Birth Weight and Risk of Adiposity among Adult Inuit in Greenland

Objective

The Inuit population in Greenland has undergone rapid socioeconomic and nutritional changes simultaneously with an increasing prevalence of obesity. Therefore, the objective was to examine fetal programming as part of the aetiology of obesity among Inuit in Greenland by investigating the association between birth weight and measures of body composition and fat distribution in adulthood.

Methods

The study was based on cross-sectional data from a total of 1,473 adults aged 18–61 years in two population-based surveys conducted in Greenland between 1999–2001 and 2005–2010. Information on birth weight was collected from birth records. Adiposity was assessed by anthropometry, fat mass index (FMI), fat-free mass index (FFMI), and visceral (VAT) and subcutaneous adipose tissue (SAT) estimated by ultrasound. The associations to birth weight were analyzed using linear regression models and quadratic splines. Analyses were stratified by sex, and adjusted for age, birthplace, ancestry and family history of obesity.

Results

Spline analyses showed linear relations between birth weight and adult adiposity. In multiple regression analyses, birth weight was positively associated with BMI, waist circumference, FMI, FFMI and SAT with generally weaker associations among women compared to men. Birth weight was only associated with VAT after additional adjustment for waist circumference and appeared to be specific and inverse for men only.

Conclusions

Higher birth weight among Inuit was associated with adiposity in adulthood. More studies are needed to explore a potential inverse association between birth size and VAT.     

Recombinant Human Growth Hormone and Rosiglitazone for Abdominal Fat Accumulation in HIV-Infected Patients with Insulin Resistance: A Randomized,Double-Blind,Placebo-Controlled,Factorial Trial

Background

Recombinant human growth hormone (rhGH) reduces visceral adipose tissue (VAT) volume in HIV-infected patients but can worsen glucose homeostasis and lipoatrophy. We aimed to determine if adding rosiglitazone to rhGH would abrogate the adverse effects of rhGH on insulin sensitivity (SI) and subcutaneous adipose tissue (SAT) volume.

Methodology/Principal Findings

Randomized, double-blind, placebo-controlled, multicenter trial using a 2×2 factorial design in which HIV-infected subjects with abdominal obesity and insulin resistance were randomized to rhGH 3 mg daily, rosiglitazone 4 mg twice daily, combination rhGH + rosiglitazone, or double placebo (control) for 12 weeks. The primary endpoint was change in SI by frequently sampled intravenous glucose tolerance test from entry to week 12. Body composition was assessed by whole body magnetic resonance imaging (MRI) and dual Xray absorptiometry (DEXA).Seventy-seven subjects were randomized of whom 72 initiated study drugs. Change in SI from entry to week 12 differed across the 4 arms by 1-way ANCOVA (P = 0.02); by pair-wise comparisons, only rhGH (decreasing SI; P = 0.03) differed significantly from control. Changes from entry to week 12 in fasting glucose and glucose area under the curve on 2-hour oral glucose tolerance test differed across arms (1-way ANCOVA P = 0.004), increasing in the rhGH arm relative to control. VAT decreased significantly in the rhGH arms (−17.5% in rhGH/rosiglitazone and −22.7% in rhGH) but not in the rosiglitazone alone (−2.5%) or control arms (−1.9%). SAT did not change significantly in any arm. DEXA results were consistent with the MRI data. There was no significant rhGH x rosiglitazone interaction for any body composition parameter.

Conclusions/Significance

The addition of rosiglitazone abrogated the adverse effects of rhGH on insulin sensitivity and glucose tolerance while not significantly modifying the lowering effect of rhGH on VAT.

Trial Registration

Clinicaltrials.gov NCT00130286     

Android fat depot is more closely associated with metabolic syndrome than abdominal visceral fat in elderly people

Background

Fat accumulation in android compartments may confer increased metabolic risk. The incremental utility of measuring regional fat deposition in association with metabolic syndrome (MS) has not been well described particularly in an elderly population.

Methods and Findings

As part of the Korean Longitudinal Study on Health and Aging, which is a community-based cohort study of people aged more than 65 years, subjects (287 male, 75.9±8.6 years and 278 female, 76.0±8.8 years) with regional body composition data using Dual energy X-ray absorptiometry for android/gynoid area, computed tomography for visceral/subcutaneous adipose tissue (VAT/SAT), and cardiometabolic markers including adiponectin and high-sensitivity CRP were enrolled. We investigated the relationship between regional body composition and MS in multivariate regression models. Mean VAT and SAT area was 131.4±65.5 cm² and 126.9±55.2 cm² in men (P = 0.045) and 120.0±46.7 cm² and 211.8±65.9 cm² in women (P<0.01). Mean android and gynoid fat amount was 1.8±0.8 kg and 2.5±0.8 kg in men and 2.0±0.6 kg and 3.3±0.8 kg in women, respectively (both P<0.01). VAT area and android fat amount was strongly correlated with most metabolic risk factors compared to SAT or gynoid fat. Furthermore, android fat amount was significantly associated with clustering of MS components after adjustment for multiple parameters including age, gender, adiponectin, hsCRP, a surrogate marker of insulin resistance, whole body fat mass and VAT area.

Conclusions

Our findings are consistent with the hypothesized role of android fat as a pathogenic fat depot in the MS. Measurement of android fat may provide a more complete understanding of metabolic risk associated with variations in fat distribution.     

Abdominal Regional Fat Distribution on MRI Correlates with Cholecystolithiasis

Aims

To determine whether abdominal regional fat distribution pattern on MRI is correlated with cholecystolithiasis.

Methods

Magnetic resonance imaging (MRI) of 163 patients with cholecystolithiasis and 163 non-cholecystolithiasis control subjects admitted to our institution between March 2011 and September 2013 were included in this cross-sectional evaluation. There were 98 women and 65 men in cholecystolithiasis group with an average age of 57±16 years (range 25–86 years). There were 87 women and 76 men in the control group with an average age of 41±16 years (range 14–77 years). Visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and total abdominal adipose tissue (TAT) of all the subjects at navel level were measured on abdominal MRI. According to the visceral adipose area (cut-off point VAT = 100 cm²), study subjects were divided into 1) increased accumulation of intra-abdominal fat and 2) normal distribution of intra-abdominal fat. Logistic regression was used to assess the association of fat with the presence of cholecystolithiasis, adjusted for age and sex.

Results

The incidence of increased intra-abdominal fat accumulation in the cholecystolithiasis group was significantly higher than that of the control group (P = 0.000). After adjusting for age and sex, cholecystolithiasis was associated with a one standard deviation increment in the waist circumference (WC) (OR = 1.44; 95%CI: 1.01,1.93; p = 0.00), VAT (OR = 4.26; 95%CI: 1.85,5.29; p = 0.00), VAT/SAT (OR = 8.66; 95%CI: 1.60,12.63; p = 0.00), and VAT/TAT (OR = 6.73; 95%CI: 4.24,12.18; p = 0.00), but not with fat content in the abdominal subcutaneous fat (p = 0.19).

Conclusions

The visceral adipose tissue and distribution proportion of abdominal adipose tissue are correlates of cholecystolithiasis.     

Evaluation of an Exercise Field Test Using Heart Rate Monitors to Assess Cardiorespiratory Fitness and Heart Rate Recovery in an Asymptomatic Population

Purpose

Measures of cardiorespiratory fitness (CRF) and heart rate recovery (HRR) can improve risk stratification for cardiovascular disease, but these measurements are rarely made in asymptomatic individuals due to cost. An exercise field test (EFT) to assess CRF and HRR would be an inexpensive method for cardiovascular disease risk assessment in large populations. This study assessed 1) the predictive accuracy of a 12-minute run/walk EFT for estimating CRF () and 2) the accuracy of HRR measured after an EFT using a heart rate monitor (HRM) in an asymptomatic population.

Methods

Fifty subjects (48% women) ages 18–45 years completed a symptom-limited exercise tolerance test (ETT) (Bruce protocol) and an EFT on separate days. During the ETT, was measured by a metabolic cart, and heart rate was measured continuously by a HRM and a metabolic cart.

Results

EFT distance and sex independently predicted. The average absolute difference between observed and predicted was 0.26±3.27 ml·kg⁻¹·min⁻¹ for our model compared to 7.55±3.64 ml·kg⁻¹·min⁻¹ for the Cooper model. HRM HRR data were equivalent to respective metabolic cart values during the ETT. HRR at 1 minute post-exercise during ETT compared to the EFT had a moderate correlation (r = 0.75, p<0.001).

Conclusion

A more accurate model to estimate CRF from a 12-minute run/walk EFT was developed, and HRR can be measured using a HRM in an asymptomatic population outside of clinical settings.     

Periaortic Brown Adipose Tissue as a Major Determinant of [18F]-Fluorodeoxyglucose Vascular Uptake in Atherosclerosis-Prone,ApoE?/? Mice

Background

[¹⁸F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE^−/−) mouse atherosclerotic lesion imaging with FDG.

Methods

ApoE^−/− mice (36±2 weeks-old) were injected with FDG (12±2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution.

Results

Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P<0.05) and the blood (all groups, P<0.01) which correlated with macrophage infiltration (R = 0.47; P<0.001). However, periaortic BAT uptake was either significantly higher (Group A, P<0.05) or similar (Group B and C, P = NS) to that observed in atherosclerotic lesions and was shown to correlate with in vivo quantified aortic FDG activity.

Conclusion

Periaortic BAT FDG uptake was identified as a confounding factor while using FDG for the non-invasive imaging of mouse atherosclerotic lesions.     

Psychometric Properties of the Hebrew Translation of the Patient Activation Measure (PAM-13)

Objective

“Patient activation” reflects involvement in managing ones health. This cross-sectional study assessed the psychometric properties of the Hebrew translation (PAM-H) of the PAM-13.

Methods

A nationally representative sample of 203 Hebrew-speaking Israeli adults answered the PAM-H, PHQ-9 depression scale, SF-12, and Self-efficacy Scale via telephone.

Results

Mean PAM-H scores were 70.7±15.4. Rasch analysis indicated that the PAM-H is a good measure of activation. There were no differences in PAM-H scores based on gender, age or education. Subjects with chronic disease scored lower than those without. Scores correlated with the Self-efficacy Scale (0.47), Total SF-12 (0.39) and PHQ-9 (−0.35, P<0.0001), indicating concurrent validity. Discriminant validity was reflected by a significant difference in the mean PAM-H score of those who scored below 10 (72.1±14.8) on the PHQ-9 (not depressed) compared to those scoring ≥10 (i.e. probable depression) (59.2±15.8; t 3.75; P = 0.001).

Conclusion

The PAM-H psychometric properties indicate its usefulness with the Hebrew-speaking Israeli population.

Practice Implications

PAM-H can be useful for assessing programs aimed at effecting changes in patient compliance, health behaviors, etc. Researchers in Israel should use a single translation of the PAM-13 so that findings can be compared, increasing understanding of patient activation.     

Expression of Obesity Markers and Persistent Organic Pollutants Levels in Adipose Tissue of Obese Patients: Reinforcing the Obesogen Hypothesis?

Introduction

Persistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity.

Objectives

The aim is twofold: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT.

Results and Conclusions

Leptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the obesogen hypothesis.     

Quantification of Left Ventricular Torsion and Diastolic Recoil Using Cardiovascular Magnetic Resonance Myocardial Feature Tracking

Objectives

Cardiovascular magnetic resonance feature tracking (CMR-FT) offers quantification of myocardial deformation from routine cine images. However, data using CMR-FT to quantify left ventricular (LV) torsion and diastolic recoil are not yet available. We therefore sought to evaluate the feasibility and reproducibility of CMR-FT to quantify LV torsion and peak recoil rate using an optimal anatomical approach.

Methods

Short-axis cine stacks were acquired at rest and during dobutamine stimulation (10 and 20 µg·kg⁻¹·min⁻¹) in 10 healthy volunteers. Rotational displacement was analysed for all slices. A complete 3D-LV rotational model was developed using linear interpolation between adjacent slices. Torsion was defined as the difference between apical and basal rotation, divided by slice distance. Depending on the distance between the most apical (defined as 0% LV distance) and basal (defined as 100% LV distance) slices, four different models for the calculation of torsion were examined: Model-1 (25–75%), Model-2 (0–100%), Model-3 (25–100%) and Model-4 (0–75%). Analysis included subendocardial, subepicardial and global torsion and recoil rate (mean of subendocardial and subepicardial values).

Results

Quantification of torsion and recoil rate was feasible in all subjects. There was no significant difference between the different models at rest. However, only Model-1 (25–75%) discriminated between rest and stress (Global Torsion: 2.7±1.5°cm⁻¹, 3.6±2.0°cm⁻¹, 5.1±2.2°cm⁻¹, p<0.01; Global Recoil Rate: −30.1±11.1°cm⁻¹s⁻¹,−46.9±15.0°cm⁻¹s⁻¹,−68.9±32.3°cm⁻¹s⁻¹, p<0.01; for rest, 10 and 20 µg·kg⁻¹·min⁻¹ of dobutamine, respectively). Reproducibility was sufficient for all parameters as determined by Bland-Altman analysis, intraclass correlation coefficients and coefficient of variation.

Conclusions

CMR-FT based derivation of myocardial torsion and recoil rate is feasible and reproducible at rest and with dobutamine stress. Using an optimal anatomical approach measuring rotation at 25% and 75% apical and basal LV locations allows effective quantification of torsion and recoil dynamics. Application of these new measures of deformation by CMR-FT should next be explored in disease states.     

Immune Surveillance by Rhinovirus-Specific Circulating CD4+ and CD8+ T Lymphocytes

Background

It is difficult to experimentally infect volunteers with RV strains to which the subject demonstrates serological immunity. However, in RV challenges, viral clearance begins before de novo adaptive immune responses would develop. We speculated that adaptive immunity to RV reflects heterologous immunity by effector memory cells.

Methods

DCs were generated from monocytes using GM-CSF and IL-4 and RV39 loading accomplished with a dose of ∼350 TCID₅₀/10⁵ cells. RV-induced maturation was established as modulation of MHC class II, CD80, CD83, and CD86. Circulating RV targeting CD4 and CD8 T cells were investigated as induction of RV-specific proliferation (CFSE-dilution).

Results

Maturation of DC by RV was confirmed as upregulation of MHC Class II (83.3±5.0% to 87.8±4.1%), CD80 (39.4±7.2% to 47.6±7.7%) and CD86 (78.4±4.7% to 84.1±3.4%). Both CD4 and CD8 memory T cells were recognized in the circulation of healthy subjects.

Conclusions

RV drives DC maturation and results in their ability to present RV antigens to both T helper and cytotoxic lymphocytes. Both CD4 and CD8 cells capable of recognizing RV-associated antigens are present in the circulation of healthy subjects where they are presumably involved in immune surveillance and explain the rapid recruitment of an adaptive immune response during RV infection.     

SDF1-A Facilitates Lin?/Sca1+ Cell Homing following Murine Experimental Cerebral Ischemia

Background

Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized.

Methods

Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin−/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade.

Results

Bone marrow demonstrated a significant increase in Lin−/Sca1+ cell counts at 24 hrs (272±60%; P<0.05 vs sham). Mobilization of Lin−/Sca1+ cells to blood was significantly elevated at 24 hrs (607±159%; P<0.05). Serum SDF1-A levels were significant at 24 hrs (Sham (103±14), 4 hrs (94±20%, p = NS) and 24 hrs (130±17; p<0.05)). Brain SDF1-A levels were significantly elevated at both 4 hrs and 24 hrs (113±7 pg/ml and 112±10 pg/ml, respectively; p<0.05 versus sham 76±11 pg/ml). Following administration of an SDF1-A antibody, Lin−/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536±65, blood cell count: 127±24; p<0.05 versus placebo). Exogenously administered Lin−/Sca1+ cells resulted in a significant reduction in infarct volume: 42±5% (stroke alone), versus 21±15% (Stroke+Lin−/Sca1+ cells), and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin−/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin−/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10±4 vs 0.7±1, p<0.05).

Conclusions

SDF1-A appears to play a critical role in modulating Lin−/Sca1+ cell migration to ischemic brain.     

Multimeric Stability of Human C-reactive Protein in Archived Specimens

Background

C-reactive protein (CRP) is a marker of inflammation and a risk predictor of cardiovascular disease. Current CRP assays are focused on the quantification of the CRP levels as pentamers. However, CRP can be present as other multimeric forms. There will be a market need to measure the CRP multimeric structure in addition to the levels in human populations. To meet this need, we investigated whether the long-term archived samples could be used instead of freshly collected samples.

Methodology/Principal Findings

The specimens of serum, plasma and tissues were collected from transgenic rats expressing the human CRP. These samples were stored at 4°C, −20°C and −80°C for different periods. Non-denaturing Western blot analysis was used to observe the influence of storage conditions to multimeric structures of human CRP. Our results showed that there was no difference on multimeric structures of human CRP between samples stored at 4°C, −20°C and −80°C, between samples stored at −80°C for twenty-four hours and three months, and between plasma and serum.

Conclusions/Significance

This study implicated that archived samples stored at these conditions in those large longitudinal studies could be used for investigating the multimeric structures of CRP. Our report may speed up these researches and save labors and budget by enabling them to use currently available archived samples rather than freshly collected samples.     

Adequately Adapted Insulin Secretion and Decreased Hepatic Insulin Extraction Cause Elevated Insulin Concentrations in Insulin Resistant Non-Diabetic Adrenal Incidentaloma Patients

Background

Insulin-resistance is commonly found in adrenal incidentaloma (AI) patients. However, little is known about beta-cell secretion in AI, because comparisons are difficult, since beta–cell-function varies with altered insulin-sensitivity.

Objectives

To retrospectively analyze beta–cell function in non-diabetic AI, compared to healthy controls (CON).

Methods

AI (n=217, 34%males, 57±1years, body-mass-index:27.7±0.3kg/m²) and CON [n=25, 32%males, 56±1years, 26.7±0.8kg/m²] with comparable anthropometry (p≥0.31) underwent oral-glucose-tolerance-tests (OGTTs) with glucose, insulin, and C–peptide measurements. 1mg-dexamethasone-suppression-tests were performed in AI. AI were divided according to post–dexamethasone-suppression–test cortisol-thresholds of 1.8 and 5µg/dL into 3subgroups: pDexa<1.8µg/dL, pDexa1.8-5µg/dL and pDexa>5µg/dL. Using mathematical modeling, whole-body insulin-sensitivity [Clamp-like-Index (CLIX)], insulinogenic Index, Disposition Index, Adaptation Index, and hepatic insulin extraction were calculated.

Results

CLIX was lower in AI combined (4.9±0.2mg·kg^-1·min^-1), pDexa<1.8µg/dL (4.9±0.3) and pDexa1.8-5µg/dL (4.7±0.3, p<0.04 vs.CON:6.7±0.4). Insulinogenic and Disposition Indexes were 35%–97% higher in AI and each subgroup (p<0.008 vs.CON), whereas C–peptide–derived Adaptation Index, compensating for insulin-resistance, was comparable between AI, subgroups, and CON. Mathematical estimation of insulin–derived (insulinogenic and Disposition) Indexes from associations to insulin-sensitivity in CON revealed that AI-subgroups had ~19%-32% higher insulin-secretion than expectable. These insulin-secretion-index differences negatively (r=-0.45, p<0.001) correlated with hepatic insulin extraction, which was 13-16% lower in AI and subgroups (p<0.003 vs.CON).

Conclusions

AI-patients show insulin-resistance, but adequately adapted insulin secretion with higher insulin concentrations during an OGTT, because of decreased hepatic insulin extraction; this finding affects all AI-patients, regardless of dexamethasone-suppression-test outcome.     

Anthropometric and Micronutrient Status of School-Children in an Urban West Africa Setting: A Cross-Sectional Study in Dakar (Senegal)

Background

Urban areas in West Africa are not immune to undernutrition with recent urbanization and high food prices being important factors. School children often have a poor nutritional status, potentially affecting their health and schooling performance. Yet, generally school children do not benefit from nutrition programs. The objective of the study was to assess the anthropometric and micronutrient status of children from state schools in the Dakar area.

Methods

School children (n = 604) aged from 5 to 17 y (52.5% girls, 47.5% ≥10 y) were selected through a two-stage random cluster sample of children attending urban primary state schools in the Dakar area (30 schools × 20 children). The prevalence of stunting (height-for-age<−2 z-scores) and thinness (BMI-for-age<−2 z-scores, WHO 2006, and three grades of thinness corresponding to BMI of 18.5, 17.0 and 16.0 kg/m2 in adults) were calculated from weight and height. Hemoglobin, plasma concentrations of ferritin (FER), transferrin receptors (TfR), retinol binding protein (RBP), and zinc, and urinary iodine concentrations were measured. Correction factors were used for FER and RBP in subjects with inflammation determined with C-reactive protein and α1-acid-glycoprotein.

Results

4.9% of children were stunted, 18.4% were thin, 5.6% had severe thinness (BMI-for-age<−3 z-scores). Only one child had a BMI-for-age>2 z-scores. Prevalence of anemia, iron deficiency and iron deficiency anemia was 14.4%, 39.1% and 10.6% respectively. 3.0% had vitamin A deficiency, 35.9% a marginal vitamin A status, and 25.9% zinc deficiency. Urinary iodine was <50 µg/L in 7.3% of children and ≥200 µg/L in 22.3%. The prevalence of marginal vitamin A, zinc deficiency, high TfR was significantly higher in boys than in girls (P<0.05). Height-for-age and retinol were significantly lower in participants ≥10 y and <10 y respectively.

Conclusion

Undernutrition, especially thinness, iron and zinc deficiencies in school children in the Dakar area requires special targeted nutrition interventions.     

Induced Autologous Stem Cell Transplantation for Treatment of Rabbit Renal Interstitial Fibrosis

Introduction

Renal interstitial fibrosis (RIF) is a significant cause of end-stage renal failure. The goal of this study was to characterize the distribution of transplanted induced autologous stem cells in a rabbit model of renal interstitial fibrosis and evaluate its therapeutic efficacy for treatment of renal interstitial fibrosis.

Methods

A rabbit model of renal interstitial fibrosis was established. Autologous fibroblasts were cultured, induced and labeled with green fluorescent protein (GFP). These labeled stem cells were transplanted into the renal artery of model animals at 8 weeks.

Results

Eight weeks following transplantation of induced autologous stem cells, significant reductions (P < 0.05) were observed in serum creatinine (SCr) (14.8 ± 1.9 mmol/L to 10.1 ± 2.1 mmol/L) and blood urea nitrogen (BUN) (119 ± 22 µmol/L to 97 ± 13 µmol/L), indicating improvement in renal function.

Conclusions

We successfully established a rabbit model of renal interstitial fibrosis and demonstrated that transplantation of induced autologous stem cells can repair kidney damage within 8 weeks. The repair occurred by both inhibition of further development of renal interstitial fibrosis and partial reversal of pre-existing renal interstitial fibrosis. These beneficial effects lead to the development of normal tissue structure and improved renal function.     

Embryonic Cardiomyocyte,but Not Autologous Stem Cell Transplantation,Restricts Infarct Expansion,Enhances Ventricular Function,and Improves Long-Term Survival

Aims

Controversy exists in regard to the beneficial effects of transplanting cardiac or somatic progenitor cells upon myocardial injury. We have therefore investigated the functional short- and long-term consequences after intramyocardial transplantation of these cell types in a murine lesion model.

Methods and Results

Myocardial infarction (MI) was induced in mice (n = 75), followed by the intramyocardial injection of 1−2×10⁵ luciferase- and GFP-expressing embryonic cardiomyocytes (eCMs), skeletal myoblasts (SMs), mesenchymal stem cells (MSCs) or medium into the infarct. Non-treated healthy mice (n = 6) served as controls. Bioluminescence and fluorescence imaging confirmed the engraftment and survival of the cells up to seven weeks postoperatively. After two weeks MRI was performed, which showed that infarct volume was significantly decreased by eCMs only (14.8±2.2% MI+eCM vs. 26.7±1.6% MI). Left ventricular dilation was significantly decreased by transplantation of any cell type, but most efficiently by eCMs. Moreover, eCM treatment increased the ejection fraction and cardiac output significantly to 33.4±2.2% and 22.3±1.2 ml/min. In addition, this cell type exclusively and significantly increased the end-systolic wall thickness in the infarct center and borders and raised the wall thickening in the infarct borders. Repetitive echocardiography examinations at later time points confirmed that these beneficial effects were accompanied by better survival rates.

Conclusion

Cellular cardiomyoplasty employing contractile and electrically coupling embryonic cardiomyocytes (eCMs) into ischemic myocardium provoked significantly smaller infarcts with less adverse remodeling and improved cardiac function and long-term survival compared to transplantation of somatic cells (SMs and MSCs), thereby proving that a cardiomyocyte phenotype is important to restore myocardial function.     

Characterisation of Age-Dependent Beta Cell Dynamics in the Male db/db Mice

Aim

To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice.

Methods

Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA_1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology.

Results

Total pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups.

Conclusions/Interpretation

The age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number.     

A Pilot Study of Telmisartan for Visceral Adiposity in HIV Infection: The Metabolic Abnormalities,Telmisartan, and HIV Infection (MATH) Trial

Background

Visceral adiposity in the setting of HIV infection and antiretroviral therapy (ART) is not fully understood, and treatment options remain limited. Telmisartan, an angiotensin receptor blocker and partial PPAR-γ agonist, has been shown to decrease visceral fat and improve metabolic and inflammatory parameters in HIV-uninfected subjects.

Methods

HIV-infected subjects with HIV-1 RNA <50 copies/mL on ART and (women/men) waist circumference >94/95 cm or waist: hip ratio >0.88/0.94 received open-label telmisartan 40 mg po daily for 24 weeks. Adipose tissue (AT) volumes were quantified by L4–L5 single slice computed tomography. Metabolic and inflammatory markers were obtained fasting. Thirty-five subjects provided 80% power to detect a 10% 24-week decrease in visceral AT (VAT, two-sided α = 0.05).

Results

Thirty-five subjects enrolled and completed the protocol. At entry (median or %): age 49 years, 43% female, 77% non-white, 91% non-smokers, CD4+ T cell count 590 cells/mm³, BMI 31 kg/m². AT responses were heterogeneous, with statistically significant losses of median (IQR) total (TAT, 2.9% (−9.8, 0.7), p = 0.03) and subcutaneous (SAT, −2.7% (−9.8, 1.1), p = 0.03) AT, but not VAT (−2.7% (−20.5, 14.2), p = 0.53). Significant decreases in waist circumference and waist:hip ratio occurred (both p<0.001) without BMI or weight changes. In an exploratory analysis, significant increases in TNF-α occurred among female subjects without changes in other inflammatory or metabolic markers. No related adverse events occurred.

Conclusions

Telmisartan was well tolerated. Small losses of AT from all depots were observed after 24 weeks of telmisartan therapy. Further study is needed to determine whether HIV-infected patients can receive metabolic benefits from telmisartan.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01088295","term_id":"NCT01088295"}}NCT01088295     

Increased Visceral Adipose Tissue as a Potential Risk Factor in Patients with Embolic Stroke of Undetermined Source (ESUS)

Purpose

The etiology of an ischemic stroke remains undetermined in 20–35% of cases and many patients do not have any of the conventional risk factors. Increased visceral adipose tissue (VAT) is a suggested new risk factor for both carotid artery atherosclerosis (CAA) and atrial fibrillation (AF), but its role in the remaining stroke population is unknown. We assessed the amount of VAT in patients with embolic stroke of undetermined source (ESUS) after excluding major-risk cardioembolic sources, occlusive atherosclerosis, and lacunar stroke.

Methods

Altogether 58 patients (mean age 57.7±10.2 years, 44 men) with ischemic stroke of unknown etiology but without CAA, known AF or small vessel disease underwent computed tomography angiography and assessment of VAT. For comparison VAT values from three different reference populations were used. Conventional risk factors (smoking, hypertension, diabetes, increased total and LDL-cholesterol, decreased HDL-cholesterol) were also registered.

Results

Mean VAT area was significantly higher in stroke patients (205±103 cm² for men and 168±99 cm² for women) compared to all reference populations (P<0.01). 50% of male and 57% of female patients had an increased VAT area. In male patients, VAT was significantly higher despite similar body mass index (BMI). Increased VAT was more common than any of the conventional risk factors.

Conclusion

Increased VAT was found in over half of our patients with ESUS suggesting it may have a role in the pathogenesis of thromboembolism in this selected group of patients.     

Assessment of Activity Limitations with the Health Assessment Questionnaire Predicts the Need for Support Measures in Patients with Rheumatoid Arthritis: A Multicenter Observational Study

Objective

This study investigated whether the Health Assessment Questionnaire (HAQ) can be used as an instrument to assess the need for social support measures that address activity limitations and participation issues in patients with rheumatoid arthritis (RA).

Methods

This multicenter observational study included patients with RA and disease duration of at least one year, consulting their rheumatologist for routine evaluation of disease activity. In the single study visit data on demographics, disease history and current treatment were collected. DAS28 values were collected to evaluate current RA disease activity. Patients were asked to fill out the HAQ and SF-36 questionnaires. Receiver Operator Characteristics (ROC) curves were constructed to evaluate the performance of the HAQ, SF-36 and DAS28 in predicting the need for nine supporting measures available for chronically ill patients in the Belgian social security system. The expert opinion of the treating rheumatologist was used as a reference.

Results

The study included 316 patients with a mean age of 59.8±12.6 years, disease duration of 11.4±9.3 years, mean DAS28 values of 2.83±1.17. Mean HAQ score was 0.95±0.73, mean SF-36 score 56.5±21.3. HAQ scores >1 were observed in 39.4% of patients. The area under the HAQ ROC curve was consistently >0.7 and higher for the HAQ than for SF-36 or DAS28 for all support measures. Rheumatologists on average recommended 3.67 support measures.

Conclusion

The HAQ score was found to be a good predictor of the need for social support measures in patients with RA.