Osteoprotegerin,Pericytes and Bone-Like Vascular Calcification Are Associated with Carotid Plaque Stability

Background and Purpose

Vascular calcification, recapitulating bone formation, has a profound impact on plaque stability. The aim of the present study was to determine the influence of bone-like vascular calcification (named osteoid metaplasia = OM) and of osteoprotegerin on plaque stability.

Methods

Tissue from carotid endarterectomies were analysed for the presence of calcification and signs of vulnerability according to AHA grading system. Osteoprotegerin (OPG), pericytes and endothelial cells were sought using immuno-histochemistry. Symptoms and preoperative imaging findings (CT-scan, MRI and Doppler-scan) were analyzed. Human pericytes were cultured to evaluate their ability to secrete OPG and to influence mineralization in the plaque.

Results

Seventy-three carotid plaques (49 asymptomatic and 24 symptomatic) were harvested. A significantly higher presence of OM (18.4% vs 0%, p<0.01), OPG (10.2% of ROI vs 3.4% of ROI, p<0.05) and pericytes (19% of ROI vs 3.8% of ROI, p<0.05) were noted in asymptomatic compared to symptomatic plaques. Consistently, circulating OPG levels were higher in the plasma of asymptomatic patients (3.2 ng/mL vs 2.5 ng/mL, p = 0.05). In vitro, human vascular pericytes secreted considerable amounts of OPG and underwent osteoblastic differentiation. Pericytes also inhibited the osteoclastic differentiation of CD14+ cells through their secretion of OPG.

Conclusions

OPG (intraplaque an plasmatic) and OM are associated with carotid plaque stability. Pericytes may be involved in the secretion of intraplaque OPG and in the formation of OM.     

Using Health Surveillance Systems Data to Assess the Impact of AIDS and Antiretroviral Treatment on Adult Morbidity and Mortality in Botswana

Introduction

Botswana''s AIDS response included free antiretroviral treatment (ART) since 2002, achieving 80% coverage of persons with CD4<350 cells/µl by 2009–10. We explored impact on mortality and HIV prevalence, analyzing surveillance and civil registration data.

Methods

Hospital natural cause admissions and deaths from the Health Statistics Unit (HSU) over 1990–2009, all-cause deaths from Midnight Bed Census (MNC) over 1990–2011, institutional and non-institutional deaths recorded in the Registry of Birth and Deaths (RBD) over 2003–2010, and antenatal sentinel surveillance (ANC) over 1992–2011 were compared to numbers of persons receiving ART. Mortality was adjusted for differential coverage and completeness of institutional and non-institutional deaths, and compared to WHO and UNAIDS Spectrum projections.

Results

HSU deaths per 1000 admissions declined 49% in adults 15–64 years over 2003–2009. RBD mortality declined 44% (807 to 452/100,000 population in adults 15–64 years) over 2003–2010, similarly in males and females. Generally, death rates were higher in males; declines were greater and earlier in younger adults, and in females. In contrast, death rates in adults 65+, particularly females increased over 2003–2006. MNC all-age post-neonatal mortality declined 46% and 63% in primary and secondary level hospitals, over 2003–2011. We estimated RBD captured 80% of adult deaths over 2006–2011. Comparing empirical, completeness-adjusted deaths to Spectrum estimates, declines over 2003–2009 were similar overall (47% vs. 54%); however, Spectrum projected larger and earlier declines particularly in women. Following stabilization and modest decreases over 1998–2002, HIV prevalence in pregnant women 15–24 and 25–29-years declined by >50% and >30% through 2011, while continuing to increase in older women.

Conclusions

Adult mortality in Botswana fell markedly as ART coverage increased. HIV prevalence declines may reflect ART-associated reductions in sexual transmission. Triangulation of surveillance system data offers a reasonable approach to evaluate impact of HIV/AIDS interventions, complementing cohort approaches that monitor individual-level health outcomes.     

Modifying Effect of a Common Polymorphism in the Interleukin-6 Promoter on the Relationship between Long-Term Exposure to Traffic-Related Particulate Matter and Heart Rate Variability

Background

Exposure to particulate matter (PM) has been associated with an increase in many inflammatory markers, including interleukin 6 (IL6). Air pollution exposure has also been suggested to induce an imbalance in the autonomic nervous system (ANS), such as a decrease in heart rate variability (HRV). In this study we aimed to investigate the modifying effect of polymorphisms in a major proinflammatory marker gene, interleukin 6 (IL6), on the relationship between long-term exposure to traffic-related PM₁₀ (TPM₁₀) and HRV.

Methods

For this cross-sectional study we analysed 1552 participants of the SAPALDIA cohort aged 50 years and older. Included were persons with valid genotype data, who underwent ambulatory 24-hr electrocardiogram monitoring, and reported on medical history and lifestyle. Main effects of annual average TPM₁₀ and IL6 gene variants (rs1800795; rs2069827; rs2069840; rs10242595) on HRV indices and their interaction with average annual exposure to TPM₁₀ were tested, applying a multivariable mixed linear model.

Results

No overall association of TPM₁₀ on HRV was found. Carriers of two proinflammatory G-alleles of the functional IL6 -174 G/C (rs1800795) polymorphism exhibited lower HRV. An inverse association between a 1 µg/m³ increment in yearly averaged TPM₁₀ and HRV was restricted to GG genotypes at this locus with a standard deviation of normal-to-normal intervals (SDNN) (GG-carriers: −1.8%; 95% confidence interval −3.5 to 0.01; p_{interaction(additive)} = 0.028); and low frequency power (LF) (GG-carriers: −5.7%; 95%CI: −10.4 to −0.8; p_{interaction(dominant)} = 0.049).

Conclusions

Our results are consistent with the hypothesis that traffic-related air pollution decreases heart rate variability through inflammatory mechanisms.     

HIV-1 Coreceptor Usage Assessment by Ultra-Deep Pyrosequencing and Response to Maraviroc

Background

Maraviroc is an HIV entry inhibitor that alters the conformation of CCR5 and is poorly efficient in patients infected by viruses that use CXCR4 as an entry coreceptor. The goal of this study was to assess the capacity of ultra-deep pyrosequencing (UDPS) and different data analysis approaches to characterize HIV tropism at baseline and predict the therapeutic outcome on maraviroc treatment.

Methods

113 patients with detectable HIV-1 RNA on HAART were treated with maraviroc. The virological response was assessed at months 1, 3 and 6. The sequence of the HIV V3 loop was determined at baseline and prediction of maraviroc response by different software and interpretation algorithms was analyzed.

Results

UDPS followed by analysis with the Pyrotrop software or geno2pheno algorithm provided better prediction of the response to maraviroc than Sanger sequencing. We also found that the H34Y/S substitution in the V3 loop was the strongest individual predictor of maraviroc response, stronger than substitutions at positions 11 or 25 classically used in interpretation algorithms.

Conclusions

UDPS is a powerful tool that can be used with confidence to predict maraviroc response in HIV-1-infected patients. Improvement of the predictive value of interpretation algorithms is possible and our results suggest that adding the H34S/Y substitution would substantially improve the performance of the 11/25/charge rule.     

Demography of plains zebras (Equus quagga) under heavy predation

In natural ecosystems, ungulate densities show strong temporal variations. The ecological processes driving these fluctuations are complex: food limitation and predation are both important and can interact. Survival rates are central to this debate, but data are sparse for tropical ecosystems. Here, we estimate age- and sex-specific survival rates for plains zebra in Hwange National Park, a nutrient-poor savanna with a high predator–prey ratio. We estimated survival from a detailed Capture-Mark-Recapture (CMR) monitoring based on 248 individual life histories, for the first time in an African grazer. We controlled for variations in detection probabilities among adult females, which resulted from their social structure. As expected, annual survival was low during the first year (0.441); increased in yearlings (0.560) and peaked at 0.795 and 0.847 in adult males and females respectively. The survival of adult females was lower during the dry season, which probably resulted from higher predation due to predictable movements of zebras to waterholes. Survival at all ages was low compared to ungulates without predators. The demographic model we constructed showed a declining trend (λ = 0.94), which was consistent with the data from road counts ( = 0.92). Life Table Response Experiment (LTRE) analyses using the Serengeti and Kruger populations as references showed that the main cause of this declining trend in the Hwange population was low survival in yearling and adult females; low foal survival also contributed. In this ecosystem, predation is likely to be the main ecological process causing low survival, and therefore a decline in the zebra population.     

Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes

The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.     

Water Selective Imaging and bSSFP Banding Artifact Correction in Humans and Small Animals at 3T and 7T,Respectively

Introduction

The purpose of this paper is to develop an easy method to generate both fat signal and banding artifact free 3D balanced Steady State Free Precession (bSSFP) images at high magnetic field.

Methods

In order to suppress fat signal and bSSFP banding artifacts, two or four images were acquired with the excitation frequency of the water-selective binomial radiofrequency pulse set On Resonance or shifted by a maximum of 3/4TR. Mice and human volunteers were imaged at 7T and 3T, respectively to perform whole-body and musculoskeletal imaging. “Sum-Of-Square” reconstruction was performed and combined or not with parallel imaging.

Results

The frequency selectivity of 1-2-3-2-1 or 1-3-3-1 binomial pulses was preserved after (3/4TR) frequency shifting. Consequently, whole body small animal 3D imaging was performed at 7T and enabled visualization of small structures within adipose tissue like lymph nodes. In parallel, this method allowed 3D musculoskeletal imaging in humans with high spatial resolution at 3T. The combination with parallel imaging allowed the acquisition of knee images with ~500μm resolution images in less than 2min. In addition, ankles, full head coverage and legs of volunteers were imaged, demonstrating the possible application of the method also for large FOV.

Conclusion

In conclusion, this robust method can be applied in small animals and humans at high magnetic fields. The high SNR and tissue contrast obtained in short acquisition times allows to prescribe bSSFP sequence for several preclinical and clinical applications.     

Bladder Cancer in HIV-infected Adults: An Emerging Issue? Case-Reports and Systematic Review

Objectives

Non-AIDS-related malignancies now represent a frequent cause of death among HIV-infected patients. Albeit bladder cancer is one of the most common malignancies worldwide, it has been rarely reported among HIV-infected patients. We wished to assess the prevalence and characteristics of bladder cancer in HIV-infected patients.

Methods

We conducted a single center retrospective study from 1998 to 2013 in a university hospital in Paris. Cases of bladder cancer among HIV-infected patients were identified using the electronic records of the hospital database and of the HIV-infected cohort. Patient characteristics and outcomes were retrieved from patients charts. A systematic review of published cases of bladder cancers in patients with HIV-infection was also performed.

Results

During the study period we identified 15 HIV-infected patients (0.2% of the cohort) with a bladder cancer. Patients were mostly men (73%) and smokers (67%), with a median age of 56 years at cancer diagnosis. Bladder cancer was diagnosed a median of 14 years after HIV-infection. Most patients were on ART (86%) with median current and nadir CD4 cell counts of 506 and 195 cells/mm³, respectively. Haematuria (73%) was the most frequent presenting symptom and HPV-associated lesions were seen in 6/10 (60%) patients. Histopathology showed transitional cell carcinoma in 80% and a high proportion of tumors with muscle invasion (47%) and high histologic grade (73%). One-year survival rate was 74.6%. The systematic review identified 13 additional cases of urothelial bladder cancers which shared similar features.

Conclusions

Bladder cancers in HIV-infected patients remain rare but may occur in relatively young patients with a low nadir CD4 cell count, have aggressive pathological features and can be fatal.