The aim of this study was to investigate whether or not the human immune system can be activated by a noninfectious stimulus, thereby improving the physiological status of the individual. The effect of a single cold water immersion (14 degrees C for 1 h) on the immune system of athletic young men, monitored immediately after immersion, was minimal. With the continuation of the cold water immersions (three times a week for a duration of 6 weeks) a small, but significant, increase in the proportions of monocytes, lymphocytes with expressed IL2 receptors (CD25) and in plasma tumour necrosis factor alpha content was induced. An increase in the plasma concentrations of some acute phase proteins, such as haptoglobin and haemopexin, was also observed. After 6 weeks of repeated immersions a trend towards an increase in the plasma concentrations of IL6 and the amount of total T lymphocytes (CD3), T helper cells (CD4), T suppressor cells (CD8), activated T and B lymphocytes (HLA-DR) and a decrease in the plasma concentration of alpha 1-antitrypsin was observed. Concentrations of IL1 beta, neopterin, C-reactive protein, orosomucoid, ceruloplasmin, macroglobulin, immunoglobulins (IgG, IgM, IgA) and C3, C4 components of the complement, as well as the total number of erythrocytes, leucocytes, granulocytes and neutrophils showed no significant changes after the repeated cold water immersions. It was concluded that the stress-inducing noninfectious stimuli, such as repeated cold water immersions, which increased metabolic rate due to shivering the elevated blood concentrations of catecholamines, activated the immune system to a slight extent. The biological significance of the changes observed remains to be elucidated.

Over the last 70 years the physiological mechanisms responsible for cold adaptation of humans have been studied intensively in several laboratories. However, in spite of this enormous effort, the principle mechanism of cold adaptation in humans has not yet been sufficiently described. Bittel (1987Bittel ( , 1992, when analysing all the data so far obtained, concluded that a hypothermic-insulative type of adaptation predominates. On the other hand, Young et al. (1986) concluded that cold acclimation in humans appears to be primarily of the insulative type. Our recent work demonstrated the existence of a metabolic type of adaptation due to an increased capacity for adrenaline thermogenesis (Lesn a et al. 1999). This paper attempts to clarify differences in the control of the thermoregulatory responses of non-cold-adapted humans and winter swimmers who are able to withstand very low water temperatures. The significance of observed changes in body temperature control and the activity of heat loss mechanisms in the resistance of humans to cold has been estimated. An attempt is also made to quantify the contribution of catecholamine thermogenesis to the total metabolic response to cold and thus to assess the significance of non-shivering thermogenesis in cold adaptation of humans.

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Predictive preventive personalized medicine Liver cancer is the fifth most common form of cancer worldwide [1], with an incidence rate almost equals the mortality rate and ranks 3 rd among causes of cancer related death [2]. The coexistence of two life threatening conditions, cancer and liver cirrhosis makes the staging challenging. However, there are some staging systems, e.g. the Barcelona staging system for Hepatocellular carcinoma (HCC) [3], that suggest treatment options and management. Whereas diagnosis in early stages gives hope for a curative outcome, the treatment regime for around 80 % [2] of the patients classified as severe stages only gears towards palliation [4]. An intra-arterial radiation approach, radioembolisation (RE) is ubiquitously applied as one of palliative approaches. Although, in general RE shows promising results in intermediate and advanced stage HCC [5], individual treatment outcomes are currently unpredictable. Corresponding stratification criteria are still unclear. We hypothesised that individual radioresistance/radiosensitivity may play a crucial role in treatment response towards RE strongly influencing individual outcomes. Further, HCC represents a highly heterogeneous group of patients which requires patient stratification according to clear criteria for treatment algorithms to be applied individually. Multilevel diagnostic approach (MLDA) is considered helpful to set-up optimal predictive and prognostic biomarker panel for individualised application of radioembolisation. Besides comprehensive medical imaging, our MLDA includes non-invasive multi-omics and sub-cellular imaging. Individual patient profiles are expected to give a clue to targeting shifted molecular pathways, individual RE susceptibility, treatment response. Hence, a dysregulation of the detoxification pathway (SOD2/Catalase) might indicate possible adverse effects of RE, and highly increased systemic activities of matrix metalloproteinases indicate an enhanced tumour aggressiveness and provide insights into molecular mechanisms/targets. Consequently, an optimal set-up of predictive and prognostic biomarker panels may lead to the changed treatment paradigm from untargeted "treat and wait" to the cost-effective predictive, preventive and personalised approach, improving the life quality and life expectancy of HCC patients. Keywords: Market access, Value, Strategy, Companion diagnostics, Cost-effectiveness, Reimbursement, Health technology assessment, Economic models, Predictive preventive personalized medicine Achieving and sustaining seamless "drug -companion diagnostic" market access requires a sound strategy throughout a product life cycle, which enables timely creation, substantiation and communication of value to key stakeholders [1, 2]. The study aims at understanding the root-cause of market access inefficiencies of companies by gazing at the "Rx-CDx" co-development process through the prism of "value", and developing a perfect co-development scenario based on the literature review and discussions with the ...

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