Peroxisome proliferator-activated receptor-alpha-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and brain.

Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.

Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin.

Toxic epidermal necrolysis (TEN, Lyell's syndrome) is a severe adverse drug reaction in which keratinocytes die and large sections of epidermis separate from the dermis. Keratinocytes normally express the death receptor Fas (CD95); those from TEN patients were found to express lytically active Fas ligand (FasL). Antibodies present in pooled human intravenous immunoglobulins (IVIG) blocked Fas-mediated keratinocyte death in vitro. In a pilot study, 10 consecutive individuals with clinically and histologically confirmed TEN were treated with IVIG; disease progression was rapidly reversed and the outcome was favorable in all cases. Thus, Fas-FasL interactions are directly involved in the epidermal necrolysis of TEN, and IVIG may be an effective treatment.

Prediction of fat-free mass using bioelectrical impedance analysis in young adults from five populations of African origin.

Background/objectives:Bioelectrical impedance analysis (BIA) is used in population and clinical studies as a technique for estimating body composition. Because of significant under-representation in existing literature, we sought to develop and validate predictive equation(s) for BIA for studies in populations of African origin.Subjects/methods:Among five cohorts of the Modeling the Epidemiologic Transition Study, height, weight, waist circumference and body composition, using isotope dilution, were measured in 362 adults, ages 25-45 with mean body mass indexes ranging from 24 to 32. BIA measures of resistance and reactance were measured using tetrapolar placement of electrodes and the same model of analyzer across sites (BIA 101Q, RJL Systems). Multiple linear regression analysis was used to develop equations for predicting fat-free mass (FFM), as measured by isotope dilution; covariates included sex, age, waist, reactance and height(2)/resistance, along with dummy variables for each site. Developed equations were then tested in a validation sample; FFM predicted by previously published equations were tested in the total sample.Results:A site-combined equation and site-specific equations were developed. The mean differences between FFM (reference) and FFM predicted by the study-derived equations were between 0.4 and 0.6âeuro0/00kg (that is, 1% difference between the actual and predicted FFM), and the measured and predicted values were highly correlated. The site-combined equation performed slightly better than the site-specific equations and the previously published equations.Conclusions:Relatively small differences exist between BIA equations to estimate FFM, whether study-derived or published equations, although the site-combined equation performed slightly better than others. The study-derived equations provide an important tool for research in these understudied populations.

Regional fat mobilization and training type on sedentary, premenopausal overweight and obese women.

OBJECTIVE: Little is known about the influence of different training types on relative fat mobilization with exercise. The purpose of this study was to analyze the changes induced by aerobic training (AT), resistance (RT) or a combination of both (AT+RT) on total fat mass (TFM) and regional fat mass (RFM). Further, the relative contribution of different regions, upper limbs (UL), lower limbs (LL), and trunk (Tr), were compared. DESIGN AND METHODS: Forty-five overweight and premenopausal women were randomized in either AT, RT or AT+RT. All training groups exercised for the same duration (60 min), 3 times per week for 5 months. Body composition was estimated using dual energy X-ray absorptiometry. RESULTS: TFM decreased significantly in all groups (-4.6 ± 1.9 kg; -3.8 ± 2.6 kg, and -4.7 ± 3.0 kg in AT, RT, and AT+RT groups respectively; P < 0.001). The relative contribution of FM into each segment changed significantly: TrFM represented 46.6% ± 5.8% of TFM at baseline and reduced to 43.1% ± 5.5% (P < 0.001); LLFM was 39.7% ± 5.8% vs. 41.6% ± 5.7% (P < 0.01); ULFM was 11.3% ± 1.3% vs. 12.2% ± 1.4% (P < 0.01). CONCLUSION: Training type did not influence changes of TFM and RFM. Fat mobilization came predominantly from Tr in all training protocols. These findings suggest that overweight and obese women can reduce TFM and RFM, independently of training type.

Blood plasma lipidomic signature of epicardial fat in healthy obese women.

OBJECTIVES: A lipidomic approach was employed in a clinically well-defined cohort of healthy obese women to explore blood lipidome phenotype ascribed to body fat deposition, with emphasis on epicardial adipose tissue (EAT). METHODS: The present investigation delivered a lipidomics signature of epicardial adiposity under healthy clinical conditions using a cohort of 40 obese females (age: 25-45 years, BMI: 28-40 kg/m(2) ) not showing any metabolic disease traits. Lipidomics analysis of blood plasma was employed in combination with in vivo quantitation of mediastinal fat depots by computerized tomography. RESULTS: All cardiac fat depots correlated to indicators of hepatic dysfunctions (ALAT and ASAT), which describe physiological connections between hepatic and cardiac steatosis. Plasma lipidomics encompassed overall levels of lipid classes, fatty acid profiles, and individual lipid species. EAT and visceral fat associated with diacylglycerols (DAG), triglycerides, and distinct phospholipid and sphingolipid species. A pattern of DAG and phosphoglycerols was specific to EAT. CONCLUSIONS: Human blood plasma lipidomics appears to be a promising clinical and potentially diagnostic readout for patient stratification and monitoring. Association of blood lipidomics signature to regio-specific mediastinal and visceral adiposity under healthy clinical conditions may help provide more biological insights into obese patient stratification for cardiovascular disease risks.

Fat embolism syndrome after combined aesthetic surgery.

Fat embolism syndrome is a rare complication that develops after extended soft tissue disruption by liposuction, in particular if combined with time consuming, multiple procedures. Early signs are non-specific and often not considered, so that diagnosis and correct management may be delayed. We report a case in which liposuction combined with other aesthetic surgical procedures caused a fat embolism syndrome in a 46-year-old woman, which was followed by multiple organ failure and the development of sepsis with perimammary abscesses. Extended liposuction of the abdomen and thighs, bilateral augmentation mammaplasty, and stripping of both greater saphenous veins were combined.

Ad libitum intake of a high-carbohydrate or high-fat diet in young men: effects on nutrient balances.

The effect of diet composition [high-carbohydrate, low-fat (HC) and high-fat, low-carbohydrate (HF) diets] on macronutrient intakes and nutrient balances was investigated in young men of normal body weight. Eleven subjects were studied on two occasions for 48 h in a whole-body indirect calorimeter in a crossover design. Subjects selected their meals from a list containing a large variety of common food, which had a food quotient > 0.85 for the HC diet and < 0.85 for the HF diet. The average ad libitum intake was 14.41 +/- 0.85 MJ/d (67%, 18%, and 15% of energy as carbohydrate, fat, and protein, respectively) with the HC diet and 18.25 +/- 0.90 MJ/d (26%, 61%, and 13% of energy as carbohydrate, fat, and protein, respectively) with the HF diet. Total energy expenditure was not significantly influenced by diet composition: 10.46 +/- 0.27 and 10.97 +/- 0.22 MJ/d for the HC and HF diets, respectively. During the 2 test days, cumulative carbohydrate storage was 418 +/- 72 and 205 +/- 47 g, and fat balance was 29 +/- 17 and 291 +/- 29 g with the HC and HF diets, respectively. Only the HF diet induced a significantly positive fat balance. These results emphasize the important role of the dietary fat content in body fat storage.

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice.

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction.

High-dose intravenous immunoglobulin treatment and cerebral vasospasm : a possible mechanism of ischemic encephalopathy?

A 46-year-old woman with a severe polyradiculoneuropathy treated with high-dose intravenous immunoglobulin (IVIg) presented an encephalopathy with increased blood flow velocities of the middle cerebral arteries (MCAs) detected by transcranial Doppler (TCD) studies. The similitude between this observation and another case recently reported of a patient suffering from Guillain-Barré syndrome (GBS) and cerebral blood flow abnormalities after IVIg treatment prompted us to investigate the responsibility of the IVIg therapy in the genesis of these blood flow alterations. We studied therefore by TCD 10 consecutive patients who underwent this treatment for different reasons. In 1 case we observed an asymptomatic, spontaneously reversible increase in the blood flow velocities of the MCAs consistent with a vasospasm and occurring 3-10 days after completion of the therapy. Stroke and ischemic encephalopathy have been reported as possible complications of IVIg treatment. In the case under discussion, clinical events appeared shortly after the administration of the IVIg therapy and responded favorably to a treatment with nimodipine. Other etiopathogenic mechanisms, in particular a CNS vasculopathic process related to the GBS itself, have to be considered as well. Further studies, with a larger number of patients, are therefore needed to evaluate the underlying mechanisms of blood flow abnormalities occurring sometimes in GBS patients after IVIg treatment.

TUḤFAT al-NAṢĀ’IḤ de Yūsuf Gadā

Dans cette copie le bāb 45 est numéroté 46 par erreur, de même que la date de composition (f. 66v) est donnée comme étant 700H.[sic] au lieu de 795H. De la main de Muḥ. Zamān, on trouve des gloses lexicographiques entre les lignes ou dans le marges. La signature d’Aussant figure au f. 1. Ce ms. (Aussant n° 38) a été acquis par la B.N. en 1798. [Anc. cote, Suppl. persan 51].

Topographical body fat distribution links to amino acid and lipid metabolism in healthy non-obese women.

Visceral adiposity is increasingly recognized as a key condition for the development of obesity related disorders, with the ratio between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reported as the best correlate of cardiometabolic risk. In this study, using a cohort of 40 obese females (age: 25-45 y, BMI: 28-40 kg/m(2)) under healthy clinical conditions and monitored over a 2 weeks period we examined the relationships between different body composition parameters, estimates of visceral adiposity and blood/urine metabolic profiles. Metabonomics and lipidomics analysis of blood plasma and urine were employed in combination with in vivo quantitation of body composition and abdominal fat distribution using iDXA and computerized tomography. Of the various visceral fat estimates, VAT/SAT and VAT/total abdominal fat ratios exhibited significant associations with regio-specific body lean and fat composition. The integration of these visceral fat estimates with metabolic profiles of blood and urine described a distinct amino acid, diacyl and ether phospholipid phenotype in women with higher visceral fat. Metabolites important in predicting visceral fat adiposity as assessed by Random forest analysis highlighted 7 most robust markers, including tyrosine, glutamine, PC-O 44∶6, PC-O 44∶4, PC-O 42∶4, PC-O 40∶4, and PC-O 40∶3 lipid species. Unexpectedly, the visceral fat associated inflammatory profiles were shown to be highly influenced by inter-days and between-subject variations. Nevertheless, the visceral fat associated amino acid and lipid signature is proposed to be further validated for future patient stratification and cardiometabolic health diagnostics.

Detection of fat embolism in cases with postmortem angiography (PMA) - Preliminary results

Introduction: Pulmonary fat embolism (PFE) can be a cause of death in cases with trauma, during orthopedic surgery and also in non-traumatic conditions, such as burns, pancreatitis, fatty liver or sickle cell disease. As PMA becomes more widespread, it is important to determine how it affects the diagnosis of PFE. Aims: The aim of this study was to determine if the oily contrast liquid used in PMA induces artefactual PFE, if such artefacts differ from original PFE and if PFE can be detected and graded before PMA. Material and methods: Cases of adults without signs of postmortem change and for which an autopsy with angiography was performed were selected for this study. Pulmonary biopsies of each lung were taken before and after the angiography as were fragments of each lung with a twin-edged knife during the autopsy. The samples were examined under the microscope without fixation or staining and after an Oil-Red O staining. PFE was graded according to Falci et al. Results: Non-artefactual (original) PFE was diagnosed in 4 cases on pre-PMA biopsies. As expected, structures with the aspect of PFE were present in all cases after angiography. The microscopical aspect of original and PMA induced PFE was identical. Grading of the PFE according to Falci et al. was depending on the quality of the biopsies. Conclusions: PMA with oily contrast induces artefactual PFE that cannot be visually differentiated from original PFE. Original PFE can however be diagnosed with pre-angiography biopsies. In order to assure the diagnosis and correct grading of PFE, the quality of the biopsy should be checked before PMA with oily contrast.

Characterization of cocoa butter and cocoa butter equivalents by bulk and molecular carbon isotope analyses: Implications for vegetable fat quantification in chocolate

The fatty acids from cocoa butters of different origins, varieties, and suppliers and a number of cocoa butter equivalents (Illexao 30-61, Illexao 30-71, Illexao 30-96, Choclin, Coberine, Chocosine-Illipe, Chocosine-Shea, Shokao, Akomax, Akonord, and Ertina) were investigated by bulk stable carbon isotope analysis and compound specific isotope analysis. The interpretation is based on principal component analysis combining the fatty acid concentrations and the bulk and molecular isotopic data. The scatterplot of the two first principal components allowed detection of the addition of vegetable fats to cocoa butters. Enrichment in heavy carbon isotope (C-13) of the bulk cocoa butter and of the individual fatty acids is related to mixing with other vegetable fats and possibly to thermally or oxidatively induced degradation during processing (e.g., drying and roasting of the cocoa beans or deodorization of the pressed fat) or storage. The feasibility of the analytical approach for authenticity assessment is discussed.

Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free liposomal doxorubicin /

Rapport de synthèseDrug uptake in a rodent sarcoma model after intravenous injection or isolated lungperfusion of free/liposomal doxorubicinIntroductionLa distribution de doxorubicine libre et doxorubicin liposomale pegylée (Liporubicin?) a été comparée après administration intraveineuse ou application via perfusion isolée du poumon (ILP) dans le parenchyme pulmonaire et dans la tumeur des poumons de rongeurs, porteurs d'une tumeur sarcomateuse.Matériel et méthodeUne tumeur sarcomateuse unique a été générée dans le poumon gauche de 36 rongeurs (Fisher rats) suivie, 10 jours plus tard, par application de doxorubicine ou Liporubicin? soit par perfusion isolée du poumon (n = 20) ou administration intraveineuse (n = 12). Deux différentes concentrations ont été utilisées (100 μg et 400 pg) à doses équimolaires pour les deux formulations de doxorubicine. La concentration des agents cytostatiques ont été mesurées dans la tumeur et le parenchyme pulmonaire à l'aide de chromatographic (HPLC).RésultatsLes résultats indiquent que pour doxorubicine libre, le taux de concentration dans la tumeur et le parenchyme pulmonaire est 3 fois (dosage de 100 μ§) et 10 fois (dosage de 400 plus élevé après ILP par rapport à l'administration intraveineuse. En revanche, pour Liporubicin , le taux de concentration est similaire dans la tumeur et le parenchyme pulmonaire entre ILP et administration intraveineuse, pour les deux doses appliquées.ConclusionPour ILP et administration intraveineuse, le ratio entre accumulation de l'agent cytostatique dans la tumeur versus dans le parenchyme pulmonaire a été comparé pour les deux formulations de doxorubicine ainsi que pour les deux dosages. Pour les deux formulations et dosages de doxorubicine, ILP aboutit à un ratio plus élevé par rapport à l'administration intraveineuse. Cependant, pour les deux formulations et dosages de doxorubicine, ILP résulte également en une distribution de l'agent cytostatique plus hétérogène dans le parenchyme pulmonaire comparé à l'administration intraveineuse.En résumé, l'application de doxorubicine par ILP aboutit donc à une accumulation tumorale élevée et à une augmentation du ratio tumeur-parenchyme pulmonaire, mais en même temps également à une distribution plus hétérogène dans le parenchyme pulmonaire par rapport à l'application intraveineuse. Ceci a été observé pour les deux formulations de doxorubicine et pour les deux dosages appliqué.

Intravenous insulin treatment in acute stroke: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Poststroke hyperglycemia has been associated with unfavorable outcome. Several trials investigated the use of intravenous insulin to control hyperglycemia in acute stroke. This meta-analysis summarizes all available evidence from randomized controlled trials in order to assess its efficacy and safety. METHODS: We searched PubMed until 15/02/2013 for randomized clinical trials using the following search items: 'intravenous insulin' or 'hyperglycemia', and 'stroke'. Eligible studies had to be randomized controlled trials of intravenous insulin in hyperglycemic patients with acute stroke. Analysis was performed on intention-to-treat basis using the Peto fixed-effects method. The efficacy outcomes were mortality and favorable functional outcome. The safety outcomes were mortality, any hypoglycemia (symptomatic or asymptomatic), and symptomatic hypoglycemia. RESULTS: Among 462 potentially eligible articles, nine studies with 1491 patients were included in the meta-analysis. There was no statistically significant difference in mortality between patients who were treated with intravenous insulin and controls (odds ratio: 1.16, 95% confidence interval: 0.89-1.49). Similarly, the rate of favorable functional outcome was not statistically different (odds ratio: 1.01, 95% confidence interval: 0.81-1.26). The rates of any hypoglycemia (odds ratio: 8.19, 95% confidence interval: 5.60-11.98) and of symptomatic hypoglycemia (odds ratio: 6.15, 95% confidence interval: 1.88-20.15) were higher in patients treated with intravenous insulin. There was no heterogeneity across the included trials in any of the outcomes studied. CONCLUSIONS: This meta-analysis of randomized controlled trials does not support the use of intravenous insulin in hyperglycemic stroke patients to improve mortality or functional outcome. The risk of hypoglycemia is increased, however.