Biomarkers for classification and class prediction of stress in a murine model of chronic subordination stress.

Selye defined stress as the nonspecific response of the body to any demand and thus an inherent element of all diseases. He reported that rats show adrenal hypertrophy, thymicolymphatic atrophy, and gastrointestinal ulceration, referred to as the stress triad, upon repeated exposure to nocuous agents. However, Selye's stress triad as well as its extended version including reduced body weight gain, increased plasma glucocorticoid (GC) concentrations, and GC resistance of target cells do not represent reliable discriminatory biomarkers for chronic stress. To address this, we collected multivariate biological data from male mice exposed either to the preclinically validated chronic subordinate colony housing (CSC) paradigm or to single-housed control (SHC) condition. We then used principal component analysis (PCA), top scoring pairs (tsp) and support vector machines (SVM) analyses to identify markers that discriminate between chronically stressed and non-stressed mice. PCA segregated stressed and non-stressed mice, with high loading for some of Selye's stress triad parameters. The tsp analysis, a simple and highly interpretable statistical approach, identified left adrenal weight and relative thymus weight as the pair with the highest discrimination score and prediction accuracy validated by a blinded dataset (92% p-value < 0.0001; SVM model = 83% accuracy and p-value < 0.0001). This finding clearly shows that simultaneous consideration of these two parameters can be used as a reliable biomarker of chronic stress status. Furthermore, our analysis highlights that the tsp approach is a very powerful method whose application extends beyond what has previously been reported.

Primary care in Switzerland gains strength.

BACKGROUND: Although there is widespread agreement on health- and cost-related benefits of strong primary care in health systems, little is known about the development of the primary care status over time in specific countries, especially in countries with a traditionally weak primary care sector such as Switzerland. OBJECTIVE: The aim of our study was to assess the current strength of primary care in the Swiss health care system and to compare it with published results of earlier primary care assessments in Switzerland and other countries. METHODS: A survey of experts and stakeholders with insights into the Swiss health care system was carried out between February and March 2014. The study was designed as mixed-modes survey with a self-administered questionnaire based on a set of 15 indicators for the assessment of primary care strength. Forty representatives of Swiss primary and secondary care, patient associations, funders, health care authority, policy makers and experts in health services research were addressed. Concordance between the indicators of a strong primary care system and the real situation in Swiss primary care was rated with 0-2 points (low-high concordance). RESULTS: A response rate of 62.5% was achieved. Participants rated concordance with five indicators as 0 (low), with seven indicators as 1 (medium) and with three indicators as 2 (high). In sum, Switzerland achieved 13 of 30 possible points. Low scores were assigned because of the following characteristics of Swiss primary care: inequitable local distribution of medical resources, relatively low earnings of primary care practitioners compared to specialists, low priority of primary care in medical education and training, lack of formal guidelines for information transfer between primary care practitioners and specialists and disregard of clinical routine data in the context of medical service planning. CONCLUSION: Compared to results of an earlier assessment in Switzerland, an improvement of seven indicators could be stated since 1995. As a result, Switzerland previously classified as a country with low primary care strength was reclassified as country with intermediate primary care strength compared to 14 other countries. Low scored characteristics represent possible targets of future health care reforms.

[The role of stress axes in cancer incidence and proliferation]. / Die Rolle der Stressachsen in der Entstehung und Proliferation einer Krebserkankung.

Psychosocial stressors can modulate the different stages of neoplastic events. It is established that there is activation of 2 well-known stress axes under stress, the hypothalamic-pituitary-adrenal axis and sympatho-adrenal-medullary axis, where especially the proliferating promoting effects on the malignant tumor events are known to depend on ß-adrenergic receptors. A new model focuses on the positive activating stress, which leads through the activation of the sympathetic hypothalamic-adipocyte axis to inhibition of tumor growth and reduction of obesity. This leads in mice to increased gene expression of the neurotrophin BDNF, which activates the sympathetic fibers of the white adipose tissue. Over consecutive stimulation of the ß-adrenergic receptors and thus the release of leptin, its promotional effect on the tumor growth is inhibited. In the clinical context, these results support the role of complex ß-adrenergic signal transduction pathways.

Toxicogenomics applied to cultures of human hepatocytes enabled an identification of novel petasites hybridus extracts for the treatment of migraine with improved hepatobiliary safety.

Butterbur extracts (Petasites hybridus) are recommended for the prevention of migraine, but pharmacovigilance reports may be suggestive of rare hepatobiliary toxicity. To evaluate its hepatotoxic potential, a series of in vivo and in vitro studies were carried out. Essentially, there were no signs of hepatocellular toxicity at estimated therapeutic C(max) levels of 60 ng/ml. Nonetheless, in a 28-day toxicity study at approximately 200-fold of therapeutic doses, induced liver transaminases and bilirubin elevations were observed. In a subsequent 6-month chronic toxicity study, the initial hepatobiliary effects were reproduced, but at the end of the study, liver function recovered and returned to normal as evidenced by clinical chemistry measurements. To identify possible mechanisms of hepatotoxicity, we investigated liver function in vitro at > 170-fold of therapeutic C(max) levels, including cytotoxicity (lactate dehydrogenase, MTT, and ATP), transaminase activities (alanine aminotransferase and aspartate aminotransferase), albumin synthesis, urea and testosterone metabolism to assay for cytochrome P450 monooxygenase activity. Only with extracts rich in petasin (37% petasin) and at high and well above therapeutic doses, liver toxicity was observed. A toxicogenomic approach applied to hepatocyte cultures enabled hypothesis generation and was highly suggestive for extracts high in petasin content to impair bile acid transport and lipid and protein metabolism. Importantly, neither chronic rat in vivo nor rat in vitro studies predicted reliably hepatotoxicity, therefore reemphasizing the utility of human-based in vitro investigations for the development of safe medicinal products. Finally, toxicogenomics enabled the characterization of a novel butterbur extract with no signals for hepatotoxicity.