Physiologic cold shock increases adherence of Moraxella catarrhalis to and secretion of interleukin 8 in human upper respiratory tract epithelial cells

Moraxella catarrhalis, a major nasopharyngeal pathogen of the human respiratory tract, is exposed to rapid and prolonged downshifts of environmental temperature when humans breathe cold air. In the present study, we show that a 26 degrees C cold shock up-regulates the expression of UspA1, a major adhesin and putative virulence factor of M. catarrhalis, by prolonging messenger RNA half-life. Cold shock promotes M. catarrhalis adherence to upper respiratory tract cells via enhanced binding to fibronectin, an extracellular matrix component that mediates bacterial attachment. Exposure of M. catarrhalis to 26 degrees C increases the outer membrane protein-mediated release of the proinflammatory cytokine interleukin 8 in pharyngeal epithelial cells. Furthermore, cold shock at 26 degrees C enhances the binding of salivary immunoglobulin A on the surface of M. catarrhalis. These data indicate that cold shock at a physiologically relevant temperature of 26 degrees C affects the nasopharyngeal host-pathogen interaction and may contribute to M. catarrhalis virulence.

Validation of the estimation of physiologic ability and surgical stress (E-PASS) score in liver surgery

BACKGROUND: The estimation of physiologic ability and surgical stress (E-PASS) has been used to produce a numerical estimate of expected mortality and morbidity after elective gastrointestinal surgery. The aim of this study was to validate E-PASS in a selected cohort of patients requiring liver resections (LR). METHODS: In this retrospective study, E-PASS predictor equations for morbidity and mortality were applied to the prospective data from 243 patients requiring LR. The observed rates were compared with predicted rates using Fisher's exact test. The discriminative capability of E-PASS was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: The observed and predicted overall mortality rates were both 3.3% and the morbidity rates were 31.3 and 26.9%, respectively. There was a significant difference in the comprehensive risk scores for deceased and surviving patients (p = 0.043). However, the scores for patients with or without complications were not significantly different (p = 0.120). Subsequent ROC curve analysis revealed a poor predictive accuracy for morbidity. CONCLUSIONS: The E-PASS score seems to effectively predict mortality in this specific group of patients but is a poor predictor of complications. A new modified logistic regression might be required for LR in order to better predict the postoperative outcome.

RNA-Seq-based analysis of the physiologic cold shock-induced changes in Moraxella catarrhalis gene expression

BACKGROUND Moraxella catarrhalis, a major nasopharyngeal pathogen of the human respiratory tract, is exposed to rapid downshifts of environmental temperature when humans breathe cold air. The prevalence of pharyngeal colonization and respiratory tract infections caused by M. catarrhalis is greatest in winter. We investigated how M. catarrhalis uses the physiologic exposure to cold air to regulate pivotal survival systems that may contribute to M. catarrhalis virulence. RESULTS In this study we used the RNA-seq techniques to quantitatively catalogue the transcriptome of M. catarrhalis exposed to a 26 °C cold shock or to continuous growth at 37 °C. Validation of RNA-seq data using quantitative RT-PCR analysis demonstrated the RNA-seq results to be highly reliable. We observed that a 26 °C cold shock induces the expression of genes that in other bacteria have been related to virulence a strong induction was observed for genes involved in high affinity phosphate transport and iron acquisition, indicating that M. catarrhalis makes a better use of both phosphate and iron resources after exposure to cold shock. We detected the induction of genes involved in nitrogen metabolism, as well as several outer membrane proteins, including ompA, m35-like porin and multidrug efflux pump (acrAB) indicating that M. catarrhalis remodels its membrane components in response to downshift of temperature. Furthermore, we demonstrate that a 26 °C cold shock enhances the induction of genes encoding the type IV pili that are essential for natural transformation, and increases the genetic competence of M. catarrhalis, which may facilitate the rapid spread and acquisition of novel virulence-associated genes. CONCLUSION Cold shock at a physiologically relevant temperature of 26 °C induces in M. catarrhalis a complex of adaptive mechanisms that could convey novel pathogenic functions and may contribute to enhanced colonization and virulence.

Physiologic and hematologic concerns of rotary blood pumps: what needs to be improved?

Over the past few decades, advances in ventricular assist device (VAD) technology have provided a promising therapeutic strategy to treat heart failure patients. Despite the improved performance and encouraging clinical outcomes of the new generation of VADs based on rotary blood pumps (RBPs), their physiologic and hematologic effects are controversial. Currently, clinically available RBPs run at constant speed, which results in limited control over cardiac workload and introduces blood flow with reduced pulsatility into the circulation. In this review, we first provide an update on the new challenges of mechanical circulatory support using rotary pumps including blood trauma, increased non-surgical bleeding rate, limited cardiac unloading, vascular malformations, end-organ function, and aortic valve insufficiency. Since the non-physiologic flow characteristic of these devices is one of the main subjects of scientific debate in the literature, we next emphasize the latest research regarding the development of a pulsatile RBP. Finally, we offer an outlook for future research in the field.

Serum calcification propensity predicts all-cause mortality in predialysis CKD

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Physiologic and pathophysiologic fundamentals of proteinuria a review

The term proteinuria is taken to mean abnormally high protein excretion in the urine. Proteinuria is the consequence of glomerular filtration of plasma proteins, their subsequent reabsorption by the proximal tubular cells and secretion of protein by the tubular cells and distal urinary tract. In physiological conditions, the structural integry of the glomerular filtration barrier prevents the abnormal passage of albumin (molecular mass 66 kDa) and high-molecular-weight proteins (> 66 kDa), whereas the passage of low-molecular-weight proteins (< 66 kDa) is almost completely unrestricted. Proteins that arrive the tubular lumen are reabsorbed by endocytosis after binding to the megalin-cubilin complex. An increased load of proteins in the tubular lumen leads to the saturation of the reabsorptive mechanism and higher urinary protein excretion. Proteinuria can originate from prerenal, renal and postrenal causes. Elevated tubular protein concentrations have been recognized to be toxic to tubular cells and associated with the progression of chronic renal disease. Therefore, the quantitative and qualitative evaluation of proteinuria is important for the diagnosis of renal disease.

Extent and distribution of calcification of both the aortic annulus and the left ventricular outflow tract predict aortic regurgitation after transcatheter aortic valve replacement

Aims: We sought to analyse local distribution of aortic annulus and left ventricular outflow tract (LVOT) calcification in patients undergoing transcatheter aortic valve replacement (TAVR) and its impact on aortic regurgitation (AR) immediately after device placement. Methods and results: A group of 177 patients with severe aortic stenosis undergoing multislice computed tomography of the aortic root followed by TAVR were enrolled in this single-centre study. Annular and LVOT calcifications were assessed per cusp using a semi-quantitative grading system (0: none; 1 [mild]: small, non-protruding calcifications; 2 [moderate]: protruding [>1 mm] or extensive [>50% of cusp sector] calcifications; 3 [severe]: protruding and extensive calcifications). Any calcification of the annulus or LVOT was present in 107 (61%) and 63 (36%) patients, respectively. Prevalence of annulus/LVOT calcifications in the left coronary cusp was 42% and 25%, respectively, in the non-coronary cusp 28% and 13%, in the right coronary cusp 13% and 5%. AR grade 2 to 4 assessed by the method of Sellers immediately after TAVR device implantation was observed in 55 patients (31%). Multivariate regression analysis revealed that the overall annulus calcification (OR [95% CI] 1.48 [1.10-2.00]; p=0.0106), the overall LVOT calcification (1.93 [1.26-2.96]; p=0.0026), any moderate or severe LVOT calcification (5.37 [1.52-18.99]; p=0.0092), and asymmetric LVOT calcification were independent predictors of AR. Conclusions: Calcifications of the aortic annulus and LVOT are frequent in patients undergoing TAVR, and both the distribution and the severity of calcifications appear to be independent predictors of aortic regurgitation after device implantation. - See more at: http://www.pcronline.com/eurointervention/77th_issue/126/#sthash.Hzodgju5.dpuf

Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials

OBJECTIVE To investigate the long-term prognostic implications of coronary calcification in patients undergoing percutaneous coronary intervention for obstructive coronary artery disease. METHODS Patient-level data from 6296 patients enrolled in seven clinical drug-eluting stents trials were analysed to identify in angiographic images the presence of severe coronary calcification by an independent academic research organisation (Cardialysis, Rotterdam, The Netherlands). Clinical outcomes at 3-years follow-up including all-cause mortality, death-myocardial infarction (MI), and the composite end-point of all-cause death-MI-any revascularisation were compared between patients with and without severe calcification. RESULTS Severe calcification was detected in 20% of the studied population. Patients with severe lesion calcification were less likely to have undergone complete revascularisation (48% vs 55.6%, p<0.001) and had an increased mortality compared with those without severely calcified arteries (10.8% vs 4.4%, p<0.001). The event rate was also high in patients with severely calcified lesions for the combined end-point death-MI (22.9% vs 10.9%; p<0.001) and death-MI- any revascularisation (31.8% vs 22.4%; p<0.001). On multivariate Cox regression analysis, including the Syntax score, the presence of severe coronary calcification was an independent predictor of poor prognosis (HR: 1.33 95% CI 1.00 to 1.77, p=0.047 for death; 1.23, 95% CI 1.02 to 1.49, p=0.031 for death-MI, and 1.18, 95% CI 1.01 to 1.39, p=0.042 for death-MI- any revascularisation), but it was not associated with an increased risk of stent thrombosis. CONCLUSIONS Patients with severely calcified lesions have worse clinical outcomes compared to those without severe coronary calcification. Severe coronary calcification appears as an independent predictor of worse prognosis, and should be considered as a marker of advanced atherosclerosis.

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs.

OBJECTIVE To validate a radioimmunoassay for measurement of procollagen type III amino terminal propeptide (PIIINP) concentrations in canine serum and bronchoalveolar lavage fluid (BALF) and investigate the effects of physiologic and pathologic conditions on PIIINP concentrations. SAMPLE POPULATION Sera from healthy adult (n = 70) and growing dogs (20) and dogs with chronic renal failure (CRF; 10), cardiomyopathy (CMP; 12), or degenerative valve disease (DVD; 26); and sera and BALF from dogs with chronic bronchopneumopathy (CBP; 15) and healthy control dogs (10 growing and 9 adult dogs). PROCEDURE A radioimmunoassay was validated, and a reference range for serum PIIINP (S-PIIINP) concentration was established. Effects of growth, age, sex, weight, CRF, and heart failure on S-PIIINP concentration were analyzed. In CBP-affected dogs, S-PIIINP and BALF-PIIINP concentrations were evaluated. RESULTS The radioimmunoassay had good sensitivity, linearity, precision, and reproducibility and reasonable accuracy for measurement of S-PIIINP and BALF-PIIINP concentrations. The S-PIIINP concentration reference range in adult dogs was 8.86 to 11.48 mug/L. Serum PIIINP concentration correlated with weight and age. Growing dogs had significantly higher S-PIIINP concentrations than adults, but concentrations in CRF-, CMP-, DVD-, or CBP-affected dogs were not significantly different from control values. Mean BALF-PIIINP concentration was significantly higher in CBP-affected dogs than in healthy adults. CONCLUSIONS AND CLINICAL RELEVANCE In dogs, renal or cardiac disease or CBP did not significantly affect S-PIIINP concentration; dogs with CBP had high BALF-PIIINP concentrations. Data suggest that the use of PIIINP as a marker of pathologic fibrosis might be limited in growing dogs.

Abdominal aortic calcification and risk of fracture among older women - The SOF study

Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor and Role of the Hypothalamic-Pituitary-Adrenal Axis

A previous study identified the peroxisome proliferator-activated receptor alpha (PPARalpha) activation biomarkers 21-steroid carboxylic acids 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11beta,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPARalpha-specific time-dependent increases in HDOPA and 20alpha-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARalpha induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPARalpha and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPARalpha activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20alpha-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARalpha resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms.