Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study

Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001). The T (vs. C) allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10^-16; minor allele frequency (MAF) = 0.04) and blacks (N = 581; P = 0.02; MAF = 0.01). In blacks, the T (vs. C) allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10^-8; MAF = 0.10) and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130–9,017) or blacks (N = 2,293–2,871) (median follow up ~20 years). We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.     

The Emergence of Regional Immigrant Concentrations in USA and Australia: A Spatial Relatedness Approach

This paper examines the patterns of the US and Australian immigration geography and the process of regional population diversification and the emergence of new immigrant concentrations at the regional level. It presents a new approach in the context of human migration studies, focusing on spatial relatedness between individual foreign-born groups as revealed from the analysis of their joint spatial concentrations. The approach employs a simple assumption that the more frequently the members of two population groups concentrate in the same locations the higher is the probability that these two groups can be related. Based on detailed data on the spatial distribution of foreign-born groups in US counties (2000–2010) and Australian postal areas (2006–2011) we firstly quantify the spatial relatedness between all pairs of foreign-born groups and model the aggregate patterns of US and Australian immigration systems conceptualized as the undirected networks of foreign-born groups linked by their spatial relatedness. Secondly, adopting a more dynamic perspective, we assume that immigrant groups with higher spatial relatedness to those groups already concentrated in a region are also more likely to settle in this region in future. As the ultimate goal of the paper, we examine the power of spatial relatedness measures in projecting the emergence of new immigrant concentrations in the US and Australian regions. The results corroborate that the spatial relatedness measures can serve as useful instruments in the analysis of the patterns of population structure and prediction of regional population change. More generally, this paper demonstrates that information contained in spatial patterns (relatedness in space) of population composition has yet to be fully utilized in population forecasting.     

Dynamics of the Golgi method: a time-lapse study of the early stages of impregnation in single sections

Brain Cell Biology - This paper describes the early stages of impregnation by the Golgi method. Sections of aldehyde-fixed and potassium dichromate-treated cerebral cortex were mounted on glass...     

Correlation between Relaxometry and Diffusion Tensor Imaging in the Globus Pallidus of Huntington’s Disease Patients

Huntington''s disease (HD) is an inherited neurodegenerative disorder with progressive impairment of motor, behavioral and cognitive functions. The clinical features of HD are closely related to the degeneration of the basal ganglia, predominantly the striatum. The main striatal output structure, the globus pallidus, strongly accumulates metalloprotein-bound iron, which was recently shown to influence the diffusion tensor scalar values. To test the hypothesis that this effect dominates in the iron-rich basal ganglia of HD patients, we examined the globus pallidus using DTI and T2 relaxometry sequences. Quantitative magnetic resonance (MR), clinical and genetic data (number of CAG repeats) were obtained from 14 HD patients. MR parameters such as the T2 relaxation rate (RR), fractional anisotropy (FA) and mean diffusivity (MD) were analysed. A positive correlation was found between RR and FA (R2=0.84), between CAG and RR (R2=0.59) and between CAG and FA (R2=0.44). A negative correlation was observed between RR and MD (R2=0.66). A trend towards correlation between CAG and MD was noted. No correlation between MR and clinical parameters was found. Our results indicate that especially magnetic resonance FA measurements in the globus pallidus of HD patients may be strongly affected by metalloprotein-bound iron accumulation.     

Normobaric Hyperoxia for Treatment of Pneumocephalus after Posterior Fossa Surgery in the Semisitting Position: A Prospective Randomized Controlled Trial

Background

Supratentorial pneumocephalus after posterior fossa surgery in the semisitting position may lead to decreased alertness and other symptoms. We here aimed to prove the efficacy of normobaric hyperoxia on the absorption of postoperative pneumocephalus according to a standardized treatment protocol.

Methods and Findings

We enrolled 44 patients with postoperative supratentorial pneumocephalus (> 30 ml) after posterior fossa surgery in a semisitting position. After randomisation procedure, patients received either normobaric hyperoxia at FiO₂ 100% over an endotracheal tube for 3 hours (treatment arm) or room air (control arm). Routine cranial CT scans were performed immediately (CT1) and 24 hours (CT2) after completion of surgery and were rated without knowledge of the therapy arm. Two co-primary endpoints were assessed: (i) mean change of pneumocephalus volume, and (ii) air resorption rate in 24 hours. Secondary endpoints were subjective alertness (Stanford Sleepiness Scale) postoperatively and attention (Stroop test), which were evaluated preoperatively and 24 hours after surgery. The mean change in pneumocephalus volume was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.001). The air resorption rate was higher in patients in the treatment arm as compared to patients in the control arm (p = 0.0015). Differences were more pronounced in patients aged 52 years and older. No difference between patients in treatment arm and control arm was observed for the Stroop test. The distribution of scores in the Stanford Sleepiness Scale differed in the treatment arm as compared to the control arm, and there was a difference in mean values (p = 0.015).

Conclusions

Administration of normobaric hyperoxia at FiO₂ 100% via an endotracheal tube for 3 hours is safe and efficacious in the treatment of pneumocephalus after posterior fossa surgery in the semisitting position. Largest benefit was found in elderly patients and particularly in older men.

Trial Registration

German Clinical Trials Register DRKS00006273     

No Outbreak of Vancomycin and Linezolid Resistance in Staphylococcal Pneumonia over a 10-Year Period

Background

Staphylococci can cause wound infections and community- and nosocomial-acquired pneumonia, among a range of illnesses. Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) have been rapidly increasing as a cause of infections worldwide in recent decades. Numerous reports indicate that S. aureus and MRSA are becoming resistant to many antibiotics, which makes them very dangerous. Therefore, this study retrospectively investigated the resistance to antimicrobial agents in all hospitalized patients suffering from community- or nosocomial-acquired pneumonia due to S. aureus and MRSA.

Methods

Information from the study groups suffering from either community- or nosocomial-acquired pneumonia caused by S. aureus or MRSA was gathered by searching records from 2004 to 2014 at the HELIOS Clinic Wuppertal, Witten/Herdecke University, Germany. The findings of antibiotic resistance were analyzed after the evaluation of susceptibility testing for S. aureus and MRSA.

Results

Total of 147 patients (63.9%, 95% CI 57.5%–69.8%), mean age 67.9 ± 18.5 years, with pneumonia triggered by S. aureus, and 83 patients (36.1%, 95% CI 30.2%–42.5%), mean age 72.3 ± 13.8 years, with pneumonia due to MRSA. S. aureus and MRSA developed no resistance to vancomycin (P = 0.019 vs. < 0.0001, respectively) or linezolid (P = 0.342 vs. < 0.0001, respectively). MRSA (95.3%) and S. aureus (56.3%) showed a high resistance to penicillin. MRSA (87.7%) was also found to have a high antibiotic resistance against ß-lactam antibiotics, compared to S. aureus (9.6%). Furthermore, MRSA compared to S. aureus, respectively, had increased antibiotic resistance to ciprofloxacin (90.1% vs. 17.0%), cefazolin (89.7% vs. 10.2%), cefuroxime (89.0% vs. 9.1%), levofloxacin (88.2% vs. 18.4%), clindamycin (78.0% vs. 14.7%), and erythromycin (76.5% vs. 20.8%).

Conclusion

No development of resistance was found to vancomycin and linezolid in patients with pneumonia caused by S. aureus and MRSA.     

Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis

IntroductionAutoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen-presenting cells (APCs). However, signaling pathways in APCs that drive autoimmune diseases, such as rheumatoid arthritis, are not understood.MethodsWe measured phenotypic maturation, cytokine production and induction of T cell proliferation of APCs derived from wt mice and mice with a myeloid-specific deletion of PTEN (myeloid PTEN^-/-) in vitro and in vivo. We induced collagen-induced arthritis (CIA) and K/BxN serum transfer arthritis in wt and myeloid-specific PTEN^-/- mice. We measured the cellular composition of lymph nodes by flow cytometry and cytokines in serum and after ex vivo stimulation of T cells.ResultsWe show that myeloid-specific PTEN^-/- mice are almost protected from CIA. Myeloid-specific deletion of PTEN leads to a significant reduction of cytokine expression pivotal for the induction of systemic autoimmunity such as interleukin (IL)-23 and IL-6, leading to a significant reduction of a Th17 type of immune response characterized by reduced production of IL-17 and IL-22. In contrast, myeloid-specific PTEN deficiency did not affect K/BxN serum transfer arthritis, which is independent of the adaptive immune system and solely depends on innate effector functions.ConclusionsThese data demonstrate that the presence of PTEN in myeloid cells is required for the development of CIA. Deletion of PTEN in myeloid cells inhibits the development of autoimmune arthritis by preventing the generation of a pathogenic Th17 type of immune response.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0742-y) contains supplementary material, which is available to authorized users.