Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1

Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1. Long-term cyclosporine (CsA) therapy is accompanied by the occurrence of hypercholesterolemia and renal interstitial fibrosis. The present study investigates the effect of dietary cholesterol on CsA-induced lipid disturbances in the rat and on CsA nephrotoxicity. Since plasminogen activator inhibitor type 1 (PAI-1) is a major inhibitor of matrix degradation and elevated plasma PAI-1 levels are reported to be associated with increased low-density lipoprotein (LDL) cholesterol, PAI-1 was examined in the kidneys of rats fed a sodium-deficient diet, with or without cholesterol. After nine weeks, both diet groups were subdivided into a CsA-treated group and a vehicle-treated group. Although cholesterol feeding significantly aggravated CsA-induced renal function impairment, CsA-induced histological lesions were comparable in both diet groups. Cholesterol feeding significantly decreased high-density lipoprotein (HDL) cholesterol irrespective of the treatment, while CsA treatment significantly elevated serum triglycerides irrespective of the diet. Cholesterol feeding alone did not increase the number of infiltrating cells in the renal interstitium. In contrast, in both diet groups CsA treatment caused a significant influx of macrophages, while combined treatment with CsA and cholesterol additionally elevated the number of T-helper cells in the cortex. In all rats, PAI-1 immunostain-ing was found mainly in intracellular vesicles (lysosomes) in proximal tubules, which stained most intensely in fibrotic areas of kidneys from CsA-treated rats. Cholesterol feeding enhanced the CsA-induced elevation of renal PAI-1 immunostaining to a significant level. These results show that, although serum creatinine, PAI-1 staining and cell influx were significantly increased in the cholesterol-fed CsA-treated group compared to the other groups, renal CsA-induced histological lesions were not influenced by cholesterol feeding after short-term (3 weeks) CsA administration. To what extent the more pronounced proximal tubular PAI-1 (inhibitor of matrix degradation) immunostaining in fibrotic areas in the cortex of cholesterol-fed CsA-treated rats contributes to the progression of CsA-induced renal fibrosis remains to be determined

Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment

Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss

Stability of far field R wave signals in different conditions

Aims The presence of far field R wave sensing (FFRS) is usually evaluated in patients with dual chamber pacemakers in supine position. To check if this approach is valid, we tested whether FFRS is consistent both in terms of amplitude threshold and timing characteristics in different daily life conditions. Methods and Results In 42 patients with a DDD pacemaker. the presence. amplitude threshold and timing parameters of FFRS were therefore determined. with patients supine. standing and at peak exercise. Measurements were made of paced and sensed R waves in unipolar and bipolar sensing configurations (at peak exercise only paced R waves and bipolar sensing). After paced R waves (bipolar sensing) amplitude thresholds/time of FFRS after Vpace were 0.32 +/- 0.18 mV/119-139 ms (supine). 0.32 +/- 0.16 mV/114-130 ms (upright) and 0.27 +/- 0.13 mV/121-136 ms (exercise) - with unipolar sensing. this was 0.49 +/- 0.27mV/101-150 ms (Supine). 0.51 +/- 0.29 mV/100-144 ms (upright). After sensed R waves (bipolar sensing) amplitude thresholds/time of FFRS after Vsense were 0.27 +/- 0.18 mV/ 24-42 ms (Supine). 0.29 +/- 0.16 mV/18 to 41 ms (upright) - with unipolar sensing. thresholds were 0.59 +/- 0.32 mV/3-50 ins (supine). 0.59 +/- 0.36 mV/2-58 ms (upright). Conclusion given the lower FFRS thresholds with bipolar sensing. bipolar sensing is superior in avoiding FFRS compared with Unipolar sensing. No differences were found in terms of amplitude thresholds and timing characteristics with patients supine. standing and at peak exercise. Thus. measurements made in the supine position Lire basically sufficient to predict the presence/absence of FFRS under different conditions

Expertise affects aesthetic evolution: Evidence from artistic fieldwork and psychological experiments

An unmade bed. A cigarette glued to the wall. A replica of a soup can box. Drippings on a canvas. Can an evolutionary approach help us understand the production and appreciation of, sometimes perplexing, modern and contemporary art? This chapter attempts at this by investigating two hypotheses about the evolution of human aesthetics in the domain of art. The first hypothesis, commonly called evolutionary aesthetics, asserts that aesthetic preferences, such as those for particular faces, body shapes and animals, have evolved in our ancestors because they motivated adaptive behavior. Artworks (e.g., those depicting facial beauty) may exploit these ancestral aesthetic preferences. In contrast, the second hypothesis states that aesthetic preferences continuously coevolve with artworks, and that they are subject to learning from, especially prestigious, other individuals. We called this mechanism prestige driven coevolutionary aesthetics. Here I report artistic fieldwork and psychological experiments we conducted. We found that while exploitation of ancestral aesthetic preferences prevails among non-experts, prestige driven coevolutionary aesthetics dominates expert appreciation. I speculate that the latter mechanism can explain modern and contemporary art’s deviations from evolutionary aesthetics as well as the existence and persistence of its elusiveness. I also discuss the potential relevance of our findings to major fields studying aesthetics, that is, empirical aesthetics, and sociological and historical approaches to art

Single dose pharmacokinetics of perindopril and its metabolites in hypertensive patients with various degrees of renal insufficiency.

1 Perindopril is a prodrug which is hydrolysed in vivo to the active metabolite perindoprilat, an angiotensin-converting enzyme inhibitor. Perindoprilat glucuronide is also found in plasma. 2 The pharmacokinetics of perindopril and its metabolites were studied after administration of a single 4 mg dose to hypertensive patients with various degrees of renal failure. 3 The absorption and elimination of perindopril were not influenced by the degree of renal failure. 4 The mean area under the serum concentration-time curve of the active metabolite perindoprilat increased from 93 ng ml-1 h in subjects with normal renal function to 1106 ng ml-1 in patients with severe renal failure, whereas its half-life varied from 5.0 to 27.4 h. 5 In the same subjects, the mean area under the curve of perindoprilat glucuronide increased from 78 to 513 ng ml-1 h, while its half-life varied from 1.8 h to 7.7 h. 6 Perindopril, perindoprilat, and perindoprilat glucuronide were dialysable. 7 The extent and duration of serum angiotensin-converting enzyme inhibition was augmented in renal failure. The mean area under the inhibition time curve (extrapolated to infinity) increased from 2490%.h in subjects with normal renal function to 42241 %.h in patients with severe renal impairment. The half-life of inhibition varied from 12.1 h to 100.4 h. This effect of renal failure on the pharmacodynamics of perindoprilat was more pronounced than its influence on perindoprilat kinetics. 8 In view of the important influence of renal impairment on the elimination and action of the active substance perindoprilat, a dosage reduction of perindopril is proposed in in patients with renal failure.(ABSTRACT TRUNCATED AT 250 WORDS