Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism

Caveolin contributes to the modulation of basal and β-adrenoceptor stimulated function of the adult rat ventricular myocyte by simvastatin: A novel pleiotropic effect

The number of people taking statins is increasing across the globe, highlighting the Importance of fully understanding statins effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (pleiotropic effects). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 μM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2]¡) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16and troponin I at Ser23/24was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive Inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered ß-adrenoceptor signalling. In addition, as caveolin is ubiquitously expressed and has myriad tissue-specific functions, the impact of statin-dependent changes in caveolin is likely to have many other functional sequelae

Sepsis at ICU admission does not decrease 30-day survival in very old patients: a post-hoc analysis of the VIP1 multinational cohort study.

BACKGROUND: The number of intensive care patients aged ≥ 80 years (Very old Intensive Care Patients; VIPs) is growing. VIPs have high mortality and morbidity and the benefits of ICU admission are frequently questioned. Sepsis incidence has risen in recent years and identification of outcomes is of considerable public importance. We aimed to determine whether VIPs admitted for sepsis had different outcomes than those admitted for other acute reasons and identify potential prognostic factors for 30-day survival. RESULTS: This prospective study included VIPs with Sequential Organ Failure Assessment (SOFA) scores ≥ 2 acutely admitted to 307 ICUs in 21 European countries. Of 3869 acutely admitted VIPs, 493 (12.7%) [53.8% male, median age 83 (81-86) years] were admitted for sepsis. Sepsis was defined according to clinical criteria; suspected or demonstrated focus of infection and SOFA score ≥ 2 points. Compared to VIPs admitted for other acute reasons, VIPs admitted for sepsis were younger, had a higher SOFA score (9 vs. 7, p < 0.0001), required more vasoactive drugs [82.2% vs. 55.1%, p < 0.0001] and renal replacement therapies [17.4% vs. 9.9%; p < 0.0001], and had more life-sustaining treatment limitations [37.3% vs. 32.1%; p = 0.02]. Frailty was similar in both groups. Unadjusted 30-day survival was not significantly different between the two groups. After adjustment for age, gender, frailty, and SOFA score, sepsis had no impact on 30-day survival [HR 0.99 (95% CI 0.86-1.15), p = 0.917]. Inverse-probability weight (IPW)-adjusted survival curves for the first 30 days after ICU admission were similar for acute septic and non-septic patients [HR: 1.00 (95% CI 0.87-1.17), p = 0.95]. A matched-pair analysis in which patients with sepsis were matched with two control patients of the same gender with the same age, SOFA score, and level of frailty was also performed. A Cox proportional hazard regression model stratified on the matched pairs showed that 30-day survival was similar in both groups [57.2% (95% CI 52.7-60.7) vs. 57.1% (95% CI 53.7-60.1), p = 0.85]. CONCLUSIONS: After adjusting for organ dysfunction, sepsis at admission was not independently associated with decreased 30-day survival in this multinational study of 3869 VIPs. Age, frailty, and SOFA score were independently associated with survival

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Effect of phosphorus content on the wettability of Ni-P coated surfaces by SAC305 alloy

Celem badań było określenie wpływu składu chemicznego pokrycia Ni-P na kinetykę zwilżania ciekłego lutowia SAC305 w kontakcie z pokryciem Ni-P. Badania przeprowadzono w próżni w temperaturze 230°C w czasie 5 minut, stosując metodę kropli leżącej w połączeniu z osobnym nagrzewaniem badanej pary materiałów, pozwalającej na eksperymentalne wyznaczanie wartości kąta zwilżania θ. Do badań użyto stop lutowniczy SAC305 (3% wag. Ag, 0,5% wag. Cu, Sn – osnowa) oraz podłoża niklowe (Ni 99,8% wag.), na które naniesione zostało pokrycie Ni-xP o dwóch różnych zawartościach fosforu (x = 4,3% wag. lub 11,6% wag.). Po badaniach zwilżalności przeprowadzono analizę strukturalną powierzchni próbek metodą skaningowej mikroskopii elektronowej, koncentrując się na obserwacji granicy SAC305/podłoże. W celu określenia wpływu zawartości fosforu w pokryciu Ni-P na wytrzymałość wytworzonych połączeń SAC305/Ni-xP/Ni poprzeczne przekroje próbek poddano testom na ścinanie, stosując udoskonaloną metodę push-off shear test. Stwierdzono, że dla wybranego zakresu 4,3 ≤ P ≤ 11,6 wzrost zawartości fosforu w pokryciu poprawia zwilżalność badanych układów ciekłym lutowiem SAC305, lecz jest to efekt pozorny wynikający z penetracji lutowia w nieciągłości strukturalne powstające w warstwie Ni-11,6P na skutek przemian fazowych. Dla próbki SAC305/ Ni-11,6P/Ni wartość kąta zwilżania θ = 54° jest mniejsza w porównaniu do próbki SAC305/Ni-4,3P/Ni, dla której θ = 75°, przy tym wytrzymałość na ścinanie wytworzonych połączeń praktycznie nie ulega zmianie, wykazując dla próbki SAC305/Ni-11,6P/Ni τmax = 15,6 MPa w porównaniu τmax = 14,2 MPa dla próbki SAC305/Ni-4,3P/Ni.The aim of this study was to determine the effect of the chemical composition of Ni-P coating on the wettability kinetics of SAC305 liquid solder in contact with the Ni-P coating. The study was conducted in vacuum, at 230°C, for 5 minutes, using the sessile drop method in combination with a separate heating of the two test materials, allowing for experimental determination of the contact angle θ. The study used a SAC305 solder (Sn base, Ag 3 wt. %, Cu 0.5 wt. %) and a nickel substrate (Ni 99.8 wt. %) onto which Ni-xP coating of two different levels of phosphorous was applied (x = 4.3 wt. %, or 11.6 wt. %). After the tests of wettability were performed, structural analysis of the surface of the samples was performed by scanning electron microscopy, focusing on the observation of the border SAC305/substrate. In order to determine the effect of phosphorus in the Ni-P coating on the strength of the SAC305/Ni-xP/Ni joints formed, cross sections of samples were tested for shear strength using the improved method of the push-off shear test. It was found that, for the selected range of 4.3 ≤ P ≤ 11.6, increase in the phosphorus content in the coating improves the wettability of the liquid systems tested with the SAC305 solder, but it is an apparent effect resulting from the solder’s penetration of the structural discontinuities formed in the layer of Ni-11.6P, due to phase transitions. For the SAC305/ Ni-11.6P/Ni sample, value of the contact angle θ = 54° is smaller, as compared to the SAC305/Ni-4.3P/Ni sample, for which θ = 75°, the shear strength of the joints produced shows virtually no changes, for the SAC305/Ni-11.6P/Ni sample τmax = 15.6 MPa, as compared to τmax = 14.2 MPa for the SAC305/Ni-4.3P/Ni sample