Biomedical subjects
C Hugo
Publications and source records attributed to C Hugo.
SPARC is expressed by mesangial cells in experimental mesangial proliferative nephritis and inhibits platelet-derived-growth-factor-medicated mesangial cell proliferation in vitro.
Mesangial cell proliferation is a characteristic feature of many glomerular diseases and often precedes extracellular matrix expansion and glomerulosclerosis. This study provides the first evidence that SPARC (secreted protein acidic and rich in cysteine) could be an endogenous factor mediating resolution of experimental mesangial proliferative nephritis in the rat. SPARC is a platelet-derived-growth-factor-binding glycoprotein that inhibits proliferation of endothelial cells and fibroblasts. We now show that SPARC is synthesized by mesangial cells in culture and that SPARC mRNA levels are increased by platelet-derived growth factor and basic fibroblast growth factor. Recombinant SPARC or the synthetic SPARC peptide 2.1 inhibited platelet-derived-growth-factor-induced mesangial cell DNA synthesis in vitro. In a model of experimental mesangioproliferative glomerulonephritis, SPARC mRNA was increased 5-fold by day 7 and was identified in the mesangium by in situ hybridization. Similarly, SPARC was increased in glomerular mesangial cells and visceral epithelial cells by day 5 and reached maximal expression levels by day 7. Mesangial cell proliferation increased by 36-fold on day 5 and decreased abruptly on day 7. Maximal expression of SPARC was correlated with the resolution of mesangial cell proliferation. We propose that SPARC functions in part as an endogenous inhibitor of platelet-derived-growth-factor-mediated mesangial cell proliferation in glomerulonephritis and that it could account for the resolution of cellular proliferation in this disease.
Thrombospondin 1 is expressed by proliferating mesangial cells and is up-regulated by PDGF and bFGF in vivo.
Thrombospondin 1 has been shown to be linked to PDGF-mediated mesangial cell proliferation and migration in vitro, but little is known regarding its expression or regulation in glomerular disease. Experimental mesangial proliferative nephritis was induced in rats by injection of anti-Thy1 antibody. Mesangial cell proliferation was associated with de novo expression of thrombospondin 1 mRNA (detected by Northern blot and in situ hybridization) and protein (by Western blot and immunostaining). Although some thrombospondin 1 was expressed by platelets and macrophages, double labeling showed that most thrombospondin 1 mRNA and protein were expressed by proliferating alpha-actin-positive mesangial cells. Thrombospondin 1 expression in anti-Thy1 nephritis was complement-dependent and could be reduced by treatment with anti-PDGF or anti-bFGF antibodies. Thrombospondin 1 could also be induced in normal rats by infusion of PDGF and in rats which were primed with low dose anti-Thy1 antibody by infusion of PDGF of bFGF. Thus, this study demonstrates that proliferating mesangial cells express thrombospondin 1 de novo in disease and that thrombospondin 1 expression in vivo is regulated by PDGF and bFGF.
Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin.
Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.
Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis.
In many glomerular diseases severe injury to the mesangium may occur, leading to matrix dissolution and damage to the glomerular capillaries. Although the destruction of glomerular architecture may lead to permanent injury, in some cases spontaneous recovery occurs. The mechanisms that mediate this recovery are unknown. In this study we provide evidence for glomerular capillary repair (angiogenesis) in the adult injured glomerulus. Injection of anti-Thy 1 antibody into rats results in severe mesangiolysis with capillary ballooning, microaneurysm formation, and loss of endothelial cells in addition to mesangial cells. Although mesangial proliferation is a major response to injury, proliferation of endothelial cells also can be documented from days 2 to 14 in association with repair of the capillaries. The endothelial cell proliferation peaks on days 2 and 7, when it is seven- to ninefold greater than normal. Many of the endothelial cells display morphological features of angiogenesis. The initial wave of endothelial cell proliferation can be reduced by 40% with neutralizing anti-basic fibroblast growth factor antibodies (P < 0.001). The later glomerular endothelial cell proliferation is associated with upregulated expression of vascular permeability factor/endothelial cell growth factor (VPF/VEGF) and an increase of flk, a VPF/VEGF receptor. Although PDGF is expressed in this model, anti-PDGF antibody treatment did not affect the endothelial cell proliferative response. In summary, glomerular endothelial cells have an active role in the glomerular response to injury. Glomeruli are capable of healing microaneurysms, and the mechanism involves basic fibroblast growth factor- and VPF/VEGF-mediated endothelial proliferative responses.
[The flab method of intraoperative radiotherapy].
PURPOSE: Improvement of the relapse rate by locally increasing the tumor dose. METHODS: To increase the dose in the tumor bed a method for intraoperative radiation therapy has been developed. The radiation is applied using a high-dose-rate afterloading system. Flexible plastic flabs are used as applicators. Each flab contains tubes for the alterloading source. The size of the applicator is chosen to correspond to the size of the target volume. In the dosage system we use the dwell times at all source positions are equal. The dwell time has been precalculated to give the reference dose at the reference position which is located at the surface of the flab in the center of the target volume. RESULTS: The dose distributions around the flab have been calculated as a function of the thickness of the flab. If the source is not placed on a regular grid within the applicator due to a non ideal positioning of the tubes within the applicator, the dose distribution is not altered too much, if the positioning error is not larger than +/- 2 mm. The influence of a curvature of the flab has been evaluated and methods to decrease the dose at critical organs are discussed. CONCLUSION: The flab methods for IORT is safe and easy and has been demonstrated for more than 150 cases. This method allows the increase in tumor dose even in regions which are not easily treated by electron IORT due to the rigid electron applicators. Because of the rapid dose fall off, the flab method can only be used for flat target volumes like the tumor bed.
Quit and win smoking cessation contests: how should effectiveness be evaluated?
BACKGROUND: In societies where there are both multiple influences on smoking cessation and a downward secular cessation trend, the attribution of cessation effects to particular interventions poses challenging evaluation problems. Quit smoking lotteries are gaining popularity as mass-reach smoking cessation strategies. Most published evaluations of the lotteries have reported impressive cessation rates within samples of entrants. However, none has considered the possibility that the lotteries merely concentrate a secular quitting trend around a researched event or whether they increase the cessation rate of the whole community from which entrants derive. RESULTS: Results from a lottery run in a smoking population (n = 101,277) are presented. Of the 1,167 people who entered, 29.2% self-reported being smoke-free at 4 months. These results are considered against a prediction that the campaign might increase the cumulative background 4-month quit rate (708/101,277 or 0.7%) by a minimum of 10%. CONCLUSION: It is concluded that such a realistic hope, even if achieved, could in practice never be measured. Implications for evaluating the impact of discrete health promotion evaluations in large communities are discussed in terms of the dilemmas posed by the case study.
Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.
In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.
Effects of aldosterone and dexamethasone on atrial natriuretic peptide levels in preoptic and hypothalamic nuclei of adrenalectomized and intact rats.
The effect of aldosterone and dexamethasone on the concentrations of atrial natriuretic peptide (ANP) in preoptic and hypothalamic nuclei was examined in adrenalectomized and intact rats. Five days after adrenalectomy, increased ANP levels in those brain areas which control water intake, i.e. in the subfornical organ, supraoptic nucleus, and in the so-called hypothalamic drinking centers (perifornical nucleus, lateral hypothalamic area) were measured. In contrast to this, adrenalectomy decreased ANP levels markedly in the organum vasculosum laminae terminalis and preoptic periventricular nucleus, which are reportedly involved in the central regulation of salt and water homeostasis. ANP contents of these two preoptic structures were restored almost completely by daily administration of 0.9% sodium chloride or aldosterone but not dexamethasone. The daily administration of aldosterone elevated ANP levels in the supraoptic, paraventricular and perifornical nuclei as well as in the lateral hypothalamus both in control and adrenalectomized rats. Dexamethasone which was without any significant effect on preoptic and hypothalamic nuclei in control rats elevated ANP levels in the supraoptic and perifornical nuclei and in the lateral hypothalamic area of adrenalectomized animals. Since neither adrenalectomy, nor aldosterone or dexamethasone treatment influenced plasma ANP levels, altered ANP contents measured in preoptic and hypothalamic nuclei may represent a direct effect of adrenal corticoids (mainly aldosterone) on brain ANP-containing neurons which may participate in the control of body fluid and electrolyte homeostasis.
Atrial natriuretic peptide in brain preoptic areas: implications for fluid and salt homeostasis.
The influence of adrenalectomy and mineralocorticoid and glucocorticoid treatment on atrial natriuretic peptide (ANP) concentration of 18 microdissected rat brain nuclei was investigated. Adrenalectomy increased ANP levels highly in those brain areas that control water intake (the subfornical organ and supraoptic nucleus) and in the drinking center (the perifornical nucleus and the lateral hypothalamus). In all of these brain regions, aldosterone elevated ANP levels in intact animals. Adrenalectomy decreased ANP levels markedly in the OVLT and preoptic periventricular nucleus, which constitute the so-called AV3V region. The ANP level of these two brain areas was nearly restored to baseline levels both after administration of sodium chloride and after replacement of aldosterone, whereas dexamethasone treatment failed to have any effect.
[Occlusal rehabilitation by selective grinding].
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