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Background Cardiometabolic diseases are a leading cause of HIV-related morbidity and mortality, yet routine screening is not undertaken in high burden countries. We aimed to assess the prevalence and risk factors of the metabolic syndrome (MetS) and its components in adult Ugandan people living with HIV (PWH) initiating dolutegravir-based antiretroviral therapy (ART). Methods We conducted a cross-sectional study using baseline sociodemographic and clinical data of PWH aged ≥ 18 years enrolled in the GLUMED (Glucose metabolism changes in Ugandan HIV patients on Dolutegravir) Study from January to October 2021. MetS was defined as having ≥ 3 of the following: abdominal obesity, hypertension (HTN), hyperglycemia, elevated triglycerides and low high-density lipoprotein cholesterol. Multiple logistic regression was used to assess associations between potential risk factors and MetS and its components. Results 309 PWH were analyzed (100% ART-naive, 59.2% female, median age 31 years and median CD4 count 318 cells/mm3). The prevalence of MetS was 13.9%. The most common cardiometabolic condition was dyslipidemia (93.6%), followed by abdominal obesity (34.0%), hyperglycemia (18.4%), and HTN (8.1%). In adjusted analysis, MetS was associated with age > 40 years (adjusted odds ratio 3.33, 95% confidence interval 1.45-7.67) and CD4 count > 200 cells/mm3 (3.79, 1.23-11.63). HTN was associated with age > 40 years (2.96, 1.32-6.64), and dyslipidemia was associated with urban residence (4.99, 1.35-18.53). Conclusion Cardiometabolic risk factors were common in this young Ugandan cohort of PWH initiating dolutegravir-based ART, underscoring the need for programmatic implementation of surveillance and management of comorbidities in Uganda and similar settings.

BackgroundCardiometabolic diseases are a leading cause of HIV-related morbidity and mortality, yet routine screening is not undertaken in high burden countries. We aimed to assess the prevalence and risk factors of the metabolic syndrome (MetS) and its components in adult Ugandan people living with HIV (PLHIV) initiating dolutegravir-based antiretroviral therapy (ART).MethodsWe analyzed baseline data of PLHIV aged ≥ 18 years enrolled in the GLUMED (Glucose metabolism changes in Ugandan HIV patients on Dolutegravir) Study from January to October 2021. MetS was defined as having 3 or more of the following: abdominal obesity, hypertension (HTN), elevated fasting glucose, elevated triglycerides and low high-density lipoprotein cholesterol. Multiple logistic regression was used to assess associations between potential risk factors and MetS and its components.Results309 PLHIV were analyzed (100% ART-naive, 59.2% female, median age 31 years and median CD4 count 318 cells/mm3). The prevalence of MetS was 13.9%. The most common cardiometabolic condition was dyslipidemia (93.6%), followed by abdominal obesity (34.0%), hyperglycemia (18.4%), and HTN (8.1%). In adjusted analysis, MetS was associated with age > 40 years (odds ratio 3.33, 95% confidence interval 1.45-7.67) and CD4 count > 200 cells/mm3(3.79, 1.23-11.63). HTN was associated with age > 40 years (2.96, 1.32-6.64), and dyslipidemia was associated with urban residence (4.99, 1.35-18.53).ConclusionCardiometabolic risk factors were common in this young Ugandan cohort of PLHIV initiating dolutegravir-based ART, underscoring the need for programmatic implementation of surveillance and management of comorbidities in Uganda and similar settings.Key pointsIn Ugandan HIV patients initiating antiretroviral treatment, the prevalence of cardiometabolic risk factors was substantial: metabolic syndrome 13.9%, dyslipidemia 93.6%, abdominal obesity 34.0%, hyperglycemia 18.4%, and hypertension 8.1%. This highlights the need for early screening and management of comorbidities.

Background Following reports of anti-retroviral therapy (ART) experienced Ugandan people living with HIV (PLHIV) presenting with diabetic ketoacidosis weeks to months following a switch to dolutegravir (DTG), the Uganda Ministry of Health recommended withholding DTG in both ART naïve and experienced PLHIV with diabetes mellitus (T2DM), as well as 3-monthly blood glucose monitoring for patients with T2DM risk factors. We sought to determine if the risk of T2DM is indeed heightened in nondiabetic ART naïve Ugandan PLHIV over the first 48 weeks on DTG. Methods Between January and October 2021, 243 PLHIV without T2DM were initiated on DTG based ART for 48 weeks. Two-hour oral glucose tolerance tests (2-h OGTT) were performed at baseline, 12, and 36 weeks; fasting blood glucose (FBG) was measured at 24 and 48 weeks. The primary outcome was the incidence of T2DM. Secondary outcomes included: incidence of pre-Diabetes Mellitus (pre-DM), median change in FBG from baseline to week 48 and 2-h blood glucose (2hBG) from baseline to week 36. Linear regression models were used to determine adjusted differences in FBG and 2hBG from baseline to weeks 48 and 36 respectively. Results The incidence of T2DM was 4 cases per 1000 PY (1/243) and pre-DM, 240 cases per 1000 person years (PY) (54/243). There was a significant increase in FBG from baseline to week 48 [median change from baseline (FBG): 3.6 mg/dl, interquartile range (IQR): − 3.6, 7.2, p-value (p) = 0.005] and significant reduction in 2hBG (2hBG: − 7.26 mg/dl, IQR: − 21.6, 14.4, p = 0.024) at week 36. A high CD4 count and increased waist circumference were associated with 2hBG increase at week 36. Conclusion We demonstrated a low incidence of T2DM in Ugandan ART-naïve patients receiving DTG. We also demonstrated that longitudinal changes in BG were independent of conventional risk factors of T2DM in the first 48 weeks of therapy. Restricting the use of dolutegravir in Ugandan ART naïve patients perceived to be high risk for diabetes mellitus may be unwarranted.

Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90–94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m(2); fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-(13)C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.

Sugar intake, particularly fructose, is implicated as a factor contributing to insulin resistance via hepatic de novo lipogenesis (DNL). A nine-day fructose reduction trial, controlling for other dietary factors and weight, in children with obesity and metabolic syndrome, decreased DNL and mitigated cardiometabolic risk (CMR) biomarkers. Ceramides are bioactive sphingolipids whose dysregulated metabolism contribute to lipotoxicity, insulin resistance, and CMR. We evaluated the effect of fructose reduction on ceramides and correlations between changes observed and changes in traditional CMR biomarkers in this cohort. Analyses were completed on data from 43 participants. Mean weight decreased (−0.9 ± 1.1 kg). The majority of total and subspecies ceramide levels also decreased significantly, including dihydroceramides, deoxyceramides and ceramide-1-phoshates. Change in each primary ceramide species correlated negatively with composite insulin sensitivity index (CISI). Change in deoxyceramides positively correlated with change in DNL. These results suggest that ceramides decrease in response to dietary fructose restriction, negatively correlate with insulin sensitivity, and may represent an intermediary link between hepatic DNL, insulin resistance, and CMR.

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web of Science, and ClinicalTrials.gov registries were searched for studies published between 1 January 2000 and 15 June 2022. Eligible studies reported incident DM or mean changes in insulin resistance measured by Homeostatic Model for Insulin Resistance (HOMA-IR) in patients on INSTIs compared with other ARTs. We performed random-effects meta-analyses to obtain pooled relative risks (RRs) with 95% CIs.A total of 16 studies were pooled: 13 studies meta-analyzed for incident diabetes with a patient population of 72 404 and 3 for changes in HOMA-IR. INSTI therapy was associated with a lower risk of incident diabetes in 13 studies (RR 0.80, 95% CI 0.67 to 0.96, I2=29%), of which 8 randomized controlled trials demonstrated a 22% reduced risk (RR 0.88, 95% CI 0.81 to 0.96, I2=0%). INSTIs had a lower risk compared with non-nucleoside reverse transcriptase inhibitors (RR 0.75, 95% CI 0.63 to 0.89, I2=0%) but similar to protease inhibitor-based therapy (RR 0.78, 95% CI 0.61 to 1.01, I2=27%). The risk was lower in studies with longer follow-up (RR 0.70, 95% CI 0.53 to 0.94, I2=24%) and among ART-naïve patients (RR 0.78, 95% CI 0.65 to 0.94, I2=3%) but increased in African populations (RR 2.99, 95% CI 2.53 to 3.54, I2=0%).In conclusion, exposure to INSTIs was not associated with increased risk of DM, except in the African population. Stratified analyses suggested reduced risk among ART-naïve patients and studies with longer follow-up.International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42021273040.

Introduction Poeple living with HIV have higher prevalence of diabetes mellitus and metabolic perturbations compared to non-HIV populations. Diabetes and metabolic syndrome co-morbidities add significant burden to HIV care. Currently, WHO recommends integrase strand transfer inhibitors (INSTIs) as the first or second line therapy in people with HIV due to overall good tolerability and safety profile. However, whether INSTI use increases the risk of incident diabetes (with or without metabolic syndrome) compared to other anti-retroviral therapies (ART) is controversial. In this systematic review and meta-analysis, we aim to examine this risk in HIV-positive populations receiving INSTIs compared to other ART regimens (not containing INSTIs). Methods and analysis The study will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. This protocol adheres to the Standard Protocol Items for reporting systematic reviews and meta-analyses checklist. Eligibility criteria will be original peer-reviewed published articles and conference abstracts with no language or geographical restriction; that report the ocurrence of diabetes mellitus as a discrete outcome or part of metabolic syndrome, in adult PLWHIV receiving INSTIs compared to other ART regimens. PubMed/ Medline, Web of Science, Embase and Cochrane Database of Systematic Reviews will be searched from 1st- January-2000 to 31st—January-2022. Per our a priori, screening, inclusion and data extraction will be conducted separately by two investigators, and a senior researcher will be consulted in case of disagreement. The quality of included studies will be assessed by the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies and the revised Cochrane risk-of-bias tool (ROB2) for randomized controlled trials. The quantitative synthesis of the study outcomes will be explored in different subgroups and sensitivity analyses. Meta regression will also be performed to further test the predictors of the outcome. Ethics and dissemination Ethical approval is waived as the study is a review of published litterature. The analyses will be presented in conferences and published as a scientific article. Trial registrartion PROSPERO registration number is; CRD42021273040.

Author(s): Erkin-Cakmak, Ayca; Bains, Yasmin; Caccavello, Russell; Noworolski, Susan M; Schwarz, Jean-Marc; Mulligan, Kathleen; Lustig, Robert H; Gugliucci, Alejandro | Abstract: ObjectiveTo investigate the link between dietary sugar consumption and two separate pathogenetic mechanisms associated with metabolic syndrome: de novo lipogenesis (DNL) and nonenzymatic glycation.Design and participantsWe assessed changes in serum d-lactate (the detoxification end-product of methylglyoxal) concentration in response to 9 days of isocaloric fructose restriction in 20 children with obesity and metabolic syndrome, and examined correlations with changes in DNL, liver fat, insulin sensitivity, and other metrics of hepatic metabolism.InterventionsNine days of dietary sugar restriction, with substitution of equal amounts of refined starch.Main outcome measuresOn days 0 and 10, children had laboratory evaluation of d-lactate levels and other analytes, and underwent oral glucose tolerance testing, magnetic resonance spectroscopy to quantify fat depots, and 13C-acetate incorporation into triglyceride (TG) to measure DNL.Resultsd-Lactate was associated with baseline liver fat fraction (P l 0.001) and visceral adipose tissue (P l 0.001) but not with subcutaneous adipose tissue. At baseline, d-lactate was positively correlated with DNL-area under the curve (AUC) (P = 0.003), liver fat fraction (P = 0.02), TG (P = 0.004), and TG/high-density lipoprotein ratio (P = 0.002). After 9 days of isocaloric fructose restriction, serum d-lactate levels reduced by 50% (P l 0.0001), and changes in d-lactate correlated with both changes in DNL-AUC and measures of insulin sensitivity.ConclusionBaseline correlation of d-lactate with DNL and measures of insulin sensitivity and reduction in d-lactate after 9 days of isocaloric fructose restriction suggest that DNL and nonenzymatic glycation are functionally linked via intermediary glycolysis in the pathogenesis of metabolic syndrome and point to fructose as a key dietary substrate that drives both pathways.

Introduction: Delayed postprandial triglyceride-rich lipoprotein (TRL) metabolism is associated with increased atherogenic risk. Dietary fructose is a preferred lipogenic substrate which contributes to NAFLD and dyslipoproteinemia. Hypothesis: Isocaloric fructose restriction reduces postprandial TRL excursions in part by affecting the modulation of lipoprotein lipase (LPL) activity and peripheral clearance rates. Methods: We determined the effect of 9 days of isocaloric fructose restriction on fasting and postprandial TRL metabolism markers in obese Latino and African American children (9-18 years old; n=30) with high habitual sugar consumption (>50 g/d). Metabolic assessments were performed on day 0 and day 10 of isocaloric fructose restriction (starch substituted for sugar, same macronutrient composition). To follow postprandial TRL metabolism, after an initial double-sized meal, single-sized meals (providing 67% of daily calories, 15% protein, 35% fat, 50% carbohydrate) were fed every 30 minutes, with blood sampled every hour for 8 hours. Fructose content of meals reduced from 12% on day 0 to 4% on day 10. Paired t-tests compared change from day 0 to day 10 within each child. Results: Fasting TG, apoCIII, and ANGPTL3 reduced by 25%, 28% and 26% respectively (p Conclusions: Short-term isocaloric fructose restriction improved postprandial chylomicron and VLDL metabolism in children with obesity. Specific and selective improvements in ANGPTL3 and apoCIII suggest differential modulation of LPL activity as a putative mechanism that deserves further exploration.

To review recent evidence for the role of dietary carbohydrate in de novo lipogenesis (DNL) and nonalcoholic fatty liver disease (NAFLD).A large body of evidence suggests that increased hepatic DNL is a significant pathway contributing to the development of NAFLD. Dietary carbohydrates, in particular, fructose, have been shown to stimulate DNL and increase liver fat, although it is debated whether this is due to excess energy or fructose per se. Recent dietary intervention studies conducted in energy balance show that high-fructose diets increase DNL and liver fat, whereas fructose restriction decreases DNL and liver fat.The association of high-carbohydrate and high-sugar diets with NAFLD may in part be explained by the effect of sugar on increasing hepatic DNL.

Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis.

Epidemiologic studies suggest a link between excess sugar consumption and obesity, fatty liver disease, metabolic syndrome, and type 2 diabetes mellitus. One important pathway that may link these metabolic diseases to sugar consumption is hepatic conversion of sugar to fat, a process known as de novo lipogenesis (DNL). Mechanistic studies have shown that diets high in simple sugars increase both DNL and liver fat. Importantly, removal of sugar from diets of children with obesity for only 9 days consistently reduced DNL and liver fat and improved glucose and lipid metabolism. Although the sugar and beverage industries continue to question the scientific evidence linking high-sugar diets to metabolic diseases, major health organizations now make evidence-based recommendations to limit consumption of simple sugars to no more than 5% to 10% of daily intake. Clear recommendation about moderating sugar intake to patients may be an important nonpharmacologic tool to include in clinical practice.

Transportreaktionen sind ein neuer Reaktionstyp zum Recyceln von Industriemetallen. Damit liesen sich manche Schwierigkeiten beim Aufarbeiten von Elektroschrott vermeiden.

Introduction: Elevated fasting and postprandial triglyceride-rich lipoproteins (TRL) are associated with increased risk for atherosclerosis. In the postprandial state circulating lipids consist of dietary fat transported from the intestine, by chylomicrons (containing ApoB48) and fat transported from the liver, in very low-density lipoproteins (VLDL, containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because current methods are inadequate to fully separate these particles. Specifically, chylomicron fractions have considerable contamination from VLDL. Hypothesis: We hypothesized that the generation of resin crosslinked to specific ApoB100 antibodies unique to VLDL would allow purification of chylomicron particles. Proof-of-principle experiments will determine: 1) individual contributions of newly synthesized fatty acids (de novo lipogenesis (DNL)), to triglycerides found in VLDL and chylomicrons; and 2) the proportion of labeled acetyl-CoA (precursor-pool value (PPV)) used to synthesize new palmitate. A difference in DNL and PPV for the purified VLDL and chylomicron fractions will confirm the successful separation of these particles. Methods: Polyclonal antibodies were produced against the C-terminus of the ApoB100 protein and crosslinked to resin generating ApoB100-specific affinity columns. To yield purified chylomicron and VLDL particles we used this technique in conjunction with stable-isotope tracer methodology in a human feeding study. Two healthy volunteers consumed a standardized diet accompanied by oral dosing of 1- 13 C-acetate every 30 minutes for 8 hours. Plasma collected hourly was used for the isolation of TRL, which was applied to the affinity resin and purified chylomicrons and VLDL collected. Triglycerides were isolated and derivatized. The enrichment of methyl-palmitate was measured by GC/MS and Mass Isotopomer Distribution Analysis was used to calculate DNL and PPV. Results: Western blots confirmed the separation of chylomicrons and VLDL by the described method. From the purified TRL fractions, the DNL-AUC (%DNL x 5 hours) values for subject 1 were chylomicron 4% and VLDL 34%, an 88% difference, and for subject 2 were chylomicron 8% and VLDL 83%, a 90% difference. The PPV calculated for each fraction in subject 1 were chylomicron 10% and VLDL 13% and in subject 2 were chylomicron 10%, VLDL 12%. On average, the PPV in the chylomicron fraction were 18% less than the VLDL fraction. Conclusions: In conclusion, results demonstrate that the immunoaffinity method effectively separated postprandial lipoproteins showing fractionated particles carry unique information regarding tissue of origin . Future applications include investigating the respective contribution of fat and sugar to atherosclerosis risk.

Background and aimsDietary fructose may play a role in the pathogenesis of metabolic syndrome (MetS). In a recently published study of obese children with MetS, we showed that isocaloric fructose restriction reduced fasting triglyceride (TG) and LDL-cholesterol (LDL-C). In these ancillary analyses, we tested the hypothesis that these effects were also accompanied by improved quantitative and qualitative changes in LDL and HDL subclasses and their apolipoproteins; as well as change in VLDL, particularly apoC-III.MethodsObese children with MetS (n=37) consumed a diet that matched self-reported macronutrient composition for nine days, with the exception that dietary fructose was reduced from 11.7±4.0% to 3.8±0.5% of daily calories and substituted with glucose (in starch). Participants underwent fasting biochemical analyses on Days 0 and 10. HDL and LDL subclasses were analyzed using the Lipoprint HDL and LDL subfraction analysis systems from Quantimetrix.ResultsSignificant reductions in apoB (78±24 vs. 66±24mg/dl) apoC-III (8.7±3.5 vs. 6.5±2.6mg/dl) and apoE (4.6±2.3 vs. 3.6±1.1mg/dl), all p&nbsp

Backgrounds and aims: Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. Methods: The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after 2H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Results: Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. Conclusions: Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions.

Atherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes.ApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 μg, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50-200 μg/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p0.001). Compared to controls, CD209 (p0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p0.001) and of phosphorylated NF-κB-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p0.001).MCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.

An ethanolic extract of Artemisia scoparia (SCO) has metabolically favorable effects on adipocyte development and function in vitro and in vivo. In diet-induced obese mice, SCO supplementation significantly reduced fasting glucose and insulin levels. Given the importance of adipocyte lipolysis in metabolic health, we hypothesized that SCO modulates lipolysis in vitro and in vivo. Free fatty acids and glycerol were measured in the sera of mice fed a high-fat diet with or without SCO supplementation. In cultured 3T3-L1 adipocytes, the effects of SCO on lipolysis were assessed by measuring glycerol and free fatty acid release. Microarray analysis, qPCR, and immunoblotting were used to assess gene expression and protein abundance. We found that SCO supplementation of a high-fat diet in mice substantially reduces circulating glycerol and free fatty acid levels, and we observed a cell-autonomous effect of SCO to significantly attenuate tumor necrosis factor-α (TNFα)-induced lipolysis in cultured adipocytes. Although several prolipolytic and antilipolytic genes were identified by microarray analysis of subcutaneous and visceral adipose tissue from SCO-fed mice, regulation of these genes did not consistently correlate with SCO’s ability to reduce lipolytic metabolites in sera or cell culture media. However, in the presence of TNFα in cultured adipocytes, SCO induced antilipolytic changes in phosphorylation of hormone-sensitive lipase and perilipin. Together, these data suggest that the antilipolytic effects of SCO on adipose tissue play a role in the ability of this botanical extract to improve whole body metabolic parameters and support its use as a dietary supplement to promote metabolic resiliency.

Objective: Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n 527) and African-American (n 516) children with obesity and metabolic syndrome. Methods: Participants consumed a diet for 9 days to deliver comparable percentages of protein, fat, and carbohydrate as their self-reported diet; however, dietary sugar was reduced from 28% to 10% and substituted with starch. Participants recorded daily weights, with calories adjusted for weight maintenance. Participants underwent dual-energy X-ray absorptiometry and oral glucose tolerance testing on Days 0 and 10. Biochemical analyses were controlled for weight change by repeated measures ANCOVA. Results: Reductions in diastolic blood pressure (25 mmHg; P 50.002), lactate (20.3 mmol/L; P

Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain.We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose.Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy.Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP.Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.

Banken konnen – wie man sagt – „Geld aus dem Nichts schopfen“ und zwar lediglich mit einer Buchung „Kredit an Kundengeld“. Erachtet eine Bank einen Kunden als kreditwurdig, schreibt sie ihm den Kreditbetrag auf seinem Bankkonto gut. Das Bild einer Bank, das Geld von Sparern einsammelt und – sobald sie genug davon zusammen hat – an Kreditnehmer ausleiht, ist somit nicht ganz korrekt.

OBJECTIVE The presence of large subcutaneous adipocytes in obesity has been proposed to be linked with insulin resistance and type 2 diabetes through the “adipose tissue expandability” hypothesis, which holds that large adipocytes have a limited capacity for expansion, forcing lipids to be stored in nonadipose ectopic depots (skeletal muscle, liver), where they interfere with insulin signaling. This hypothesis has, however, been largely formulated by cross-sectional findings and to date has not been prospectively demonstrated in the development of insulin resistance in humans. RESEARCH DESIGN AND METHODS Twenty-nine men (26.8 ± 5.4 years old; BMI 25.5 ± 2.3 kg/m2) were fed 40% more than their baseline requirement for 8 weeks. Before and after overfeeding, insulin sensitivity was determined using a two-step hyperinsulinemic-euglycemic clamp. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) were measured by 1H-MRS and abdominal fat by MRI. Subcutaneous abdominal adipose and skeletal muscle tissues were collected to measure adipocyte size and markers of tissue inflammation. RESULTS Subjects gained 7.6 ± 2.1 kg (55% fat) and insulin sensitivity decreased 18% (P < 0.001) after overfeeding. IHL increased 46% from 1.5% to 2.2% (P = 0.002); however, IMCL did not change. There was no association between adipocyte size and ectopic lipid accumulation. Despite similar weight gain, subjects with smaller fat cells at baseline had a greater decrease in insulin sensitivity, which was linked with upregulated skeletal muscle tissue inflammation. CONCLUSIONS In experimental substantial weight gain, the presence of larger adipocytes did not promote ectopic lipid accumulation. In contrast, smaller fat cells were associated with a worsened metabolic response to overfeeding.

Botanical compounds and extracts are widely used as nutritional supplements for the promotion of health or the prevention of disease. An extract of Artemisia dracunculus (PMI 5011) has been shown to improve insulin action, yet the precise mechanism is not known. The aim of this study is to demonstrate that the mechanism by which PMI 5011 and two related Artemisia extracts improve insulin action is associated with a down-regulation of de novo lipogenesis (DNL) in the liver and an increase in DNL in the adipose tissue.Diet-induced obese 16-wk-old male mice (C57 BL/6 J) were divided into four groups: (control, 5011, Santa, and Scopa) and fed for 30 d with respective extracts incorporated into the diet at 1% (w/w). Deuterium was administered on day 30 for the measurement of DNL in blood, liver, and white adipose tissue. Individual fatty acids and glycerol levels were also measured.No statistically significant differences were seen in DNL between the control group and the three botanical treatments. Plasma levels of all four long-chain fatty acids were significantly lower in the three treatment groups. Glycerol in the plasma was lower in the treatment groups compared with the control group; however, this did not reach statistical significance in all cases. Tissue levels of the fatty acids and glycerol did not differ between any of the treatment groups.These results suggest that botanicals may not affect fractional DNL in animals on a high-fat diet. However, there were decreases in long-chain fatty acids and in glycerol coming from the newly synthesized triglycerides in plasma.

Background Changes in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled. The objective of this study was to compare the changes of glucose and pancreatic hormones [C-peptide, glucagon, and pancreatic polypeptide (PP)] during a meal tolerance test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic–hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese nondiabetic patients. Methods Two groups were studied at baseline and at 14 days: the RYGB followed by caloric restriction group (RYGB, n=12) and the equivalent caloric restriction alone group (Diet, n=10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months to assess the changes after substantial weight loss. During MTT, the early and overall changes in glucose and pancreatic hormone concentrations were determined, and during the clamp, steady-state insulin and FFA concentrations were assessed. Results After 14 days, RYGB patients had enhanced postprandial glucose, C-peptide, and glucagon responses, and decreased postprandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB patients, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in postprandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to presurgical values. Conclusions In morbidly obese nondiabetic patients, RYGB produces early changes in postmeal glucose, C-peptide, glucagon, and PP responses, and it appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months postsurgery. The early changes cannot be explained by caloric restriction alone.

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies.This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

The use of nanoparticles in tumor imaging, molecular imaging, and drug delivery has significantly expanded in the last few years. The relatively new field of “theranostics” combines their capacity for drug delivery with their potential as contrast agents. Depending on the imaging modality used, several types of nanoparticles are available, such as gold for optical imaging or superparamagnetic iron oxide for magnetic resonance imaging. This review will give a short overview of the different types of nanoparticles as well as their development and potential application in recent years. Furthermore, it describes the research on classic imaging modalities as well as on new techniques to image nanoparticles in vivo and focuses on magnetic-based imaging modalities.

Cancer is one of the biggest challenges facing the medical research in our time. The goals are to improve not only the therapeutic outcome, even in the cases of advanced and metastatic cancer, but also the methods of treatment, which often have considerable adverse effects. In addition, the current developments, such as demographic change, population growth, and increasing healthcare costs, have to be taken into consideration. In all likelihood, nanotechnology and, in particular, the use of magnetic nanoparticles consisting of the elements nickel, cobalt, and iron can make a significant contribution. The greatest potential can be ascribed to the drug delivery systems: magnetic nanoparticles are functionalized by binding them to various substances, including chemotherapeutic agents, radionuclides, nucleic acids, and antibodies. They can then be guided and accumulated using a magnetic field. Hyperthermia can be induced with an alternating magnetic field, providing another therapeutic option. Magnetic nanoparticles may be useful in overcoming cancer drug resistance. They also contribute to realizing a combination of diagnostic investigation and therapy in the field of “theranostics”. The multifaceted and promising results of research in the recent years offer the prospect of a real advance in cancer therapy in the near future.

The effects of dietary sugar on risk factors and the processes associated with metabolic disease remain a controversial topic, with recent reviews of the available evidence arriving at widely discrepant conclusions.There are many recently published epidemiological studies that provide evidence that sugar consumption is associated with metabolic disease. Three recent clinical studies, which investigated the effects of consuming relevant doses of sucrose or high-fructose corn syrup along with ad libitum diets, provide evidence that consumption of these sugars increase the risk factors for cardiovascular disease and metabolic syndrome. Mechanistic studies suggest that these effects result from the rapid hepatic metabolism of fructose catalyzed by fructokinase C, which generates substrate for de novo lipogenesis and leads to increased uric acid levels. Recent clinical studies investigating the effects of consuming less sugar, via educational interventions or by substitution of sugar-sweetened beverages for noncalorically sweetened beverages, provide evidence that such strategies have beneficial effects on risk factors for metabolic disease or on BMI in children.The accumulating epidemiological evidence, direct clinical evidence, and the evidence suggesting plausible mechanisms support a role for sugar in the epidemics of metabolic syndrome, cardiovascular disease, and type 2 diabetes.

Background & Aims Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). Methods Children (9−18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. Results Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%−14.8%) to 3.8% (IQR, 1.7%−15.5%) ( P 3 (IQR, 85−145 cm 3 ) to 110 cm 3 (IQR, 84–134 cm 3 ) ( P P P Conclusions Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043.

In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with β-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.

Author(s): Stanhope, Kimber L; Griffen, Steven C; Bremer, Andrew A; Vink, Roel G; Schaefer, Ernst J; Nakajima, Katsuyuki; Schwarz, Jean-Marc; Beysen, Carine; Berglund, Lars; Keim, Nancy L; Havel, Peter J | Abstract: BackgroundConsumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI).ObjectiveWe determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures.DesignThe subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption.ResultsConsumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P l 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P l 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups.ConclusionThe results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853.

Context: Adipose tissue in obese individuals is characterized by reduced capillary density and reduced oxygenation.Objective: Our objective was to test whether hypoxia is associated with reduced antilipolytic effect of insulin.Participants, Design, and Setting: Twenty-one lean and obese individuals participated in this cross-sectional study at a university-based clinical research center.Intervention: In all subjects, in situ adipose tissue (AT) oxygenation [AT oxygen partial pressure (ATpO2)] was measured with a Clark electrode, insulin sensitivity as well as basal and insulin-suppressed lipolysis (continuous infusion of (2H5)glycerol) were measured during a euglycemic-hyperinsulinemic clamp, and abdominal sc AT biopsies were collected to assess fat cell size (Coulter counting of osmium-fixed cells), capillary density (by staining of histological sections), and gene expression (by quantitative RT-PCR).Main Outcome Measure: In situ ATpO2 was evaluated.Results: The ability of insulin to suppress lipolysis (percent) was positively correlated with insulin sensitivity (r = 0.43; P < 0.05), ATpO2 (r = 0.44; P < 0.05), vascular endothelial growth factor mRNA (r = 0.73; P < 0.01), and capillary density (r = 0.75; P < 0.01).Conclusion: These results indicate that low capillary density and ATpO2 in AT are potentially upstream causes of AT dysfunction.

Background: Despite limited soft tissue resolution flat-detector computed tomography (FD-CT) provides substantial superior spatial resolution in comparison with multislice computed tomography (MS-CT). This may add value in the visualization of small vascular structures if intravenous contrast application leads to substantial opacification and visibility of intracranial vessels or aneurysms. Purpose: To evaluate the feasibility of visualization of vascular structures by FD-CT angiography (FD-CTA) after intravenous contrast injection compared with MS-CTA and intra-arterial digital subtracted angiography (IADSA) in an animal model. Material and Methods: Aneurysms were created in the right common carotid artery in six New Zealand White Rabbits using the elastase technique. Imaging was performed using FD-CTA, MS-CTA (injection of 1 ml/kg body weight) and IADSA. Anonymized volume rendering reconstruction (VRT), maximum intensity projection (MIP), and multiplanar reconstruction (MPR) images were reconstructed and evaluated by two experienced reviewers for aneurysm geometry and vascular structure anatomy using standard tools of a dedicated workstation. Results: Aneurysms could be successfully created in all animals. Measurements of aneurysm geometry (aneurysm height, width, neck width) and vascular structures (brachiocephalic trunk, carotid artery diameter and plane) were nearly identical in all three modalities. Intra- and inter-observer correlations of the different parameters showed high r values between 0.83 and 0.99. Conclusion: Our results show the feasibility of FD-CTA in comparison with MS-CTA and IADSA in an animal model. Despite limited soft tissue resolution, opacification of vascular structures with sufficient contrast to the surrounding structures was possible in all animals. Vascular structures appeared better delineated in FD-CTA than in MS-CTA, probably due to the superior spatial resolution.

Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide, and is commonly associated with the metabolic syndrome. Secular trends in the prevalence of these diseases may be associated with the increased fructose consumption observed in the Western diet. NAFLD is characterized by two steps of liver injury: intrahepatic lipid accumulation (hepatic steatosis), and inflammatory progression to nonalcoholic steatohepatitis (NASH) (the 'two-hit' theory). In the first 'hit', hepatic metabolism of fructose promotes de novo lipogenesis and intrahepatic lipid, inhibition of mitochondrial beta-oxidation of long-chain fatty acids, triglyceride formation and steatosis, hepatic and skeletal muscle insulin resistance, and hyperglycemia. In the second 'hit', owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants. Many patients with NASH also have micronutrient deficiencies and do not have enough antioxidant capacity to prevent synthesis of ROS, resulting in necroinflammation. We postulate that excessive dietary fructose consumption may underlie the development of NAFLD and the metabolic syndrome. Furthermore, we postulate that NAFLD and alcoholic fatty liver disease share the same pathogenesis.

Rationale and Objectives The aim of this study was to compare tumor signal and contrast media uptake characteristics on contrast-enhanced T1-weighted sequences at 3 Tesla over 30 minutes after double-dose administration of different contrast agents in an animal model of brain glioma. Materials and Methods Nine rats underwent magnetic resonance imaging (MRI) after stereotactic F98 glioma cell implantation before and repetitively for 30 minutes after injection of gadobutrol, gadopentetate, and gadobenate, respectively. Signal-to-noise ratio (SNR) and tumor contrast-to-noise ratio (CNR) were evaluated and MRI-derived tumor volumes were compared to histology. Results Postcontrast tumor SNR and CNR peaked at 4 minutes after contrast application. While contrast-enhancement within the tumor was fading, tumor volume increased by continuous contrast-uptake of peripheral parts between 4 minutes (137 ± 29 mm3, 126 ± 16 mm3, 141 ± 24 mm3) and 20 minutes (182 ± 35 mm3, 164 ± 32 mm3, 191 ± 25 mm3), respectively. At 8 and 12 minutes, 84% and 91% of the tumor volume were definable, respectively. Conclusion Optimal correlation between MRI-derived tumor volume and histology is achieved by imaging up to 20 minutes after contrast application. At 4 minutes (this delay is mostly used in clinical routine), only 75% of the enhancing tumor volume is assessable. A delay of 8 minutes already reveals 84% of the tumor and seems to be a practical clinical compromise.

BACKGROUND HIV protease inhibitors have been shown to worsen glucose and lipid metabolism. Recent studies have suggested that protease inhibitors can impair insulin secretion in HIV-infected patients. We studied the effects of the protease inhibitor combination lopinavir and ritonavir on insulin secretion, insulin sensitivity, and lipid metabolism in HIV-negative persons. METHODS A combination dose of lopinavir 400 mg and ritonavir 100 mg was given twice daily to eight HIV-seronegative men for 4 weeks. Fasting glucose, insulin, lipid, and lipoprotein profiles; oral glucose tolerance; insulin secretion and insulin-mediated glucose disposal by hyperglycemic clamp; and body composition by dual energy X-ray absorptiometry were determined before and after lopinavir/ritonavir administration. RESULTS There was no change in first-phase insulin secretion (2.82 +/- 0.30 versus 2.71 +/- 0.31 nmol/l; P = 0.60), as well as fasting insulin and glucose levels, oral glucose tolerance, or insulin-mediated glucose disposal after 4 weeks administration of lopinavir/ritonavir. However, there were significant increases in fasting triglycerides (1.02 +/- 0.13 versus 2.20 +/- 0.31 mmol/l; P = 0.001), total cholesterol (4.42 +/- 0.30 versus 5.70 +/- 0.60 mmol/l; P = 0.007), and apo B-100 levels (0.86 +/- 0.07 versus 1.07 +/- 0.11 g/l; P = 0.0009). High-density lipoprotein cholesterol decreased (0.99 +/- 0.11 versus 0.82 +/- 0.10 mmol/l; P = 0.005). There were no changes in body composition, weight, or body fat. CONCLUSION Although administration of lopinavir/ritonavir to healthy, HIV-seronegative volunteers for 4 weeks resulted in increased triglyceride and decreased high-density lipoprotein cholesterol levels, there was no change in first-phase insulin secretion during the hyperglycemic clamp. The reported effects of protease inhibitor on insulin secretion in HIV-infected individuals may be due to changes in HIV-related factors and not a direct drug effect.

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so-called perifocal edema or brain swelling imposes in T2-weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin-4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2-weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment.

The aim of this study was to evaluate the potential of a novel micro-CT system to image in vivo the extent of tumor in a rat model of malignant glioma compared to 3T magnetic resonance imaging (MRI) and histology. Fourteen animals underwent double dose contrast-enhanced imaging with micro-CT and 3T MRI using a clinical machine at day 10 after stereotactic F98 glioma cell implantation. Calculation of the volume of the contrast-uptaking part of the tumor was done by manually outlining the tumor contours by two experienced neuroradiologists. The micro-CT- and MRI-derived tumor volumes were compared to histology as gold standard (hematoxylin and eosin staining and fluorescence staining). There was high interobserver reability regarding the tumor volumes (Crombach's alpha>0.81). Also, there was good correlation of micro-CT- and high-field MRI-derived tumor volumes compared to histology: 72+/-21 mm3 and 69+/-23 mm3 compared to 81+/-14 mm3, respectively (r>0.76). Both the micro-CT- and MRI-derived tumor volumes were not significantly smaller compared to histology (P>0.14). In conclusion, micro-CT allows in vivo imaging of the contrast-enhancing part of experimental gliomas with an accuracy comparable to high-field MRI.

Despite considerable progress in tumor treatment achieved over the last decades, cancer remains one of the leading causes of death worldwide. New treatment strategies based on magnetic nanoparticles have a great potential to significantly improve tumor therapy. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) constitute a versatile platform for targeted drug delivery both as carriers of drugs and/or targeting molecules, as well as by offering the possibility of increased drug accumulation in the diseased area by external magnetic field. Moreover, these nanoparticles can be visualized by imaging modalities like magnetic resonance imaging (MRI), magnetorealxometry (MRX) or magnetic particle imaging (MPI), which allows direct qualitative and/or quantitative insight into the particle distribution in the tumor area. In this way, the control of drug targeting and an estimation of the therapeutic efficacy will be possible in the future.

Pharmacologic doses of growth hormone (GH) reduce HIV-associated fat accumulation but may worsen glucose metabolism. We investigated the effects of a low dose of GH (1 mg per day) in HIV-infected men with fat accumulation and found that such treatment reduced total fat and increased lean body mass without significant changes in glucose tolerance or insulin sensitivity. Visceral adipose tissue (VAT) levels did not change significantly for the group as a whole, although a reduction in the VAT level was seen in patients with a greater VAT level at baseline.

Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60-180 min) insulin reached comparable levels (394 +/- 13 versus 390 +/- 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 +/- 2.2 microM and the 2-h area under the curve was 13.5 +/- 3.1 microM.h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 +/- 1.2 to 9.2 +/- 0.8 mg/kg.min per microUI/ml (95% confidence interval for change, 3.7-6.1; P0.001) on indinavir (average decrease, 34.1 +/- 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 +/- 1.8 to 1.9 +/- 0.9 mg/kg.min (P0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.