Mathematical modeling heat transfer in closed two-phase thermosyphon

Проведен численный анализ теплопереноса в замкнутом двухфазном термосифоне цилиндрической формы в условии подвода теплоты на нижней крышке. Для описания исследуемого процесса предложена упрощенная математическая модель, отличающаяся от известной описанием только процессов теплопроводности в системе "корпус термосифона - паровой канал - пленка конденсата". Сформулированная краевая задача решена методом конечных разностей. Получены поля температур в термосифоне для типичных тепловых нагрузок и режимов работы

Bias-Variation Dilemma Challenges Clinical Trials: Inherent Limitations of Randomized Controlled Trials and Meta-Analyses Comparing Hernia Therapies

Purpose: Evaluation of hernia therapies according to the current rules of Evidence Based Medicine is widely reduced to results of RCTs or meta-analyses. RCTs have been accepted as a most important tool to confirm a superior effect of an intervention. Unfortunately, in hernia surgery, comparisons of RCTs and correspondingly their use in meta-analyses, are not, surprisingly often, able to confirm any significant impact of a specific procedure due to intrinsic restrictions in a multi-causal\ud setting with its web of influences. Methods: Based on our own experiences of clinical studies in surgery, the present article outlines several situations, with their respective reasons, which argue the severe limitations of RCTs and meta-analysis to define an optimum treatment. Results: Metaanalyses accumulate the variations of each trial, which then may cover any clear causal relationship. RCTs usually are dealing with subgroups of standard patients thus excluding the majority of our patients. Low statistical power of current cohort sizes restricts the analysis of subgroups or of effects with low incidences. Simple comparisons of means frequently are hampered by nonlinear relationships to outcome. The relevance of a specific variable is difficult to separate from other influences. The limited surveillance period of studies ignores a delayed change in outcome. Randomization cannot guarantee a standardized patient’s condition. All the arguments have to be considered as a crucial and fundamental consequence of the bias-variance dilemma or principle of uncertainty in medicine, and underline the many limitations of RCTs to evaluate any specific impact of hernia therapies on e.g. infection, pain or recurrence. Conclusions: Many surgical issues\ud cannot be and should not be investigated by RCTs, in particular, if a marked patients’ heterogeneity\ud has to be considered or the low incidences of the outcome readout cannot be addressed with sufficient statistical power without getting lost in the variation mire. Registries with their non-restricted data-acquisition should be regarded as reliable alternatives for postoperative outcome quality surveillance studies

Formation of translational risk score based on correlation coefficients as an alternative to Cox regression models for predicting outcome in patients with NSCLC

<p>Abstract</p> <p>Background</p> <p>Personalised cancer therapy, such as that used for bronchial carcinoma (BC), requires treatment to be adjusted to the patient's status. Individual risk for progression is estimated from clinical and molecular-biological data using translational score systems. Additional molecular information can improve outcome prediction depending on the marker used and the applied algorithm. Two models, one based on regressions and the other on correlations, were used to investigate the effect of combining various items of prognostic information to produce a comprehensive score. This was carried out using correlation coefficients, with options concerning a more plausible selection of variables for modelling, and this is considered better than classical regression analysis.</p> <p>Methods</p> <p>Clinical data concerning 63 BC patients were used to investigate the expression pattern of five tumour-associated proteins. Significant impact on survival was determined using log-rank tests. Significant variables were integrated into a Cox regression model and a new variable called integrative score of individual risk (ISIR), based on Spearman's correlations, was obtained.</p> <p>Results</p> <p>High tumour stage (TNM) was predictive for poor survival, while CD68 and Gas6 protein expression correlated with a favourable outcome. Cox regression model analysis predicted outcome more accurately than using each variable in isolation, and correctly classified 84% of patients as having a clear risk status. Calculation of the integrated score for an individual risk (ISIR), considering tumour size (T), lymph node status (N), metastasis (M), Gas6 and CD68 identified 82% of patients as having a clear risk status.</p> <p>Conclusion</p> <p>Combining protein expression analysis of CD68 and GAS6 with T, N and M, using Cox regression or ISIR, improves prediction. Considering the increasing number of molecular markers, subsequent studies will be required to validate translational algorithms for the prognostic potential to select variables with a high prognostic power; the use of correlations offers improved prediction.</p

Evaluation of the collaborative network of highly correlating skin proteins and its change following treatment with glucocorticoids

<p>Abstract</p> <p>Background</p> <p>Glucocorticoids (GC) represent the core treatment modality for many inflammatory diseases. Its mode of action is difficult to grasp, not least because it includes direct modulation of many components of the extracellular matrix as well as complex anti-inflammatory effects. Protein expression profile of skin proteins is being changed with topical application of GC, however, the knowledge about singular markers in this regard is only patchy and collaboration is ill defined.</p> <p>Material/Methods</p> <p>Scar formation was observed under different doses of GC, which were locally applied on the back skin of mice (1 to 3 weeks). After euthanasia we analyzed protein expression of collagen I and III (picrosirius) in scar tissue together with 16 additional protein markers, which are involved in wound healing, with immunhistochemistry. For assessing GC's effect on co-expression we compared our results with a model of random figures to estimate how many significant correlations should be expected by chance.</p> <p>Results</p> <p>GC altered collagen and protein expression with distinct results in different areas of investigation. Most often we observed a reduced expression after application of low dose GC. In the scar infiltrate a multivariate analysis confirmed the significant impact of both GC concentrations. Calculation of Spearman's correlation coefficient similarly resulted in a significant impact of GC, and furthermore, offered the possibility to grasp the entire interactive profile in between all variables studied. The biological markers, which were connected by significant correlations could be arranged in a highly cross-linked network that involved most of the markers measured. A marker highly cross-linked with more than 3 significant correlations was indicated by a higher variation of all its correlations to the other variables, resulting in a standard deviation of > 0.2.</p> <p>Conclusion</p> <p>In addition to immunohistochemical analysis of single protein markers multivariate analysis of co-expressions by use of correlation coefficients reveals the complexity of biological relationships and identifies complex biological effects of GC on skin scarring. Depiction of collaborative clusters will help to understand functional pathways. The functional importance of highly cross-linked proteins will have to be proven in subsequent studies.</p

Differential effects of aldosterone and angiotensin II on end-organ damage

Titelblatt, Publikationsliste Inhaltsverzeichnis 1\. Zusammenfassung 2\. Einleitung, Frage- und Zielstellung der Untersuchungen 3\. Darstellung einzelner Studienergebnisse 4\. Diskussion 5\. Ausblick 6\. Literaturverzeichnis 7\. Danksagung Eidesstattliche VersicherungDie vorliegende Arbeit befasst sich mit der Rolle von Aldosteron bei der Ausprägung des Angiotensin II-induzierten Endorganschadens in vivo und der Interaktion zwischen Angiotensin II, Aldosteron und seinen Rezeptoren in vitro. In einem Tiermodell, in dem die Organschädigung unabhängig vom Blutdruck durch erhöhte Spiegel vom Angiotensin II ausgelöst wird, wurden die Auswirkungen von Aldosteron untersucht. In diesem Tiermodell konnte gezeigt werden, dass die alleinige Blockade des Rezeptors von Aldosteron vor einem Angiotensin II-vermittelten Organschaden und dem Funktionsverlust der Endorgane schützt. Dabei ist die Infiltration von Entzündungszellen reduziert, es wird weniger Bindegewebe produziert und abgelagert und die Aktivität von Transkriptionsfaktoren, welche im Gewebeumbau entscheidend sind, ist vermindert. Weiterführende Untersuchungen zur Rolle des lokalen und des zirkulierenden Aldosterons beim Angiotensin II-induzierten Endorganschaden ließen erkennen, dass dem in den Nebennieren produzierten Aldosteron die vorrangige Bedeutung beim kardialen und renalen Endorganschaden zukommt. In Zellkulturversuchen konnte belegt werden, dass bereits in der von Transkriptionsprozessen unabhängigen und unmittelbar nach Ligand-Rezeptor- Interaktion induzierten Signaltransduktion eine enge Wechselwirkung von Angiotensin II und Aldosteron stattfindet. Das Peptid Angiotensin II und das Steroid Aldosteron stimulieren zum Teil dieselben Signalwege in der Zelle. Dabei potenzieren sich die Wirkung von Peptid und Steroid auf die Signaltransduktion, und nach Blockade des Aldosteronrezeptors ist die Angiotensin II-induzierte Signaltransduktion deutlich vermindert. Weiterhin konnte durch Zellkulturversuche demonstriert werden, dass die Rezeptortyrosinkinase Axl und ihr Ligand Gas6 zu den mögliche Mittlerproteinen der Aldosteron-induzierten Effekte gehören. Die Ergebnisse tragen zu einem detaillierten Verständnis der Interaktionen zwischen Aldosteron und Angiotensin II bei und werden der Entwicklung spezifischer Pharmaka, die eine Gewebeentzündung und fibrose hemmen, dienen.The role of aldosterone in angiotensin II-induced end-organ damage and the interaction between angiotensin II, aldosterone and their receptors has been investigated. For the in vivo studies a blood pressure independent rat model of angiotensin II-induced severe inflammatory and fibrotic end-organ damage has been used. Blockade of the aldosterone receptor reduced mortality and protected from development of the severe phenotype compared to untreated rats. Infiltration of inflammatory cells, deposition of fibrous tissue and the activity of the transcription factors AP-1 and NF-kB were reduced. Further studies on the pathophysiological role of circulating and locally produced aldosterone identified the adrenal aldosterone as the major mediator for the observed cardiac and renal end-organ damage. In vitro we studied early, from transcription independent signal transduction of aldosterone and angiotensin II and their interaction. The peptide angiotensin II and the hormone aldosterone stimulated similar signaling pathways and potentiated each other in their effects. In addition, blockade of the aldosterone receptor inhibited angiotensin II induced signaling. Further we could identify the receptor tyrosin kinase Axl and its ligand Gas6 as mediators for aldosterone induced effects. The results contribute to a detailed understanding of the interaction between aldosterone and angiotensin II and might be used for the development of new pharmacologic agents in the treatment of tissue inflammation and fibrosis

Aldosterone, mineralocorticoid receptors, and vascular inflammation

Purpose of Review: Aldosterone and its mineralocorticoid receptor represent an ancient signaling system. Indeed, the mineralocorticoid receptor is older than its agonist. Both have probably served various functions through the eons and salt preservation may be relatively recent. A large body of evidence suggests that aldosterone conducts signaling in vascular cells and contributes substantially to vascular remodeling and target organ damage. A blood pressure and salt balance-independent effect was first observed in two large heart failure trials. Recent Findings: Mineralocorticoid receptor blockade has now been shown to reduce proteinuria even in the face of angiotensin converting enzyme inhibition and AT1 receptor blockade. Mineralocorticoid receptor blockade effectively reduces target organ damage in every hypertensive model tested, irrespective of circulating renin and aldosterone levels. Protection is also observed in nonhypertensive diabetic and hyperlipidemic models. Signaling in vascular cells involves primarily the mitogen activated protein kinase pathway with participation of the epidermal growth factor receptor. Novel signaling molecules have been shown to participate in aldosterone-mediated actions including the murine double-minute type 2 protein that participates in antiapoptotic and proliferative effects. Clinically, mutations in the mineralocorticoid receptor have shed additional light on its importance. Summary: A resurgence of interest in aldosterone reflects its importance and clinical relevance for vascular remodeling and target organ damage