determined by flow cytometry. DCs were identified on the basis of forward- and side-scatter characteristics of CD14-negative mononuclear cells with expression of CD172a. Dendritic cells were subclassified as either plasmacytoid (pDCs) (CD172a(dim), CD4(+), CD14(-)) or conventional (cDCs) (CD172a(high), CD4(-), CD14(-)). Remote ischemic conditioning did not affect the number of circulating cDCs or pDCs within the 10h after transplantation studied. Regardless of rIC, the number of pDCs decreased after graft reperfusion and then returned to baseline levels. In contrast, the number of circulating cDCs increased after reperfusion and later returned to baseline levels.

Do all patients with type 2 diabetes need breakfast?

OBJECTIVES: To evaluate if an improved daily glycemic profile could be achieved in patients with type 2 diabetes by withholding breakfast, but maintaining the same total daily intake of calorie and the same composition of carbohydrates, fat and protein. METHODS: Thirteen type 2 diabetic patients participated in this randomized crossover study. Following an initial fasting night the study consisted of 4 consecutive days. Patients were randomized to diets including breakfast days 1 and 3, and excluding breakfast days 2 and 4, or vice versa. RESULTS: The mean plasma glucose level was 0.24 mmol/l higher after the breakfast diet compared with the non-breakfast diet, but reflected only a tendency (P=0.066). The standard deviation based on plasma glucose was 32% higher after the breakfast diet compared with the non-breakfast diet (P<0.0001). CONCLUSIONS: Not all patients with type 2 diabetes may need breakfast. Moreover, a non-breakfast diet reduces glycemic variability.

PNMT transgenic mice have an aggressive phenotype.

PNMT (phenylethanolamine-N-methyl-transferase) is the enzyme that catalyzes the formation of epinephrine from norepinephrine. In transgenic mice over-expressing PNMT, observations revealed a very high level of aggression compared to their background strain, C57BL/6J. To evaluate the influence of PNMT on aggression and emotionality in this transgenic line, single-sex male and female groups were independently established that consisted of either four wild-type mice or four transgenic mice overexpressing PNMT. The members of each group were littermates. Mixed single-sex groups consisting of two transgenic mice and two wild-type mice were also established. Almost no fights were observed within the female groups. In males, the transgenic line showed a significantly higher level of fighting than controls (p=0.007) and mixed male groups (p=0.02). Housing mice from the transgenic line in mixed groups with wild-type mice seems to decrease the level of aggression in the transgenic line. In conclusion, this is the first study to demonstrate a clear, significant increase in aggression arising from PNMT overexpression. This suggests an important role for central epinephrine levels in aggressive behavior.

The association between the val/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency.

BACKGROUND: Energy expenditure may partly be determined by genetic variations in uncoupling proteins. We have previously found an increased physical activity but a similar 24-h energy expenditure (EE) in subjects with the val/val-55 UCP2 genotype compared to those with the ala/ala genotype which indicates that the val-55 allele is statistically associated with a higher metabolic efficiency. DESIGN: EE during bicycling was determined by indirect calorimetry at three different loads (30, 40 and 60% of VO2max in eight subjects with the val/val-55 genotype (35+/-6 y weight=76.8+/-13.6 kg, VO2max=2.79+/-0.71 l/min) and eight subjects with the ala/ala-55 genotype (37+/-3 y, weight=78.3+/-16.5 kg, VO2max=2.66+/-0.41 l/min). RESULTS: Incremental exercise efficiency across the three different work levels was higher in the val/val (25.3%, c.i. 24.2-26.4%) than in the ala/ala (23.6%, c.i. 22.5-24.7%) genotype P<0.05. Gross exercise efficiency at 40% VO2max was higher in the val/val (15.3+/-0.6%) than in the ala/ala (13.5+/-0.4%) group. CONCLUSION: As the val/ala-55 polymorphism is located in a domain of the protein without any known function, the different exercise efficiency between the two genotypes most likely reflects a linkage disequilibrium with a functionally significant polymorphism in UCP2 or in the neighbouring UCP3 gene. The study suggests that variations in the UCP genes may affect not only basal metabolic rate but also influence energy costs of exercise.

Chromosomal abnormalities and developmental kinetics in in vivo-developed cattle embryos at days 2 to 5 after ovulation.

The frequency of chromosome abnormalities was investigated in cattle embryos (n = 256) derived from superovulated heifers (n = 35) on Days 2, 3, 4, and 5 postovulation (PO). Interphase nuclei (n = 4358) were analyzed for chromosome abnormalities using fluorescent in situ hybridization with chromosome 6- and chromosome 7-specific probes and the developmental rate was described by scoring cell numbers. We found that 93%, 85%, 84%, and 69% of the embryos from Days 2, 3, 4, and 5 PO, respectively, displayed a normal diploid chromosome number in all cells. Of the embryos containing abnormal cells, mixoploidy was significantly more frequent than polyploidy. The percentage of mixoploidy at Days 2, 3, 4, and 5 PO was 5%, 13%, 16%, and 31%, respectively, whereas the percentages of polyploidy were 2%, 2%, 0%, and 0%, respectively. The mean number of cells per embryo was 4.7, 8, 11.5, and 48.3, respectively, at Days 2, 3, 4, and 5 PO. Thus, in vivo-developed embryos were significantly more advanced than the in vitro-produced (IVP) embryos except for Day 2. In conclusion, a significantly lower frequency of chromosomally abnormal embryos, in particular displaying polyploidy early after fertilization, was seen in in vivo versus IVP embryos, and these chromosomal abnormalities may be inherent to the process of IVP in cattle.