Coexistence of foam cells and hypocholesterolemia in mice lacking the ABC transporters A1 and G1

The concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.     

Adipose Tissue-derived Stem Cells: The Friendly Side of a Classic Cardiovascular Foe

Recently, the existence of a population of stem cells located in the adipose tissue has been observed. Adipose-derived stem cells are able to differentiate into multiple cell lineages including cardiac myocytes. Hence, adipose-derived cells are emerging as a new source of adult stem cells for cardiovascular repair. In this review, we discuss the basic principles of adipose-derived stem cells (types and characteristics, obtention processes, immunophenotypic characterization, and cell potency), the initial experimental studies, and the currently ongoing clinical trials.     

Thermal conditions during juvenile development affect adult dispersal in a spider

Understanding the causes and consequences of dispersal is a prerequisite for the effective management of natural populations. Rather than treating dispersal as a fixed trait, it should be considered a plastic process that responds to both genetic and environmental conditions. Here, we consider how the ambient temperature experienced by juvenile Erigone atra, a spider inhabiting crop habitat, influences adult dispersal. This species exhibits 2 distinct forms of dispersal, ballooning (long distance) and rappelling (short distance). Using a half-sib design we raised individuals under 4 different temperature regimes and quantified the spiders' propensity to balloon and to rappel. Additionally, as an indicator of investment in settlement, we determined the size of the webs build by the spiders following dispersal. The optimal temperature regimes for reproduction and overall dispersal investment were 20 °C and 25 °C. Propensity to perform short-distance movements was lowest at 15 °C, whereas for long-distance dispersal it was lowest at 30 °C. Plasticity in dispersal was in the direction predicted on the basis of the risks associated with seasonal changes in habitat availability; long-distance ballooning occurred more frequently under cooler, spring-like conditions and short-distance rappelling under warmer, summer-like conditions. Based on these findings, we conclude that thermal conditions during development provide juvenile spiders with information about the environmental conditions they are likely to encounter as adults and that this information influences the spider's dispersal strategy. Climate change may result in suboptimal adult dispersal behavior, with potentially deleterious population level consequences.     

Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin's lymphoma--a population-based study

Objective: Classical Hodgkin’s lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype. Methods: In a population‐based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n = 448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein‐x (EPX) gene polymorphisms were determined. Associations were assessed in regression models. Results: Self‐reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR) = 2.22, 95% CI 1.06–4.64, P = 0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs) = 1.84, 95% CI 1.02–3.30, P = 0.04]. Lower number of eosinophils was seen in Epstein–Barr virus (EBV)‐positive tumours (univariate RL = 0.52, 95% CI 0.3–0.9, P = 0.02) and in older patients (univariate RL = 0.85, 95% CI 0.73–0.99, P = 0.03). Well‐known factors such as young age, female sex and EBV‐negative status predicted nodular sclerosis histology. Conclusion: The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.     

Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance

CTLA-4, an Ig superfamily molecule with homology to CD28, is one of the most potent negative regulators of T-cell responses. In vivo blockade of CTLA-4 exacerbates autoimmunity, enhances tumor-specific T-cell responses, and may inhibit the induction of T-cell anergy. Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. In our studies, we show that during in vivo memory CD8(+) T-cell responses to Listeria monocytogenes infection, CTLA-4 blockade enhances bacterial clearance and increases memory CD8(+) T-cell expansion. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α. We also demonstrate that in a vaccination setting, blocking CTLA-4 during CD8(+) T-cell priming leads to increased expansion and maintenance of antigen-specific memory CD8(+) T cells without adversely affecting the overall T-cell repertoire. This leads to an increase in memory cell effector function and improved protective immunity against further bacterial challenges. These results indicate that transient blockade of CTLA-4 enhances memory CD8(+) T-cell responses and support the possible use of CTLA-4-blocking antibodies during vaccination to augment memory formation and maintenance.     

Stillbirths: how can health systems deliver for mothers and babies?

The causes of stillbirths are inseparable from the causes of maternal and neonatal deaths. This report focuses on prevention of stillbirths by scale-up of care for mothers and babies at the health-system level, with consideration for effects and cost. In countries with high mortality rates, emergency obstetric care has the greatest effect on maternal and neonatal deaths, and on stillbirths. Syphilis detection and treatment is of moderate effect but of lower cost and is highly feasible. Advanced antenatal care, including induction for post-term pregnancies, and detection and management of hypertensive disease, fetal growth restriction, and gestational diabetes, will further reduce mortality, but at higher cost. These interventions are best packaged and provided through linked service delivery methods tailored to suit existing health-care systems. If 99% coverage is reached in 68 priority countries by 2015, up to 1·1 million (45%) third-trimester stillbirths, 201?000 (54%) maternal deaths, and 1·4 million (43%) neonatal deaths could be saved per year at an additional total cost of US$10·9 billion or $2·32 per person, which is in the range of $0·96-2·32 for other ingredients-based intervention packages with only recurrent costs.     

Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA). METHODS: Three hundred sixty-seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti-TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within-subject between-visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time-integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time-integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59). CONCLUSION: These findings indicate that PDUS is a valid method for monitoring response to anti-TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.     

Maintenance of resting energy expenditure after weight loss in premenopausal women: potential benefits of a high-protein, reduced-calorie diet

The number of contemporary diet plans promoting high protein intakes for weight management has increased dramatically. Complementing this dietary approach with increased physical activity has proven to be beneficial. Recent studies have suggested that protein intakes in excess of the current Recommended Dietary Allowance (0.8 g/kg) may be of metabolic benefit during weight loss. This investigation assessed changes in resting energy expenditure and substrate oxidation in overweight and obese premenopausal women in response to a weight loss intervention that combined a high-protein, reduced-calorie diet with increased physical activity. Thirty-nine overweight and obese premenopausal women (age, 30.9 +/- 1.5 years; body mass index, 30.2 +/- 0.5 kg/m2) participated in a 10-week weight loss program in which they ate a reduced-calorie diet for which protein provided 30% of total energy and approximated 1.4 g/kg. Subjects incrementally increased physical activity (ie, steps walking) throughout the diet intervention period. Resting energy expenditure, substrate oxidation, and body composition were assessed before (PRE) and after (POST) the 10-week weight loss program. Subjects experienced a 5% decrease in body weight, with significant decreases in both fat mass (PRE, 35.5 +/- 1.2 kg; POST, 32.4 +/- 1.1 kg; P < .0001) and fat-free mass (PRE, 44.6 +/- 0.7 kg; POST, 43.6 +/- 0.7 kg; P < .0001). Changes in body weight or body composition did not alter resting energy expenditure. Protein oxidation increased (PRE, 18% +/- 1%; POST, 20% +/- 1%; P < .05) and fat oxidation decreased (PRE, 37% +/- 3%; POST, 30% +/- 3%; P < .05) after the 10-week intervention. These findings illustrate that a weight loss intervention combining consumption of a high-protein, reduced-calorie diet with increased physical activity promotes weight loss without negatively impacting resting energy expenditure in this population of women.