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Showing papers in "Journal of Clinical Investigation in 1984"


Journal ArticleDOI
TL;DR: All light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions.
Abstract: Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.

1,230 citations


Journal ArticleDOI
TL;DR: The oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia, and restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.
Abstract: During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.

978 citations



Journal ArticleDOI
TL;DR: In conclusion, the use of intravenous 1,25(OH)2D3 administered intravenously rather than orally may result in a greater delivery of the vitamin D metabolite to peripheral target tissues other than the intestine and allow a greater expression of biological effects of 2D3 in peripheral tissues.
Abstract: Current evidence suggests that administration of 1,25(OH)2D3 to patients with chronic renal insufficiency results in suppression of secondary hyperparathyroidism only if hypercalcemia occurs. However, since the parathyroid glands possess specific receptors for 1,25(OH)2D3 and a calcium binding protein, there is considerable interest in a possible direct effect of 1,25(OH)2D3 on parathyroid hormone (PTH) secretion independent of changes in serum calcium. Recent findings indicate substantial degradation of 1,25(OH)2D3 in the intestine, therefore, it is possible that while oral administration of the vitamin D metabolite increases intestinal calcium absorption, the delivery of 1,25(OH)2D3 to peripheral target organs may be limited. We therefore compared the effects of orally or intravenously administered 1,25(OH)2D3 on the plasma levels of 1,25(OH)2D3 and the effects of these two modes of treatment on PTH secretion. Whereas oral administration of 1,25(OH)2D3 in doses adequate to maintain serum calcium at the upper limits of normal did not alter PTH levels, a marked suppression (70.1 +/- 3.2%) of PTH levels was seen in all 20 patients given intravenous 1,25(OH)2D3. Temporal studies suggested a 20.1 +/- 5.2% decrease in PTH without a significant change in serum calcium with intravenous 1,25(OH)2D3. In five patients the serum calcium was increased by the oral administration of calcium carbonate, the decrement in serum i-PTH was only 25 +/- 6.65% when compared with 73.5 +/- 5.08% (P less than 0.001) obtained by the administration of intravenous 1,25(OH)2D3. Thus, a similar serum calcium achieved by intravenous 1,25(OH)2D3 rather than calcium carbonate has a greater suppressive effect in the release of PTH. These studies indicate that 1,25(OH)2D3 administered intravenously rather than orally may result in a greater delivery of the vitamin D metabolite to peripheral target tissues other than the intestine and allow a greater expression of biological effects of 1,25(OH)2D3 in peripheral tissues. The use of intravenous 1,25(OH)2D3 thus provides a simple and extremely effective way to suppress secondary hyperparathyroidism in dialysis patients.

686 citations



Journal ArticleDOI
TL;DR: A rapid one-stage clotting assay for protein S to quantitate the level of protein S in their plasma is developed and suggests that protein S deficiency may result in recurrent thrombotic disease.
Abstract: Recent studies have demonstrated that protein C deficiency is associated with recurrent familial thrombosis In plasma, activated protein C functions as an anticoagulant This anticoagulant response requires a vitamin K-dependent plasma protein cofactor, referred to as protein S Since the anticoagulant activity of activated protein C is dependent on protein S, we hypothesized that patients lacking functional protein S might have associated thrombotic disease Two related individuals with otherwise normal coagulation tests are described whose plasma is not effectively anticoagulated with activated protein C Addition of purified human protein S to their plasma restores a normal anticoagulant response to activated protein C We have developed a rapid one-stage clotting assay for protein S to quantitate the level of protein S in their plasma Plasma is depleted of protein S by immunoadsorption with immobilized antiprotein S antibodies The resultant plasma responds poorly to activated protein C, but is effectively anticoagulated in a dose-dependent fashion upon addition of purified protein S or small quantities of plasma The affected individuals possess less than 5% protein S activity Using Laurell rockets, protein S antigen was detected in the plasma but was at reduced levels of 13 and 18% in the two individuals When the barium eluate of the patient plasma was chromatographed on quaternary aminoethyl Sephadex, a single peak of protein S antigen devoid of protein S anticoagulant cofactor activity was detected early in the chromatogram In contrast, the barium eluate from normal donors separated into two peaks, one emerging early and also devoid of anticoagulant cofactor, and the second peak with anticoagulant activity emerging later The first peak of protein S antigen, from both the normal donor and the patient, chromatographed in the region of the complement component C4-binding protein-protein S complex These studies suggest that protein S deficiency may result in recurrent thrombotic disease

602 citations


Journal ArticleDOI
TL;DR: The results suggest that omega-3 fatty acids may be an essential nutrient, and that 22:6 omega 3 may have a specific function in the photoreceptor membranes of the retina.
Abstract: Linolenic acid (18:3 omega 3) is a dietary precursor of docosahexaenoic acid (22:6 omega 3), the major fatty acid in the photoreceptor membranes of the retina. We hypothesized that rhesus monkeys deprived of dietary omega-3 fatty acids during prenatal and postnatal development would show plasma depletion of these fatty acids and visual impairment. Semipurified diets low in omega-3 fatty acids were fed to one group of adult female rhesus monkeys throughout pregnancy and to their infants from birth. A control group of mothers and infants received similar diets but supplying ample linolenic acid. In the plasma phospholipids of deficient infants, linolenic acid was generally undetectable and 22:6 omega 3 levels became progressively depleted, falling from 42% of control values at birth to 21% at 4 wk, 9% at 8 wk, and 6% at 12 wk of age. In the other plasma lipid classes, 22:6 omega 3 was undetectable by 12 wk. The visual acuity of the deprived infants, as measured by the preferential looking method, was reduced by one-fourth at 4 wk (P less than 0.05) and by one-half at 8 and 12 wk (P less than 0.0005) compared with control infants. These results suggest that omega-3 fatty acids may be an essential nutrient, and that 22:6 omega 3 may have a specific function in the photoreceptor membranes of the retina.

588 citations


Journal ArticleDOI
TL;DR: The highly polyunsaturated fatty acids in fish oils lower the plasma triglyceride concentration and presumptive evidence for substantial independent influx of LDL during the fish oil diet is found, based on the precursor-product relationship between the intermediate density lipoprotein and LDL apoprotein B specific radioactivity-time curves.
Abstract: The highly polyunsaturated fatty acids in fish oils lower the plasma triglyceride concentration We have studied the effect of a diet rich in fish oil on the rate of production of the triglyceride-transporting very low density lipoprotein (VLDL) Seven subjects, five normal and two with hypertriglyceridemia received up to 30% of daily energy needs from a fish oil preparation that was rich in eicosapentaenoic acid and docosahexaenoic acid, omega-3 fatty acids with five and six double bonds, respectively Compared with a diet similarly enriched with safflower oil (in which the predominant fatty acid is the omega-6 linoleic acid, with two double bonds), the fish oil diet lowered VLDL lipids and B apoprotein concentrations profoundly High density lipoprotein lipids and A1 apoprotein were also lowered, but the effect on low density lipoprotein (LDL) concentration was inconsistent The daily production or flux of VLDL apoprotein B, calculated from reinjected autologous 125I-labeled lipoprotein, was substantially less in six subjects studied after 3 wk of fish oil, compared with after safflower oil This effect on flux was more consistent than that on the irreversible fractional removal rate, which was increased in the four normolipidemic but inconsistent in the hypertriglyceridemic subjects This suggests that fish oil reduced primarily the production of VLDL The daily production of VLDL triglyceride, calculated from the kinetics of the triglyceride specific radioactivity-time curves after [3H]glycerol was injected, also showed very substantial reductions in five subjects studied The marked suppression in VLDL apoprotein B and VLDL triglyceride formation was found not to be due to diminished plasma total free fatty acid or plasma eicosapentaenoic flux, calculated during constant infusions of [14C]eicosapentaenoic acid and [3H]oleic acid in four subjects In two subjects there was presumptive evidence for substantial independent influx of LDL during the fish oil diet, based on the precursor-product relationship between the intermediate density lipoprotein and LDL apoprotein B specific radioactivity-time curves

581 citations


Journal ArticleDOI
TL;DR: Assessment of the arteriovenous difference for GSSG across the lungs after paraquat administration demonstrated that the lung may be a significant source of plasma G SSG.
Abstract: Regulation of the biliary excretion of reduced glutathione (GSH) and glutathione disulfide (GSSG) and responses to selected model toxins were examined in male Sprague-Dawley rats. In control and phenobarbital-pretreated rats in which the intrahepatic concentration of GSH was modulated by the administration of diethyl maleate or acetaminophen, the biliary concentration of GSH was consistently lower than, but directly proportional to, the intrahepatic concentration of GSH. Furthermore, increments in bile flow produced by the infusion of sulfobromophthalein (BSP)-glutathione were associated with proportional increases in the biliary excretion of GSH, suggesting that GSH passes into bile passively along a concentration gradient. In contrast, GSSG appears to be secreted into bile against a steep concentration gradient. An increased hepatic production and biliary excretion of GSSG resulted from the administration of t-butyl hydroperoxide. Measurement of biliary GSSG and BSP during a constant infusion of the GSH adduct of BSP indicated that GSSG shares a common excretory mechanism with GSH adducts. Diquat, nitrofurantoin, and paraquat also markedly stimulated the biliary excretion of GSSG. On a molar basis, these compounds generated much more GSSG than a direct substrate for glutathione peroxidase such as t-butyl hydroperoxide, indicating that the compounds undergo redox-cycling with concomitant production of hydrogen peroxide. Aminopyrine (0.8 mmol/kg) also significantly increased biliary GSSG. This increase, however, was associated with a proportional increase in bile flow and in the biliary excretion of GSH such that the GSSG/GSH ratio in bile did not change. Acetaminophen and chloroform, two compounds generating electrophilic metabolites that deplete intrahepatic GSH, led to a progressive decrease in the biliary excretion of GSH and GSSG. Furosemide and dimethylnitrosamine, the electrophilic metabolites of which do not deplete hepatic GSH, minimally altered biliary GSH and GSSG. Similarly, carbon tetrachloride and iproniazid, which yield organic radical metabolites that can peroxidize membrane lipids, did not increase the biliary excretion of GSSG. This finding indicates that membrane-bound lipid hydroperoxides may not be good substrates for glutathione peroxidases. The measurement of the biliary excretion of GSSG and of the GSSG/GSH ratio in bile is a sensitive index of oxidative stress in vivo and thus complements other in vivo parameters for the study of reactive intermediates of xenobiotics such as the determination of covalent binding, the formation of lipid hydroxy acids, and the depletion of intracellular GSH.

555 citations


Journal ArticleDOI
TL;DR: Human monocyte-derived macrophages took up and esterified the cholesterol from modified low density lipoprotein more extensively than from native low densitylipoprotein.
Abstract: Modification of low density lipoproteins by human arterial smooth muscle cells was characterized by increased electrophoretic mobility and increased content of malondialdehyde-like oxidation products reactive with thiobarbituric acid. Lipoprotein modification was promoted by micromolar concentrations of iron or copper in the culture medium and was metal ion concentration- and time-dependent. The ability of diverse media to promote smooth muscle cell-mediated low density lipoprotein modification correlated with their iron concentration. Therefore, metal ion concentration of culture media contributes substantially to low density lipoprotein modification in vitro. Human monocyte-derived macrophages took up and esterified the cholesterol from modified low density lipoprotein more extensively than from native low density lipoprotein. Metal ion-mediated modification of low density lipoprotein may be a contributing factor to the pathogenesis of arteriosclerosis.

526 citations


Journal ArticleDOI
TL;DR: It is suggested that patients with NIDDM possess markedly decreased maximal insulin responsiveness to the potentiating effects of glucose, which indicates the presence of a reduced B cell secretory capacity and suggests a marked generalized impairment of B cell function in patients withNIDDM.
Abstract: In order to assess whether patients with noninsulin-dependent diabetes mellitus (NIDDM) possess normal insulin secretory capacity, maximal B cell responsiveness to the potentiating effects of glucose was estimated in eight untreated patients with NIDDM and in eight nondiabetic controls. The acute insulin response to 5 g intravenous arginine was measured at five matched plasma glucose levels that ranged from approximately 100-615 mg/dl. The upper asymptote approached by acute insulin responses (AIRmax) and the plasma glucose concentration at half-maximal responsiveness (PG50) were estimated using nonlinear regression to fit a modification of the Michaelis-Menten equation. In addition, glucagon responses to arginine were measured at these same glucose levels to compare maximal A cell suppression by hyperglycemia in diabetics and controls. Insulin responses to arginine were lower in diabetics than in controls at all matched glucose levels (P less than 0.001 at all levels). In addition, estimated AIRmax was much lower in diabetics than in controls (83 +/- 21 vs. 450 +/- 93 microU/ml, P less than 0.01). In contrast, PG50 was similar in diabetics and controls (234 +/- 28 vs. 197 +/- 20 mg/dl, P equals NS) and insulin responses in both groups approached or attained maxima at a glucose level of approximately 460 mg/dl. Acute glucagon responses to arginine in patients with NIDDM were significantly higher than responses in controls at all glucose levels. In addition, although glucagon responses in control subjects reached a minimum at a glucose level of approximately 460 mg/dl, responses in diabetics declined continuously throughout the glucose range and did not reach a minimum. Thus, A cell sensitivity to changes in glucose level may be diminished in patients with NIDDM. In summary, patients with NIDDM possess markedly decreased maximal insulin responsiveness to the potentiating effects of glucose. Such a defect indicates the presence of a reduced B cell secretory capacity and suggests a marked generalized impairment of B cell function in patients with NIDDM.

Journal ArticleDOI
TL;DR: The results of this study indicate that in the human luteal phase, the frequency of pulsatile release of LH declines progressively and correlates well with the duration of exposure to progesterone, and the amplitude of LH pulses varies with the appearance of an increased percentage of smaller pulses correlatingwell with the acute level of progestersone.
Abstract: The pattern of episodic gonadotropin release was studied in 15 normal female volunteers during the luteal phase of the menstrual cycle with 24 h of blood sampling for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 10-min intervals. Six subjects (two in the early, two in the mid-, and two in the late luteal phase) also had each of these specimens processed for progesterone levels. A progressive slowing of LH pulsations was present across the luteal phase with the mean LH pulse frequency declining from 15.2 pulses/24 h in the early to 8.4/24 h in the late luteal phase. A trend towards reduction in the amplitude of LH pulses was also observed (12.3 +/- 2.2 SD mIU/ml in the early vs. 8.6 +/- 3.4 mIU/ml in the late luteal phase; NS). In addition, LH pulses of heterogeneous amplitude were identified during the same 24-h study. The mean +/- SD of the larger and of the smaller LH pulses was 16.9 +/- 4.7 and 2.3 +/- 1.0 mIU/ml, respectively (P less than 0.001). While the slowing of the frequency of all LH pulses correlated well (r = 0.80, P less than 0.001) with the day of the luteal phase and poorly with the actual plasma progesterone levels, the incidence of the small LH pulses was highest in the mid-luteal phase and correlated well with the mean progesterone plasma levels (r = 0.63, P less than 0.01). In the early luteal phase, the pattern of progesterone secretion was stable over the 24-h studies and showed no relationship to episodic LH release. In contrast, in the mid- and late luteal phase, plasma progesterone concentrations rapidly fluctuated during the 24-h studies from levels as low as 2.3 to peaks of 40.1 ng/ml, often within the course of minutes. Progesterone increments closely attended episodes of LH release, as documented by the significant (P less than 0.05) cross-correlation between LH and progesterone levels, at time lags of 25-55 min. The results of this study indicate that in the human luteal phase: (a) the frequency of pulsatile release of LH declines progressively and correlates well with the duration of exposure to progressively and correlates well with the duration of exposure to progesterone; (b) the amplitude of LH pulses varies with the appearance of an increased percentage of smaller pulses correlating well with the acute level of progesterone; (c) in the early luteal phase, the pattern of progesterone secretion is stable; (d) in the mid- and late luteal phase, progesterone secretion is episodic, and correlates with LH pulsatile release; and (e) single progesterone estimations in the mid- and late luteal phase do not accurately reflect corpus luteum adequacy.

Journal ArticleDOI
TL;DR: Although examination of DNA synthesis in erythroid marrow cells in vitro revealed no decreased methylcytidine incorporation, Eco RI + Hpa II digestion of DNA revealed that hypomethylation of gamma-genes had taken place in vivo after treatment, suggesting that hydroxyurea is a potentially useful agent for the treatment of sickle cell anemia and that demethylation of the gamma-globin genes accompanies increased gamma- globin gene activity.
Abstract: Hydroxyurea, a widely used cytotoxic/cytostatic agent that does not influence methylation of DNA bases, increases fetal hemoglobin production in anemic monkeys. To determine its effect in sickle cell anemia, we treated two patients with a total of four, 5-d courses (50 mg/kg per d, divided into three oral doses). With each course, fetal reticulocytes increased within 48-72 h, peaked in 7-11 d, and fell by 18-21 d. In patient I, fetal reticulocytes increased from 16.0 +/- 2.0% to peaks of 37.7 +/- 1.2, 40.0 +/- 2.0, and 32.0 +/- 1.4% in three successive courses. In patient II the increase was from 8.7 +/- 1.2 to 50.0 +/- 2.0%. Fetal hemoglobin increased from 7.9 to 12.3% in patient I and from 5.3 to 7.4% in patient II. Hemoglobin of patient I increased from 9.0 to 10.5 g/dl and in patient II from 6.7 to 9.9 g/dl. Additional single-day courses of hydroxyurea every 7-20 d maintained the fetal hemoglobin of patient I t 10.8-14.4%, and the total hemoglobin at 8.7-10.8 g/dl for an additional 60 d. The lowest absolute granulocyte count was 1,600/mm3; the lowest platelet count was 390,000/mm3. The amount of fetal hemoglobin per erythroid burst colony-forming unit (BFU-E)-derived colony cell was unchanged, but the number of cells per BFU-E-derived colony increased. Although examination of DNA synthesis in erythroid marrow cells in vitro revealed no decreased methylcytidine incorporation, Eco RI + Hpa II digestion of DNA revealed that hypomethylation of gamma-genes had taken place in vivo after treatment. This observation suggests that hydroxyurea is a potentially useful agent for the treatment of sickle cell anemia and that demethylation of the gamma-globin genes accompanies increased gamma-globin gene activity.

Journal ArticleDOI
TL;DR: Free superoxide dismutase and catalase injected intravenously in the absence of liposomes did not increase corresponding lung enzyme activities, affect pleural effusion volume, lung wet weight, or extend the mean survival time of rats exposed to 100% oxygen.
Abstract: Survival of rats exposed to 100% oxygen was increased from 69.5 +/- 1.5 to 118.1 +/- 9.9 h (mean +/- SEM, P less than 0.05) when liposomes containing catalase and superoxide dismutase were injected intravenously before and during exposure. The increased survival time in 100% oxygen was also associated with significantly less fluid in the pleural cavity. Rats injected with catalase- and superoxide dismutase-containing liposomes, which had increased survival in 100% oxygen, had increased lung wet weight upon autopsy compared with saline-injected controls (2.9 +/- 0.2 g/lung vs. 4.8 +/- 0.4 g/lung, mean +/- SE, P less than 0.05). Intravenous injection of control liposomes along with catalase and superoxide dismutase in the suspending buffer decreased the mean pleural effusion volume 89% and had no significant effect on survival time. Lung catalase and superoxide dismutase activities were increased 3.1- and 1.7-fold, respectively, 2 h after a single intravenous injection of liposomes containing catalase or superoxide dismutase. Superoxide dismutase activity was also significantly greater than controls in both air- and 100% oxygen-exposed rat lungs, when enzyme activity was assayed 24 h after cessation of injection of control and oxygen-exposed rats with enzyme-containing liposomes every 12 h for 36 h. Free superoxide dismutase and catalase injected intravenously in the absence of liposomes did not increase corresponding lung enzyme activities, affect pleural effusion volume, lung wet weight, or extend the mean survival time of rats exposed to 100% oxygen. The clearance of liposome-augmented 125I-labeled catalase from lung and plasma obeyed first order kinetics according to a one-compartment model. When clearance of liposome-augmented catalase activity or radioactivity were the parameters used for pharmacokinetic studies, the half-life of augmented lung catalase was 1.9 and 2.6 h, respectively. The half-life of liposome-entrapped catalase and superoxide dismutase activity in the circulation was 2.5 and 4 h, respectively, while intravenously injected catalase and superoxide dismutase had a circulation half-life of 23 and 6 min, respectively.

Journal ArticleDOI
TL;DR: The results suggest that the in vivo as well as in vitro interaction of PMN with a nonphagocytosable foreign body induces a complex PMN defect, which may be partly responsible for the high susceptibility to infection of foreign bodies.
Abstract: Implanted foreign bodies are highly susceptible to pyogenic infections and represent a major problem in modern medicine. In an effort to understand the pathogenesis of these infections, we studied the phagocytic function in the vicinity of a foreign body by using a recently developed guinea pig model of Teflon tissue cages subcutaneously implanted (Zimmerli, W., F.A. Waldvogel, P. Vaudaux, and U.E. Nydegger, 1982, J. Infect. Dis., 146:487-497). Polymorphonuclear leukocytes (PMN) purified from tissue cage fluid had poor bactericidal activity against a catalase-positive microorganism. When compared with blood or exudate PMN, they exhibited a significant reduction in their ability to generate superoxide in response to a particulate or a soluble stimulus (72 and 57%, respectively, P less than 0.001). Not only their total contents in myeloperoxidase, beta-glucuronidase, lysozyme, and B12 binding protein were significantly reduced (by 62, 21, 47, and 63%, respectively, P less than 0.01), but also their capability for further secretion of residual B12 binding protein upon stimulation. Ingestion rates of endotoxin-coated opsonized oil particles were reduced by 25% (P less than 0.05). In an effort to reproduce these abnormalities in vitro, fresh peritoneal exudate PMN were incubated with Teflon fibers in the presence of plasma. Interaction of PMN with the fibers led to significant increases in hexose monophosphate shunt activity and exocytosis of secondary granules (P less than 0.01). PMN eluted after such interaction showed defective bactericidal activity, oxidative metabolism, and granular enzyme content similar to those observed in tissue cage PMN. The local injection of fresh blood PMN into tissue cages at the time of, or 3 h after, inoculation with 100 microorganisms (Staphylococcus aureus Wood 46) reduced the infection rate from 50 to 56 cages to 1 of 21 (P less than 0.001) and 3 of 8 cages (P less than 0.001), respectively. These results suggest that the in vivo as well as in vitro interaction of PMN with a nonphagocytosable foreign body induces a complex PMN defect, which may be partly responsible for the high susceptibility to infection of foreign bodies.

Journal ArticleDOI
TL;DR: Calcitriol is a potent inhibitor of PHA-induced lymphocyte blast transformation and that this effect is mediated, in part, through suppression of IL-2 production, and appears to possess immunoregulatory properties that have been unapp appreciated heretofore.
Abstract: Recent studies have suggested that vitamin D may have other important biologic activities in addition to its well-characterized role in the maintenance of calcium homeostasis. Discovery of cytosolic receptors for vitamin D in human peripheral blood monocytes and lectin-stimulated lymphocytes prompted us to study the effects of 1,25-dihydroxyvitamin D3 (calcitriol), the most biologically active metabolite of vitamin D, upon phytohemagglutinin (PHA)-induced lymphocyte blast transformation. We have found that calcitriol is a potent inhibitor of PHA-induced lymphocyte proliferation, achieving 70% inhibition of tritiated thymidine incorporation after 72 h in culture. Furthermore, calcitriol suppressed interleukin-2 (IL-2) production by PHA-stimulated peripheral blood mononuclear cells in a concentration-dependent fashion. Lastly, the suppressive effect of calcitriol on cellular proliferation was partially reversed by the addition of saturating amounts of purified IL-2. We conclude that calcitriol is a potent inhibitor of PHA-induced lymphocyte blast transformation and that this effect is mediated, in part, through suppression of IL-2 production. Thus, calcitriol appears to possess immunoregulatory properties that have been unappreciated heretofore.

Journal ArticleDOI
TL;DR: It is demonstrated that 1,25-(OH)2-D3 is a potent inhibitor of human PBM Ig production in vitro and suggested that this action is mediated through the hormone's antiproliferative effect on Ig-producing B cells and/or helper T cells.
Abstract: Activated B and T lymphocytes from normal human subjects are known to have the specific high-affinity receptor for 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). In an attempt to determine a functional role for the sterol in such cells, we studied the effect of 1,25-(OH)2-D3 on DNA synthesis and Ig production by normal human peripheral blood mononuclear (PBM) cells activated in vitro by the polyclonal lymphocyte activators pokeweed mitogen and phytohemagglutinin, and the specific antigen dermatophyton O. A dose-dependent inhibition of [3H]thymidine incorporation was observed in cells incubated with 1,25-(OH)2-D3 in concentrations ranging from 10(-10) to 10(-7) M. Production of IgG and IgM, determined by enzyme-linked immunosorbent assay, was similarly inhibited by increasing concentrations of 1,25-(OH)2-D3. Half-maximal inhibition of DNA and Ig synthesis was found at 10(-10) to 10(-9) M 1,25-(OH)2-D3. This suppressive effect was specific for 1,25-(OH)2-D3; of the other vitamin D metabolites examined, only 10(-7) M 24R,25 dihydroxyvitamin D3 (24,25-(OH)2-D3) had a similar inhibitory effect. 1,25-(OH)2-D3 was not cytotoxic and did not affect unactivated PBMs. These data demonstrate that 1,25-(OH)2-D3 is a potent inhibitor of human PBM Ig production in vitro and suggest that this action is mediated through the hormone's antiproliferative effect on Ig-producing B cells and/or helper T cells.

Journal ArticleDOI
TL;DR: Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.
Abstract: The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.

Journal ArticleDOI
TL;DR: It is suggested that the variant TTR represents the specific biochemical cause of the disease, and that this abnormal form of TTR selectively deposits in tissues as the amyloid characteristic of the Alzheimer's disease.
Abstract: Amyloid fibril protein in patients with familial amyloidotic polyneuropathy is known to be chemically related to transthyretin (TTR), the plasma protein that is usually referred to as prealbumin. A genetically abnormal TTR may be involved in this disease. Studies were conducted on amyloid fibril protein (AFp) isolated from tissues of two Portuguese patients who died with familial amyloidosis, and on TTR isolated from sera of patients with this disease. AFp, purified by affinity chromatography on retinol-binding protein linked to Sepharose, resembled plasma TTR in forming a stable tetrameric structure, and in its binding affinities for both thyroxine and retinol-binding protein. The structural studies included: (a) comparative peptide mappings by reverse-phase high performance liquid chromatography (HPLC) after trypsin digestion; (b) cyanogen bromide cleavage studies; and (c) amino acid microsequence analysis of selected tryptic and CNBr peptides. On the basis of the known amino acid sequence of TTR, comparative tryptic peptide maps showed the presence of a single aberrant tryptic peptide (peptide 4, residues 22-34) in AFp as compared with TTR. This aberrant peptide contained a methionine residue, not present in normal tryptic peptide 4. CNBr cleavage of AFp produced two extra peptide fragments, which were demonstrated, respectively, by HPLC analysis and by sodium dodecyl sulfate-gel electrophoresis. Sequence analyses indicated the presence of a methionine-for-valine substitution at position 30 in AFp as compared with TTR. Thus, the purified amyloid fibril protein comprised a TTR variant with a methionine-forvaline substitution at position 30. A single nucleotide change in a possible codon for valine 30 could explain the substitution. The variant TTR was also present in the TTR isolated from the pooled sera of amyloidoses patients, together with larger (four- to six-fold) amounts of the normal TTR. Thus, in these patients, the variant TTR was circulating in plasma, along with larger amounts of normal TTR. We suggest that the variant TTR represents the specific biochemical cause of the disease, and that this abnormal form of TTR selectively deposits in tissues as the amyloid characteristic of the disease.

Journal ArticleDOI
TL;DR: The occurrence of this enzyme in various human tissues that were removed from two accidental death victims and in 19 different human cultured cell lines was determined, and most tissues contained more extracellular-superoxide dismutase than did the investigated cell lines.
Abstract: Extracellular-superoxide dismutase is a tetrameric copper-containing glycoprotein that previously has been demonstrated to be the major superoxide dismutase of human extracellular fluids. The occurrence of this enzyme in various human tissues that were removed from two accidental death victims and in 19 different human cultured cell lines was determined. All investigated tissues were found to contain extracellular-superoxide dismutase. There was a larger variation between tissues in the concentration of this enzyme than in CuZn superoxide dismutase and Mn superoxide dismutase. No relation could be demonstrated between the content of extracellular-superoxide dismutase and the content of the other superoxide dismutase isoenzymes in the various tissues. In uterus there was more extracellular-superoxide dismutase than Mn superoxide dismutase, but in all other tissues the content of extracellular-superoxide dismutase was lower than the content of the other isoenzymes. The concentration of extracellular-superoxide dismutase was higher in all investigated human tissues than in human plasma. 19 human cultured cell lines were found to be devoid of or to contain very little extracellular-superoxide dismutase. Most tissues contained more extracellular-superoxide dismutase than did the investigated cell lines.

Journal ArticleDOI
TL;DR: It is reported that stimulated polymorphonuclear leukocytes mobilize iron from human and horse ferritin, but not from human transferrin, and it is proposed that this reaction may potentiate the formation of the OH.
Abstract: During inflammation, the superoxide anion (O-2) and hydrogen peroxide (H2O2) are produced by stimulated polymorphonuclear leukocytes and macrophages. The toxic effects of these reactive oxygen intermediates increase when traces of iron are present, because iron catalyzes the formation of the hydroxyl radical (OH.). Partially saturated iron-binding proteins, such as transferrin and ferritin, are unable to catalyze OH. formation in vitro. Mobilization of iron from these proteins is necessary for iron stimulation of OH. formation. This paper reports that stimulated polymorphonuclear leukocytes mobilize iron from human and horse ferritin, but not from human transferrin. Iron release from ferritin depends on O-2 because it can be prevented by the addition of superoxide dismutase. Catalase and dimethylsulfoxide have no inhibitory effect on iron mobilization. The efficiency of the iron release increases at low levels of O-2 production. Only O-2 produced by granulocytes is sufficient for iron mobilization, because solid potassium superoxide is also able to release iron from ferritin. We propose that this reaction may potentiate the formation of the OH. radical in inflammatory states.

Journal ArticleDOI
TL;DR: Elevated levels of EGF receptor are detected in biopsy specimens of human squamous cell carcinomas of the lung with a murine monoclonal antibody, EGF-R1, which binds specifically to the receptor, and may be an excellent marker for epidermoid malignancies.
Abstract: Epidermal growth factor (EGF) promotes the growth of cultured benign and malignant cells. Recent studies have demonstrated that the amount of EGF receptor is elevated in squamous cell carcinoma cells in tissue culture when compared with normal epidermal cells. This study demonstrates that elevated levels of EGF receptor are detected in biopsy specimens of human squamous cell carcinomas of the lung with a murine monoclonal antibody, EGF-R1, which binds specifically to the receptor. The increased receptor ranged from 2.5- to 5-fold that of normal skin. These findings have been observed in 11 of 11 squamous carcinomas and two of two epidermoid head and neck cancers. Seven of eight adenocarcinomas, two of two small cell, and four of eight undifferentiated lung cancers had negligible amounts of EGF receptor. The EGF receptor antibody did not bind significantly to normal lung tissues and 35 nonepidermoid tumors. Therefore, EGF receptor may be an excellent marker for epidermoid malignancies.

Journal ArticleDOI
TL;DR: It is demonstrated that both CR3 and CR1 expression increase rapidly upon activation of PMN and that isolated cells can be used to study this phenomenon, which may be a critical part of neutrophil function in vivo.
Abstract: We used monoclonal antibodies and flow cytometry to study the expression of the receptors for the complement fragments C3bi (CR3) and C3b (CR1) on human polymorphonuclear neutrophil leukocytes (PMN). Expression of both receptors was minimal on cells stained in anticoagulated whole blood incubated at 0 degree or 37 degrees C. PMN isolated with Percoll density gradients and held at 0 degree C also had only minimal expression of both receptors. With the isolated cells, however, a spontaneous increase in expression of both receptors occurred upon warming to 37 degrees C. This did not represent complete expression of either receptor since additional increments in surface expression could be induced upon stimulation with N-formyl-methionyl-leucyl-phenylalanine or Raji cell supernatant. The increases in complement receptor (CR) expression appeared to be specific since there were no changes in expression of the Fc gamma receptor or beta-2-microglobulin under any of these conditions. The increased CR expression seems to involve translocation from an intracellular pool since it is complete within minutes and is not blocked by puromycin or cycloheximide. These results demonstrate that both CR3 and CR1 expression increase rapidly upon activation of PMN and that isolated cells can be used to study this phenomenon, which may be a critical part of neutrophil function in vivo.

Journal ArticleDOI
TL;DR: It is shown that platelets contain an inhibitor which is released by thrombin, inhibits both urokinase and tissue-type plasminogen activator, and is immunologically similar to an inhibitor produced by endothelial cells, which may represent a new class of inhibitors, the antiactivators.
Abstract: In this study, we demonstrate the presence of a previously undescribed fibrinolytic inhibitor in human serum. It has an apparent molecular weight of 50,000 and is not detected in serum derived from platelet-poor plasma, suggesting that it originates from platelets. This conclusion is supported by a number of observations. For example, extracts of washed, gel-filtered human platelets contain an inhibitor of similar activity and size, and physiological concentrations of thrombin induce its release from the platelets. Moreover, the kinetics and dose dependency of this release are similar to those observed for the release of platelet factor 4, and the release of both molecules is blocked by pretreating the platelets with prostaglandin E1 and theophylline. Mixing experiments, which were devised to investigate the specificity of the inhibitor, showed that the fibrinolytic activity initiated by both urokinase and tissue-type plasminogen activator was blocked by platelet releasate in a dose-dependent manner. In both cases, the amount of inhibition increased when the releasates were preincubated with the purified activators, indicating a direct interaction between the activators and an inhibitor(s). The inhibitory activity was removed by preincubating the releasates with antiserum prepared against an antiactivator purified from cultured bovine aortic endothelial cells. These results indicate that platelets contain an inhibitor which is released by thrombin, inhibits both urokinase and tissue-type plasminogen activator, and is immunologically similar to an inhibitor produced by endothelial cells. This molecule may represent a new class of inhibitors, the antiactivators, which function together with alpha 2-antiplasmin to regulate the fibrinolytic system of the blood. Its release from platelets by thrombin may protect the growing thrombus against premature dissolution initiated by plasminogen activators released by the endothelium.

Journal ArticleDOI
TL;DR: The results showed that muscle glycogen synthase activity at the end of the euglycemic clamp was well correlated with insulin-mediated glucose storage rates at both low and high insulin concentrations, and suggested the possible importance of glycogen synthesis in muscle in determining in vivo insulin- mediated glucose disposal rates in man.
Abstract: We have studied the relationship between in vivo insulin-mediated glucose disposal rates, muscle glycogen content, and muscle glycogen synthase activity in 25 southwest American Indians with normal glucose tolerance and with varying degrees of glucose intolerance. Insulin-mediated glucose disposal (M) was measured by using the hyperinsulinemic euglycemic clamp technique at plasma insulin concentrations of 134 +/- 7 and 1709 +/- 72 microU/ml, with simultaneous indirect calorimetry to assess glucose oxidation and storage rates. Muscle glycogen content and glycogen synthase activity were measured in percutaneous muscle biopsy samples obtained from the vastus lateralis muscle before and after the euglycemic clamp procedure. The results showed that muscle glycogen synthase activity at the end of the euglycemic clamp was well correlated with insulin-mediated glucose storage rates at both low (r = 0.50, P less than 0.02) and high (r = 0.78, P less than 0.0001) insulin concentrations; and also correlated with M (r = 0.66, P less than 0.001 and r = 0.76, P less than 0.0001). Similar correlations were observed between the change in muscle glycogen synthase activity and glucose storage rates and M. The change in muscle glycogen synthase activity correlated with the change in muscle glycogen content (r = 0.46, P less than 0.03) measured before and after the insulin infusions. The change in muscle glycogen content did not correlate with glucose storage rates or M. The data suggest the possible importance of glycogen synthesis in muscle in determining in vivo insulin-mediated glucose disposal rates in man.

Journal ArticleDOI
TL;DR: Findings are relevant to (i) transendothelial transport and the metabolism of macromolecules in normal endothelium and the role of hemodynamic factors in the localization of atherosclerotic lesions in vivo.
Abstract: The relationships between fluid shear stress, a physiologically relevant mechanical force in the circulatory system, and pinocytosis (fluid-phase endocytosis) were investigated in cultured bovine aortic endothelial cells using a specially designed apparatus. Continuous exposure to steady shear stresses (1-15 dyn/cm2) in laminar flow stimulated time- and amplitude-dependent increases in pinocytotic rate which returned to control levels after several hours. After 48 h continuous exposure to steady shear stress, removal to static conditions also resulted in a transient increase in pinocytotic rate, suggesting that temporal fluctuations in shear stress may influence endothelial cell function. Endothelial pinocytotic rates remained constant during exposure to rapidly oscillating shear stress at near physiological frequency (1 Hz) in laminar flow. In contrast, however, a sustained elevation of pinocytotic rate occurred when cells were subjected to fluctuations in shear stress amplitude (3-13 dyn/cm2) of longer cycle time (15 min), suggesting that changes in blood flow of slower periodicity may influence pinocytotic vesicle formation. As determined by [3H]thymidine autoradiography, neither steady nor oscillating shear stress stimulated the proliferation of confluent endothelial cells. These observations indicate that: (a) alterations in fluid shear stress can significantly influence the rate of formation of pinocytotic vesicles in vascular endothelial cells, (b) this process is force- and time-dependent and shows accommodation, (c) certain patterns of fluctuation in shear stress result in sustained elevation of pinocytotic rate, and (d) shear stresses can modulate endothelial pinocytosis independent of growth stimulation. These findings are relevant to (i) transendothelial transport and the metabolism of macromolecules in normal endothelium and (ii) the role of hemodynamic factors in the localization of atherosclerotic lesions in vivo.

Journal ArticleDOI
TL;DR: Testing the effect of short term restriction and supplementation of dietary intake of phosphorus on the plasma concentration of 1,25-(OH)2D, the serum concentrations of immunoreactive parathyroid hormone (iPTH) and phosphorus, and the fractional renal excretion of phosphorus demonstrated that in children with moderate renal insufficiency.
Abstract: The hyperparathyroidism characteristic of patients with moderate renal insufficiency could be caused by decreases in the plasma concentration of ionized calcium (Ca++) evoked by: (a) recurring increases in the plasma concentration of inorganic phosphorus that may be detectable only in the post-prandial period; (b) a reversible, phosphorus-mediated suppression of renal 25-hydroxyvitamin D-1 alpha-hydroxylase that decreases the plasma concentration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) enough to decrease both gut absorption and bone resorption of Ca++; (c) both of these. In a group of eight children with moderate renal insufficiency, mean glomerular filtration rate (GFR) 45 +/- 4 (SE) ml/min per 1.73 M2, ages 6-17 yr, we tested these hypotheses by determining the effect of short term (5 d) restriction and supplementation of dietary intake of phosphorus on the plasma concentration of 1,25-(OH)2D, the serum concentrations of immunoreactive parathyroid hormone (iPTH) and phosphorus, and the fractional renal excretion of phosphorus ( FEPi ). When dietary phosphorus was normal, 1.2 g/d, the serum concentrations of phosphorus throughout the day were not greater than those of normal control children, and the serum concentrations of carboxyl-terminal iPTH (C-iPTH) were greater, 59 +/- 9 vs. 17 +/- 3 mu leq/ml, and unchanging; the serum concentration of intact-iPTH was also greater, 198 +/- 14 vs. 119 +/- 8 pg/ml. The plasma concentration of 1,25-(OH)2D was lower than that of age-matched controls, 27 +/- 3 vs. 36 +/- 2 pg/ml (P less than 0.01). When dietary phosphorus was restricted to 0.35 g/d, the plasma concentration of 1,25-(OH)2D increased by 60% to a mean value not different from that of normal controls, while serum concentrations of C-iPTH and intact-iPTH decreased by 25%, the latter concentration to a mean value not different from that of controls. FEPi decreased from 31 to 9%. When dietary phosphorus was supplemented to 2.4 g/d, the plasma concentration of 1,25-(OH)2D decreased 32%, while those of C-iPTH and intact-iPTH increased by 131 and 45%, respectively; FEPi increased from 27 to 53%. Plasma concentrations of 25-hydroxyvitamin D remained normal and unchanged, and GFR did not change when dietary phosphorus was manipulated. The data demonstrate that in children with moderate renal insufficiency: (a) A normal dietary intake of phosphorus in attended by a decreased circulating concentration of 1,25-(OH)2D and an increased concentration of iPTH, but not by recurring increases in the serum concentration of phosphorus at any time of the day; (b) Dietary phosphorus is, however, a major determinant of the circulating concentrations of both 1,25-(OH)2D and iPTH, which vary inversely and directly, respectively, with dietary intake of phosphorus, and increase and decrease, respectively, to normal values when phosphorus is restricted for 5 d; (c) Restriction and supplementation of dietary phosphorus induces changes in the serum concentration of iPTH that correlate strongly but inversely with those induced in the plasma concentration of 1,25-(OH)2D (r = -0.88, P < 0.001); and (d) The physiologic responsiveness of the renal tubule to changes in dietary phosphorus is to a substantial extent intact. The data provide support for the second hypothesis stated.

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TL;DR: It is concluded that an impaired ability of the aging kidney to synthesize 1,25(OH)2D could contribute to the pathogenesis of senile osteoporosis.
Abstract: Calcium absorption decreases with aging, particularly after age 70 yr. We investigated the possibility that this was due to abnormal vitamin D metabolism by studying 10 normal premenopausal women (group A), 8 normal postmenopausal women within 20 yr of menopause (group B), 10 normal elderly women (group C), and 8 elderly women with hip fracture (group D) whose ages (mean +/- SD) were 37 +/- 4, 61 +/- 6, 78 +/- 4, and 78 +/- 4 yr, respectively. For all subjects, serum 25-hydroxyvitamin D [25(OH)D] did not decrease with age, but serum 1,25-dihydroxyvitamin D [1,25(OH)2D], the physiologically active vitamin D metabolite, was lower (P = 0.01) in the elderly (groups C and D; 20 +/- 3 pg/ml) than in the nonelderly (groups A and B; 35 +/- 4 pg/ml). The increase of serum 1,25(OH)D after a 24-h infusion of bovine parathyroid hormone fragment 1-34, a tropic agent for the enzyme 25(OH)D 1 alpha-hydroxylase, correlated inversely with age (r = -0.58; P less than 0.001) and directly with glomerular filtration rate (r = 0.64; P less than 0.001). The response was more blunted (P = 0.01) in elderly patients with hip fracture (13 +/- 3 pg/ml) than in elderly controls (25 +/- 3 pg/ml). We conclude that an impaired ability of the aging kidney to synthesize 1,25(OH)2D could contribute to the pathogenesis of senile osteoporosis.

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TL;DR: This pattern of actin expression represents a new reliable protein-chemical marker of experimental and human atheromatous smooth muscle cells and is presented as a novel marker of rat and human aortic intimal thickening.
Abstract: Actin of smooth muscle cells of rat and human aortic media shows a predominance of the alpha-isoform. In experimental rat aortic intimal thickening, in human atheromatous plaque, and in cultured aortic smooth muscle cells, there is a typical switch in actin expression with a predominance of the beta-form and a noticeable amount of gamma-form. This pattern of actin expression represents a new reliable protein-chemical marker of experimental and human atheromatous smooth muscle cells.