Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression?

In severely depressed patients, emotional arousal, cognitive abnormality and vulnerability to psychotic episodes are linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis and high levels of circulating cortisol. The susceptibility pathways underlying these disturbed brain functions are influenced by genetic factors, early-life priming experiences and later-life events. Cortisol is an important determinant in this so-called three hit model. The action of cortisol is protective, but can become harmful if exposure of susceptibility pathways to the stress hormone is excessive and sustained or inadequate. In this article we argue that this change in role of cortisol from protective into harmful depends on the functioning of the mineralocorticoid and glucocorticoid receptors and the context in which the organism experiences the stressor. Actions mediated by the mineralocorticoid and glucocorticoid receptors are complementary and operate in different time domains of the stress response: the mineralocorticoid receptor normally prevents stress-induced disturbances, but if such disturbances occur the glucocorticoid receptor helps the recovery process. An imbalance in these receptor-mediated actions is thought to increase vulnerability to stress-related psychiatric disorders in predisposed individuals. Correction of the imbalance between the mineralocorticoid receptor and the glucocorticoid receptor can, therefore, facilitate recovery processes still present in the diseased brain, provided that the right psychological context is offered to the individual.     

Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737

Background

Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer (CRC). Our previous work shows that oxaliplatin induces the pro-apoptotic protein Noxa in CRC cells. The Bcl2-inhibitor ABT-737 is particularly effective in cells with high Noxa levels. Therefore, we tested whether oxaliplatin and ABT-737 display synergy in killing CRC cells.

Methods

A panel of CRC cell lines was treated with oxaliplatin and ABT-737, either alone or in combination. Apoptosis was measured by FACS analysis of sub-G1 DNA content and by Western blot analysis of caspase-3 processing. Noxa expression was suppressed by lentiviral RNA interference.

Results

Oxaliplatin and ABT-737 displayed a strong synergistic apoptotic response, which was dependent on wildtype TP53 and oncogenic KRAS. TP53 and KRAS were required for drug-induced Noxa expression and this was essential for tumor cell apoptosis. Oxaliplatin, but not ABT-737, induced p53 accumulation, but both drugs stimulated Noxa expression. Combination treatment of mice with subcutaneous tumor xenografts drastically reduced tumor volume, while single drug treatment had no effect.

Conclusion

ABT-737 synergizes with oxaliplatin to kill colorectal cancer cells. This requires induction of Noxa by wildtype TP53 and oncogenic KRAS. Future studies should explore the anti-tumor efficacy of this drug combination in mouse models for spontaneous CRC development and in patient-derived tumor cell cultures and xenografts.     

A calibration friendly approach to identify drugs of abuse mixtures with a portable near-infrared analyzer

Both the increasing number and diversity of illicit-drug seizures complicate forensic drug identification. Traditionally, colorimetric tests are performed on-site, followed by transport to a laboratory for confirmatory analysis. Higher caseloads increase laboratory workload and associated transport and chain-of-evidence assurance performed by police officers. Colorimetric tests are specific only for a small set of drugs. The rise of new psychoactive substances therefore introduces risks for erroneous results. Near-infrared (NIR)-based analyzers may overcome these encumbrances by their compound-specific spectral selectivity and broad applicability. This work introduces a portable NIR analyzer that combines a broad wavelength range (1300–2600 nm) with a chemometric model developed specifically for forensic samples. The application requires only a limited set of reference spectra for time-efficient model training. This calibration-light approach thus eliminates the need of extensive training sets including mixtures. Performance was demonstrated with 520 casework samples resulting in a 99.6% true negative and 97.6% true positive rate for cocaine. Similar results were obtained for MDMA, methamphetamine, ketamine, and heroin. Additionally, 236 samples were analyzed by scanning directly through their plastic packaging. Also here, a >97% true positive rate was obtained. This allows for non-invasive, operator-safe chemical identification of potentially potent drugs of abuse. Our results demonstrate the applicability for multiple drug-related substances. Ideally, the combination of this NIR approach with other portable techniques, such as Raman and IR spectroscopy and electrochemical tests, may eventually eliminate the need for subsequent laboratory analysis; therefore, saving tremendous resources in the overall forensic process of confirmatory illicit drug identification.     

Structural genomic variation in childhood epilepsies with complex phenotypes

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.     

3D MRA coronary axis determination using a minimum cost path approach.

A method is introduced to automatically find the coronary axis based on two or more user-defined points, even in the presence of a severe stenosis. The coronary axis is determined by finding a minimum cost path (MCP) in a feature image in which the tubular-like structures are enhanced. The results of the proposed method were compared with manually drawn central axes to estimate the accuracy. In 32 3D TFE-EPI acquisitions of patients and volunteers, 14 right coronary arteries (RCAs), 15 left anterior descending arteries (LADs), and eight left circumflex arteries (LCXs) were manually tracked twice by two operators to determine a reference axis and to assess the inter- and intra-user variability. On average, the maximum distance to the reference axis, based on only two user-defined points, is less than 1.5 mm; the average distance is around 0.65 mm, which is less than the average in-plane resolution. The results of the method are comparable to those of the manual operators.     

Levels of analysis in knee surgery

Knee Surgery, Sports Traumatology, Arthroscopy -     

Efficacy of confrontational counselling for smoking cessation in smokers with previously undiagnosed mild to moderate airflow limitation: study protocol of a randomized controlled trial

Background  

The use of spirometry for early detection of chronic obstructive pulmonary disease (COPD) is still an issue of debate, particularly because of a lack of convincing evidence that spirometry has an added positive effect on smoking cessation. We hypothesise that early detection of COPD and confrontation with spirometry for smoking cessation may be effective when applying an approach we have termed "confrontational counselling"; a patient-centred approach which involves specific communication skills and elements of cognitive therapy. An important aspect is to confront the smoker with his/her airflow limitation during the counselling sessions. The primary objective of this study is to test the efficacy of confrontational counselling in comparison to regular health education and promotion for smoking cessation delivered by specialized respiratory nurses in current smokers with previously undiagnosed mild to moderate airflow limitation.