Alterations of cathepsins B, H and L in proximal tubules from polycystic kidneys of the Han:SPRD rat

Alterations of cathepsins B, H and L in proximal tubules from polycystic kidneys of the Han:SPRD rat. Abnormalities of tubular matrix metalloproteinases have been shown recently to occur early in the course of polycystic kidney disease (PKD). The present study was conducted to determine whether lysosomal cysteine proteinases were altered in proximal tubules from 2-month-old, heterozygous Han:SPRD rats. The activities of cathepsins B (-45%), H (-39%) and L (-37%) were significantly lower in proximal tubules from PKD rats as compared to healthy offspring. Enzyme proteins were also decreased (cath. B, 2.4 ± 0.7-fold; cath. H, 1.9 ± 0.6-fold; N = 4, P < 0.05), while mRNA levels for cathepsins B, H and L were not different. Tubular cystatin C, a major inhibitor of cathepsins, was normal with regard to protein and mRNA levels in PKD animals. The decrease in cathepsins in PKD was specific for tubules, as enzyme activities in glomeruli and liver tissue were unchanged and limited to the lysosomal compartment, since marker enzymes for cytoplasm, endoplasmatic reticulum and mitochondria were all normal. Intralysosomally, soluble enzymes like cathepsins and β-NAG were decreased, while membrane-bound acid phosphatase was unchanged. The presence of cathepsins could be demonstrated in cyst fluid from homozygous PKD rats and urinary excretion of cathepsins was enhanced in heterozygous animals. Taken together, these findings indicate that the reduction in tubular cathepsins B, H and L was neither due to decreased gene expression nor to upregulation of specific inhibitors, but was likely due to enhanced apical secretion of these enzymes

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. Thickening of the tubular basement membrane is one of the hallmarks of polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 ± 8 vs. 58 ± 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 ± 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 ± 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 ± 1.1-fold and TIMP-2 mRNA 3.8 ± 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD

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Heartburn or angina? Differentiating gastrointestinal disease in primary care patients presenting with chest pain: a cross sectional diagnostic study

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal (GI) disease is one of the leading aetiologies of chest pain in a primary care setting. The aims of the study are to describe clinical characteristics of GI disease causing chest pain and to provide criteria for clinical diagnosis.</p> <p>Methods</p> <p>We included 1212 consecutive patients with chest pain aged 35 years and older attending 74 general practitioners (GPs). GPs recorded symptoms and findings of each patient and provided follow up information. An independent interdisciplinary reference panel reviewed clinical data of each patient and decided about the aetiology of chest pain. Multivariable regression analysis was performed to identify clinical predictors that help to rule in or out the diagnosis of GI disease and Gastroesophageal Reflux Disease (GERD).</p> <p>Results</p> <p>GI disease was diagnosed in 5.8% and GERD in 3.5% of all patients. Most patients localised the pain retrosternal (71.8% for GI disease and 83.3% for GERD). Pain worse with food intake and retrosternal pain radiation were associated positively with both GI disease and GERD; retrosternal pain localisation, vomiting, burning pain, epigastric pain and an average pain episode < 1 hour were associated positively only with GI disease. Negative associations were found for localized muscle tension (GI disease and GERD) and pain getting worse on exercise, breathing, movement and pain location on left side (only GI disease).</p> <p>Conclusions</p> <p>This study broadens the knowledge about the diagnostic accuracy of selected signs and symptoms for GI disease and GERD and provides criteria for primary care practitioners in rational diagnosis.</p

Загрязнение ландшафтов и водных объектов при авариях на трубопроводах (на примере месторождений Западной Сибири)

Based on direct numerical simulations of forced turbulence, shear turbulence, decaying turbulence, a turbulent channel flow as well as a Kolmogorov flow with Taylor based Reynolds numbers Reλ between 69 and 295, the normalized probability density function of the length distribution ˜ P( ˜ l ) of dissipation elements, the conditional mean scalar difference at the extreme points as well as the scaling of the two-point velocity difference along gradient trajectories are studied. Using the field of the instantanous turbulent kinetic energy k as a scalar, we find a good agreement between the model equation for ˜ P ( ˜ l ) as proposed by Wang and Peters (2008) and the results obtained in the different DNS cases. This confirms the independance of the model solution from both, the Reynolds number and the type of turbulent flow, so that it can be considered universally valid. In addition, we show a 2/3 scaling for the mean conditional scalar difference. In the second part of the paper, we examine the scaling of the conditional two-point velocity difference along gradient trajectories. In particular, we compare the linear s/τ scaling, where τ denotes an integral time scale and s the separation arclength along a gradient trajectory in the inertial range as derived by Wang (2009) with the s·a_∞ scaling, where a_∞ denotes the asymtotic value of the conditional mean strain rate of large dissipation elements

Critical Behaviour of Superfluid 4^4He in Aerogel

We report on Monte Carlo studies of the critical behaviour of superfluid $^4$He in the presence of quenched disorder with long-range fractal correlations. According to the heuristic argument by Harris, uncorrelated disorder is irrelevant when the specific heat critical exponent $\alpha$ is negative, which is the case for the pure $^4$He. However, experiments on helium in aerogel have shown that the superfluid density critical exponent $\zeta$ changes. We hypothesize that this is a cross-over effect due to the fractal nature of aerogel. Modelling the aerogel as an incipient percolating cluster in 3D and weakening the bonds at the fractal sites, we perform XY-model simulations, which demonstrate an increase in $\zeta$ from $0.67 \pm 0.005$ for the pure case to an apparent value of $0.722\pm 0.005$ in the presence of the fractal disorder, provided that the helium correlation length does not exceed the fractal correlation length.Comment: 4 pages, RevTex, 3 postscript figures, LaTeX file and figures have been uuencoded

Accuracy of General Practitioners’ Assessment of Chest Pain Patients for Coronary Heart Disease in Primary Care: Cross-sectional Study with Follow-up

Aim To estimate how accurately general practitioners’ (GP) assessed the probability of coronary heart disease in patients presenting with chest pain and analyze the patient management decisions taken as a result. Methods During 2005 and 2006, the cross-sectional diagnostic study with a delayed-type reference standard included 74 GPs in the German state of Hesse, who enrolled 1249 consecutive patients presenting with chest pain. GPs recorded symptoms and findings for each patient on a report form. Patients and GPs were contacted 6 weeks and 6 months after the patients’ visit to the GP. Data on chest complaints, investigations, hospitalization, and medication were reviewed by an independent panel, with coronary heart disease being the reference condition. Diagnostic properties (sensitivity, specificity, and predictive values) of the GPs’ diagnoses were calculated. Results GPs diagnosed coronary heart disease with the sensitivity of 69% (95% confidence interval [CI], 62-75) and specificity of 89% (95% CI, 87-91), and acute coronary syndrome with the sensitivity of 50% (95% CI, 36-64) and specificity of 98% (95% CI, 97-99). They assumed coronary heart disease in 245 patients, 41 (17%) of whom were referred to the hospital, 77 (31%) to a cardiologist, and 162 (66%) to electrocardiogram testing. Conclusions GPs’ evaluation of chest pain patients, based on symptoms and signs alone, was not sufficiently accurate for diagnosing or excluding coronary heart disease or acute coronary syndrome

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in critically ill COVID-19 patients in comparison to patients with severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19 as opposed to ARDS-influenza. Using confocal and electron microscopy, we showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to ARDS-infleunza subjects. Dysregulatated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19 patients. Together, compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to high incidence of thrombotic events in COVID-19