Biomedical subjects

C Schmid

Publications and source records attributed to C Schmid.

At least 199 records · Page 11Linked to original sources

PubMed1996

(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]: a purine analogue with trypanocidal activity in vitro and in vivo.

The unique features of purine salvage systems of pathogenic haemoflagellates render them selectively susceptible to the cytotoxic effects of purine analogues. A series of acyclic nucleoside phosphonates were evaluated for activity against pathogenic haemoflagellates in vitro. One of the phosphonylmethoxyalkylpurines, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was active in vitro against bloodstream forms of Trypanosoma brucei rhodesiense, T. b. gambiense, multidrug-resistant T. b. brucei, T. congolense and T. evansi, but not against intracellular T. cruzi or Leishmania donovani. Cytotoxic effects against mammalian cells were observed at 4900-27 300-fold higher concentrations than those necessary to inhibit T. b. rhodesiense. (S)-HPMPA was able to eliminate T. b. rhodesiense and multidrug-resistant T. b. brucei in an acute rodent model with two administrations of 10 mg/kg each.

Acute Disease↗

PubMed1996

Effects and fate of human IGF-binding protein-5 in rat osteoblast cultures.

Osteoblasts prepared from calvaria of newborn rats produce insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP), IGFBP-5 was discovered in bone extracts. However, we could not detect IGFBP-5 in the medium of newborn rat osteoblasts, although we found mRNA expression. To find an explanation for this discrepancy and to learn more about the physiological role of IGFBP-5 in these cells, we studied the biological activity and the fate of recombinant human (rh) IGFBP-5 in comparison to rhIGFBP-3. IGFBP-5 but not IGFBP-3 stimulated thymidine incorporation into DNA both in the absence and presence of IGF-I. However, IGFBP-5 did not enhance uridine incorporation into RNA and glucose incorporation into glycogen. 125I-rhIGFBP-5 but not 125I-rhIGFBP-3 rapidly disappeared from the culture medium consistent with the observation that endogenous (rat) IGFBP-3 but not IGFBP-5 accumulated in the medium. However, intact 125I-labeled or unlabeled rhIGFBP-5 was associated with the cell-layer matrix, whereas IGFBP-5 fragments appeared in the medium. Trapping of IGFBP-5 in the cell layer matrix may enhance local availability of IGF.

Animals↗

PubMed1996

Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells.

This study examined 1) effects of prostaglandins (PG) on renin secretion and renin gene expression from isolated juxtaglomerular granular cells and 2) expression of cyclooxygenases in juxtaglomerular structures. Incubation of granular cell cultures with PGE2, -I2, -F2 alpha, and thromboxane B2 identified PGI2 and PGE2 as stimulators of renin secretion; the effects were dose and time dependent. PGE2 also increased renin mRNA accumulation time and dose dependent. PGE2 and PGI2 activated adenylate cyclase concentration dependent in granular cells. PGE2 stimulations of renin secretion and renin mRNA were nonadditive to those of forskolin and were inhibited by endothelin. The findings are compatible with cellular actions through adenosine 3',5'-cyclic monophosphate (cAMP). On total RNA harvested from whole kidneys, from microdisected glomeruli with attached afferent arterioles and from mesangial cells in primary culture, reverse transcription-polymerase chain reaction revealed significant expression of cyclooxygenase I and II. By direct interaction with PG receptors on renal juxtaglomerular cells, PGE2 and PGI2 can act as potent and rapid stimulators of renin secretion and renin mRNA probably through cAMP-dependent pathways.

Adenylyl Cyclases↗

PubMed1996

Investigations on the point mutations at nt 5460 of the mtDNA in different neurodegenerative and neuromuscular diseases.

Point mutations of the mitochondrial genome are often considered to be the cause of certain neurodegenerative disorders and mitochondrial myopathies. Recently, there has been a report on Alzheimer's disease (AD) point mutations at position 5460 of the mitochondrial genome located within the ND2 gene. Using allele-specific PCR with a sensitivity of detection of less than 1% mutated mtDNA, we investigated postmortem brain samples from 48 patients with AD and blood samples of 15 patients with clinically diagnosed AD. In addition, we investigated tissue samples of patients with different neuromuscular disorders and patients with Downs syndrome. Independent of the tissue analysed very few of all the tested samples of patients showed a point mutation at nt 5460 with a base substitution from G to A. Two out of 19 brain and 48 blood samples from controls carried this mutation. The G to T transversion was not found in any of the so far tested samples. Our results do not support the previously reported significant high frequency of these mutations in AD.A polymorphism seems more likely.

Alleles↗

PubMed1996

Comparative study of power-based versus mean frequency-based transcranial color-coded duplex sonography in normal adults.

BACKGROUND AND PURPOSE: Power-based transcranial color-coded duplex sonography (p-TCCD) is a new ultrasonic method that has advantages compared with frequency-based TCCD (f-TCCD), since it is essentially independent of the angle of insonation, not subject to aliasing, and has a better signal-to-noise ratio. The purpose of this study was to evaluate the ability of p-TCCD to visualize flow in cerebral parenchyma and to compare the advantages, limitations, and reliability of velocity measurements of p-TCCD versus f-TCCD in the major basal cerebral arteries of normal subjects. METHODS: Two investigators performed 15 p-TCCD and 15 f-TCCD studies in 30 normal subjects with adequate ultrasonic windows. Each investigator did a p-TCCD or f-TCCD study in every patient, and each was blinded in every case to the results of the other. Peak systolic (Vs) and end-diastolic (Vd) velocities were determined in the anterior, middle, and posterior cerebral, basilar, and vertebral arteries. The reliability of p-TCCD velocimetry was evaluated by calculating both the correlation coefficient (r) of the difference between p-TCCD versus f-TCCD measurements and the coefficient of variation (CV), defined as the difference between the mean values for p-TCCD and f-TCCD divided by the mean values for f-TCCD measurements, expressed as percent. RESULTS: p-TCCD did not display flow in cerebral parenchyma but depicted arteries with a course perpendicular to that of the ultrasound beam and showed good reliability of velocity measurements in all examined arteries: for Vs, r was .84 to .93 (P < .001) and CV was 7.7% to 10.8%; for Vd, r was .87 to .90 (P < .001) and CV was 10.3% to 13.7%. The lack of directional and velocity information and tissue motion artifacts were unimportant limitations in p-TCCD. CONCLUSIONS: Compared with f-TCCD, p-TCCD had no important advantages but had several unimportant limitations in a study of normal adults with adequate ultrasonic windows.

Adult↗

PubMed1996

Clinical relevance of intracranial microembolic signals in patients with left ventricular assist devices. A prospective study.

BACKGROUND AND PURPOSE: The use of left ventricular assist devices has become an established method in bridging patients with end-stage cardiac failure to heart transplantation. Since thromboembolism is one of the major complications, we undertook this study to evaluate the clinical significance of Doppler microembolic signals (MES) in patients with left ventricular assist devices. METHODS: Six patients with left ventricular assist devices were monitored for MES with transcranial Doppler ultrasonography during the first 30 postoperative days. Additionally, repeated (10 per day and patient) and prolonged (3 hours per patient) monitorings were performed to assess the adequacy of the 30-minute recordings. Three observers evaluated 30 randomly assigned monitorings in a blinded fashion to assess the interobserver variability. The relation between MES counts and clinical, radiological, hemostaseological, and pump flow parameters and the predictive value of MES counts regarding the occurrence of embolic events was evaluated. RESULTS: Ten ischemic cerebrovascular accidents and 2 peripheral thromboembolic events occurred during the observation period of 177 days (total incidence, 6.8%). MES were found in 143 of 170 monitorings (84.1%). Their counts were significantly higher on days with clinically manifest embolic events as compared with event-free days (18.5 [3-74] versus 4 [0-52], respectively, median and 95% CI; P < .001, Mann-Whitney). The predictive value of MES counts above 7 per 30 minutes was high (75%). Significant differences in the incidence and counts of MES as well as in the incidence of clinically manifest embolic events were noted among the six patients (all P < .01) without equal differences in anticoagulant treatment or pump flow. Interobserver agreement was high (p = .78 to .89, unpaired Student's t test). Considerable short- and long-term intrapatient variations of MES counts, without consistent pattern, were noted. CONCLUSIONS: Serial monitoring for MES is prognostically superior to single monitorings in patients with left ventricular assist devices. In the future, this new application mode may individually guide anticoagulation strategies and even influence the decision regarding early cardiac transplantation versus long-term use of the assist devices.

Adult↗

PubMed1996

Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone.

Insulin-like growth factor I (IGF-I) is considered to mediate some of the growth-promoting and metabolic effects of growth hormone (GH). Growth hormone treatment of healthy and GH-deficient subjects is accompanied by increased conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues. Whether these effects are mediated by IGF-I is unknown. To assess the respective roles of these hormones on thyroid hormone metabolism we have treated two groups of subjects. The first group consisted of eight healthy subjects who were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 5 days). The second group consisted of eight subjects with combined GH and thyrotropin (TSH) deficiency due to acquired pituitary disease. They were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 7 days), GH (2 IU m-2 sc q.i.d.) or both hormones together. The IGF-I treatment in healthy subjects led to an increase in free T3 (FT3) and a reduction in TSH levels, whereas FT4 and total T4 (TT4) levels remained unchanged. In the second group-in which all subjects were substituted with oral L-thyroxine-treatment with IGF-I led to an elevation of FT3 in the face of unchanged T4 levels. Growth hormone alone and GH plus IGF-I resulted in a more pronounced elevation in T3 level. The results suggest that IGF-I partially mediates the well-known effects of GH on peripheral conversion of T4 to T3. However, GH has more pronounced effects on thyroid hormones that apparently are not mediated by IGF-I.

Adult↗

PubMed1996

Effects of controlled exposure of sunlight on plasma and skin levels of beta-carotene.

We conducted a randomized placebo-controlled double-blind study in 20 healthy young female students (skin type II + III, body mass index 18-22) in order to evaluate the efficacy of 10 weeks of moderate dose (30 mg/d) beta-carotene (BC) on plasma and skin beta-carotene levels during 12 days of time and intensity controlled sunlight exposure at sea level (30 degrees latitude, Red Sea, Eilath, Israel). After 12 days of controlled sun exposure (total UV dose of about 10.000J/cm2), plasma beta-carotene decreased in the placebo (p < 0.01) and beta-carotene group (not significant). In addition cutaneous beta-carotene decreased significantly in both groups. Plasma alpha-tocopherol decreased significantly (p < 0.01) during exposure time in both groups. In the supplemented group, however, the decrease of a-tocopherol was significantly greater (p < 0.01) than in the placebo group. We conclude that sunlight influences the beta-carotene and alpha-tocopherol content of blood and tissues.

Adult↗

PubMed1996

Effects of mycophenolic acid mofetil on acute rejection of kidney allografts in rats.

Mycophenolic acid mofetil (MMF) is an agent which has recently gained a lot of attention. In clinical trials MMF has reduced the rate of acute rejection episodes in human recipients of kidney allografts by inhibiting inosin-monophosphat-dehydrogenasis (IMPDH), an enzyme involved in the purin metabolism and related to the expression of adhesion molecules. The aim of the present study was to analyze the effects of MMF upon the expression of adhesion molecules in transplanted kidney allografts. LBNF1 kidneys were orthotopically transplanted into Lewis rats and either treated with MMF (20 mg/kg/day) or vehicle. Rats were harvested 3, 5 and 7 days following transplantation. Immunohistology was performed with various monoclonal antibodies. In general, MMF resulted in a better preservation of graft structure by 7 days. Cellular infiltration and tubular atrophy were less pronounced. At day 3, macrophages were diminished in MMF-treated animals to a high extent, while the number of T-cells was almost identical as compared to controls. In addition, the number of cells positive for MHC class II and LFA-1 was reduced in the MMF-treated animals. In conclusion, MMF resulted in a markedly reduced leukocyte infiltrate, presumably based on a reduced expression of lymphocytic adhesion molecules and an interaction with macrophages.

Animals↗

PubMed1996

Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts.

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.

Analysis of Variance↗

PubMed1996

[Intravascular sonographic findings after orthotopic heart transplantation: comparison with clinical factors].

30 patients (mean age 51.4 +/- 11.6 years; female n = 6) were studied early after orthotopic heart transplantation (11.6 +/- 5.5 weeks). Twelve recipients had undergone specific treatment for biopsy proven rejection. Using a mechanical intravascular ultrasound device (3.5-F catheter), 153 coronary artery segments (16 left coronary main stem, 122 left anterior descending artery, 15 left circumflex artery) were studied. Intimal index and circumferential extension of a three-layer appearance of the vessel wall were assessed. In all segments, systolic-diastolic changes in area (delta A) with respect to vessel area and pressure (delta P) were used to study normalized compliance (normalized compliance = [delta A/A]/delta P [mm Hg-1 x 10(3)]). Intravascular ultrasound findings were correlated to perioperative ischemia time, LDL/HDL-ratio, Lp(a) and donor age. In a subgroup of 13 recipients, intravascular ultrasound investigation was repeated after an interval of 67.4 +/- 10.2 weeks. At first investigation, mean intimal index of all coronary segments was 0.07 +/- 0.10. Mean circumferential extension of a three-layer appearance of the vessel wall was 84 +/- 112 degrees. Normalized compliance was 2.43 +/- 1.90 mm Hg-1 in the left main stem 2.45 +/- 1.47 mm Hg-1 within the left anterior descending artery, and 2.66 +/- 1.72 mm Hg-1 within the circumflex artery (differences n.s.). No correlation was found between intimal index and normalized compliance (r = -0.322), nor between circumferential extension of intimal thickening and normalized compliance (r = -0.362). Furthermore, there was no correlation between normalized compliance and donor age. Normalized compliance was significantly lower in recipients with proven rejection than in those without (1.76 +/- 0.81 versus 2.95 +/- 1.22 mm Hg-1, p = 0.005). Both, intimal index and circumferential extension of intimal thickening, were significantly higher in recipients following rejection periods (p < 0.05). The extent of coronary vessel wall alterations on ultrasound correlated to donor age but not to perioperative ischemia time, LDL/HDL-ratio and Lp(a). Re-investigation of a subgroup of 13 recipients 67.4 +/- 10.2 weeks after the first study showed an insignificant increase of the intimal index (from 0.03 to 0.09) and of the circumferential extension of intimal thickening (from 40 to 111 degrees). Normalized compliance changed from 2.53 +/- 1.48 to 2.87 +/- 1.33 mm Hg-1 (differences n.s.). Early after orthotopic heart transplantation, a significant correlation between atherosclerotic coronary vessel wall alterations assessed by intravascular ultrasound and donor age can be confirmed. Heart recipients following rejection periods present with significantly more atherosclerotic vessel wall alterations and a severely reduced compliance of the coronary vessels.

Adult↗

PubMed1995

Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts.

We have examined the effects of rapamycin (RPM) on transplant vasculopathy in long-surviving F344 rat heart allografts transplanted heterotopically into Lewis recipients. RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and daily throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 (5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combination with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppression with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (group 6) were also examined. F344 isograft recipients treated with RPM (0.5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Grafts of group 1 were removed at 50, 75, 100, 150, and 200 days and infiltrating cell populations and surface molecules were compared with those of the other groups at 100 days. All allografts in treated hosts functioned > 100 days; in contrast, grafts in untreated recipients were rejected acutely by 8 +/- 1 days (MST +/- SD). The incidence of transplant vasculopathy in group 1 increased progressively (MST +/- SD = 10 +/- 2%, 59 +/- 7%, 85 +/- 15%, and 80 +/- 12% at 50, 100, 150, and 200 days, respectively), as manifested by myointimal proliferation with dense mononuclear infiltration (predominantly ED1+ macrophages). Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhesion molecules and cytokines. The incidence of graft disease and extent of cellular infiltration at 100 days was significantly lower in animals receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25 +/- 15%, 22 +/- 11%, and 10 +/- 3%, respectively; P < 0.005). CsA treatment either in combination with RPM or alone (groups 5 and 6) failed to improve transplant vasculopathy, but reduced mononuclear cell infiltration. Isografts (groups 7 and 8) and naive hearts (group 9) developed no structural abnormalities throughout the follow-up period, regardless of RPM treatment. We conclude that the extent of transplant vasculopathy can be reduced markedly in this rat cardiac transplant model with maintenance RPM. Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.

Animals↗

PubMed1995

Elucidation of crystal packing by X-ray diffraction and freeze-etching electron microscopy. Studies on GTP cyclohydrolase I of Escherichia coli.

A monoclinic crystal modification of GTP cyclohydrolase I (space group P2(1), a = 204.2 A, b = 210.4 A, c = 71.8 A, alpha = gamma = 90 degrees, beta = 95.8 degrees) was studied by freeze-etching electron microscopy and by Patterson correlation techniques. The freeze-etched samples were either shadowed with Pt/C or decorated with monolayers of gold, silver or platinum. Correlation averaged electron micrographs of decoration replicas indicated 5-fold molecular symmetry. In conjunction with the molecular mass of the active GTP cyclohydrolase I enzyme complex of about 210,000 Da, which had been reported in the literature, and a molecular mass of the protomers of 24,700 Da, the electron microscopic observation suggests that the enzyme is a decamer with 5-fold symmetry. The processed images of decorated crystal surfaces also showed that the four protein multimers in the crystal unit cell are related by 4-fold pseudosymmetry. A Patterson analysis of the X-ray data showed two non-crystallographic 5-fold axes, inclined at 12 degrees to each other, thus confirming and extending the electron microscopic findings. Additionally, local 2-fold axes were found in planes perpendicular to the 5-fold particle axes. Thus, the combined X-ray and electron microscope data indicate that GTP cyclohydrolase I is a decamer with D5 symmetry. A procedure for hkl assignments of the crystal planes observed in electron micrographs was developed. On this basis, it was possible to determine the approximate molecular positions in the ab plane. Independent information on the crystal packing was obtained by single isomorphous replacement and electron density averaging. The 5-fold averaged 6 A electron density shows that the GTP cyclohydrolase I decamer is torus-shaped with an approximate diameter of 100 A and a thickness of 65 A. The study demonstrates that the combination of freeze-etching electron microscopy with Patterson analysis of X-ray data is a powerful approach for the solution of complex crystallographic problems. The procedure for this analysis as well as possible pitfalls are discussed in detail.

Crystallization↗

PubMed1995

Effects of insulin-like growth factor (IGF) binding proteins (BPs) -3 and -6 on DNA synthesis of rat osteoblasts: further evidence for a role of auto-/paracrine IGF I but not IGF II in stimulating osteoblast growth.

IGFBP-3 and IGFBP-6 were used to study whether both IGF I and IGF II play a role in auto-/paracrine stimulation of rat osteoblast growth. Both IGFBPs decreased basal DNA synthesis in neonatal rat calvaria cells but with different potencies. Consistent with their IGF binding affinities, IGFBP-3 blocked both IGF I- and IGF II-stimulated DNA synthesis, whereas IGFBP-6 preferentially blocked IGF II-stimulated DNA synthesis. These inhibitory effects of the two IGFBPs can be fully explained by the sequestration of IGFs. Because IGFBP-6 preferentially binds IGF II and is much less potent than IGFBP-3 in decreasing basal DNA synthesis in calvaria cells, IGF I but not IGF II appears to be an important auto-/paracrine stimulator of DNA synthesis.

Animals↗

PubMed1995

Atomic structure of GTP cyclohydrolase I.

BACKGROUND: Tetrahydrobiopterin serves as the cofactor for enzymes involved in neurotransmitter biosynthesis and as regulatory factor in immune cell proliferation and the biosynthesis of melanin. The biosynthetic pathway to tetrahydrobiopterin consists of three steps starting from GTP. The initial reaction is catalyzed by GTP cyclohdrolase I (GTP-CH-I) and involves the chemically complex transformation of the purine into the pterin ring system. RESULTS: The crystal structure of the Escherichia coli GTP-CH-I was solved by single isomorphous replacement and molecular averaging at 3.0 A resolution. The functional enzyme is a homodecameric complex with D5 symmetry, forming a torus with dimensions 65 A x 100 A. The pentameric subunits are constructed via an unprecedented cyclic arrangement of the four-stranded antiparallel beta-sheets of the five monomers to form a 20-stranded antiparallel beta-barrel of 35 A diameter. Two pentamers are tightly associated by intercalation of two antiparallel helix pairs positioned close to the subunit N termini. The C-terminal domain of the GTP-CH-I monomer is topologically identical to a subunit of the homohexameric 6-pyruvoyl tetrahydropterin synthase, the enzyme catalyzing the second step in tetrahydrobiopterin biosynthesis. CONCLUSIONS: The active site of GTP-CH-I is located at the interface of three subunits. It represents a novel GTP-binding site, distinct from the one found in G proteins, with a catalytic apparatus that suggest involvement of histidines and, possibly, a cystine in the unusual reaction mechanism. Despite the lack of significant sequence homology between GTP-CH-I and 6-pyruvoyl tetrahydropterin synthase, the two proteins, which catalyze consecutive steps in tetrahydrobiopterin biosynthesis, share a common subunit fold and oligomerization mode. In addition, the active centres have an identical acceptor site for the 2-amino-4-oxo pyrimidine moiety of their substrates which suggests an evolutionarily conserved protein fold designed for pterin biosynthesis.

Alcohol Oxidoreductases↗

PubMed1995

Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts.

No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344-to-Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low-dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow-up period. Non-RS61443-treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM-1 on endothelium), cytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-allospecific IgG and IgM peaked at 1-2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow-up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow-up period. Proteinuria was virtually absent, and morphological and immunohistological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.

Animals↗

PubMed1995

Insulin-like growth factors.

The insulin-like growth factors I and II are single chain polypeptides homologous to proinsulin. IGF I and IGF II contribute to cell regulation and stimulate protein synthesis via signaling through type 1 receptors which are homologous to insulin receptors and activate phosphorylation cascades. IGFs enhance the proliferation of chondocytes and the proliferation of their collagen and proteoglycan matrix; IGFs stimulate longitudinal (endochondral) bone growth. Throughout life, IGFs are constitutively expressed ubiquitous factors which help to maintain the survival of differentiated cells, Increased expression is found during growth and tissue repair, Six specific binding proteins, IGFBP 1-6, allow additional tissue compartment specific control of IGF activity; IGFBP production favours storage and IGFBP cleavage leads to activation.

Animals↗

PubMed1995

Expression of sodium-dependent phosphate (NadPi) transport in Xenopus laevis oocytes induced by mRNA from 1 alpha, 25-dihydroxyvitamin D3-treated rat osteoblast-like cells.

Injection of messenger ribonucleic acid (mRNA) isolated from 1 alpha, 25-dihydroxyvitamin D3-treated osteoblast-like (PyMS) cells leads to an enhanced sodium-dependent phosphate (NadPi) transport in Xenopus laevis oocytes, when compared to untreated cells. After mRNA size fractionation, mRNA with an average size of 2.2-3.8 kilobases showed up to a 1.8-fold stimulation of NadPi transport encoding either directly a NadPi transporter(s) or proteins controlling their activity. No hybridization was observed in Northern blots with RNA from rat bone or PyMS cells with the recently cloned rat renal brush border NadPi transporter NaPi-2; hybrid depletion with a NaPi-2 antisense oligonucleotide did not abolish the PyMS mRNA-induced NadPi transport in oocytes. We present the first evidence for functional expression in Xenopus laevis oocytes of a new type of NadPi transport system in bone cells, which is different from the renal type.

Animals↗