Mammary-derived growth inhibitor (MDGI).
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Amino Acid Sequence↗
Biomedical subjects
A Kurtz
Publications and source records attributed to A Kurtz.
Disparate effects of calcium channel blockers on pressure dependence of renin secretion and flow in the isolated perfused rat kidney.
Using the model of isolated perfused rat kidneys this study was performed to investigate whether or not voltage-operated calcium channels are essentially involved in the pressure control of renin secretion from the kidneys. At a perfusion pressure of 100 mm Hg (13.3 kPa) renin secretory rates were 4.2 +/- 0.7 (ng angiotensin I h-1) min-1 g-1. Stepwise reduction of renal perfusion pressure to 80, 60, and 40 mm Hg (10.6, 8.0, 5.3 kPa) resulted in an increase of renin release yielding a 30-fold stimulation at 40 mm Hg vs 100 mm Hg. Increasing the perfusion pressure above 100 mm Hg did not further significantly decrease renin secretion. The perfusate flow rate was also pressure-dependent. Flow rates increased linearly with pressure and reached a plateau at 100 mm Hg, which was maintained up to 160 mm Hg (21.3 kPa). The averaged flow rate at the plateau was 15.5 ml min-1 g-1. In the presence of the three different calcium antagonists nifedipine (5 microM), nitrendipine (3 microM) and verapamil (5 microM), myogenic autoregulation of flow was abolished as indicated by the rise of the pressure/flow curve between 40 and 160 mm Hg. At the same time, however, these calcium channel blockers did not alter the relationship between perfusion pressure and renin secretion. Moreover, the calcium channel agonist Bay K 8644 (5 microM) caused a strong and long-lasting vasoconstriction, without changing renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Identification and localization of microsatellite markers covering human chromosome 18.
To generate microsatellite markers from chromosome 18, we have cytogenetically localized a large number of lambda phage using a deletion mapping panel of somatic cell hybrids. Here we describe the identification of 65 new CA-repeat-containing phage and the localization of five markers developed in other laboratories. This approach allows the selection of a subset of markers that are well spaced across the chromosome and can be developed as genetic markers. The use of PCR-based markers should allow for the rapid genomic screening of disease genes on chromosome 18.
Base Sequence↗
Contribution of fine needle aspiration cytology to diagnosis and management of thyroid disease.
AIMS: To determine the role of fine needle aspiration cytology (FNAC) in the diagnosis and management of thyroid disease. METHODS: Clinical histories of 144 patients who had undergone FNAC of the thyroid were analysed. Clinical presentation, non-invasive investigations including hormone assays, ultrasound, and isotope scan procedures were compared with FNAC diagnoses in all cases and with histological diagnosis in the 28 cases (19%) that had undergone surgery. Clinical management was decided upon combining all of the above investigations. The relative contribution of the FNAC was divided into: essential, additional and non-contributory, misleading. RESULTS: FNAC diagnoses included: 29 (16%) benign colloid goitre, 56 (39%) benign cystic goitre, 24 (17%) thyroiditis, and 22 (15%) neoplasms. Nineteen (13%) of the specimens were unsatisfactory. When compared with clinical diagnoses based on non-invasive diagnostic investigations FNAC represented no improvement on the diagnosis of benign colloid/cystic goitre (55% v 54% respectively). It represented an improvement on the diagnosis of thyroiditis (9% v 17% respectively). FNAC decreased clinically suspicious lesions in which 22 neoplasms were diagnosed from 37% to 15%. Eleven patients with neoplasms underwent surgery and neoplasms were confirmed histologically. Others including lymphoma, metastatic carcinoma, and analplastic carcinoma were managed conservatively. There were four false negative FNAC diagnoses (3%) in clinically suspicious lesions, found on histology to be benign follicular adenomas. CONCLUSIONS: FNAC had an essential role in the diagnosis and management of 23% of our patients, a confirmatory role in 61% of patients, a non-contributory role in 13% when specimens were inadequate, and was misleading in 3% where results were false negative. The positive identification of thyroiditis and neoplasia stands on its own as a justification for FNAC.
Adolescent↗
Phorbol ester inhibits erythropoietin production in human hepatoma cells (Hep G2).
Using the human hepatoma cell line Hep G2, we have studied a possible role of protein kinase C (PKC) activity for regulation of erythropoietin (EPO) production. During a 72-h incubation, EPO production by the cells was stimulated sevenfold by exposure to low oxygen tension (1%) and threefold by exposure to cobaltous chloride (100 microM). The phorbol ester phorbol 12-myristate-13 acetate (PMA) led to a concentration-dependent inhibition of basal and stimulated EPO formation (ED50 10 nM). This decrease of EPO production, which was apparent already after 1 h of incubation with PMA, reached its maximal effect after 24 h and held on for 72 h. It was paralleled by an inhibition of the increase of EPO mRNA levels in response to stimulation. A 24-h preincubation of the cells with PMA (100 nM) virtually blunted the effect of hypoxia on EPO formation. Recovery of EPO synthesis after removal of PMA took 48-72 h. The effect of PMA on EPO production was mimicked by phorbol 12,13-dibutyrate (ED50 1 microM) but not by 4 alpha-phorbol 12,13-didecanoate. The synthetic diacylglycerol analogues oleolyl-acetylglycerol and dioctanoylglycerol (2-200 microM) also had no effect on either basal or stimulated EPO production. Treatment with PMA caused a translocation of the alpha-isoenzyme of PKC from the cytosol to the membrane after 1 h and a disappearance of the membrane-bound form after 24 h of incubation. Staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, two structurally different inhibitors of PKC activity, inhibited basal and stimulated EPO production with ED50 values of 9 nM and 50 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Insulin-like growth factors decrease oxygen-regulated erythropoietin production by human hepatoma cells (Hep G2).
We examined the effects of insulin-like growth factors (IGFs) and insulin on erythropoietin (EPO) production by human hepatoma cells (Hep G2). Compared with normoxia (20% O2), EPO production by Hep G2 cells during a 72-h incubation was stimulated fivefold by exposure to low oxygen tension (1% O2) and nearly threefold by exposure to cobalt chloride (100 microM). IGF-I caused a concentration-dependent attenuation of EPO formation under normoxic conditions and inhibited (maximally 50%) EPO production stimulated by either low oxygen tension or cobalt [half-maximal effect (ED50) approximately 5 nM]. The increase of EPO mRNA levels in response to hypoxia was significantly reduced by IGF-I. Similarly to IGF-I, IGF-II (ED50 approximately 8 nM) and insulin (ED50 approximately 80 nM) also inhibited EPO formation in Hep G2 cells. IGF-I (100 pM-100 nM) stimulated the incorporation of radiolabeled alanine as a measure for total protein synthesis, 3H-labeled thymidine incorporation into DNA, and glycogen synthesis at 20 and 1% O2 in a concentration-dependent fashion. IGF-I exhibited a high affinity for the IGF-I receptor (apparent Kd approximately 3 nM). Unlabeled insulin was greater than 100-fold less potent than IGF-I in competing for 125I-IGF-I binding (apparent Kd approximately 360 nM). Conversely, insulin bound to the insulin receptor with high affinity (apparent Kd approximately 0.3 nM), whereas IGF-I was less than 1% as potent in competing for 125I-insulin binding. In summary, IGFs and insulin exert a negative control function on oxygen-regulated EPO production in Hep G2 cells. The inhibitory effect of IGFs and insulin on EPO formation appears to be mediated via the IGF-I receptor.
Animals↗
Calmodulin antagonists stimulate renin secretion and inhibit renin synthesis in vitro.
To find out whether calmodulin activity could be a common denominator for the cellular control of renin secretion and synthesis, we have examined the effects of calmodulin antagonists on the secretion and the synthesis of renin in primary cultures of mouse juxtaglomerular (JG) cells. We found that the calmodulin antagonists calmidazolium (CMDZ), N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), and trifluoperazine (TFP) strongly stimulated renin release from isolated JG cells with a rank order of potency CMDZ greater than TFP greater than W-7. With the same order of potency as on renin secretion, CMDZ, TFP, and W-7 also inhibited de novo synthesis of renin. This decrease of renin synthesis went in parallel with a general inhibition of protein synthesis in the cultured JG cells. A comparable inhibition of total protein synthesis and renin synthesis as with CMDZ was achieved with cycloheximide. Cycloheximide, however, did not alter renin secretion within 20 h of incubation. Taken together, our findings suggest that inhibition of calmodulin activity exerts a powerful stimulatory effect on the exocytosis of renin in renal JG cells. Calmodulin activity on the other hand is also essentially required for protein and renin synthesis in JG cells. It is not very likely therefore that calmodulin activity positively links renin synthesis and renin secretion in JG cells.
Animals↗
Renal innervation plays no role in oxygen-dependent control of erythropoietin mRNA levels.
To assess the role of renal innervation in O2-dependent control of erythropoietin (EPO) formation, we have determined EPO mRNA levels in both kidneys of unilaterally denervated rats and sham-operated controls using RNase protection. To investigate whether possible effects of renal nerve input are related to the type of hypoxic stimulus and the degree of stimulation, animals were studied under basal conditions, after exposure to normobaric hypoxia (8% O2, 4 h) or CO (0.1%, 4 h), and after acute hemorrhage (decrease in hematocrit from 40.8 +/- 0.5 to 12.7 +/- 0.5% within 7 h; mean +/- SE, n = 6). Serum EPO levels rose on average 22-, 49-, and 48-fold under the three stimuli and were unaffected by unilateral denervation. Renal EPO mRNA levels in unilaterally denervated animals, when expressed in arbitrary units revealed by comparison with an external standard, were 7.0 +/- 1.5 vs. 6.3 +/- 2.0 (normoxia), 432 +/- 136 vs. 451 +/- 156 (normobaric hypoxia), 971 +/- 93 vs. 930 +/- 120 (CO), and 604 +/- 170 vs. 689 +/- 203 (hemorrhagic anemia) in the intact vs. the denervated kidney (mean +/- SE, n = 3). Furthermore, there was no difference between EPO mRNA levels of either kidney of unilaterally denervated animals and levels in sham-operated controls. We conclude that renal nerve input plays no significant role in the control of the EPO gene under both basal and stimulated conditions.
Anemia↗
Age-dependent expression of the erythropoietin gene in rat liver and kidneys.
Using RNAse protection, we have made quantitative measurements of erythropoietin (EPO) mRNA in liver and kidneys of developing rats (days 1-54), to determine the relative contribution of both organs to the total EPO mRNA, to monitor changes which occur with development, and to compare the hypoxia-induced accumulation of EPO mRNA with the changes in serum EPO concentrations. To determine whether developmental and organ-specific responsiveness is related to the type of hypoxic stimulus, normobaric hypoxia was compared with exposure to carbon monoxide (functional anemia). Under both stimuli EPO mRNA concentration in liver was maximal on day 7 and declined during development. In contrast, EPO mRNA concentration in kidney increased during development from day 1 when it was 30-65% the hepatic concentration to day 54 when it was 12-fold higher than in liver. When organ weight was considered the liver was found to contain the majority of EPO mRNA in the first three to four weeks of life, and although, in stimulated animals, the hepatic proportion declined from 85-91% on day 1, it remained approximately 33% at day 54 and was similar for the two types of stimuli. When normalized for body weight the sum of renal and hepatic EPO mRNA in animals of a particular age was related linearly to serum hormone concentrations. However, the slope of this regression increased progressively with development, suggesting age-dependent alterations in translational efficiency or EPO metabolism.
Age Factors↗
The biological role, site, and regulation of erythropoietin production.
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Erythropoietin↗
Insulin-like growth factor I: a modulator of erythropoiesis in uraemic patients?
Anaemia is a feature almost invariably complicating chronic renal failure. Its pathophysiology is multifactorial but the most important cause is erythropoietin (Epo) deficiency. However, either no relation or even a weakly positive relation generally exists between serum immunoreactive (i) Epo and haematocrit values in uraemic anaemia, whereas in anaemias of non-renal origin the correlation is most often strongly negative. Recent evidence indicates that growth hormone also stimulates erythropoiesis. Moreover, late erythroid progenitor cells (CFU-E) require insulin and/or insulin-like growth factor I (IGF-I) for development in vitro. IGF-I has been shown to have a synergistic action with Epo. We have measured serum iEpo and IGF-I levels in 17 haemodialysis patients with severe hyperparathyroidism (mean +/- SEM serum iPTH, 988 +/- 88 pg/ml). Mean age and duration of dialysis treatment were 46.1 +/- 3.4 and 8.8 +/- 1.0 years respectively. Mean haematocrit and haemoglobin values wer 28.1 +/- 1.7% and 9.39 +/- 0.54 g/dl respectively. Mean serum iEpo and IGF-I levels were 20.3 +/- 4.7 mU/ml and 320 +/- 20 ng/ml respectively (normal values for serum iEpo and IGF-I, 17.9 +/- 6 mU/ml and 91 +/- 23 ng/ml respectively). We found that serum IGF-I concentrations were well correlated with haematocrit values (r = 0.68, n = 15, P less than 0.004) whereas serum iEpo values were not (r = 0.41, n = 12, P = 0.18). IGF-I could therefore be an important factor regulating erythropoiesis in uraemic patients, at least when associated with severe hyperparathyroidism.
Adult↗
Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney.
The kidney is the main site of erythropoietin (EPO) formation. Oxygen sensing in the kidney itself plays a major role in the control of EPO synthesis. By in situ hybridization it has been established that the EPO-producing cells are situated in the interstitium of the cortical labyrinth, but they have not been precisely identified. Morphological findings provide new insights into the location and mechanism of oxygen sensing in the kidney. In addition to causing an increase in the number of cells containing EPO messenger RNA, anemia provokes structural changes exclusively in the cortical labyrinth. Specifically, the fibroblasts become enlarged and show increased activity of 5'-nucleotidase, and the S1 segment of the proximal tubule shows similar alterations as in various models of hypoxia. Thus, structures that are situated in the close vicinity of the EPO-producing cells appear to be sensitive to decreased oxygen delivery.
Anemia↗
Oxygen-dependent erythropoietin production by the isolated perfused rat kidney.
In this study we have investigated the role of oxygen delivery and of classic second messengers on erythropoietin production by the isolated perfused rat kidney. We found that the rat kidney was capable of de novo synthesis of erythropoietin. The erythropoietin production rate was inversely related to the oxygen pressure in the perfusate and increased from 0.17 to 1.85 U erythropoietin h-1 g kidney-1 when arterial PO2 was lowered from 500 mmHg to 30 mmHg. Addition of forskolin (10 microM) and 8-bromo-cGMP (100 microM) to the perfusate elicited significant effects on the renal vascular resistance, but had no significant effect on erythropoietin production. Hypoxia-induced erythropoietin formation, however, was blocked by calmidazolium (1 microM) and W-7 (10 microM), two structurally different putative calmodulin antagonists. Calmidazolium and W-7 had no effect on other functional parameters of the isolated perfused rat kidney such as flow rate, glomerular filtration rate or sodium reabsorption. Our findings suggest that the oxygen-sensing mechanism that controls renal erythropoietin production is primarily located in the kidney itself. A calcium/calmodulin-dependent cellular reaction could be involved in the signal transduction process.
Animals↗
Amiloride enhances the secretion but not the synthesis of renin in renal juxtaglomerular cells.
In this study we have examined a potential role of the sodium/proton exchange system in the regulation of renin secretion. We found that the inhibitors of the Na+/H+ antiport, amiloride (1 mM) and ethylisopropylamiloride (EIPA, 50 microM), led to a 125% increase of renin secretion from cultured mouse juxtaglomerular cells. The stimulatory effect of EIPA on renin secretion was dependent on the extracellular concentrations of sodium and hydrogen ions. While lowering the extracellular pH from 7.3 to 7.0, and lowering [Na+]e from 130 mM to 5 mM had no effect on basal renin release, it markedly attenuated or even blunted the effect of EIPA on renin secretion. The stimulatory effect of forskolin on renin secretion, however, was not altered by decreases of extracellular pH and of sodium. Inhibition of basal renin release was achieved with angiotensin II (1 microM). In the presence of EIPA the inhibitory effect angiotensin II was markedly attenuated. Although effective on renin secretion, neither amiloride nor EIPA exerted a significant effect on the denovo synthesis of renin in cultured mouse JG cells. These findings are compatible with the idea that an amiloride-sensitive transport process, presumably the Na+/H+ exchanger, acts indirectly as an inhibitory signal transduction system for renin secretion from renal juxtaglomerular cells.
Amiloride↗
Purification, biological assay, and immunoassay of mammary-derived growth inhibitor.
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Amino Acid Sequence↗
Serial immunoreactive erythropoietin levels in autologous blood donors.
The variations in plasma erythropoietin (EPO) concentration during preoperative deposit of autologous blood were studied in 12 patients (8 men, 4 women). Four donations were scheduled at weekly intervals. A predonation hemoglobin concentration of 11 g per dL (110 g/L) was required. Hemoglobin concentration decreased from 14.3 +/- 1.1 g per dL (143 +/- 11 g/L) (mean +/- SD) before the first donation to 11.7 +/- 0.7 g per dL (117 +/- 7 g/L) on Day 22 (p less than or equal to 0.0001). Reticulocyte counts increased from a median of 31,800 (range, 4900-95,000) per microL (median, 32 x 10(9)/L [range, 5-95 x 10(9)/L]) to 93,800 (16,800-194,900) per microL (median, 94 x 10(9)/L [range, 17-195 x 10(9)/L]) on Day 28 (p less than or equal to 0.01). Plasma EPO concentration was 17.8 +/- 5.1 mU per mL prior to the first donation and displayed a small and transient peak after each donation. A sustained elevation followed each peak. Although plasma EPO concentration differed significantly from the baseline value after the first donation, only the peak concentrations after the second (35.5 +/- 15.5 mU/mL), third (38.0 +/- 14.5 mU/mL), and fourth (36.1 +/- 11.0 mU/mL) donations exceeded the normal range. The moderate, biphasic increase in plasma EPO concentration and the moderate increase in erythropoiesis suggest two strategies in autologous blood donation that should be investigated with respect to efficiency and safety: 1) more aggressive donation schemes, which reduce donation intervals and/or the minimum hemoglobin concentration and 2) the administration of recombinant human EPO.
Adult↗
A controlled study of psychoanalytic treatment of brittle diabetes.
The study compared two equivalent groups of 11 diabetic children with grossly abnormal blood glucose profiles necessitating repeated admissions to a hospital. Patients in the treatment group were offered an intensive inpatient treatment program including psychoanalytic psychotherapy three to four times a week, which took place on the hospital ward and lasted an average of 15 weeks. The intervention was highly effective in improving the diabetic control of the children, and this was maintained at a 1 year follow-up. Patients in the comparison group, who were offered only inpatient medical intervention, returned to their prehospitalization level of metabolic control within a period of 3 months from discharge.
Adolescent↗
Differential response of renin secretion to vasoconstrictors in the isolated perfused rat kidney.
1. We have examined whether an increase of renal vascular resistance is generally accompanied by an inhibition of renin secretion. The effects of vasoconstriction produced by angiotensin II (Ang II), arginine-vasopressin (AVP), and potassium (KCl) depolarization on vascular resistance and on renin release from isolated rat kidneys perfused at constant pressure of 100 mmHg were investigated. 2. Histological examination performed on some representative kidneys revealed that the tubular lumina of all segments within the cortex were patent and the brush borders of the proximal tubules were well preserved. The renal vasculature and the juxtaglomerular region appeared to be morphologically intact. By immunocytochemistry, renin-positive cells were found exclusively in the wall of the afferent arterioles. 3. Basal flow rate through isolated kidneys was 14.5 +/- 2.0 ml min-1 (g kidney weight (gkw))-1 (mean +/- S.E.M., n = 10). Under control conditions renin secretory rates were in the range of 30-40 (ng Ang I h-1) min-1 gkw-1. 4. Ang II (100 pM) caused a decrease of renal flow rate to 42 +/- 2% of control which was accompanied by a reduction of renin secretion rates by a factor of 4. 5. AVP (10 pM to 1 nM) reduced renal perfusate flow in a dose-dependent fashion to a minimum of 25 +/- 3% of control. The vasoconstrictor effect of AVP was paralleled by a concentration-dependent increase of renin secretory rates reaching a factor of maximally 5 when AVP was used at a concentration of 1 nM. The stimulatory effect of AVP on renin release could be mimicked by [deamino-Cys1, D-Arg8]-vasopressin (dDAVP), a vasopressin analogue with prevalent V2 receptor agonistic properties. In the presence of dDAVP (100 nM, 1 microM) renal flow rate reversibly increased by 8 and 12% of control values, respectively. 6. Depolarizing concentrations of KCl (30 mM) decreased perfusate flow to 20 +/- 4% of control. The vasoconstrictor effect of KCl was paralleled by an increase of the arterio-venous difference of perfusate renin activity to such an extent that the rate of renin release remained unaltered. 7. Our findings suggest that there exists no general inverse relationship between renal arteriolar resistance and renin secretion. Our study, moreover, does not support a functional role of potential operated calcium channels in the control of renin secretion. Finally, we conclude that V2 receptors are present on juxtaglomerular epithelioid cell membranes and mediate the stimulatory effect of AVP on renin release from isolated rat kidneys.
Angiotensin II↗