Dehydroepiandrosterone modulates T-cell response after major abdominal surgery

Background

The immune balance controlled by T-helper (Th)1 and Th2 cells is critical in protecting the host from pathogenic invasion, and its imbalance may increase susceptibility to infection in patients undergoing major surgery. The differentiation of naive T cells to Th1 and Th2 cells is largely driven by cytokines. In addition, steroid hormones have been shown to affect Th1/Th2 balance, particularly in autoimmune diseases. The regulation of Th1/Th2 balance in patients undergoing surgery and its potential clinical relevance remain unclear.

Materials and methods

Blood samples were obtained from patients both before and 2 h after major abdominal surgery. Peripheral blood mononuclear cells were isolated and cultured in wells coated with either anti-CD3 (direct T-cell stimulation) or phytohemagglutinin (PHA) (indirect T-cell stimulation), with or without 10⁻⁵ M dehydroepiandrosterone (DHEA). The release of interleukin (IL)-2, interferon gamma, and IL-10 was measured by an enzyme-linked immunosorbent assay, and the expression of CD4, CD8, and CD69 was determined by flow cytometry.

Results

DHEA decreased the release of IL-2 and IL-10 in directly (anti-CD3) and indirectly (PHA)-stimulated T cells from postoperative samples, whereas the release of interferon gamma in PHA-stimulated T cells was not affected. The distribution of CD4/CD8 was not significantly different after surgery or DHEA. DHEA was associated with a decrease in the expression of the activation marker CD69 on CD4⁺ T cells, whereas the activation of CD8⁺ T cells remained unchanged.

Conclusions

These results demonstrate that DHEA plays a critical role in controlling Th1/Th2 balance in the immediate postoperative period. Attenuation of both the Th1 and Th2 responses has been suggested to have immunoprotective effects. The role of DHEA in the regulation of Th1/Th2 balance in patients undergoing major abdominal surgery may, therefore, also be of significant clinical relevance and warrants further investigation.     

Cortisol modifies extinction learning of recently acquired fear in men

Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS−) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS− than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS− differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear.     

Development of twenty-one polymorphic microsatellite markers for the fungus-growing ant,Mycocepurus goeldii (Formicidae: Attini), using Illumina paired-end genomic sequencing

Obligate social parasites, or inquilines, exploit the colonies of free-living social species and evolved at least 80 times in ants alone. Most species of the highly specialized inquiline social parasites are rare, only known from one or very few, geographically isolated populations, and the sexual offspring of most inquiline species mates inside the maternal colony. Therefore, inquiline populations are believed to be small and genetically homogeneous due to inbreeding. To comparatively study the genetic diversity of the socially parasitic fungus-growing ant, Mycocepurus castrator, and its only known host species, Mycocepurus goeldii, and to infer the parasite’s conservation status, we developed 21 microsatellite markers for the host species, M. goeldii, and evaluated whether these markers cross-amplify in the social parasite, M. castrator. We isolated and characterized a total of 21 microsatellite loci for M. goeldii. The loci were screened for 24 individuals from geographically distant and genetically divergent populations in Brazil. The number of alleles per locus ranged from 18 to 4, the observed heterozygosity ranged from 0.25 to 0.636, and the probability of identity values ranged from 0.011 to 0.146. Preliminary analyses show that these markers cross amplify in the closely related social parasite species M. castrator. These newly developed loci provide tools for studying the genetic diversity and the evolution of social parasitism in the Mycocepurus host–parasite system.     

Temsirolimus in Daily Use: Results of a Prospective Multicentre Noninterventional Study of Patients with Metastatic Kidney Cancer

Background

Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.

Objective

The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.

Design, setting, and participants

Metastatic RCC patients treated with 25 mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.

Outcome measurements and statistical analysis

All data were centrally analysed by an independent clinical research organisation.

Results and limitations

This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79–100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0–23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2–5.6) and 11.6 mo (95% CI, 9.3–13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.

Conclusions

TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.     

Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan

As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron‐rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age‐related changes of susceptibility were in good agreement with the findings from R2^* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing. Hum Brain Mapp 35:2698–2713, 2014. © 2013 Wiley Periodicals, Inc .