EFFECTS OF DIETARY-PROTEIN, ANGIOTENSIN-I CONVERTING-ENZYME INHIBITION AND MESANGIAL OVERLOAD ON THE PROGRESSION OF ADRIAMYCIN-INDUCED NEPHROPATHY

Adriamycin, a commonly used antineoplastic antibiotic, induces glomerular lesions in rats, resulting in persistent proteinuria and glomerulosclerosis. We studied the effects of dietary protein and of an angiotensin I converting enzyme inhibitor on the progression of this nephropathy and the evolution of the histological lesions, as well as mesangial macromolecule flow. Adriamycin nephropathy was induced by injecting a single iv dose of adriamycin (3 mg/kg body weight) into the tail vein of male Wistar rats (weight, 180-200 g). In Experiment I animals with adriamycin-induced nephropathy were fed diets containing 6% (Low-Protein Diet Group = LPDG), 20% (Normal-Protein Diet Group = NPDG) and 40% (High-protein Diet Group = HPDG) protein and were observed for 30 weeks. In Experiment II the rats with adriamycin nephropathy were divided into 2 groups: ADR, that received adriamycin alone, and ADR-ENA, that received adriamycin plus enalapril, an angiotensin I converting enzyme inhibitor. The animals were sacrificed after a 24-week observation period. Six hours before sacrifice the animals were injected with I-131-ferritin and the amount of I-131-ferritin in the glomeruli was measured. In Experiment III, renal histology was performed 4, 8 and 16 weeks after adriamycin injection. At the end of Experiment I the tubulointerstitial lesion index was 2 for LPDG, 8 for NPDG, and 7.5 for HPDG (P<0.05); the frequency of glomerulosclerosis was 19 +/- 6.1% in LPDG, 42.6 +/- 6% in NPDG, and 54 +/- 9% in HPDG (P<0.05); and proteinuria was 61.1 +/- 25 mg/24 h in LPDG, 218.7 +/- 27.5 mg/24 h in NPDG, and 324.5 +/- 64.8 mg/24 h in HPDG (P<0.05). In Experiment II, at sacrifice, 24-h proteinuria was 189 +/- 16.1 mg in ADR, and 216 +/- 26.1 mg in ADR-ENA (P>0.05); the tubulointerstitial lesion index was 5 for ADR, and 5 for ADR-ENA (P>0.05); the frequency of glomerulosclerosis was 40 +/- 5.2% in ADR and 44 +/- 6% in ADR-ENA (P>0.05); the amount of I-131-ferritin in the mesangium was 214.26 +/- 22.71 cpm/mg protein in ADR and 253.77 +/- 69.72 cpm/mg protein in ADR-ENA (P>0.05). In Experiment III, sequential histological analysis revealed an acute tubulointerstitial cellular infiltrate at week 4, which was decreased at week 8. Tubular casts and dilatation were first seen at week 8 and increased at week 16 when few glomerular lesions were found. The results suggest that the tubulointerstitial lesions may play a role in the development of glomerulosclerosis in adriamycin-induced nephropathy.

Effect of overload cycles on thin steel roof claddings during cyclonic winds

During an investigation on thin steel roof claddings under simulated cyclonic wind loading, it was found that trapezoidal roof claddings behaved quite differently to corrugated (arc and tangent type) roof claddings due to the presence of overload cycles. The overload cycles caused a reduction in fatigue life for corrugated roofing whereas the reverse occurred for trapezoidal roofing. This contrasting behavior of the two crest-fixed roof claddings was investigated using small scale roofing models instead of the commonly used large scale two-span roof claddings. It was found that overload cycles formed a weaker locally dimpled mechanism around the fastener holes of corrugated roofing and thus accelerated the fatigue-caused pull-through failure. In contrast, a stronger deformed shape was formed in trapezoidal roofing which delayed the pull-through failure. Both laboratory testing and finite element analysis of small scale models were used to study the contrasting behavior of roof claddings.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.

Trauma overload

Reporting on death and accidents in regional and rural areas can exact a heavy toll on reporters. News reporters necessarily report on trauma. Overseas correspondents who report from war zones or areas of conflict or natural disaster are often exposed to physical risk and are sometimes required to confront extreme trauma. To an extent reporters embarking on overseas assignments are mentally prepared to face traumatic situations. Their supervisors are more or less aware of the reporter’s isolation and vulnerability...

A fuzzy control for network overload alleviation

This paper presents a prototype of a fuzzy system for alleviation of network overloads in the day-to-day operation of power systems. The control used for overload alleviation is real power generation rescheduling. Generation Shift Sensitivity Factors (GSSF) are computed accurately, using a more realistic operational load flow model. Overloading of lines and sensitivity of controlling variables are translated into fuzzy set notations to formulate the relation between overloading of line and controlling ability of generation scheduling. A fuzzy rule based system is formed to select the controllers, their movement direction and step size. Overall sensitivity of line loading to each of the generation is also considered in selecting the controller. Results obtained for network overload alleviation of two modified Indian power networks of 24 bus and 82 bus with line outage contingencies are presented for illustration purposes.

Fluxgate magnetic sensor with overload detection

A measurement system for magnetic fields and electric currents uses a single-core fluxgate device driven with a radio frequency excitation source and is provided with a means to indicate saturation of the core of the sensor. A means is provided for detecting overload of the sensor as the core approaches continuous saturation using a pair of demodulators and a comparator.

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice.

Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

Level of beta-adrenergic receptor kinase 1 inhibition determines degree of cardiac dysfunction after chronic pressure overload-induced heart failure.

BACKGROUND: Heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased level of myocardial betaAR kinase 1 (betaARK1). Our previous studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of betaARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart failure. METHODS AND RESULTS: Transgenic (TG) mice with varying degrees of cardiac-specific expression of betaARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial betaARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of betaARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low betaARKct expression developed severe heart failure, whereas mice with high betaARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of betaARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal betaAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in betaAR function, similar to the WT mice. CONCLUSIONS: These data show that the level of betaARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.

Reducing Electronic Information Overload

College students receive a wealth of information through electronic communications that they are unable to process efficiently. This information overload negatively impacts their affect, which is officially defined in the field of psychology as the experience of feeling or emotion. To address this problem, we postulated that we could create an application that organizes and presents incoming content in a manner that optimizes users’ ability to process information. First, we conducted surveys that quantitatively measured each participant’s psychological affect while handling electronic communications, which was used to tailor the features of the application to what the user’s desire. After designing and implementing the application, we again measured the user's affect using this product. Our goal was to find that the program promoted a positive change in affect. Our application, Brevitus, was able to match Gmail on affect reduction profiles, while succeeding in implementing certain user interface specifications.

CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice

Background: The endocannabinoid system is known to play a role in regulating myocardial contractility, but the influence of cannabinoid receptor 1 (CB1) deficiency on chronic heart failure (CHF) remains unclear. In this study we attempted to investigate the effect of CB1 deficiency on CHF induced by pressure overload and the possible mechanisms involved. Methods and results: A CHF model was created by transverse aortic constriction (TAC) in both CB1 knockout mice and wild-type mice. CB1 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC (p = 0.021). Five weeks after TAC, in contrast to wild-type mice, CB1 knockout mice had a higher left ventricular (LV) end-diastolic pressure, lower rate of LV pressure change (± dp/dt max), lower LV contractility index, and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild-type mice (all p < 0.05-0.001). Phosphorylation of the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (P38 and ERK) was higher in CB1 knockout mice than that in wild-type mice. In cultured neonatal rat cardiomyocytes, a CB1 agonist reduced cAMP production stimulated by isoproterenol or forskolin, and suppressed phosphorylation of the EGFR, P38, and ERK, while the inhibitory effect of a CB1 agonist on EGFR phosphorylation was abrogated by CB1 knockdown. Conclusion: These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen-activated protein kinases. © 2012 Elsevier Ireland Ltd.

The Sports Overload Injuries of the Lower Extremities from the Biomechanical Point of View

This work studies the major sports overload injuries of the lower extremities from the biomechanical point of view. At the same time, the main paradigms of podiatric biomechanics and the application of new biomechanical theories in the study of these lesions are reviewed. With current legislation, clinical gait biomechanical studies should be carried out in health centres and the only health professionals who can perform them are podiatrists and doctors (because they both can diagnose). Graduates in physical education can carry out studies in the field or in the sports court for the sole purpose of improving athletic performance, but never intended to treat a pathology overload.