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Renal malacoplakia is an unusual form of chronic tubulointerstitial nephritis with a predilection for patients with recurrent urinary tract infections and an immunocompromised state. Its characteristic feature is the parenchymal infiltration by macrophages with ample cytoplasm containing abundant periodic acid-Schiff-positive granules, known as von Hansemann cells, and the presence of diagnostic extracytoplasmic or intracytoplasmic calcospherites, known as Michaelis-Gutmann bodies. Renal malacoplakia is more common in women (female to male ratio 3:1), in whom the lesions develop in a younger age group (third to fifth decade) than in men (over 50 years). Enlarged kidneys in the presence of persistent urinary infection should lead to the consideration of this entity. The diagnosis can only be established by pathologic examination of renal tissue. Renal biopsy early in the course of the disease is essential since in an increasing number of cases medical therapy has resulted in resolution of the disease process and preservation of renal function.

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Alterations in the balance of several cations have been shown to affect the severity of acute renal failure. It has been suggested in both clinical and experimental studies that changes in phosphate balance can markedly potentiate as well as ameliorate the renal dysfunction seen in both acute and chronic nephropathies. To determine the role phosphate plays in the course of gentamicin-induced acute renal failure, we examined rats maintained on control, phosphate-supplemented, and phosphate-depleted diets. In both control and phosphate-supplemented groups of rats, the degree and severity of gentamicin-induced acute renal failure was similar. By contrast, renal function was better preserved in the phosphate-depleted group. Furthermore, morphologic evaluation revealed a significantly lower number of necrotic proximal tubule cells in phosphate-depleted rats when compared to the control or phosphate-replete rats. Renal cortical gentamicin concentrations were not different between the phosphate-depleted and phosphate-supplemented groups. We conclude that phosphate depletion is protective against nephrotoxicity. This effect appears to be independent of alterations in serum calcium, urinary calcium excretion and renal cortical gentamicin concentration.

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The minipig has a multilobar kidney with a wide cortex and short papilla. The vascular bundles are of a simple type. Although short and long looped nephrons are both present, the short looped kind predominates. The minipig has many morphological similarities to dog and human kidneys. One particularly unique feature of the minipig papillary collecting duct cells, however, is the presence of electron-dense granules in the basal cytoplasm which appear to be secreted into the lateral intercellular spaces, perhaps forming a water-tight seal in a manner analogous to membrane-coating granules found in the epidermis of skin.

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The effects of systemically infused angiotensin II (ANG II) (5, 50, and 100 ng X min-1 X 100 g body wt-1; groups 1, 2, and 3, respectively) were studied in Sprague-Dawley rats. All doses increased systemic blood pressure, fractional excretion of sodium, and urine flow rate but decreased glomerular filtration rate. Scanning electron microscopy revealed no detectable changes in the visceral epithelium or measurable alterations in the total area of endothelial capillary surface occupied by pores. Glomerular basement membrane surface densities of outer (OCG) and inner (ICG) cortical glomeruli averaged 0.22 micron2/micron3 of glomerular tuft volume in all groups. Volume ratios of the individual glomerular tufts to that of their Bowman's capsule of OCG were less (P less than 0.05) in groups 1 and 2 (52 +/- 3 and 63 +/- 9%) than the control group (72 +/- 1%). The volume fraction of the glomerular capillaries to their Bowman's capsules remained approximately 25% in all groups. However, the volume fraction of parenchyma to Bowman's capsule was reduced in group 1 to 30 +/- 4% and 38 +/- 5% in group 2 compared with the control value of 47 +/- 2% (P less than 0.05). Thus ANG II reduced glomerular tuft volume and parenchyma but did not alter filtration surface area or capillary endothelial epithelial surface characteristics.

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Cis-platinum (CP) is an important antineoplastic chemotherapeutic agent which causes significant renal toxicity in humans and experimental animals. This present study was designed to determine whether the free radical scavenger, O-(beta-hydroxyethyl)-rutoside (HR), exerts beneficial effects on the kidneys of rats receiving an intravenous injection of 6 mg/kg body weight of CP. Renal functional and structural changes were evaluated and quantitated in three groups of Fischer 344 female rats. Group HR/S control rats received HR treatment and a sham injection of sterile saline (S). Group S/CP rats were treated with S and intravenous CP while rats in group HR/CP received both HR and CP. The experimental group S/CP and HR/CP rats had markedly elevated blood urea nitrogen and creatinine concentrations, increased fractional excretion of sodium chloride, and decreased glomerular filtration rate when compared to group HR/S controls. Group HR/CP rats, however, had significantly lower blood urea nitrogen and creatinine values when compared to the group S/CP rats, 69 +/- 14 mg/dl versus 267 +/- 41, and 1.5 +/- 0.4 versus 5.9 +/- 0.9, respectively (p less than 0.001 for both). Renal function was also better preserved in group HR/CP rats when compared to those in group S/CP. The glomerular filtration rate in group HR/CP rats, 329 +/- 67 microliter/min/gm of kidney weight and urinary osmolality, 586 +/- 42 mOsmoles/kg H2O, was significantly greater than in group S/CP rats, 46 +/- 19 microliter/min/gm of kidney weight, and 374 +/- 28 mOsmoles/kg H2O, respectively (p less than 0.005 for both). The fractional sodium excretion was also less in group HR/CP rats, 2.7% +/- 0.6, when compared to group S/CP rats, 10.2% +/- 0.8 (p less than 0.001). There were no apparent pathological changes in group HR/S rats. In contrast, renal tubular injury and necrosis were observed in both group S/CP and HR/CP rats which were both treated with CP. The injury was confined to the S3 segment of the proximal tubule located in the outer stripe region of the outer medulla. While the injury was readily apparent in both experimental groups, group HR/CP rats had significantly less proximal tubule injury than group S/CP rats when the Wilcoxon nonparametric rank sum test was applied to the morphological data. We conclude that the free radical scavenger, O-(beta-hydroxyethyl)-rutoside, provides partial protection against the structural and functional alterations which are induced in the kidney after the intravenous administration of cis-platinum.

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The 40-minute infusion of norepinephrine (NE) into the renal artery of dogs produces a reversible ischemic model of acute renal failure. While the physiology of this model has been extensively studied, no complete description of the pathology exists. This study uses light microscopy and transmission electron microscopy to describe and quantitate the structural and ultrastructural changes which occur in the kidneys of dogs 1, 3, and 24 hours after the intrarenal infusion of 0.75 mg/kg/minute of NE. One hour after a 40-minute NE infusion the majority of convoluted and straight proximal tubules showed apical blebs, loss of brush border, microvillar whorl formation, and mitochondrial condensation and high-amplitude swelling with flocculent densities. Necrotic cells were occasionally seen at 1 hour. The injury was progressive after 3 hours and by 24 hours animals had either complete or partial patchy necrosis of all regions of the proximal tubule. The percentages of injured and necrotic proximal tubules in outer, mid-, and inner cortical regions are presented. We conclude that the extent and pattern of injury seen after NE infusion differs significantly from the renal artery clamping model of ischemia.

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Major differences in elemental and water content in cells of rat papillae have been reported by investigators using the frozen hydrated/frozen dried method versus that using external standards for x-ray microanalysis. These differences could not be ascribed to either cryosectioning at warmer temperatures or to the analytical algorithm used by either group. In this study, six paired left and right renal papillae were subjected to x-ray analysis. The frozen hydrated/frozen dried method was used on undipped papilla, while both methods were applied simultaneously to contralateral papillae dipped in albumin standard. No significant differences were seen between the physiologic state of the left and right kidneys prior to freezing. Our results demonstrated two major problems with application of an albumin peripheral standard: 1) albumin dipping significantly changed elemental and water content in papillary collecting duct cells, epithelial cells and interstitium, but interstitial cells were not affected; 2) the peripheral albumin standard itself also changed water and elemental content in a direction consistent with movement of Na and Cl from tissue to standard, and water from standard to tissue.

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Major differences in elemental and water content in cells of rat papillae in antidiuresis have been reported using x-ray microanalysis. The reason for these reported differences in unknown. In order to determine if the differing microprobe techniques used in these reports could account for the differences measured, we analyzed elemental concentrations in rat proximal tubule cells using both methods simultaneously on the same cells. Both methods provided comparable results. Furthermore, no differences in element or water content of proximal tubule cells cryosectioned with albumin at -53 degrees C and those cells cryosectioned at -80 degrees C were seen. Therefore, the differing values previously reported for elemental analysis of rat kidney cannot be ascribed to either cryosectioning at a warmer temperature or to the analytical algorithm used by either group.

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Previous studies have shown that a single dose of the antitumor drug, cis-platinum, causes renal cyst formation in rats 1-6 months after drug injection. This observation led to a further evaluation of the long-term effects of cis-platinum on the kidney of the rat. Fisher 344 rats (N = 13) were given either a single intraperitoneal injection of cis-platinum (6 mg/kg body weight) or saline (control) and 15 months later renal function and pathology were assessed. The glomerular filtration rate and urinary osmolality in the cis-platinum-treated rats at 15 months were significantly reduced compared to controls, 520 +/- 59 microliter/min/gm kidney weight versus 799 +/- 100 (P less than .05) and 871 +/- 194 mOsm/kg H2O versus 1471 +/- 162 (P less than .05), respectively. Renal injury was less marked and of a more chronic type than to that originally described 6 months after cis-platinum. Morphometric evaluation of renal injury revealed cis-platinum-treated rats had greater numbers of abnormal proximal tubules (atrophic or hyperplastic) when compared to control rats. Glomerular sclerosis and interstitial fibrosis were also more prevalent in the animals injected with cis-platinum. In the inner stripe of the outer medulla, numerous markedly dilated tubules filled with hyaline casts and lined by simple squamous cells were present. To assess why cis-platinum exerts a chronic effect on the kidney, total platinum levels were measured in different regions of the kidney as a function of time after drug injection. Platinum levels were significantly elevated in the cortex, outer and inner stripe regions, and in the inner medulla for as long as 1 month after cis-platinum treatment. By 2 months, however, the values were no greater than controls. In summary, cis-platinum exerts a significant long-term chronic effect on the structure and function of the rat kidney.

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The present study examined whether a pre- or postischemic infusion of verapamil (V) or a postischemic infusion of nifedipine (N), drugs which block calcium (Ca++) influx across plasma membranes, provides protection against ischemic acute renal failure (ARF) in dogs. Renal hemodynamics and excretory function were examined 1 h (initiation phase) and 24 h (maintenance phase) after a 40-min intrarenal infusion of norepinephrine (NE). In each case, the uninfused contralateral kidney served as control. Four groups were studied: (a) dogs receiving NE alone; (b) dogs receiving an intrarenal infusion of V for 30 min before NE (V + NE); (c) dogs in which intrarenal V was infused for 2 h, beginning immediately after completion of NE infusion (NE + V); and (d) dogs in which intrarenal N was infused for 2 h, beginning immediately after completion of NE infusion (NE + N). Glomerular filtration rate (GFR) in the NE kidneys, as assessed by inulin clearance, at 1 and 24 h averaged 2.4 +/- 1.1 and 5.0 +/- 2.0 ml/min, respectively, as compared with control kidney GFRs of 28.0 +/- 3.5 and 43.8 +/- 5.0 ml/min, respectively (both at least P less than 0.01). In the V + NE group, GFR at 1 and 24 h averaged 15.0 +/- 5.5 and 31.0 +/- 4.5 ml/min, respectively, both at least P less than 0.05 as compared with values from NE kidneys. GFRs in the NE + V group averaged 15.0 +/- 2.4 and 16.3 +/- 3.6 ml/min at 1 and 24 h, both at least P less than 0.02 as compared with values from NE kidneys. GFR in the NE + N group averaged 18.6 +/- 6.0 ml/min at 24 h (P less than 0.05 as compared with GFRs in the NE kidneys). In addition, function of cortical mitochondria (Mito) was examined at the end of the 40-min NE infusion and after 1 and 24 h of reperfusion in the NE alone and NE + V groups. Mito respiration, assessed by acceptor control ratios, was reduced at each period in the NE alone kidneys. After 24 h, these Mito had accumulated Ca++ and exhibited reduced Ca++ uptake and increased Ca++ release rates. Mito from NE + V kidneys respired normally, did not accumulate Ca++, and exhibited no alterations in Ca++ uptake or release. Light and electron microscopy also demonstrated morphological protection of V against tubular necrosis and cell injury. Mito from the NE + N kidneys also respired normally and did not accumulate significant amounts of Ca++. The results of the present studies therefore demonstrated that chemically dissimilar calcium entry blockers exert substantial functional, cellular, and morphological protection against experimental ischemic ARF. These findings are compatible with the hypothesis that increased cytosolic Ca++ is critically important in the maintenance of renal vasoconstriction and the development of cellular necrosis with subsequent tubular obstruction in NE-induced ischemic ARF. V or N may provide protection against renal injury by retarding any increase in cytosolic Ca++ in renal vasculature and epithelium.

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Proliferative lesions in inbred F344 rat kidneys were studied at 6 and 15 months after a single injection of 6 mg cisplatin [CAS: 15663-27-1; cis-diamminedichloroplatinum (ll)]/kg body weight. Solid or cystic lesions developed from altered proximal tubular epithelial cells. The lesions affecting the renal proximal tubules had both granular (organelle-rich) and clear (organelle-poor) variants. These altered cells retained microvilli and contained numerous lysosomes, mitochondria, and abundant rough-surfaced endoplasmic reticulum and free ribosomes. In addition, papillary hyperplasia was seen at 15 months and involved the epithelium lining the renal papilla. The hyperplastic changes of the papillary epithelium were morphologically similar to those produced by other drugs.

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Previous studies have demonstrated that the anesthetic amine, chlorpromazine hydrochloride (CPZ), prevents cell necrosis in experimentally induced ischemic liver and heart disease and decreases the extent of galactosamine-induced cell death in the liver. The present model was designed to determine whether CPZ exerts a similar beneficial effect in kidney in a nephrotoxic model of acute renal failure in rats induced by the administration of mercuric chloride (2 mg/kg of body weight). The functional and structural changes in the kidney were evaluated and quantitated in animals pretreated with CPZ (40 mg/kg of body weight) or saline and then subjected to nephrotoxic injury. Compared to controls, the glomerular filtration rate was significantly lower (p less than 0.001) in saline- and CPZ-pretreated rats receiving mercuric chloride. Twenty-four hours after mercuric chloride administration the glomerular filtration rate was 446 +/- 38 microl/minute/gm of kidney weight, the fractional sodium excretion was 0.4 +/- 0.2%, and the urinary osmolality was 1440 +/- 193 mOsmoles/kg of H2O in the CPZ-treated animals compared to 26 +/- 18 microl/minute/gm of kidney weight (p less than 0.001), 10.1 +/- 9.8% (p less than 0.025), and 353 +/- 28 mOsmoles/kg of H2O (p less than 0.005), respectively, in the animals receiving mercuric chloride alone. The percentage of proximal tubule cell necrosis was 26.5 +/- 8.9% in the CPZ-pretreated group compared to 88.1 +/- 3.6% in the untreated group (p less than 0.001). Metabolic cage studies were performed to follow the time course of this model for 48, 72, and 96 hours after mercury injection. The serum creatinine values and fractional sodium excretions were significantly less in animals receiving CPZ compared to the untreated group at all time intervals examined. The serum urea nitrogen concentration and glomerular filtration rate were similar for the two groups after 48 hours, but the serum urea nitrogen level was significantly lower and the glomerular filtration rate higher after 72 and 96 hours in the animals pretreated with CPZ. In agreement with these findings were observations that animals pretreated with CPZ had significantly fewer necrotic cells 48 and 72 hours after mercury administration, and tubular regeneration appeared to be markedly accelerated. These results suggest that pretreatment with CPZ markedly lessens the degree of structural and functional impairment seen in mercuric chloride-induced acute renal failure in rats and increases the rate of recovery.

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Previous studies have demonstrated that the sympathomimetic agent clonidine, administered intravenously immediately prior to injury, provides partial protection against the acute structural and functional impairments associated with experimental ischemic and nephrotoxic ARF. To determine the effect of clonidine, administered orally, on the prolonged course of HgCl2-induced ARF, two groups of rats were studied for a period of 5 days after injury. For 5 days before HgCl2 administration (2 mg/kg s.c.) and throughout the study group I drank water while group II had clonidine (5 mg/L) added to water. The fatality rate was 77% in group I as compared to 11% in group II (p less than 0.001). Renal function (CCr and FENa) was better preserved and recovered more rapidly in group II rats protected with clonidine. Both groups showed varying degrees of proximal tubular cell injury, but group II had significantly fewer necrotic cells and demonstrated earlier evidence of regeneration. Whereas none of the injured cells in the clonidine-pretreated group revealed evidence of calcification, on the second day half the cells of the pars recta in the outer stripe of the medulla were calcified in group I. In group III animals, oral clonidine was started 2 hr after the injection of HgCl2 and also resulted in a significant reduction in fatality rate from 40% in control group to 0% in the clonidine-treated group. In addition, CCr and FENa were better preserved and recovered more rapidly in this group of clonidine-treated rats. These results indicate that oral clonidine, administered either before or shortly after HgCl2-induced ARF, exerts a salutory effect on the course and mortality of ARF by providing protection of renal function and enhancement of the recovery process.

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A reduction in glomerular capillary endothelial pore size and density has been reported in several models of acute renal failure. It has been suggested that these changes underlie the decrease in glomerular filtration rate and altered glomerular capillary hemodynamics measured in various experimental models of acute renal failure. We have thoroughly quantitated the surface characteristics of glomerular capillaries in control rats and in rats with either mercuric chloride-induced acute renal failure (2 mg/kg body wt) evaluated at 6 and 24 h after administration of the nephrotoxin or with gentamicin (G)1-induced acute renal failure evaluated after 8-9 d of 40 mg/kg body wt twice a day. Despite reductions in glomerular filtration rate in the experimental groups, no significant differences were observed between control (C) and any experimental group with respect to percent areas occupied by fenestrated endothelium (C = 53.6 +/- 2.7%; 6 h HgCl2 = 50.9 +/- 1.9%; 24 h HgCl2 = 53.9 +/- 5.7%; G = 56.7 +/- 2.4%), by cytoplasmic ridges (C = 31.2 +/- 1.5%; 6 h HgCl2 = 29.8 +/- 1.9%; 24 h HgCl2 = 30.6 +/- 3.1%; G = 26.5 +/- 1.5%), nonfenestrated endothelium (C = 15.5 +/- 4.0%; 6 h HgCl2 = 19.3 +/- 2.0%; 24 h HgCl2 = 15.6 +/- 4.3%; G = 16.9 +/- 2.3%), in the individual pore area expressed in square nanometers (C = 1,494 +/- 75; 6 h HgCl2 = 1,326 +/- 48; 24 h HgCl2 = 1,559 +/- 130; G = 1,340 +/- 101), or in the percentage of total pore area within fenestrated areas that were measured (C = 12.8 +/- 0.8%; 6 h HgCl2 = 11.2 +/- 0.7%; 24 h HgCl2 = 10.9 +/- 0.8%; G = 10.9 +/- 0.7%). These results provide quantitative data on the normal glomerular capillary endothelial surface characteristics and suggest that reductions of glomerular filtration rate in acute renal failure are not always associated with alterations in glomerular endothelial capillaries.

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Potassium deprivation has recently been reported to potentiate the degree of functional impairment in a gentamicin-induced model of acute renal failure. The present study investigated the effects of two different states of potassium homeostasis on the development of cellular injury in the early stage of gentamicin nephrotoxicity in dogs. Gentamicin (15 mg. per kg. intramuscularly twice daily) was administered for 4 and 7 days to potassium-depleted or potassium-supplemented animals. The results show that potassium supplementation markedly lessens the severity of pathologic alterations induced by gentamicin. In both groups of animals, the S1 and S2 segments of the proximal tubule were the most consistently damaged regions of of the nephron. Potassium-supplemented dogs had a significantly higher number of normal proximal tubule cells than did the animals deprived of potassium and viewed 7 days after gentamicin treatment (77.3 versus 36.9 per cent; p less than 0.025). The degree of total injury to the proximal tubule was significantly higher in potassium-depleted animals than in those supplemented with potassium (59.9 versus 21.9 per cent; p less than 0.05). Only those dogs depleted of potassium prior to the administration of gentamicin had a markedly elevated plasma creatinine level of proximal tubular injury and functional impairment (r = 0.81; p less than 0.005). Potassium supplementation appears to lessen the extent of structural alterations seen in this model of gentamicin-induced acute renal failure in dogs.

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The presence of carbonic anhydrase activity in rabbit and mouse kidneys was examined using a histochemical procedure with plastic embedded sections stained by the modified version of the cobalt-phosphate method (Hansson, 1967, 1968; Ridderstrale, 1976). Proximal convoluted tubules (S1 and S2 segments) in both species were strongly positive for carbonic anhydrase activity on the membranes of the luminal, lateral, and basal surfaces. The apical cytoplasm beneath the brush border and the nuclei also stained positively for carbonic anhydrase. The S3 segment (pars recta) of the proximal tubule in the rabbit was positive on the luminal membrane, with somewhat less intensity seen on the lateral and basal surfaces. This segment in the mouse was completely negative. The first part of the thin limbs of long-looped nephrons exhibited strong staining in the mouse. Faint luminal staining was present on descending thin limbs of short-looped nephrons in the mouse. In the rabbit, both the medullary and cortical ascending thick segments of the limb of Henle were completely negative. In contrast, the medullary and cortical ascending thick limbs in the mouse kidney showed staining on all plasma membranes. The intercalated cells in the cortical and medullary portion of the collecting tubules stained positively for carbonic anhydrase in both species. The principal cells of the collecting duct in the cortex were negative in the rabbit and faintly positive in the mouse. The principal cells in the upper medullary collecting tubules in both species stained intensely along the luminal, lateral, and basal cell membranes. The papillary collecting ducts were largely negative in both the rabbit and the mouse. Some interstitial cells in the rabbit in the region of the papillary tip were strongly positive. We conclude that there is a marked difference in carbonic anhydrase activity within and between the renal tubular segments of the rabbit and the mouse. In addition, these distinct differences that exist between the two species correlated with known physiological roles in ion transport.

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Carbonic anhydrase is a zinc metalloenzyme widely distributed throughout the tissues of the body. This enzyme exists in a number of isozymic forms in most mammalian species. Significant advances over the past decade have been made in characterizing the nature of renal carbonic anhydrase. In the kidney, this enzyme is thought to play a pivotal role in urinary acidification and bicarbonate reabsorption. Two distinct isozymes of carbonic anhydrase have now been identified in the mammalian kidney. A soluble cytoplasmic form, similar if not identical to human erythrocyte carbonic anhydrase C, accounts for the bulk of the renal carbonic anhydrase activity. In addition, a membrane-bound form constituting only about 2--5% of the renal activity has been found in the brush border and basolateral fractions of kidney homogenates. The histochemical and immunocytochemical localization of these isozymes along the nephron and collecting duct system of various mammalian species suggests that marked heterogeneity exists. The Editorial Review examines the biochemical and morphological approaches that have been used to elucidate the nature of renal carbonic anhydrase and to assess its distribution along the urinary tubule. Possible physiological roles for the renal carbonic anhydrases are considered for the different segments of the nephron and collecting duct system.

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