The effect of bariatric surgery type on cardiac reverse remodelling.

INTRODUCTION: Bariatric surgery is effective in reversing adverse cardiac remodelling in obesity. However, it is unclear whether the three commonly performed operations; Roux-en-Y Gastric Bypass (RYGB), Laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Adjustable Gastric Band (LAGB) are equal in their ability to reverse remodelling. METHODS: Fifty-eight patients underwent CMR to assess left ventricular mass (LVM), LV mass:volume ratio (LVMVR) and LV eccentricity index (LVei) before and after bariatric surgery (26 RYGB, 22 LSG and 10 LAGB), including 46 with short-term (median 251-273 days) and 43 with longer-term (median 983-1027 days) follow-up. Abdominal visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) were also assessed. RESULTS: All three procedures resulted in significant decreases in excess body weight (48-70%). Percentage change in VAT and EAT was significantly greater following RYGB and LSG compared to LAGB at both timepoints (VAT:RYGB -47% and -57%, LSG -47% and -54%, LAGB -31% and -25%; EAT:RYGB -13% and -14%, LSG -16% and -19%, LAGB -5% and -5%). Patients undergoing LAGB, whilst having reduced LVM (-1% and -4%), had a smaller decrease at both short (RYGB: -8%, p < 0.005; LSG: -11%, p < 0.0001) and long (RYGB: -12%, p = 0.009; LSG: -13%, p < 0.0001) term timepoints. There was a significant decrease in LVMVR at the long-term timepoint following both RYGB (-7%, p = 0.006) and LSG (-7%, p = 0.021), but not LAGB (-2%, p = 0.912). LVei appeared to decrease at the long-term timepoint in those undergoing RYGB (-3%, p = 0.063) and LSG (-4%, p = 0.015), but not in those undergoing LAGB (1%, p = 0.857). In all patients, the change in LVM correlated with change in VAT (r = 0.338, p = 0.0134), while the change in LVei correlated with change in EAT (r = 0.437, p = 0.001). CONCLUSIONS: RYGB and LSG appear to result in greater decreases in visceral adiposity, and greater reverse LV remodelling with larger reductions in LVM, concentric remodelling and pericardial restraint than LAGB.

Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.

BACKGROUND: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). METHODS: C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. RESULTS: In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and ß-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). CONCLUSIONS: EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.

AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss.

OBJECTIVES: Recent literature suggests that ectopic fat deposition in the pancreas may contribute to endocrine and exocrine organ dysfunction, such as type 2 diabetes (T2D), pancreatitis or pancreatic cancer. The aim of this study was to determine factors associated with pancreatic triglyceride content (PTGC), and to investigate the impact of bariatric surgery on ectopic fat pads, pancreatic fat (PTGC) and hepatic fat (HTGC). SUBJECTS: In all, 45 subjects (13 lean, 13 obese nondiabetics and 19 T2D, matched for age and gender) underwent 1H-magnetic resonance spectroscopy, computed tomography of the visceral abdominal fat, metabolic and lipidomic analysis, including insulin-resistance homeostasis model assessment (HOMA-IR), insulin-secretion homeostasis model assessment (HOMA-B) and plasma fatty-acid composition. Twenty obese subjects were reassessed 6 months after the bariatric surgery. RESULTS: PTGC was significantly higher in type 2 diabetic subjects (23.8±3.2%) compared with obese (14.0±3.3; P=0.03) and lean subjects (7.5±0.9%; P=0.0002). PTGC remained significantly associated with T2D after adjusting for age and sex (ß=0.47; P=0.004) or even after adjusting for waist circumference, triglycerides and HOMA-IR (ß=0.32; P=0.04). T2D, C18:1n-9 (oleic acid), uric acid, triglycerides and plasminogen activator inhibitor-1 were the five more important parameters involved in PTGC prediction (explained 80% of PTGC variance). Bariatric surgery induced a huge reduction of both HTGC (-51.2±7.9%) and PTGC (-43.8±7.0%) reaching lean levels, whereas body mass index remained greatly elevated. An improvement of insulin resistance HOMA-IR and no change in HOMA-B were observed after bariatric surgery. The PTGC or HTGC losses were not correlated, suggesting tissue-specific mobilization of these ectopic fat stores. CONCLUSION: Pancreatic fat increased with T2D and drastically decreased after the bariatric surgery. This suggests that decreased PTGC may contribute to improved beta cell function seen after the bariatric surgery. Further, long-term interventional studies are warranted to examine this hypothesis and to determine the degree to which ectopic fat mobilization may mediate the improvement in endocrine and exocrine pancreatic functions.

Tongue-mandible coupling movements during saliva swallowing.

The purpose of this study was to measure the tongue and mandible positions and displacements in relation to the maxilla in the midsagittal plane to characterize the different saliva swallowing patterns by recording their kinematics. A 2D electromagnetic articulograph using four transducer coils, three attached to the upper surface of the tongue midline plus one attached to the chin anterior part allowed continuous evaluation of tongue and chin movements in twelve young adults in good general health. During 170 s sequences recorded at a frequency of 100 Hz, subjects were at rest, silently reading a text they had chosen. The subjects were free to swallow during the sequence. Deglutition of accumulated saliva was analysed after averaging all values obtained during successive 250 ms periods. We identified three elementary swallowing patterns. Mean duration of tongue-mandible movements were 1·51 ± 0·17 s, 1·63 ± 0·14 s and 2·00 ± 0·08 s for the first, second and third patterns respectively. In the light of other studies based on intra-oral pressure recordings, our results help to understand the tongue-mandible coupling behaviours involved in managing an in-mouth saliva bolus during the three elementary swallowing patterns identified.

Epicardial fat: more than just an "epi" phenomenon?

Regional body-fat distribution is one of the key variables that explains the metabolic heterogeneity of obesity and its related cardiovascular risks. According to the ectopy concept, the inability of subcutaneous adipose tissue to store surplus triglycerides may lead to the development of fat in ectopic sites, such as the heart. Epicardial adipose tissue is a metabolically active endocrine organ that produces numerous factors that can modulate cardiac structure and function. The development of in vivo noninvasive imaging has made it possible to quantify its thickness and volume with increasing accuracy. In this review, we discuss the local interaction and cross-talk between epicardial fat and neighboring structures, such as coronary arteries and myocardium, and its relevance to cardiac diseases, such as coronary-artery disease or atrial fibrillation. Beneficial and harmful effects of epicardial adipose tissue are described and analyzed. What leads to an imbalance between protective and deleterious actions has to be further explored. We believe that epicardial fat, which has been neglected for years, plays a key role in cardiovascular disease pathophysiology and represents a "new world" exploration for therapeutic targets, which will be addressed in future clinical and research studies. Elucidating the mechanisms that drive the deposition or mobilization of cardiac adiposity between other ectopic-fat stores needs to be accomplished within the next few years.

Mood-induced variations of mandible and tongue postures.

Twelve young adults in a good general health were observed during habitual posture of tongue and jaw in different emotional conditions induced by watching three video sequences. The position of the mandible was tracked by the displacements of an electromagnetic sensor glued to the chin. The tongue-to-palate distance was obtained by 2-D location of three electromagnetic sensors placed on the tongue upper midline surface. Head displacements were evaluated with a sensor fixed to an upper central incisor and were subtracted from corresponding displacements of tongue and chin sensors to obtain the real tongue and mandible positions during continuous recording sequences. Emotional conditioning by a fear movie influenced the vertical position of the mandible: the mean interarch distances during the fear movie (2·34 ± 0·24 mm) were significantly different from those measured during the tender (3·13 ± 0·35) and neutral (3·42 ± 0·80) movies, respectively (anova repeated measure, SNK; P < 0·05). anova repeated measure indicated that the tongue-to-palate distance differed significantly when the subjects were watching the conditioning movies (P = 0·003), the tip of the tongue taking a lower position during the fear movie than during the tender and neutral movies.

Using e-learning to train dentists in the development of standardised oral health promotion interventions for persons with disability.

BACKGROUND: This study aims to evaluate whether an e-learning curriculum was sufficient to impart the necessary knowledge to dentists to allow them to implement an oral health promotion intervention in an institution for persons with disability. MATERIALS AND METHODS: Participants were asked to complete a 10-module online training course and to implement a standardised intervention in an institution. The outcome measures were as follows: online tracking of progress; multiple choice questionnaires completed at the end of most modules; self-efficacy questionnaire completed before and after online training; completion of training and calibration in the use of a standardised risk assessment form; initiation and full completion of an oral health promotion intervention in an institution; satisfaction of participants with the online training experience; and evaluation of the impact of the intervention by the institution staff. RESULTS: The study sample included 26 dentists. The 10 modules were passed by 24 dentists, and the mean value of the highest overall score recorded in the multiple questionnaires was 88.4% (± 4.0). Twenty participants completed the self-efficacy questionnaire before and after training; the mean values of scores after training were statistically different and higher than those at baseline. Questionnaire regarding satisfaction with the online training experience was completed by 22 participants; all of them stated that they were satisfied with the online training experience. CONCLUSIONS: The results indicate that the online training course helped participants to increase self-efficacy and to provide interventions in institutions. This study could have implications for both undergraduate and postgraduate dental education in France.

Changes in epicardial and visceral adipose tissue depots following bariatric surgery and their effect on cardiac geometry.

Introduction: Obesity affects cardiac geometry, causing both eccentric (due to increased cardiac output) and concentric (due to insulin resistance) remodelling. Following bariatric surgery, reversal of both processes should occur. Furthermore, epicardial adipose tissue loss following bariatric surgery may reduce pericardial restraint, allowing further chamber expansion. We investigated these changes in a serial imaging study of adipose depots and cardiac geometry following bariatric surgery. Methods: 62 patients underwent cardiac magnetic resonance (CMR) before and after bariatric surgery, including 36 with short-term (median 212 days), 37 medium-term (median 428 days) and 32 long-term (median 1030 days) follow-up. CMR was used to assess cardiac geometry (left atrial volume (LAV) and left ventricular end-diastolic volume (LVEDV)), LV mass (LVM) and LV eccentricity index (LVei - a marker of pericardial restraint). Abdominal visceral (VAT) and epicardial (EAT) adipose tissue were also measured. Results: Patients on average had lost 21kg (38.9% excess weight loss, EWL) at 212 days and 36kg (64.7% EWL) at 1030 days following bariatric surgery. Most VAT and EAT loss (43% and 14%, p<0.0001) occurred within the first 212 days, with non-significant reductions thereafter. In the short-term LVM (7.4%), LVEDV (8.6%) and LAV (13%) all decreased (all p<0.0001), with change in cardiac output correlated with LVEDV (r=0.35,p=0.03) and LAV change (r=0.37,p=0.03). Whereas LVM continued to decrease with time (12% decrease relative to baseline at 1030 days, p<0.0001), both LAV and LVEDV had returned to baseline by 1030 days. LV mass:volume ratio (a marker of concentric hypertrophy) reached its nadir at the longest timepoint (p<0.001). At baseline, LVei correlated with baseline EAT (r=0.37,p=0.0040), and decreased significantly from 1.09 at baseline to a low of 1.04 at 428 days (p<0.0001). Furthermore, change in EAT following bariatric surgery correlated with change in LVei (r=0.43,p=0.0007). Conclusions: Cardiac volumes show a biphasic response to weight loss, initially becoming smaller and then returning to pre-operative sizes by 1030 days. We propose this is due to an initial reversal of eccentric remodelling followed by reversal of concentric remodelling. Furthermore, we provide evidence for a role of EAT contributing to pericardial restraint, with EAT loss improving markers of pericardial restraint.

Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat.

OBJECTIVE: To assess epicardial fat volume (EFV), myocardial TG content (MTGC) and metabolic profile in severely obese patients, and to determine whether ectopic fat depots are linked to metabolic disorders or myocardial function. RESEARCH DESIGN AND METHODS: Sixty-three subjects with normal LV function and no coronary artery disease, including 33 lean (BMI: 21.4 ± 2.0 kg m(-2)) and 30 obese (BMI: 41.8 ± 6 kg m(-2)) patients, underwent 3-T cardiovascular MRI, and anthropometric, biological and visceral abdominal fat (VAT) assessments. EFV was measured by short-axis slice imaging and myocardial (intra-myocellular) TG content was measured by proton magnetic resonance spectroscopy. RESULTS: EFV and MTGC were positively correlated (r=0.52, P<0.0001), and were both strongly correlated with age, BMI, waist circumference and VAT, but not with severity of obesity. EFV and MTGC were significantly higher in obese patients than in lean controls (141 ± 18 versus 79 ± 7 ml, P=0.0001; 1.0 ± 0.1 versus 0.6 ± 0.1%, P=0.01, respectively), but some differences were found between the two cardiac depots: EFV was higher in diabetic obese subjects as compared with that in non-diabetic obese subjects (213 ± 34 versus 141 ± 18 ml, P=0.03), and was correlated with parameters of glucose tolerance (fasting plasma glucose, insulin and HOMA-IR), whereas MTGC was not. EFV and MTGC were both associated with parameters of lipid profile or inflammation (TGs, CRP). Remarkably, this was VAT-dependent, as only VAT remained independently associated with metabolic parameters (P<0.01). Concerning myocardial function, MTGC was the only parameter independently associated with stroke volume (ß=-0.38, P=0.01), suggesting an impact of cardiac steatosis in cardiac function. CONCLUSIONS: These data show that VAT dominates the relationship between EFV, MTGC and metabolic measures, and uncover specific partitioning of cardiac ectopic lipid deposition.

Substantiation of an artificial saliva formulated for use in a masticatory apparatus.

The aim of this work was to substantiate artificial saliva prepared for use in a masticator apparatus. Mastication's goal is to produce a viscous and plastic food bolus where these properties authorize a safe swallow. Apart from its biochemical contribution, saliva is mainly used in this kind of apparatus to provide a viscous component to the bolus. Artificial saliva was prepared with water and minerals, and completed with mucin and amylase. Different physico-chemical conditions were applied and the resultant viscosity was compared to that of human saliva. Mechanically- or chemically-stimulated salivas of ten healthy subjects were collected. Viscosity was measured with a capillary viscometer in response to changes in measurement's temperature, air exposure or pH. The effects of circadian saliva collection and the stimulation type on viscosity of human saliva were also studied. Viscosity of artificial and human salivas was comparable. An increase in the measurement's temperature or a 30 min-exposure of saliva to air led to a significant decrease in viscosity of both types of saliva. Amylase in artificial saliva did not change viscosity. The viscosity of human saliva displayed important subject variability as well as a dependence on the stimulation type of saliva production. This work allowed a useful evaluation of the formulated artificial saliva. It exhibited similar viscosity as the natural saliva in response to different methodological conditions. Therefore the proposed artificial saliva satisfies the major requirement of viscosity for a use in the masticator apparatus designed to prepare a food bolus.

Is the tongue position influenced by the palatal vault dimensions?

The influence of the palatal vault dimensions on tongue position is here studied through evaluation of the in-mouth air cavity (IMAC) volume when the mandible is in maximal intercuspal position. A sample of 35 women (mean age 21.2 +/- 1.0) and 15 men (mean age 22.1 +/- 0.9) was selected. The sagittal cross-section area of the IMAC, which is modulated by the tongue position, was measured on lateral cephalograms. Dental casts were used to measure the palatal vault volume, which was defined by the occlusal plane, the hard palate and the posterior face of the second molars. Palatal vault volume allowed deduction of the IMAC volume through a rule of three procedure relating volume to area ratios. No IMAC could be calculated from cephalograms of 10 subjects who had the tongue stuck to the palate. For the 40 other subjects, the IMAC volume was 8.9 +/- 4.8 mL. It was 2 mL larger in men (n = 14) than in women (n = 26) and was the largest in skeletal Class III and the smallest in skeletal Class II (P > 0.05). IMAC volume was strongly correlated with palatal vault height but neither with palatal width nor length. It was thus assumed that the height of the palatal vault could influence the most observed position of the tongue but this does not exclude a possible growth influence of the tongue on its surrounding skeletal structures.

Bariatric surgery affects obesity-related protein requirements.

CONTEXT: Following bariatric surgery, protein deficiency intakes are reported in morbidly obese patients, whereas post-bariatric protein requirements are not specifically defined with validated method in this population. OBJECTIVE: To assess average protein requirement (APR) in obese subjects, before, 3 months and 12 months after bariatric surgery using the validated method of nitrogen balance. DESIGN AND SETTING: Prospective longitudinal study conducted in 21 morbidly obese patients (BMI 43.9 ± 1.4 kg/m2) before (M0), 3 months (M3) and 12 months (M12) after sleeve gastrectomy or Roux-en-Y gastric by-pass. An additional larger cross-sectional study was performed to validate APR before surgery in non-operated matched obese patients (n = 106). APR was evaluated at M0, M3, M12 by measuring 3 days dietary intakes together with losses of nitrogen in urine and stools. MAIN OUTCOME MEASURE: APR was defined as the mean value of protein intake required to achieve balance nitrogen equilibrium. RESULTS: Before surgery, APR in morbidly obese patients was 0.76 [95%CI, 0.66-0.92] g/kg Body Weight (BW)/d in the experimental group, and 0.74 [0.70-0.80] g/kg BW/d in the validation group. APR was 0.62 [0.51-0.75] g/kg/d at M3 and 0.87 [0.75-0.98] g/kg/d at M12, with no difference between surgical procedures. Spontaneous protein intakes were respectively 0.80 ± 0.05, 0.43 ± 0.03 and 0.71 ± 0.04 g/kg BW/d respectively at M0, M3 and M12. CONCLUSION: This study demonstrates a temporal change in protein requirement after bariatric surgery whatever the type of surgery. Spontaneous protein intakes following bariatric surgery does not cover protein requirements for most patients, suggesting that specific dietary protein recommandations have to be adapted in obese patients with bariatric surgery. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01249326.

Comparison of the gut microbiota of obese individuals from different geographic origins.

Few studies have examined the interaction of human geography, microbial community structure and obesity. We tested obese adult volunteers from France, Saudi Arabia, French Polynesia and from a traditional population in the village of Trois-Sauts in French Guiana by sequencing the V3-V4 region. We also sequenced homemade fermented cachiri beers that were obtained from the traditional Amazonian population and are highly consumed by this population. We found that French and Saudis had significantly less richness and biodiversity in their gut microbiota than Amazonians and Polynesians (p <0.05). Principle coordinate analysis of the overall composition of the genera communities revealed that the microbiomes of Amazonians clustered independently from the other obese individuals. Moreover, we found that Amazonians presented significantly stricter anaerobic genera than the Saudis, French and Polynesians (p < 0.001). Polynesians presented significantly lower relative abundance of Lactobacillus sp. than French (p 0.01) and Saudis (p 0.05). Treponema berlinense and Treponema succinifaciens were only present in the gut microbiome of Amazonians. The cachiri beers presented significantly more bacterial species in common with the gut microbiome of Amazonians (p < 0.005). Obese individuals with different origins present modifications in their gut microbiota, and we provide evidence that the cachiri beers influenced the gut microbiome of Amazonians.

Treponema species enrich the gut microbiota of traditional rural populations but are absent from urban individuals.

There is a significant gap in our knowledge of the microbe-host relationship between urban and traditional rural populations. We conducted a large-scale study to examine the gut microbiota of different traditional rural and urban lifestyles in human populations. Using high-throughput 16S ribosomal RNA gene amplicon sequencing, we tested urban French, Saudi, Senegalese, Nigerian and Polynesian individuals as well as individuals living in traditional rural societies, including Amazonians from French Guiana, Congolese Pygmies, Saudi Bedouins and Algerian Tuaregs. The gut microbiota from individuals living in traditional rural settings clustered differently and presented significantly higher diversity than those of urban populations (p 0.01). The bacterial taxa identified by class analysis as contributing most significantly to each cluster were Phascolarctobacterium for traditional rural individuals and Bifidobacterium for urban individuals. Spirochaetae were only present in the gut microbiota of individuals from traditional rural societies, and the gut microbiota of all traditional rural populations was enriched with Treponema succinifaciens. Cross-transmission of Treponema from termites or swine to humans or the increased use of antibiotics in nontraditional populations may explain why Treponema is present only in the gut microbiota of traditional rural populations.

Active cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study.

OBJECTIVE: Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a l new mediator of bone metabolism. Cushing syndrome (CS), is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF. DESIGN: This was a cross-sectional study. Seventeen active and seventeen cured ACTH-dependent CS patients along with seventeen controls (matched with the active group for age and sex) were included. METHODS: the BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. BMD was evaluated in patients using dual-energy X-ray absorptiometry. RESULTS: Active CS patients had higher BMF content both in the femur (82.5±2.6%) and vertebrae (70.1±5.1%) compared to the controls (70.8±3.6%, p=0.013 and 49.0±3.7% p=0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3±2.9% (femur) and 46.7%±5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients . CONCLUSIONS: Accumulation of BMF is induced by hypercortisolism. In remission patients BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.

Non-invasive imaging correlates with histological and molecular characteristics of an osteosarcoma model: application for early detection and follow-up of MDR phenotype.

BACKGROUND: In an orthotopic rat osteosarcoma model, histological and molecular findings were compared with the results of non-invasive imaging methods to assess disease progression at the primary site, the pattern of metastatic dissemination and the chemoresistance phenotype. MATERIALS AND METHODS: Primary tumor engraftment, vascularization, growth and metastatic spread were evaluated using 18FDG tomoscintigraphy. Bone neoformation in the primary tumor and metastasis was determined using 18FNa confirmed by classical histological studies. Chemoresistance phenotype was assessed by analysis of MDR1 and MRP1 genes expression compared to 99mTc MIBI imaging. RESULTS: 99mTc MIBI imaging correlated with the overexpression of the MDR1 and MRP1 genes. 18FDG, 18FNa and 99mTc tomoscintigraphies revealed that the pattern of vascularization, bone neoformation and hematogeneous metastatic dissemination in our animal model mimics its human counterpart. CONCLUSION: Multimodality, non-invasive imaging is a valid surrogate marker of histological and molecular characteristics in an orthotopic osteosarcoma model in immunocompetent rats; it allows extensive in vivo follow-up of osteosarcoma, including longitudinal analysis of chemoresistance.

11beta-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients. OBJECTIVES: We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction. PATIENTS AND METHODS: Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated. RESULTS: Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid. CONCLUSIONS: Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.

Tumor endothelial cells are targets for selective therapies: in vitro and in vivo models to evaluate antiangiogenic strategies.

Angiogenesis is a complicated process, essential for tumor progression and metastasis. Extensive work has been done to understand the mechanisms of tumor angiogenesis and identify angiogenesis inhibitors. It is now recognised that tumor endothelial cells present different functional and phenotypic characteristics than normal resting endothelial cells. These differences and advances in molecular biology have allowed the development of selective agents targeting tumor endothelial cells as therapeutic approaches for cancer. These new targeted strategies need to be evaluated in relevant models before being transferred from the laboratory bench to the clinic. In vivo tumor models remain a good way to evaluate the effect of these agents on tumor growth and metastasis. Nevertheless, in parallel to the development of tumor angiogenesis inhibitors, in vitro models have been designed to mimic angiogenesis steps and enable the evaluation of these new drugs. In this paper, after reviewing the phenotypic characteristics of tumor endothelial cells that make them easy to target for antiangiogenic therapy, some of the most commonly used in vitro and in vivo models, which enable the evaluation of antiangiogenic agents, are presented and discussed.

Pioglitazone in adult rats reverses immediate postnatal overfeeding-induced metabolic, hormonal, and inflammatory alterations.

Immediate postnatal overfeeding in rats, obtained by reducing the litter size, results in early-onset obesity. Such experimental paradigm programs overweight, insulin resistance, dyslipidemia, increased adipose glucocorticoid metabolism [up-regulation of glucocorticoid receptor (GR) and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1)], and overexpression of proinflammatory cytokines in mesenteric adipose tissue (MAT) in adulthood. We studied the effects of pioglitazone, a PPARγ agonist, treatment on the above-mentioned overfeeding-induced alterations. Nine-month-old rats normofed or overfed during the immediate postnatal period were given pioglitazone (3 mg/kg/day) for 6 weeks. Pioglitazone stimulated weight gain and induced a redistribution of adipose tissue toward epididymal location with enhanced plasma adiponectin. Treatment normalized postnatal overfeeding-induced metabolic alterations (increased fasting insulinemia and free fatty acids) and mesenteric overexpression of GR, 11ß-HSD11, CD 68, and proinflammatory cytokines mRNAs, including plasminogen-activator inhibitor type 1. Mesenteric GR mRNA levels correlated positively with mesenteric proinflammatory cytokines mRNA concentrations. In vitro incubation of MAT obtained from overfed rats demonstrated that pioglitazone induced a down-regulation of GR gene expression and normalized glucocorticoid-induced stimulation of 11ß-HSD1 and plasminogen-activator inhibitor type 1 mRNAs. Our data show for the first time that the metabolic, endocrine, and inflammatory alterations induced by early-onset postnatal obesity can be reversed by pioglitazone at the adulthood. They demonstrate that pioglitazone, in addition to its well-established effect on adipose tissue redistribution and adiponectin secretion, reverses programing-induced adipose GR, 11ß-HSD1, and proinflammatory cytokines overexpression, possibly through a GR-dependent mechanism.