Heat shock proteins (HSPs) are abundantly produced in cells that are under stress or injury by acting as a chaperone or promoting folding, unfolding, packing, degradation or denaturing of proteins or peptides. This study evaluated the role of HSP60, HSP70 or HSP90 in the rostral ventrolateral medulla (RVLM), in experimental endotoxemia in the rat. Adult, male Sprague-Dawley rats maintained by i.v. infusion propofol (25 mg/kg/h) were used. During experimental endotoxemia induced by intravenous administration of E. coli lipopolysaccharide (LPS, 30 mg/kg; serotype 0111:B4), the power density of the vasomotor component of systemic arterial pressure (SAP) spectrum underwent a decrease (Phase I), followed by an increase (Phase II; ¡§pro-life¡¨) and a secondary decrease (Phase III; ¡§pro-death¡¨). Western blot analysis revealed that HSP60 expression in the RVLM was significantly increased during Phase II and Phase III endotoxemia; and HSP70 expression was maximally increased during Phase II. HSP90 protein expression in the RVLM was not significantly changed during endotoxemia. We further studied the role of HSP60, HSP70 or HSP90 at the RVLM in experimental endotoxemia by pretreating animals with bilaterally microinjection of an anti-HSP serum (HSPAb, 1:20), normal mouse serum, antisense oligodeoxynucleotide (hsp AODN, 50 pmol), sense oligodeoxynucleotide (hsp SODN) or scrambled AODN (hsp SC). Pretreatment with HSP60Ab or hsp60 AODN resulted in significantly higher mortality, shorter survival time and shorter Phase II duration. In addition, the augmented power density of the vasomotor component of SAP signals during Phase II endotoxemia was significantly reduced. Even more detrimental effects were obtained on local application of HSP70Ab or hsp70 AODN into the RVLM. Pretreatment with HSP90Ab or hsp90 AODN was ineffective. We conclude that the expression of HSP60 and HSP70 in the RVLM may play a ¡§pro-life¡¨ role in fatal experimental endotoxemia; and HSP90 may not be involved.

<b>Background:</b> 'Competing risks' are events that either preclude or alter the probability of experiencing the primary study outcome(s). Many standard survival models fail to account for competing risks, introducing an unknown level of bias in their measures of absolute and relative risk. Individuals with type 2 diabetes mellitus (T2DM) and albuminuria are at increased risk of multiple competing causes of mortality, including cardiovascular disease (CVD), cancer and renal disease, yet studies to date have not implemented competing risks methodology. <b>Aim:</b> Using albuminuria in T2DM as a case study, this Thesis set out to quantify differences between standard- and competing-risks-adjusted survival analysis estimates of absolute and relative risk for the outcomes of cardiovascular and cancer mortality. <b>Methods:</b> 86,962 patients aged &ge;35 years with T2DM present on or before 2005 were identified in the Clinical Practice Research Datalink. To quantify differences in measures of absolute risk, cumulative risk estimates for cardiovascular and cancer mortality from standard survival analysis methods (Kaplan-Meier estimator) were compared to those from competing-risks-adjusted methods (cumulative incidence competing risk estimator). Cumulative risk estimates were stratified by patient albuminuria level (normoalbuminuria vs albuminuria). To quantify differences in measures of relative risk, estimates for the effect of albuminuria on the relative hazards of cardiovascular and cancer mortality were compared between standard cause-specific hazard (CSH) models (Cox-proportional-hazards regression), competing risk CSH models (unstratified Lunn-McNeil model), and competing risk subdistribution hazard (SDH) models (Fine-Gray model). <b>Results:</b> Patients with albuminuria, compared to those with normoalbuminuria, were older (p&LT;0.001), had higher systolic blood pressure (p&LT;0.001), had worse glycaemic control (p&LT;0.001), and were more likely to be current or ex-smokers (p&LT;0.001). Over the course of nine years of follow-up 22,512 patients died; 8,800 from CVD, 5,239 from cancer, and 8,473 from other causes. Median follow-up was 7.7 years. In patients with normoalbuminuria, nine-year standard and competing-risks-adjusted cumulative risk estimates for cardiovascular mortality were 11.1% (95% confidence interval (CI): 10.8-11.5%) and 10.2% (95% CI: 9.9-10.5%), respectively. For cancer mortality, these figures were 8.0% (95% CI: 7.7-8.3%) and 7.2% (95% CI: 6.9-7.5%). In patients with albuminuria, standard and competing-risks-adjusted estimates for cardiovascular mortality were 21.8% (95% CI: 20.9-22.7%) and 18.5% (95% CI: 17.8-19.3%), respectively. For cancer mortality, these figures were 10.7% (95% CI: 10.0-11.5%) and 8.6% (8.1-9.2%). For the effect of albuminuria on cardiovascular mortality, hazard ratios from multivariable standard CSH, competing risks CSH, and subdistribution hazard ratios from competing risks SDH models were 1.75 (95% CI: 1.63-1.87), 1.75 (95% CI: 1.64-1.87), and 1.58 (95% CI: 1.48-1.69), respectively. For the effect of albuminuria on cancer mortality, these values were 1.27 (95% CI: 1.16-1.39), 1.28 (95% CI: 1.17-1.40), and 1.11 (95% CI: 1.01-1.21). <b>Conclusions:</b> When evaluating measures of absolute risk, differences between standard and competing-risks-adjusted methods were small in absolute terms, but large in relative terms. For the investigation of epidemiological relationships using relative hazards models, standard survival analysis methods produced near-identical risk estimates to the CSH competing risks methods for the clinical associations evaluated in this Thesis. For the evaluation of risk prediction using relative hazards models, CSH models produced consistently higher risk estimates than SDH models, and their use may lead to over-estimation of the predictive effect of albuminuria on either outcome. Where outcomes are less common (like cancer) CSH models provide poor estimates of risk prediction, and SDH models should be used. This research demonstrates that differences can be present between risk estimates derived using CSH and SDH methods, and that the two are not necessarily interchangeable. Moreover, such differences may be present in other clinical areas.

Background: Factors predicting survival in men with lymph node-positive prostate cancer are still poorly defined. Patients and Methods: 193 prostate cancer patients with histopathologically proven lymph node involvement with a median follow-up of 7.3 years were studied. 94% of patients received immediate hormonal therapy. Kaplan-Meier curves were calculated to evaluate overall survival rates and compared with the log-rank test. Cumulative disease-specific and competing mortality rates were calculated by competing risk analysis and compared with the Pepe-Mori test. Cox proportional hazard models were used to determine the independent significance of predictors of all-cause mortality. Results: Age (70 years or older vs. younger), Gleason score (8–10 vs. 7 or lower) and the number of involved nodes (3 or more vs. 1–2) were identified as independent predictors of all-cause mortality. When patients with 0–1 of these risk factors were compared with those with 2–3 risk factors, all-cause (rates after 10 years 21% vs. 71%, p < 0.0001), disease-specific (12 vs. 37%, p = 0.009) and competing mortality (9 vs. 33%, p = 0.02) differed significantly. Conclusions: Some of the excess mortality in patients with poor-risk lymph node-positive prostate cancer may be attributed to increased competing mortality, possibly caused by an interaction between comorbid diseases and hormonally treated persistent or progressive prostate cancer. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.