Association between CMV-related graft injury and circulating cytokine-producing CD8+ memory cells.
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Antigens, CD↗
Biomedical subjects
F Kern
Publications and source records attributed to F Kern.
Late acute rejection in long-term renal allograft recipients. Diagnostic and predictive value of circulating activated T cells.
Episodes of acute rejection can occur in functional renal grafts even at a very late stage after transplantation. They are not necessarily due to patient noncompliance. The incidence of late acute rejection is commonly underestimated because the diagnosis generally requires histopathology in order to rule out other origins of declining graft function, even more so, as the typical signs of acute rejection as seen in the early posttransplantation period (sudden and rapid increase of creatinine serum level, inflammatory signs) are missing. Histology revealed acute rejection in 157 of 412 renal allograft recipients suffering from progressive graft deterioration between the 2nd and 18th year after Tx. Late acute rejection was clearly associated with elevated levels of activated HLA-DR+ T cells in the peripheral blood. These cells were characterized by flow cytometry to be postmitotic activated effector-T cells belonging to the CD4+ and CD8+ "memory" T cell pool. The high sensitivity (97%) and specificity (88%) of flow cytometric analysis allows for the discrimination between late acute rejection and other causes of deteriorating graft function (infection, toxicity, arteriopathy, chronic rejection). Additionally, this immune monitoring can predict the success of antirejection therapy as early as a few days after initiation of treatment while conventional parameters do not reflect the therapeutic result until 1-3 weeks later. In addition to this, peripheral T cell activation also seems to identify a subgroup of patients with chronic rejection who would respond, at least partially, to steroid bolus therapy. As a result, this parameter is very useful for the clinical management of patients suffering from late deterioration of renal graft function.
Acute Disease↗
ATP stimulates Ca2+ mobilization by a nucleotide receptor in glomerular endothelial cells.
The present study investigates ATP effects on Ca2+ mobilization in bovine glomerular endothelial cells (GEC) and the receptors mediating ATP response. Extracellular ATP stimulated a rise in inositol 1,4,5-trisphosphate and cytosolic free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. Extracellular Ca2+ depletion did not prevent [Ca2+]i rise. ATP effects were not mediated by P1, P2x, and P2t purinoceptors, since the P1 receptor agonist adenosine and the P2x receptor agonist [alpha,beta-CH2]ATP had no effect on inositol 1-monophosphate (IP) formation and Ca2+ mobilization and ATP does not activate P2t receptors. The P2y receptor antagonist reactive blue (10(-3) M) had little inhibitory effect on ATP (10(-5) M)-stimulated IP formation (15.6 +/- 4.2%) and Ca2+ rise (7.0 +/- 3.0%). According to the classification of purinoceptors, ATP is less potent than 2-methylthioadenosine 5'-triphosphate (2-MeS-ATP) in stimulating P2y receptors. In GEC, however, the rank order of potency in stimulating IP and [Ca2+]i rise was ATP > 2-MeS-ATP > ADP. The pyrimidine nucleotide UTP (10(-3) M) induced maximal IP formation (653 +/- 37%) and Ca2+ mobilization (591 +/- 22 nM) similar to ATP (IP 647 +/- 27%; [Ca2+]i 583 +/- 15 nM). At submaximal (10(-5) M) but not at maximal (10(-3) M) doses ATP and UTP effects were additive. ATP and UTP induced specific cross-desensitization. It is concluded that the purinergic nucleotide ATP and pyrimidine nucleotide UTP mediate their effects by a common nucleotide receptor. This receptor differs from P2z and P2y1 receptors, since by definition UTP does not activate these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate↗
Discordant expression of LFA-1, VLA-4alpha, VLA-beta 1, CD45RO and CD28 on T-cell subsets: evidence for multiple subsets of 'memory' T cells.
Several adhesion molecules and CD45RO have been reported to be upregulated on the cell surface of 'memory' T cells. Using triple-color flow cytometry, we compared the levels of typical 'memory' cell markers on peripheral blood T-cell subpopulations in a number of kidney transplant recipients, patients with systemic lupus erythematosus, newborn infants and healthy donors. CD45RO, VLA-beta 1 (CD29), VLA-5 alpha (CD49e), LFA-1 (CD11a/18), and CD2 were found to be closely coregulated on CD4+ T cells, while regulation of VLA-2 alpha (Cd49b), VLA-4 alpha (CD49d) and CD44 was quite discordant. In CD8+ T cells, by contrast, multiple subsets of 'memory'-type cells were distinguished. Unlike TCR alpha/beta T cells, which expressed either high or low levels of LFA-1, TCR gamma/delta cells all expressed high levels of LFA-1 (CD11a/CD18). Examination of T cells from kidney graft fine-needle aspiration biopsies during rejection revealed intragraft accumulation of 'memory'-type T cells expressing high levels of CD2 and LFA-1 (CD11a/CD18). Regarding peripheral blood T-cell subsets, differences between patients and healthy controls were only of a quantitative nature.
Adult↗
Effects of dietary cholesterol on cholesterol and bile acid homeostasis in patients with cholesterol gallstones.
We examined changes in cholesterol and bile acid metabolism produced by dietary cholesterol in gallstone subjects and matched controls. Healthy women were recruited and, after confirming the presence or absence of radiolucent gallstones, they were studied on regular diets and again on the same diet supplemented with five eggs daily for 15-18 d. Studies included plasma lipids, lipoproteins and apolipoproteins, dietary records, cholesterol absorption, cholesterol synthesis, plasma clearance of chylomicron remnants, biliary lipid composition, and secretion and bile acid kinetics. On low cholesterol, gallstone subjects absorbed a slightly lower fraction of dietary cholesterol, synthesized more cholesterol, and had smaller bile acid pools and faster fractional turnover rate (FTR) of bile acids. On high cholesterol, the fraction of cholesterol absorbed decreased in both groups and cholesterol synthesis decreased, especially in the gallstone group. Biliary cholesterol secretion increased in the gallstone group only. FTR of bile acids did not change in either group. Bile acid synthesis and pool tended to increase (P = NS) in the controls, but in gallstone subjects, synthesis and pool size decreased. We concluded that in gallstone subjects cholesterol and bile acid homeostasis is significantly altered, and that increasing dietary cholesterol increases biliary cholesterol secretion and decreases bile acid synthesis and pool, changes associated with cholesterol gallstone formation.
Adult↗
Expression of soluble and insoluble fibronectin in rat aorta: effects of angiotensin II and endothelin-1.
This study has investigated the influence of the vasoconstrictor peptides angiotensin II (Ang II) and endothelin-1 (ET-1) on fibronectin expression by vascular smooth muscle cells (VSMC). In confluent, quiescent cultures of VSMC, Ang II and ET-1 elevated fibronectin mRNA levels in a time- and dose-dependent fashion. ET-1 and Ang II also induced a time-dependent expression of immunoreactive fibronectin in cultures of aortic organoids, and for both peptides the fibronectin immunoreactivity was most prominent within those medial smooth muscle cell layers close to the vessel lumen. Immunoprecipitation of biosynthetically labelled fibronectin elaborated by cultured VSMC revealed a predominant expression of soluble fibronectin in response to Ang II, whereas for ET-1 the newly synthesized fibronectin was predominantly incorporated into the extracellular matrix deposit of the cells. These findings indicate that Ang II and ET-1 may exert disparate effects on smooth muscle cell phenotype and migration.
Angiotensin II↗
The renin-angiotensin system and extracellular matrix.
A hallmark of vascular disease is the inappropriate proliferative and synthetic behaviour of vascular smooth muscle cells. This phenotypically immature behaviour arises as a consequence of the myocytes undergoing phenotypic conversion and/or clonal proliferation of a "fetal" type of smooth muscle cell preexisting in the vessel wall. De-differentiation and initiation of proliferation is not only induced by endothelial desquamation and acute exposure of smooth muscle cells to platelet-derived mitogens, but also occurs in the uninjured blood vessel. Therefore normal components of the blood vessel are implicit in the pathological process. These include vasoconstrictor peptides, growth factor peptides and extracellular matrix molecules. In vitro and in vivo experimentation has indicated that while some of these compounds individually are only mild stimulators of smooth muscle proliferative metabolism, they may act synergistically to induce robust responses. Here we discuss the effects of the vasoconstrictor peptide angiotensin II, which can be locally generated within the vessel wall itself, on the expression of extracellular matrix molecules in vitro and in vivo. We focus on the angiotensin II-modulated expression of extracellular matrix glycoproteins, e.g. thrombospondin, tenascin, fibronectin and laminin.
Angiotensin II↗
Peptide vasoconstrictors, vessel structure, and vascular smooth-muscle proliferation.
The peptide vasoconstrictors angiotensin II (Ang II) and endothelin-1 (ET-1), originally thought to derive exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of such sources. Local tissue angiotensin-generating systems are well documented, and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth-muscle cells (VSMC). There is increasing evidence from in vitro studies that local production of these vasoconstrictor peptides may contribute to blood vessel homeostasis and the development of vascular pathologies. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, Ang II and ET-1 act as potent biological effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in VSMC. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The best-recognized autocrine feedback loops of VSMC are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of Ang II and ET-1. Because both vasoconstrictors (via their induction of autocrine growth modulators) may influence the composition of the extracellular matrix of VSMC, the effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance. Ang II and ET-1 promote the synthesis and secretion of the glycoproteins thrombospondin, fibronectin, and tenascin.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Altered cholesterol metabolism in patients with cholesterol gallstones: responses to reduced dietary cholesterol.
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Adult↗
Effects of endothelin-1 on vascular smooth muscle cell phenotypic differentiation.
Endothelin-1 (ET-1) produced by vascular endothelial cells has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMCs) in vivo, exerting a variety of short- and long-term effects. Although some of the in vitro ET-1-mediated effects are related to growth-promoting events, the physiological significance of these observations remains to be clarified. Reported discrepancies of the mitogenic potential of ET-1 may relate to differences in culturing conditions (submitogenic levels of serum in combination with ET-1). Because ET-1 has been implicated in proliferation of vascular SMCs (VSMCs) at sites of vascular injury, as well as pathological events during atherogenesis, a clarification of the mitogenic effects of ET-1 is important. This study demonstrates the possible autocrine role for ET-1 in the regulation of the vasculature, its influence on VSMC cell cycle, and autocrine and phenotypic regulation of VSMCs. Stimulation of quiescent VSMCs with a variety of peptides resulted in the secretion of biologically active ET-1 by VSMCs. In contrast to previous reports, long-term exposure (12-15 days) of VSMCs to ET-1 in nonmitogenic medium did not promote cycling of cells. On the contrary, ET-1 attenuated the cycling of VSMCs in the S and G2/M phases and interrupted progression through the cell cycle at late G1/early S phase. Subsequent to ET-1 exposure, VSMCs expressed increased levels of smooth muscle-specific alpha-actin. Therefore, autocrine-produced ET-1 may contribute to phenotypic differentiation of VSMCs.
Actins↗
Expression of tenascin by vascular smooth muscle cells. Alterations in hypertensive rats and stimulation by angiotensin II.
The extracellular matrix glycoprotein tenascin is associated with remodeling events in many embryonic and pathologic tissues. The expression of tenascin has been investigated by immunohistochemistry in blood vessels of Wistar-Kyoto (normotensive) and spontaneously hypertensive rats. Weak tenascin staining was present throughout the tunica media of large and small arteries from normotensive animals; strong staining was only detectable at branching sites. In arteries from hypertensive animals, foci of strong tenascin staining were scattered throughout the tunica media. The expression of tenascin mRNA and protein by rat aortic smooth muscle cells cultured in serum-free medium was induced by the vasoconstrictor peptide angiotensin II. Transforming growth factor-beta and platelet-derived growth factor also stimulated tenascin mRNA expression. Vascular smooth muscle cells attached specifically to a substratum of tenascin, but remained rounded. Thus, increased focal tenascin expression by vascular smooth muscle cells is associated with hypertension, and may mediate angiotensin II-induced changes in vascular structure in hypertension.
Angiotensin II↗
The effect of temperature on cerebral metabolism and blood flow in adults during cardiopulmonary bypass.
The effect of temperature on cerebral blood flow and metabolism was studied in 41 adult patients scheduled for operations requiring cardiopulmonary bypass. Plasma levels of midazolam and fentanyl were kept constant by a pharmacokinetic model-driven infusion system. Cerebral blood flow was measured by xenon 133 clearance (initial slope index) methods. Cerebral blood flow determinations were made at 27 degrees C (hypothermia) and 37 degrees C (normothermia) at constant cardiopulmonary bypass pump flows of 2 L/min/m2. Blood gas management was conducted to maintain arterial carbon dioxide tension (not corrected for temperature) 35 to 40 mm Hg and arterial oxygen tension of 150 to 250 mm Hg. Blood gas samples were taken from the radial artery and the jugular bulb. With decreased temperature there was a significant (p less than 0.0001) decrease in the arterial venous-oxygen content difference, suggesting brain flow in excess of metabolic need. For each patient, the cerebral metabolic rate of oxygen consumption at 37 degrees C and 27 degrees C was calculated from the two measured points at normothermia and hypothermia with the use of a linear relationship between the logarithm of cerebral metabolic rate of oxygen consumption and temperature. The temperature coefficient was then computed as the ratio of cerebral metabolic rate of oxygen consumption at 37 degrees C to that at 27 degrees C. The median temperature coefficient for man on nonpulsatile cardiopulmonary bypass is 2.8. Thus reducing the temperature from 37 degrees to 27 degrees C reduces cerebral metabolic rate of oxygen consumption by 64%.
Aged↗
Tumor growth dependent on Kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate.
A neoangiogenic response is critical for the unrestricted growth of solid tumors beyond a few millimeters in diameter. Release of adequate growth-stimulating activity from tumor cells is obviously required for the stimulation of blood vessel growth, and blockade of such stimulatory activity should repress tumor growth at the microscopic level. To test this hypothesis and to study appropriate inhibitors, we used a human adrenal cancer cell line (SW-13/K-fgf) engineered to secrete Kaposi's sarcoma-derived fibroblast growth factor (K-FGF), which we previously showed to induce growth of highly vascularized subcutaneous tumors in animals by autocrine and paracrine stimuli. In the present study, we tested different polysulfates for their selective inhibition of proliferation induced by K-FGF versus proliferation independent of K-FGF. Suramin and dextran sulfate showed slight selective inhibition of K-FGF-induced proliferation, ie, inhibition three- and five-fold greater, respectively, than the inhibition of proliferation independent of K-FGF. In contrast, heparin was inactive. The heparin analogue pentosan polysulfate (PPS), however, showed selective inhibition that was more than 2000-fold greater. The inhibitory effects of PPS on growth of SW-13/K-fgf cells, as well as endothelial cells, were fully reversible by an excess of added FGF. Daily intraperitoneal injections of PPS were tolerated well by athymic nude mice and prevented growth of subcutaneous SW-13/K-fgf tumor xenografts. PPS will be a useful tool to elucidate the effects of FGFs in vitro and in vivo and appears to be a prototype for the development of tumoricidal therapy based on targeting of growth factors.
Adrenal Gland Neoplasms↗
Normal plasma cholesterol in an 88-year-old man who eats 25 eggs a day. Mechanisms of adaptation.
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Adaptation, Physiological↗
Ammoniated mercury ointment as a cause of peripheral neuropathy.
A 72-year-old Caucasian man with widespread psoriasis presented with a sensory-motor peripheral neuropathy following 40 years' use of an ammoniated mercury ointment. No clinical involvement of his central nervous system was noted and no other possible causative factors for his peripheral nerve disease were found. D-Penicillamine treatment induced mercuriuresis and blood levels of mercury fell to normal. His peripheral neuropathy improved slowly after normalisation of the serum mercury. It is believed that his condition was caused by percutaneous absorption of mercury. Ammoniated mercury ointments should have no role in the current management of skin disorders.
Administration, Topical↗
Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism.
Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.
Adult↗
Immunohistochemical studies on human pituitary gland and adenomas.
To study coexpression patterns in normal and adenomatous pituitaries, frozen (n = 4) and paraffin-embedded (n = 10), normal human glands and 34 pituitary adenomas were investigated, using immunoperoxidase and double-labeling immunofluorescence methods. Broad range monoclonal antibodies (mAB) against cytokeratins (CK) (lu-5, A45-B/B3, AE1/3, CAM 5.2) as well as anti-CK18 (DC10) and anti CK19 (A53-B/A2) were compared with mAB's against vimentin, epithelial membrane antigen (EMA), epithelial sialomucin (ESM 140 C1), GFAP (GF-2), neurofilament (2F11), Leu-7 (HNK-1) and polyclonal AB's against pituitary hormones (ACTH, FSH, LH, TSH, GH, PRL). CK and vimentin coexpressing endocrine cells, mainly of the ACTH type, were observed in the pars intermedia in 5 of 14 normal pituitaries. All hormone producing cells expressed CK. The mAB A53-B/A2 (CK19) stained selectively the folliculo-stellate cells in frozen and paraffin sections. EMA, sialomucin and Leu-7 antigen localized to different structures of normal pituitaries. 25 of 34 pituitary adenomas exhibited CK positive tumor cells. Coexpression of vimentin or neurofilament protein was rare (2 cases of each). 9 CK negative adenomas were also negative for other intermediate filament proteins. 6 hormone producing adenomas showed unusual positivity for CK19. Whereas EMA and sialomucin reactivity disappeared in adenoma tissues, an enhanced Leu-7 antigen expression in the GH and prolactin adenoma group was noted. The heterogeneity of antigen expression seen in normal and neoplastic pituitary cells calls for further functional studies and usage of a broad range of mAB's against intermediate filaments in immunohistochemical studies of the pituitary.
Adenoma↗
Accurate mass determination of short-lived isotopes by a tandem Penning-trap mass spectrometer.
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Journal Article↗