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Biomedical subjects

P Maldague

Publications and source records attributed to P Maldague.

At least 37 records · Page 2Linked to original sources
PubMed1989

Effects of alinidine on metabolic response to high-demand myocardial ischemia.

Alinidine is a new bradycardic agent that interferes with ion channels and the if pacemaker current. To determine if alinidine had antiischemic effects unrelated to its bradycardic action, myocardial metabolism was studied during a pacing-stress test in 20 patients with coronary artery disease and angina pectoris, before and after intravenous infusion of alinidine (10 mg, n = 10; 50 mg, n = 10). When compared to the control pacing-stress test, the low dose of alinidine had no significant effect on aortic pressure, coronary sinus flow (-3%, NS), myocardial oxygen extraction, or myocardial lactate uptake. After the high dose of alinidine, aortic pressure and coronary sinus flow remained unchanged but the arteriocoronary sinus difference in oxygen content increased (12.2 +/- 1.3 to 12.7 +/- 1.4 ml/100 ml; p less than 0.0002) above the values observed during the control pacing-stress test, while both the chemical lactate extraction fraction (-19 +/- 30 to 15 +/- 21%; p less than 0.025) and the L-[1-14C]lactate extraction fraction increased. Accordingly, the net myocardial lactate uptake (corrected for production) had increased from 14 +/- 32 during the control pacing-stress test to 29 +/- 24 mumol/min during the pacing repeated after the high dose of alinidine (p less than 0.05). After the high dose of alinidine, the free fatty acid uptake also rose slightly (+23%; NS) and the alanine production was reduced in 7 of 10 patients (-3.6 +/- 1.7 to -1.4 +/- 0.6 mumol/min; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Tissue injury and proliferative response induced in rat kidney by cis-diamminedichloroplatinum (II).

Cis-diamminedichloroplatinum (II) (cisplatin), an inorganic platinum salt used in cancer chemotherapy, is characterized by a renal toxicity recognized both in experimental animals and in patients treated with the compound. The purpose of the present study was to explore by both light and electron microscopy the morphological alterations induced in the rat kidney by cisplatin administration and, in particular, to analyse the tissue repair reaction following nephrotoxic injury. Experimental animals (four rats per group) were treated i.p. with 2, 4 or 8 mg/kg cisplatin administered in four consecutive daily injections. The rats were sacrificed 4 days after the last injection. In addition, the persistence of renal lesions and the duration of the repair reaction were determined in rats given 8 mg/kg cisplatin and killed 4, 7, 14 or 21 days after the last injection. The cell proliferation associated with tissue repair was estimated both quantitatively (rate of DNA synthesis) and qualitatively (histoautoradiography and electron microscopy examination) 1 h after in vivo exposure to [3H] thymidine. Renal tissue alterations and the repair reaction were minimal after the administration of 2 or 4 mg/kg cisplatin. In contrast, 8 mg/kg cisplatin caused a spectrum of morphological abnormalities affecting proximal, distal and collecting tubules, and ranging from sublethal cell alterations to tubular necrosis and cystic dilatation. The latter degenerative change primarily involved the straight portion of proximal tubules and seemed to develop over the weeks following cisplatin administration. Concomitantly with the tissue lesions, a burst of cell proliferation, associated with stimulation of DNA synthesis, was apparent in the renal cortex and outer medulla. Whereas a very high incidence of S-phase cells was encountered in seemingly undifferentiated tubules, they also appeared in differentiated proximal, distal and collecting tubules, but were infrequent in cystic tubules. Proliferation of fibroblasts was also stimulated in the renal interstitium. The proliferative response persisted for the whole duration of the experiment, indicating incomplete tissue repair. The long-lasting tubular injury and the slowness of repair are consistent with the chronic renal dysfunction (polyuria and hypomagnesemia) that cisplatin is known to induce in both man and experimental animals.

Acute Kidney Injury↗
PubMed1988

Light and electron microscopic characterization of the proliferative response induced by tobramycin in rat kidney cortex.

Administration of aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to renal dysfunction. Previously, we have shown that renal tissue injury due to aminoglycoside nephrotoxicity elicits a process of tissue repair characterized by stimulation of cell proliferation. The present study was undertaken to examine both quantitatively and qualitatively the cell proliferation associated with renal tissue repair. Female Sprague-Dawley rats (180-200 g body weight) were treated ip for 10 days with various doses of tobramycin (10, 20, or 50 mg/kg twice daily). Each animal received 200 microCi [3H]thymidine 1 hr before sacrifice to evaluate the extent of cell proliferation in renal cortex. The rate of DNA synthesis in renal cortex was estimated by measuring the specific radioactivity of the nucleic acid. The frequency and localization of S-phase cells in cortex tissue were determined on paraffin and plastic tissue sections processed for histoautoradiography. In addition, the ultrastructure of proliferating cells was characterized by electron microscopic examination of consecutive ultrathin sections. An excellent correlation (r = 0.993) was found between the rate of DNA synthesis and the frequency of S-phase cells evaluated in rats receiving various doses of tobramycin. The stimulation of cell proliferation involved mostly proximal tubular cells and interstitial cells. The latter cells had the ultrastructural appearance of fibroblasts at various stages of differentiation. Similarly, S-phase cells in proximal tubules were either fully differentiated epithelial cells or immature elements. Taken together, the present experimental data illustrate the capacity of the kidney to trigger complex tissue reactions in response to nephrotoxic injury.

Animals↗
PubMed1987

Evaluation of the nephrotoxic potential of styrene in man and in rat.

The urinary excretion of beta 2-microglobulin, retinol-binding protein and albumin was measured in 65 workers exposed to styrene at levels averaging 50 percent of the current threshold limit value (215 mg/m2) for 1-13 years (mean: 6 years). By comparison with a control group matched for age and socioeconomic status, no significant difference was observed in the urinary excretion of proteins. In rats, styrene was weakly nephrotoxic. No functional or morphological renal change could be disclosed in rats exposed to 565 mg of styrene/m3, 5 days/week for 13 weeks. The repeated i.p. injection of 1 g styrene/kg (1/5 of oral LD50) for 10 days induced only a slight tubular dysfunction as evidenced by a 5-fold increase in beta 2-microglobulinuria. Altogether, these epidemiological and experimental data suggest that the current threshold limit value for styrene (215 mg/m3) proposed by the American Conference of Governmental and Industrial Hygienists does not entail any risk of renal toxicity.

Adult↗
PubMed1987

[Lymphomatoid papulosis of the eyelid].

Lymphomatoid papulosis is an infrequent skin disease characterized by lesions which are clinically benign and histologically malignant. We report a case of lymphomatoid papulosis of the lid: the patient was 62 year old and the lesion appeared as a rapidly growing ulcerated tumor of the outer canthus with histological features of malignity. Complete removal of the tumor was performed and the lid was reconstructed during the same time. Similar preexisting and self healing skin lesions helped to make subsequently the accurate diagnosis.

Diagnosis, Differential↗
PubMed1986

Reduction of gentamicin nephrotoxicity by the concomitant administration of poly-l-aspartic acid and poly-l-asparagine in rats.

Williams and Hottendorf (1985) recently reported that poly-l-aspartic acid (pAsp) and poly-l-asparagine (pAsn) inhibit gentamicin (G) binding to brush border membrane vesicles in vitro and protect from G-induced nephrotoxicity in vivo. A model of infused rats was used to check for the early tissue alterations induced by G in animals receiving either G alone or the combination G + pAsp or G + pAsn. The cortical tissue was analysed 2 h or 2 days after the end of a 12 h infusion for signs of i) lysosomal phospholipidosis due to interference of G on phospholipids catabolism assessed by both biochemical (measurement of sphingomyelinase activity and of the total phospholipids content in renal cortex) and morphological analysis and ii) tubular regeneration and peritubular cells infiltration subsequent to focal necroses. While no reduction of G cortical levels was detected, significant changes in these parameters showed that G + pAsp and G + pAsn caused less phospholipidosis than G alone. Thus pAsp and pAsn decrease the severity of the early renal alterations induces by G.

Animals↗
PubMed1986

Morphology and fibrinolytic activity of canine autogenous mesothelium used as venous substitute.

Autogenous mesothelium was used as venous substitute in ten dogs. Patches of mesothelium of three different origins were grafted into the anterior wall of the common iliac veins (CIV): peritoneum taken from and including the posterior rectus sheath (PRS), simple peritoneum (P) and mesentery (M). Animals were killed after 2, 4, 8, and 16 days and after 3 months. The segments of CIV, including the patches, were removed for study. On light microscopy, the PRS grafts showed a normal mesothelium but marked submesothelial fibrosis. The M and P grafts showed normal mesothelium and only mild fibrous thickening. On scanning electron microscopy, there was a perfect continuity of the mesothelial cells and the normal endothelium at the suture line. In the center of the graft, the cells had become elongated along the axis of blood flow. Fibrinolytic activity (FA) was measured by a standardized fibrin plate technique and quantitated in tissue activator units per gram of tissue (TAU/g). The mean FA of iliac vein specimens was 1101.7 +/- 133.3 TAU/g (mean +/- SEM). The mean FA determined before grafting for each kind of mesothelium was the following: PRS = 418.8 +/- 26.9 TAU/g; P = 873.0 +/- 107.1 TAU/g; M = 1142.3 +/- 91.4 TAU/g where only PRS showed values significantly lower than iliac vein mean FA (P less than 0.001). Postoperatively, the mesothelial FA, after an initial reduction, increased on day 4 and reached values significantly higher than the control values (1445.7 +/- 204.1 TAU/g tissue vs 853.1 +/- 62.3 TAU/g tissue; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Morphological alterations in distal and collecting tubules of the rat renal cortex after aminoglycoside administration at low doses.

Ultrastructural alterations in the cortical, distal and collecting tubules have been examined in female Sprague-Dawley rats treated with various aminoglycosides in clinical use. Gentamicin, dibekacin (10 mg/kg X day), netilmicin, tobramycin (4 or 10 mg/kg X day) or amikacin (37.5 mg/kg X day) were administered intraperitoneally twice a day over different periods of time, extending from 4 to 14 days. The kidney cortex was examined after 4, 7, 10 or 14 days of aminoglycoside administration by light (semithin sections) and electron microscopy. After 7 or more days of treatment, lysosomes in collecting tubular cells (and to a lesser extent in distal tubular cells) contained concentric lamellar material (myeloid bodies), an ultrastructural alteration typical of drug-induced lysosomal phospholipidosis. Although this alteration appeared qualitatively similar to that observed in proximal tubular cells, it was less conspicuous and occurred later during treatment. In addition, distal tubular cells occasionally showed marked vacuolization and disruption of the basal cell architecture. The possible relationship between these alterations and the urine hypo-osmolality characteristic of aminoglycoside-induced renal dysfunction is discussed.

Aminoglycosides↗
PubMed1986

Isoparaffinic solvent-induced nephrotoxicity in the rat.

Prolonged inhalation exposure to 6.5 mg/l of an isoparaffinic solvent consisting of saturated aliphatic hydrocarbons (SAHC) resulted in both functional and morphological renal changes in male rats to the exclusion of female or castrated rats. Functionally, the increased excretion of lactate dehydrogenase in the absence of an increased beta-N-acetyl-D-glucosaminidase excretion together with a decreased urinary concentrating ability upon water deprivation and slower antinatriuretic response when the sodium intake is abruptly reduced, suggest a distal tubular alteration. beta 2-Microglobulin excretion is unchanged indicating good proximal tubular cell function. The increased excretion of albumin and slightly lowered glomerular filtration rate suggest a moderate glomerular impairment. Light microscopy shows prominent hyaline droplet accumulation in proximal tubular cells and a few scattered foci of regenerative epithelia in both proximal and distal cells of the deep cortex. The urinary clearance of the major male rat urinary protein, alpha 2u-globulin, is similar in control and exposed rats but the latter have a 10-fold greater renal accumulation of this protein while the hepatic levels are identical in both groups. It is concluded that SAHC exposure causes moderate and reversible tubular and also glomerular changes in the male rat kidney.

Acetylglucosaminidase↗
PubMed1986

Response of human and rat small intestinal mucosa to oral administration of Saccharomyces boulardii.

To evaluate the response of the small intestinal mucosa to Saccharomyces boulardii (S.b.), a yeast widely used in some countries as an adjuvant drug with oral antimicrobial therapy, seven healthy adult volunteers were treated with high doses of lyophilized S.b. (250 mg four times per day) for 2 wk. A peroral jejunal suction biopsy was performed on days 0 and 15 of the study. Compared to the initial biopsy, histological examination of the posttrial biopsy revealed no morphological alteration nor change in villus height or crypt depth. After treatment, the specific activity (per U protein) of sucrase, lactase, and maltase was, respectively, increased by 82% (p less than 0.05) 77% (p less than 0.05), and 75% (p less than 0.05) over the basal activity of the enzymes measured on day 0, whereas mucosal protein content remained unchanged. Similar findings were found in the jejunum of adult rats treated for 5 days with either viable or killed S.b. cells. The changes in total enzyme activity (per jejunal segment) paralleled the changes in specific enzyme activity. In vitro assays on freshly prepared suspensions of S.b. (6.0 X 10(8) viable cells/ml) evidenced a high activity for sucrase (mean +/- SE: 8 364 +/- 1280 U X g X protein-1) but no maltase, neutral lactase, acid beta-galactosidase, or aminopeptidase activity. To determine whether treatment with S.b. could influence the incorporation rate of neutral lactase into the brush border membrane, 14-day-old sucklings treated either with saline or with S.b. were given intraperitoneally a dose of 20 microCi D-[1(14)C] glucosamine 3 hours before sacrifice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Tissue repair in rat kidney cortex after short treatment with aminoglycosides at low doses. A comparative biochemical and morphometric study.

The tissue repair subsequent to aminoglycoside-induced tubular necrosis has been evaluated for five different derivatives given at low doses. Gentamicin, dibekacin, netilmicin, and tobramycin were administered intraperitoneally three times a day at 10 mg/kg per day; amikacin was given intraperitoneally twice a day at 37.5 mg/kg per day. The drugs were administered for 4 or 10 days. Tissue regeneration in kidney cortex was assessed by: the rate of DNA synthesis (i.e., the specific radioactivity of DNA measured 1 hour after intraperitoneal injection of 200 microCi of [3H] thymidine per animal); the occurrence of less differentiated cells estimated by the morphometry of peroxisomes. In mature cells, identified by the presence of drug-induced myelin-like figures, peroxisomes occupied 3.0% of the cytoplasmic area, whereas in less differentiate cells devoid of myelin-like figures, the same organelles made 1.4% of the cytoplasmic area (mean values obtained from 20 treated animals). Gentamicin and amikacin were both shown to induce a dose-related enhancement of DNA synthesis in kidney cortex, except that the latter antibiotic was about 10 times less potent as compared to the former. When the five drugs were compared on the basis of their effect on DNA synthesis after 10 days of treatment, they gave the following ranking: gentamicin (5.6 times the mean control value) greater than or equal to dibekacin greater than netilmicin greater than tobramycin greater than amikacin (1.6 times the mean control value). The differences were less striking after 4 days of treatment. For each antibiotic, sections of proximal tubular cells obtained from four animals treated for 10 days (total surface, 2.10(4) microns2) were scanned for the presence of regenerative tissue (areas poor in peroxisomes). In gentamicin-treated rats, the areas poor in peroxisomes represented more than 18% of the scanned cytoplasmic surface in proximal tubular cells, as compared to about 4.5% in controls. The ranking of the five antibiotics according to the estimated area of undifferentiated tissue in proximal tubules was parallel to that found for DNA synthesis i.e., in gentamicin-treated rats undifferentiated tissue was much more prominent, as compared to amikacin-treated animals (about 6% of the scanned area). Since the relative extent of kidney cortex regeneration induced by each antibiotic at low dose is likely to reflect the degree of tubular necrosis, we conclude that the ranking outlined above indicates a difference in potential nephrotoxicity.

Aminoglycosides↗
PubMed1985

Muscle regeneration induced by cells autografted in adult rats.

Right triceps surae of 3-week-old Wistar rats were minced and devitalized with liquid nitrogen, a treatment which completely inhibits their ability to regenerate when they are orthotopically autografted. In a first series of experiments, cells were isolated from the left triceps surae, mixed with the devitalized right mince and autografted; in a second series, cells were moreover allowed to proliferate in vitro for a few weeks before being grafted. The regenerates were examined 60 days after surgery. In the first series, all the regenerates were contractile and developed a maximal isometric tetanic force of 18 +/- 6 mN (n = 5); they contained 152 +/- 80 muscle fibres located proximally, the number of which decreased along the proximo-distal axis, being 24 +/- 24 in the median part of the regenerate. The muscle fibres appeared histologically normal except for their shortness (less than 10 mm) and narrowness (mean luminal diameter: 30 microns). In the second series, 2 out of 5 regenerates were comparable with those of the first series except that their fibres were shorter; the 3 other regenerates were unexcitable. These experiments demonstrate that cells isolated from an adult striated muscle are able to regenerate striated muscle fibres in an adult animal and that these cells can retain this property if they are grown in culture.

Animals↗
PubMed1984

A 2'guanidyl derivative of gentamicin (S86451) with reduced nephrotoxicity studies at low and medium dose levels in the rat.

The nephrotoxic potential of S86451 (2'guanidyl, 2'deamino gentamicin C1) has been investigated in Sprague-Dawley rats at 10 and 25 mg/kg, in comparison with gentamicin at 4 and 10 mg/kg. The criteria were (i) the severity of the lysosomal phospholipidosis, as assessed by both biochemical and morphological investigations; (ii) the degree of tubular regeneration, a consequence of the aminoglycoside-induced focal necrosis measured by 3H-thymidine incorporation into kidney cortex DNA. S86451 was found at least 2-5 times less toxic than gentamicin. Thus, this compound should be a safer antibiotic than gentamicin in combating organisms with a similar sensitivity to either drug.

Animals↗
PubMed1984

Tubular regeneration in rat kidney cortex during treatment with gentamicin at a low dose.

Tissue injury induced in rat kidney cortex by gentamicin at a low dose (10 mg/kg) has been studied by measuring subsequent regeneration after treatment for 4, 7, and 14 days. Cell proliferation was demonstrated by the incorporation of [3H]-thymidine into kidney cortex DNA. In treated animals, the specific radioactivity of DNA increased up to 4.6 times the mean value found in the controls. Autoradiography showed labelling of nuclei in proximal tubular cells. Electron microscopy showed that a subpopulation of tubular cells, devoid of myeloid bodies, which are characteristic of gentamicin intoxication, is also poorer in peroxisomes, and therefore may belong to less differentiated, regenerating cells. It is concluded that a low dose of gentamicin induces measurable tissue regeneration.

Animals↗
PubMed1984

Cadmium, analgesics, and the chronic progressive nephrosis in the female Sprague-Dawley rat.

Female Sprague-Dawley rats received phenacetin or aspirin at average daily doses of 135 and 27 mg/kg respectively in the diet and either demineralized water (DMW) or a 100 ppm cadmium (Cd) solution as their drinking water for 12 months. This dose of Cd produced borderline tubular toxicity, as measured by the excretion of IV-injected human beta 2-microglobulin. The kidney accumulation of Cd just reached the critical level of 200 ppm in all groups at the end of the study. The various treatments did not significantly affect growth, creatinine clearance, urine osmolality and the urinary excretion of beta-N-acetyl-D-glucosaminidase and aminoacids. No interaction resulted from the concomitant administration of analgesics and Cd. Both aspirin subgroups (receiving DMW or Cd) showed an attenuation of the age-related decline of the renal function as revealed by a lower urinary excretion of albumin and total protein. The accentuation of the mesangial matrix seen upon aging was also partly inhibited in the aspirin rats.

Acetylglucosaminidase↗