Adipose tissue‐specific modulation of galectin expression in lean and obese mice: Evidence for regulatory function

Objective:

Galectins (Gal) exert many activities, including regulation of inflammation and adipogenesis. We evaluated modulation of Gal‐1, ‐3, ‐9 and ‐12 in visceral (VAT) and subcutaneous (SAT) adipose tissue in mice.

Design and Methods:

We used two mouse models of obesity, high‐fat diet induced obesity (DIO) and ob/ob mice. We also evaluated the response of Gal‐1 KO mice to DIO.

Results:

Both age and diet modulated expression of galectins, with DIO mice having higher serum Gal‐1 and Gal‐3 versus lean mice after 13‐17 weeks of high‐fat diet. In DIO mice there was a progressive increase in expression of Gal‐1 and Gal‐9 in SAT, whereas Gal‐3 increased in both VAT and SAT. Expression of Gal‐12 declined over time in VAT of DIO mice, similar to adiponectin. Obesity lead to increased production of Gal‐1 in adipocytes, whereas the increased Gal‐3 and Gal‐9 of obesity mostly derived from the stromovascular fraction. Expression of Gal‐12 was restricted to adipocytes. There was increased production of Gal‐3 and Gal‐9, but not Gal‐1, in CD11c^? and CD11c⁺ macrophages from VAT of DIO versus lean mice. Expression of Gal‐1, ‐3 and ‐12 in VAT and SAT of ob/ob mice followed a trend comparable to DIO mice. Rosiglitazone reduced serum Gal‐1, but not Gal‐3 and modulated expression of Gal‐3 in VAT and Gal‐9 and Gal‐12 in SAT of DIO mice. High‐fat feeding lead to increased adiposity in Gal‐1 KO versus WT mice, with loss of correlation between leptin and adiposity and no alterations in glucose and insulin levels.

Conclusions:

Obesity leads to differential modulation of Gal‐1, 3, 9 and 12 in VAT and SAT, with Gal‐1 acting as a modulator of adiposity.

     

VAT=TAAT‐SAAT: Innovative anthropometric model to predict visceral adipose tissue without resort to CT‐Scan or DXA

Objective:

To investigate whether a combination of a selected but limited number of anthropometric measurements predicts visceral adipose tissue (VAT) better than other anthropometric measurements, without resort to medical imaging.

Hypothesis:

Abdominal anthropometric measurements are total abdominal adipose tissue indicators and global measures of VAT and SAAT (subcutaneous abdominal adipose tissue). Therefore, subtracting the anthropometric measurement the more correlated possible with SAAT while being the least correlated possible with VAT, from the most correlated abdominal anthropometric measurement with VAT while being highly correlated with TAAT, may better predict VAT.

Design and Methods:

BMI participants' range was from 16.3 to 52.9 kg m^?2. Anthropometric and abdominal adipose tissues data by computed tomography (CT‐Scan) were available in 253 patients (18‐78 years) (CHU Nord, Marseille) and used to develop the anthropometric VAT prediction models.

Results:

Subtraction of proximal thigh circumference from waist circumference, adjusted to age and/or BMI, predicts better VAT (Women: VAT = 2.15 × Waist C ? 3.63 × Proximal Thigh C + 1.46 × Age + 6.22 × BMI ? 92.713; R² = 0.836. Men: VAT = 6 × Waist C ? 4.41 × proximal thigh C + 1.19 × Age ? 213.65; R² = 0.803) than the best single anthropometric measurement or the association of two anthropometric measurements highly correlated with VAT. Both multivariate models showed no collinearity problem. Selected models demonstrate high sensitivity (97.7% in women, 100% in men). Similar predictive abilities were observed in the validation sample (Women: R² = 76%; Men: R² = 70%). Bland and Altman method showed no systematic estimation error of VAT.

Conclusion:

Validated in a large range of age and BMI, our results suggest the usefulness of the anthropometric selected models to predict VAT in Europides (South of France).

     

A cross‐sectional study of osteocalcin and body fat measures among obese adolescents

Osteocalcin (OCN), a marker of osteoblast activity, has been implicated in the regulation of energy metabolism by the skeleton and thus may affect body fat measures.

Objective:

To examine the relationships of OCN to body fat measures and whether they vary according to markers of energy and vitamin D metabolism.

Design and Methods:

Data were obtained from 58 obese adolescents aged 13‐17.9 years (38 females, 8 black or African‐American). Total fat mass (FM) [dual X‐ray absorptiometry (DXA)] and visceral adipose tissue (VAT) [computerized axial tomography (CT)] were calculated. Blood tests included leptin, OCN, 25‐hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), thyroid function tests, and triglycerides. Markers of glucose metabolism were obtained from fasting and OGTT samples.

Results and Conclusions:

Adolescents with 25(OH)D <20 ng mL^?1 were considered deficient (n = 17/58); none had high PTH (PTH ≥ 65 pg mL^?1). OCN was associated with lower VAT (?84.27 ± 33.89 mm²) and BMI (?0.10 ± 0.05 kg m^?2), not FM (P = 0.597) in a core model including age, sex, race, geographic latitude, summer, height z‐score, and tanner stage. Adding 25(OH)D deficiency and PTH attenuated the inverse association of OCN to VAT. There was a significant interaction of OCN and 25(OH)D deficiency on FM (0.37 ± 0.18 kg, P = 0.041) and BMI (0.28 ± 0.10 kg m^?2, P = 0.007) in this adjusted model, which was further explained by leptin. Adding A1C to the core model modified the relationship of OCN to VAT (?93.08 ± 35.05 mm², P = 0.011), which was further explained by HOMA‐IR. In summary, these findings provide initial evidence for a relationship between OCN and body fat measures that is dependent on energy metabolism and vitamin D status among obese adolescents.

     

ERRγ enhances UCP1 expression and fatty acid oxidation in brown adipocytes

Objective:

Estrogen‐related receptors (ERRs) are important regulators of energy metabolism. Here we investigated the hypothesis that ERRγ impacts on differentiation and function of brown adipocytes.

Design and Methods:

We characterize the expression of ERRγ in adipose tissues and cell models and investigate the effects of modulating ERR? activity on UCP1 gene expression and metabolic features of brown and white adipocytes.

Results:

ERRγ was preferentially expressed in brown compared to white fat depots, and ERRγ was induced during cold‐induced browning of subcutaneous white adipose tissue and brown adipogenesis. Overexpression of ERRγ positively regulated uncoupling protein 1 (UCP1) expression levels during brown adipogenesis. This ERRγ‐induced augmentation of UCP1 expression was independent of the presence of peroxisome proliferator‐activated receptor coactivator‐1 (PGC‐1α) but was associated with increased rates of fatty acid oxidation in adrenergically stimulated cells. ERR? did not influence mitochondrial biogenesis, and its reduced expression in white adipocytes could not explain their low expression level of UCP1.

Conclusions:

Through its augmenting effect on expression of UCP1, ERRγ may physiologically be involved in increasing the potential for energy expenditure in brown adipocytes, a function that is becoming of therapeutic interest.

     

A clinical model of obesity treatment is more effective in preschoolers and Spanish speaking families

Objective:

Preschool and minority children have not been well represented in obesity treatment studies. This analysis of clinical obesity treatment was carried out within a diverse population of children 2‐12 years to identify demographic characteristics associated with successful treatment.

Design and Methods:

A medical record review captured BMI and demographics for children 2‐12 years who began treatment during a 42‐month period (n = 479). Associations of body mass index z‐score (BMI‐Z) change with child and family demographics were examined with logistic regression and time‐to‐event analysis.

Results:

Treatment led to a mean BMI‐Z decrease of 0.18. Half of children with follow‐up (n = 273) exceeded the a priori cut‐off for successful treatment of ?0.1 BMI‐Z. Preschoolers and children of Spanish‐speakers were more likely to succeed, (Adjusted OR: 5.8 [95% CI: 2.7‐12.2] and 2.3 [95% CI: 1.1, 4.9]). The hazard ratio for treatment failure was 3.7 [95% CI: 2.1, 6.8] for children starting treatment at 6‐12 years compared to preschoolers, adjusted for other demographics.

Conclusions:

This mode of treatment was more likely to succeed among children treated before school age and among children whose parents spoke only Spanish. Screening and treatment for obesity in preschoolers and Hispanic immigrant families deserve further prospective study.

     

The species–area relationship does not have an asymptote!

Aim

To attack a widespread myth.

Location

World‐wide.

Methods

Simple mathematical logical and empirical examples.

Results

As both species and area are finite and non‐negative, the species–area relationship is limited at both ends. The log species–log area relationship is normally effectively linear on scales from about 1 ha to 10⁷ km². There are no asymptotes. At the intercontinental scale it may get steeper; at small scales it may in different cases get steeper or shallower or maintain its slope.

Main conclusion

The species–area relationship does not have an asymptote.

     

Objectively measured sedentary behavior,physical activity,and plasma lipids in overweight and obese children

Objective:

This study examines the associations between objectively measured sedentary behavior, light physical activity (LPA), and moderate‐to‐vigorous physical activity (MVPA), and plasma lipids in overweight and obese children.

Design and Methods:

Cross‐sectional analyses were conducted among 126 children aged 5.5‐9.9 years. Sedentary behavior, LPA, and MVPA were assessed using accelerometry. Fasting blood samples were analyzed for plasma lipids (high‐density lipoprotein cholesterol [HDL‐C], low‐density lipoprotein cholesterol [LDL‐C], total cholesterol [TC], and triglycerides [TG]).

Results:

MVPA was not related to plasma lipids (P > 0.05). Independent of age, sex, energy intake, and waist circumference z‐score, sedentary behavior and LPA were associated with HDL‐C (β = ?0.23, 95% CI ?0.42 to ?0.04, P = 0.020; β = 0.20, 95% CI 0.14 to 0.39, P = 0.036, respectively). The strength of the associations remained after additionally adjusting for MVPA (sedentary behavior: β = ?0.22, 95% CI ?0.44 to 0.006, P = 0.056; LPA: β = 0.19, 95% CI ?0.005 to 0.38, P = 0.056, respectively).

Conclusion:

Substituting at least LPA for sedentary time may contribute to the development of healthy HDL‐C levels among overweight and obese children, independent of their adiposity. Comprehensive prevention and treatment strategies to improve plasma HDL‐C among overweight and obese children should target reductions in total sedentary time and promote the benefits of LPA, in addition to promoting healthy levels of adiposity, healthy dietary behaviors, and MVPA.

     

Patterning of children's sedentary time at and away from school

Objective:

Sedentary behavior in children is positively associated with an increased risk of both obesity and insulin resistance. Children spend a considerable portion of their awake time in sedentary behavior; however, the pattern of accumulation is not known. Thus the objective of this study was to describe the patterning of sedentary behavior of children at and away from school.

Design and Methods:

The patterns of sedentary time in a sample of 53 children (28 girls) aged 10‐12 years during school‐term time were examined. Children wore an accelerometer for 1 week. Total sedentary time, prolonged sequences (bouts) of sedentary time, and frequency of active interruptions to sedentary were examined on school days and weekends and within school time and non‐school time on school days.

Results:

The data did not support our hypothesis that children accumulated more sedentary time on school days when compared with weekend days (mean [SD]: 64.4% [5.3] vs. 64.9% [9.0], P = 0.686). However, when comparing school time with non‐school time on school days, children accumulated more sedentary time at school (66.8% [7.3] vs. 62.4% [5.2], P < 0.001) and spent more time at school in sustained sedentary sequences, that is, uninterrupted sedentary time for 30 min or more (75.6 min [45.8] vs. 45.0 min [26.8], P < 0.002). The children also recorded less breaks per sedentary hour within school time when compared with non‐school time (8.9 h^?1 vs. 10.2 h^?1, P < 0.001).

Conclusion:

Reducing total sedentary time spent both in and out of school remains an important challenge. Interrupting sedentary time more often in the “working” (school) day could also reap important musculoskeletal and metabolic health rewards for children.

     

Body adiposity index assess body fat with high accuracy in nondialyzed chronic kidney disease patients

Objective:

High body fat (BF) is an alarming condition that also affects nondialyzed chronic kidney disease (CKD) patients. Distinct methods are used to evaluate BF; however, in CKD population it remains unclear which one is more reliable showing high accuracy. Dual‐energy X‐ray absorptiometry (DXA), used as reference method to estimate adiposity, is expensive and time consuming to be applied in clinical settings. Recently, a new body adiposity index (BAI), that estimates BF from easily accessible measures, was validated in the general population. The aim of this study was to evaluate which simple and practical method, routinely used to estimate BF, shows the highest accuracy compared with DXA, in nondialyzed CKD patients.

Design and Methods:

In this cross‐sectional study BF was estimated by DXA, bioelectrical impedance analysis (BIA), anthropometry (ANTHRO), and BAI. Serum leptin levels were determined.

Results:

Studied patients (n = 134) were 55% males, 54% overweight/obese, and 64.9 ± 12.5 years old, with estimated glomerular filtration rate (eGFR) = 29.0 ± 12.7 ml/min. The correlation coefficient was higher between DXA vs. ANTHRO (r = 0.76) and BAI (r = 0.61) than with BIA (r = 0.57), after adjusting for gender, age, and eGFR (P < 0.0001). Therefore, the Lin's concordance correlation coefficient and Bland–Altman plots were performed to measure the accuracy (C_b) between DXA with both ANTHRO and BAI. A higher accuracy (C_b = 0.82) and lower mean difference (?3.4%) was observed for BAI than for ANTHRO (C_b = 0.61; ?8.4%). Leptin levels correlated (P < 0.0001) with DXA (r = 0.56) and BAI (r = 0.59).

Conclusions:

These findings suggest that BAI estimates BF with high accuracy in nondialyzed CKD patients and may be helpful in the treatment of this population with increased BF.

     

Novel promoter/transactivator configurations for macrolide- and streptogramin-responsive transgene expression in mammalian cells

Background

The recently developed heterologous macrolide‐ (E.REX system) and streptogramin‐ (PIP system) responsive gene regulation systems show significant differences in their regulation performance in diverse cell lines.

Methods

In order to provide optimal regulation modalities for a wide variety of mammalian cell lines, we have performed a detailed analysis of E.REX and PIP systems modified in (i) the transactivation domains of the antibiotic‐dependent transactivators, (ii) the type of minimal promoter used, and (iii) the spacing between the operator module and the minimal promoter.

Results

These novel E.REX and PIP regulation components showed not only dramatically improved regulation performance in some cell types, but also enabled their use in cell lines which had previously been inaccessible to regulated transgene expression.

Conclusions

Due to their modular set‐up the novel E.REX and PIP regulation systems presented here are most versatile and ready for future upgrades using different cell‐specific key regulation components. Copyright © 2002 John Wiley & Sons, Ltd.

     

Utility‐based quality of life associated with overweight and obesity: The australian diabetes,obesity, and lifestyle study

Objective:

This study aimed to estimate utility‐based quality of life (UQoL) differences between healthy body weight and excess body weight categories.

Design and Methods:

Cross‐sectional analysis of 10,959 adults, participating in baseline data collection of the nationally representative Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study was undertaken. Height and weight were measured by trained personnel. Body weight categories were assigned as healthy weight, overweight, and obesity subclasses I, II and III. UQoL was assessed using the SF‐6D, which captures physical functioning, role limitation, social functioning, pain, mental health, and vitality on a score of 0.00–1.00 (worst‐best). The relationship between body weight categories and UQoL was assessed using linear regression, adjusting for age, sex, education, and smoking.

Results:

Relative to the healthy weight group (mean UQoL score 0.77), mean adjusted UQoL differences (95% confidence intervals) were 0.001 (?0.008, 0.010) for overweight, ?0.012 (?0.022, ?0.001) for class‐I obese, ?0.020 (?0.041, 0.001) for class‐II obese, and ?0.069 (?0.099, ?0.039) for class‐III obese groups. Adding metabolic syndrome markers to the covariates had little impact on these differences.

Conclusion:

Results confirmed an inverse dose–response relationship between body weight and UQoL in this study of Australian adults. This highlights the need to incorporate UQoL measures which are sensitive to the subclasses of obesity when evaluating obesity interventions.

     

Body Composition Percentiles in Urban South Indian Children and Adolescents

Objective

This study aimed to generate age‐ and sex‐specific percentiles for body composition indices in children and to assess the variability in these indices, in relation to BMI.

Methods

Anthropometry and body fat were measured with the BOD POD (Cosmed; Rome, Italy) in 9,702 children from Bangalore, India. Smoothed percentile curves using the lambda‐mu‐sigma method were obtained for BMI, fat‐free mass index (FFMI), fat mass index (FMI), and body fat percentage (% BF).

Results

Percentile curves for % BF and FMI in boys increased from 6 to 12 years and declined from 13 years on, while in girls, it increased until 15 years. The FFMI percentile curves increased with age in both sexes. The mean FMI declined from 12 years on in boys, corresponding to a large increase in FFMI from that age, while in girls, both FMI and FFMI continued to increase. The 75th percentile of % BF and FMI had greater sensitivity to identify children with obesity.

Conclusions

This study developed smoothed percentile curves for body composition in Indian children and suggests FMI and FFMI as good indicators of growth in children.

     

Transfer of maternally administered fusogenic liposome-DNA complexes into monkey fetuses in a pregnancy model

Background

Materno‐fetal transfer of intravenously administered liposome‐plasmid DNA complexes has been demonstrated only in mice. Studies on its materno‐fetal transfer in the pregnant monkey model is needed because of critical differences in placental structure between primates including humans and rodents.

Methods

The reporter plasmid pEGFP‐C1 was formulated in cationic lipid containing polybrene and vesicular stomatitis virus G protein. The fusogenic liposome‐plasmid DNA complexes were intradermally injected into pregnant common marmosets (N=2), a New World monkey, near term. DNA extracted from fetal tissues was subjected to PCR for detection of the egfp gene. Confocal microscopy and immunostaining were performed to determine the sites of transgene expression in the fetal organs.

Results

The egfp gene was detected in fetal blood and major organs (heart, liver, lung). The encoded protein was mainly produced in the endothelial cells of blood vessels in the fetal lungs.

Conclusions

This is the first report on materno‐fetal transfer of intradermally administered fusogenic liposome‐plasmid DNA complexes and fetal expression of a transgene in primates. Copyright © 2002 John Wiley & Sons, Ltd.

     

Associations of testosterone and sex hormone binding globulin with adipose tissue hormones in midlife women

Objective:

Regulators of adipose tissue hormones remain incompletely understood, but may include sex hormones. As adipose tissue hormones have been shown to contribute to numerous metabolic and cardiovascular disorders, understanding their regulation in midlife women is of clinical importance. Therefore, we assessed the associations between testosterone (T) and sex hormone binding globulin (SHBG) with leptin, high molecular weight (HMW) adiponectin, and the soluble form of the leptin receptor (sOB‐R) in healthy midlife women.

Design and Methods:

Cross‐sectional analyses were performed using data from 1,881 midlife women (average age 52.6 (±2.7) years) attending the sixth Annual follow‐up visit of the multiethnic Study of Women's Health Across the Nation.

Results:

T was weakly negatively associated with both HMW adiponectin and sOB‐R (r = ?0.12 and r = ?0.10, respectively; P < 0.001 for both), and positively associated with leptin (r = 0.17; P < 0.001). SHBG was more strongly and positively associated with both HMW adiponectin and sOB‐R (r = 0.29 and r = 0.24, respectively; P < 0.001 for both), and more strongly and negatively associated with leptin (r = ?0.27; P < 0.001). Adjustment for fat mass, insulin resistance, or waist circumference only partially diminished associations with HMW adiponectin and sOB‐R, but attenuated associations with leptin. In conclusion, in these midlife women, lower SHBG values, and to a lesser extent, higher T levels, were associated with lower, or less favorable, levels of adiponectin and sOB‐R, independent of fat mass.

Conclusions:

These data suggest that variation in these adipose hormones resulting from lower SHBG levels, and possibly, though less likely, greater androgenicity, may contribute to susceptibility for metabolic and cardiovascular outcomes during midlife in women.

     

Single-step, multiple retroviral transduction of human T cells

Background

Retroviral transduction of human peripheral blood T cells has considerable potential in the development of gene therapy strategies for immunological disorders. New vectors and experimental procedures have been developed for efficient transduction of several genes into human T cells.

Methods

Bicistronic retroviral vectors encoding distinct cell markers were used for the simultaneous multiple transduction of a human T‐cell line (MT‐2), as well as of human peripheral blood T cells from normal donors. Transduction efficiencies were evaluated by flow cytometry and double‐ and triple‐transduced cells were isolated by fluorescence cell sorting.

Results

Four new bicistronic retroviral vectors were developed that express different gene markers under the control of the internal ribosome entry site (IRES) of the encephalomyocarditis virus. These markers are, respectively, enhanced green fluorescent protein (EGFP), β‐galactosidase, and truncated versions of human nerve growth factor receptor (ΔNGFR) and human growth hormone receptor (ΔGHR). A single 1 h spinoculation infection, performed in the presence of polybrene and using transiently produced amphotropic retroviral particles, was sufficient to obtain transduction efficiencies consistently greater than 50% on human peripheral blood T lymphocytes which had been previously stimulated for 3 days with immobilized anti‐CD3. The transient production of viral particles encoding EGFP, ΔNGFR, and ΔGHR markers in the same viral supernatant has allowed up to three different genes to be introduced simultaneously into human T cells.

Conclusions

This study describes new experimental conditions for efficient single‐step multiple transduction of human primary T lymphocytes. The procedure could be of interest for the development of gene therapy approaches. Copyright © 2002 John Wiley & Sons, Ltd.

     

Effect of chitosan‐alginate nanoparticles and ultrasound on the efficiency of gene transfection of human cancer cells

Background

Gene therapy has been used to treat a variety of health problems, but transfection inefficiency and the lack of safe vectors have limited clinical progress. Fabrication of a vector that is safe and has high transfection efficiency is crucial for the development of successful gene therapy. The present study aimed to synthesize chitosan‐alginate nanoparticles that can be used as carriers of the pAcGFP1‐C1 plasmid and to use these nanoparticles with an ultrasound protocol to achieve high efficiency gene transfection.

Methods

Chitosan was complexed with alginate and the pAcGFP1‐C1 plasmid at different charge ratios to create chitosan‐alginate‐DNA nanoparticles (CADNs). The average particle size and loading efficiency were measured. Plasmid DNA retardation and integrity were analysed on 1% agarose gels. The effect of CADNs and ultrasound on the efficiency of transfection of cells and subcutaneous tumors was evaluated.

Results

In the CADNs, the average size of incorporated plasmid DNA was 600–650 nm and the loading efficiency was greater than 90%. On the basis of the results of the plasmid DNA protection test, CADNs could protect the transgene from DNase I degradation. The transgene product expression could be enhanced efficiently if cells or tumor tissues were first given CADNs and then treated with ultrasound.

Conclusions

The use of CADNs combined with an ultrasound regimen is a promising method for safe and effective gene therapy. Copyright © 2009 John Wiley & Sons, Ltd.

     

Non-viral vector-mediated uptake,distribution, and stability of chimeraplasts in human airway epithelial cells

Background

Chimeraplasty is a novel methodology that uses chimeric RNA/DNA oligonucleotides (chimeraplasts) to stimulate genomic DNA repair. Efficient uptake and nuclear localization of intact chimeraplasts are key parameters to achieve optimal correction of mutation defects into specific cell types.

Methods

A 5′‐end FITC‐labeled 68‐mer RNA/DNA oligonucleotide was complexed with the polycation polyethylenimine (PEI) and the cationic lipids Cytofectin and GenePorter. Flow cytometry was employed to evaluate chimeraplast uptake under different conditions. Intracellular chimeraplast distribution and co‐localization with endocytosis markers were assessed by confocal microscopy. Relative quantification of chimeraplast metabolism was performed by denaturing PAGE and GeneScan^? analysis.

Results

In airway epithelial cells, optimized chimeraplast uptake reached near 100% efficiency with the carriers tested. However, chimeraplast nuclear localization could only be achieved using PEI or Cytofectin. Chimeraplast/GenePorter lipoplexes were retained in the cytoplasm. PEI polyplexes and Cytofectin lipoplexes displayed different uptake rates and internalization mechanisms. Chimeraplast/PEI polyplexes were internalized at least partially by fluid‐phase endocytosis. In contrast, phagocytosis may have contributed to the internalization process of large‐sized chimeraplast/Cytofectin lipoplexes. Moreover, significant chimeraplast degradation was detected 24 h after transfection with both PEI polyplexes and Cytofectin lipoplexes, although the latter seemed to confer a higher degree of protection against nuclease degradation.

Conclusion

Both Cytofectin and PEI are efficient for chimeraplast nuclear uptake into airway epithelial cells. However, despite the distinct structures and trafficking pathways of the corresponding complexes, none of them could prevent nuclease‐mediated metabolism of the chimeric oligonucleotides. These findings should be taken into account for future investigations of chimeraplast‐mediated gene repair in airway epithelial cells. Copyright © 2002 John Wiley & Sons, Ltd.

     

A randomized,phase 3 trial of naltrexone SR/bupropion SR on weight and obesity‐related risk factors (COR‐II)

Objective:

To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight‐related risk factors in overweight and obese participants.

Design and Methods:

CONTRAVE Obesity Research‐II (COR‐II) was a double‐blind, placebo‐controlled study of 1,496 obese (BMI 30‐45 kg/m²) or overweight (27‐45 kg/m² with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained‐release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co‐primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28.

Results:

Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (?6.5% vs. ?1.9%) and week 56 (?6.4% vs. ?1.2%). More NB32‐treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant‐reported weight‐related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo.

Conclusion:

NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option.

     

Neural crest and cardiovascular development: a 20-year perspective

Background

Twenty years ago this year was the first publication describing a region of neural crest cells necessary for normal cardiovascular development. Ablation of this region in chick resulted in persistent truncus arteriosus, mispatterning of the great vessels, outflow malalignments, and hypoplasia or aplasia of the pharyngeal glands.

Methods

We begin with a historical perspective and then review the progress that has been made in the ensuing 20 years in determining the direct and indirect contributions of the neural crest cells, now termed cardiac neural crest cells, in cardiovascular and pharyngeal arch development. Many of the molecular pathways that are now known to influence the specification, migration, patterning and final targeting of the cardiac neural crest cells are also reviewed.

Results

Although much knowledge has been gained by using many genetic manipulations to understand the cardiac neural crest cells' role in cardiovascular development, most models fail to explain the phenotypes seen in syndromic and non‐syndromic human congenital heart defects, such as the DiGeorge syndrome.

Conclusions

We propose that the cardiac neural crest exists as part of a larger cardiocraniofacial morphogenetic field and describe several human syndromes that result from abnormal development of this field. Birth Defects Research (Part C) 69:2–13, 2003. © 2003 Wiley‐Liss, Inc.