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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 235 records · Page 13Linked to original sources
PubMed1990

In vitro studies of erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes.

Erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes (MDS) was evaluated by measuring the in vitro response of primitive (BFU-E) and relatively mature (CFU-E) erythroid progenitors from 12 patients and from eight healthy donors to recombinant human erythropoietin (rhEPO), and by quantifying relationships between circulating EPO levels and progenitor cell frequencies in MDS marrow. Half-maximal growth of MDS CFU-E and BFU-E was detected at a 4-fold higher rhEPO concentration than required by control erythroid progenitors. Nine of the patients evaluated exhibited maximal growth of erythroid colonies at 5- to 20-fold higher than control saturating rhEPO concentrations. Circulating EPO levels in MDS patients were elevated, with a mean value approximately 35-fold higher than that of controls. The frequency of MDS marrow CFU-E and BFU-E was 57 +/- 42% and 18 +/- 9% of the mean control values, respectively. Correlation analysis of the relationships between MDS EPO levels and erythroid progenitors indicated that the anemia in MDS is not attributable to an abnormality in the capacity of EPO to induce the generation of CFU-E, but may be influenced by the BFU-E population, whose severe deficiency results in insufficient influx of EPO-responsive cells. Our findings therefore suggest that treatment of MDS patients with rhEPO may be of limited benefit, since the generation of BFU-E from more primitive ancestors and the initial growth requirements of these cells are not under the regulatory influence of this hormone.

Adolescent↗
PubMed1989

von Willebrand factor multimer patterns in pregnancy-induced hypertension.

Microangiopathy and disseminated platelet aggregation have been reported in thrombotic thrombocytopenic purpura (TTP) and pregnancy-induced hypertension (PIH). Since unusually large von Willebrand factor (vWF) multimers have been implicated in the evolvement of TTP, we analyzed factor VIII/vWF parameters in patients with PIH. Mean vWF: Ag level was significantly higher in 27 patients with PIH as compared to 20 matched healthy pregnant women (358 +/- 160 u/dl vs. 274 +/- 125 u/dl. p less than 0.05). Moreover, plasma vWF: Ag levels and the ratio of vWF: Ag to factor VIII were found to be linearly correlated to the severity of PIH. In contrast, no significant differences in mean levels of factor VIII and ristocetin cofactor were observed between these groups. Crossed immunoelectrophoresis of vWF revealed a higher incidence of a pre-peak and an increased migration index in the PIH group as compared to the control group (60% vs. 44% and 1.27 +/- 0.26 vs. 1.19 +/- 0.18, p less than 0.01 respectively). Analysis of plasma vWF multimer patterns by 1.4% agarose electrophoresis in 0.1% SDS revealed excessive amounts of large, medium and small size multimers in the PIH patients. Conceivably, the quantitative changes in vWF multimers reflect endothelial injury and may play a role in the microangiopathy observed in PIH.

Adult↗
PubMed1989

Thromboxane A2 and prostacyclin generation in the microvasculature of patients with atherosclerosis--effect of low-dose aspirin.

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Relation of plasma D-dimer concentrations to coronary artery reperfusion before and after thrombolytic treatment in patients with acute myocardial infarction.

This study was designed to investigate the possible role of pre- and posttreatment plasma D-dimer concentration as a reflection of coronary artery thrombolysis. Blood was collected from 206 patients with angiographically documented acute coronary occlusion presenting within 6 hours of symptom onset who were enrolled in a prospective study comparing intravenous APSAC (30 U) (IV-APSAC) with intracoronary streptokinase (160,000 U) (IC-SK). D-dimer concentrations in 104 patients after IV-APSAC therapy were higher than in 90 patients after IC-SK (mean +/- standard error, 1,009 +/- 60 vs 603 +/- 45, p less than 0.001), but there was no difference in patients with and without reperfusion (1,096 +/- 88 vs 875 +/- 67, p = 0.1 for IV-APSAC, and 587 +/- 48 vs 634 +/- 95, p = 0.6 for IC-SK). The median concentrations before treatment were similar in the IV-APSAC and IC-SK groups (93 and 90 ng/ml, respectively). These were higher than the value in 25 ambulatory control subjects (72 ng/ml) but lower than in 29 post-AMI (6 to 30 hours) patients and in preoperative orthopedic patients (140 ng/ml each). There was no difference in D-dimer concentrations in patients with grade 0 or grade 1 coronary artery occlusion (median 85 vs 90 ng/ml) or in patients with or without ultimate successful reperfusion (median 85 vs 93 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Structures of actomyosin crossbridges in relaxed and rigor muscle fibers.

It was shown previously that a significant fraction of the myosin crossbridges is attached to actin in the skinned rabbit psoas fibers under relaxed conditions at low ionic strength and low temperature (Brenner, B., M. Schoenberg, J. M. Chalovich, L. E. Greene, and E. Eisenberg. 1982. Proc. Natl. Acad. Sci. USA. 79:7288-7291; Brenner, B., L. C. Lu, and R. J. Podolsky. 1984. Biophys. J. 46:299-306). In the present work, the structure of the attached crossbridges in the relaxed state between ionic strengths of 20 and 100 mM, as compared with that in the rigor state, is further examined by equatorial x-ray diffraction. Mass distributions projected along the fiber axis are reconstructed based on the first five equatorial reflections such that the spatial resolution is 128 A. The fraction of crossbridges attached under relaxed conditions are estimated to be in the range of 30% (at 100 mM ionic strength) and 60% (at 20 mM). The reconstructed density maps suggest that in the relaxed state, upon attachment the part of the crossbridge that centers around the thin filament is small, and the attachment does not significantly alter the center of mass of the myosin head distribution around the thick filament backbone. In contrast, accretion of mass in the rigor state occurs in a wider region surrounding the thin filament. In this case, mass in the surface region of the thick filament backbone is shifted slightly outward, probably by approximately 10 A. A schematic model for interpreting the present data is presented.

Actomyosin↗
PubMed1989

Lidocaine pharmacokinetics during water immersion in normal humans.

Water immersion produces a marked diuresis, natriuresis, and kaliuresis in association with suppression of the renin-aldosterone system. These effects are mediated primarily by an increase in central blood volume. Consequently, this redistribution and the resultant marked increase in cardiac output is associated with alterations in the circulating levels of several volume regulatory hormones, including plasma renin activity and plasma aldosterone. Although the changes in these blood hormonal levels probably reflect perturbation of hormonal release, it is conceivable that the above-mentioned central hemodynamic modifications result in an altered splanchnic blood flow, thereby modulating hormonal clearances. We assessed the effects of immersion on hepatic blood flow by determining the pharmacokinetics of single doses of lidocaine administered intravenously. Seven normal male subjects were studied during a time-control period and during water immersion to the neck. The clearance of lidocaine was unaltered by immersion, suggesting that the presumed marked central hypervolemia and increased cardiac output was not associated with changes in splanchnic blood flow.

Adult↗
PubMed1989

Increased immunoreactivity of plasma after fibrinolytic activation in an anti-DD ELISA system. Role of soluble crosslinked fibrin polymers.

After addition of a low concentration of thrombin to normal plasma, a progressive and significant increase in crosslinked fibrin polymers was found by sodium dodecyl sulfate agarose gel electrophoresis, reaching 27% of total fibrinogen and fibrin before gel formation. As measured by enzyme-linked immunosorbent assay with a monoclonal antibody specific for an epitope near the gamma gamma crosslink site, increased immunoreactivity of plasma did not occur after adding thrombin despite formation of crosslinked fibrin polymers, which indicates that the antibody does not recognize the epitope in the polymers. Addition of tissue-type plasminogen activator (t-PA) to plasma resulted in a more rapid degradation of fibrin polymers than of fibrinogen, indicating that the fibrin specificity of t-PA is retained with soluble fibrin. Coincident with degradation of plasma crosslinked fibrin polymers, plasma DD immunoreactivity increased 70-fold from 50.3 +/- 4.5 (mean +/- SD) to 3,560 +/- 1,235 ng/ml. The presence of increased crosslinked fibrin polymers produced by adding thrombin to plasma significantly increased maximum immunoreactivity after t-PA-induced degradation to 18,500 +/- 11,780 ng/ml. The increase in DD immunoreactivity was dependent on t-PA concentration; no elevation occurred below 0.01 micrograms/ml, and maximal increases occurred above 100 micrograms/ml. Analysis of gel electrophoretic patterns of thrombin and t-PA-treated plasma samples suggests that the DD reactivity of t-PA-treated plasma is mainly due to degradation of soluble crosslinked fibrin polymers. Our findings indicate that plasmic degradation of soluble fibrin polymers in plasma may be an important source of fragment DD during thrombolytic therapy.

Antibodies, Monoclonal↗
PubMed1989

The role of soluble cross-linked fibrin in D dimer immunoreactivity of plasmic digests.

Monoclonal antibody DD/3B6 reacts with a site near the gamma gamma isopeptide cross link and has been used to detect cross-linked fibrin degradation products in plasma as a marker for clot lysis. However, interpretation of the results is potentially complicated, because soluble cross-linked fibrin polymers contain a gamma gamma cross-link and may also react with the antibody before or after plasmic degradation. We have prepared plasmic digests of fibrinogen, soluble cross-linked fibrin polymers, and cross-linked particulate fibrin clot, have characterized their composition by electrophoresis, and have compared their D dimer immunoreactivities. Undegraded soluble cross-linked fibrin polymer showed no reactivity below 20 micrograms/ml, indicating that the epitope recognized by DD/3B6 is poorly reactive before plasmic degradation. The D dimer immunoreactivity of plasmic digests of particulate or of soluble cross-linked fibrin increased with progressive degradation, with stage 3 digests having 20-fold to 40-fold higher immunoreactivity than stage 1 digests. A stage 3 digest of fully cross-linked particulate fibrin reacted fourfold and 10-fold more than stage 3 digests of soluble fibrin polymers and untreated fibrinogen, which contained 21% and 8.5% soluble fibrin, respectively. Thus, D dimer immunoreactivity in stage 3 digests correlated with the amount of soluble cross-linked fibrin polymer in the undegraded starting material. These findings demonstrate that degradation of soluble or particulate cross-linked fibrin increases D dimer immunoreactivity progressively, with maximal reaction attained with stage 3 digests.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-Linking Reagents↗
PubMed1988

Evidence for an increased generation of prostacyclin in the microvasculature and an impairment of the platelet alpha-granule release in chronic renal failure.

The formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the alpha-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is--at least partially--due to an acquired defect of the platelet alpha-granule release and an increased generation of PGI2 in the microvasculature.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Small intestinal myeloid metaplasia.

Extramedullary hematopoiesis is rarely found in the gastrointestinal tract. A patient with postpolycythemic myeloid metaplasia who previously underwent splenectomy presented with recurrent, protracted gastrointestinal tract hemorrhage. Elaborate workup failed to reveal the source of bleeding. Intraoperative endoscopy with transillumination disclosed multiple submucosal lesions along the entire small bowel, which proved to be extramedullary hematopoiesis. After institution of hydroxyurea therapy, the rate of bleeding diminished considerably.

Aged↗
PubMed1988

Acute respiratory failure in hyperleukocytotic acute myeloid leukemia: the role of perfusion lung scintigraphy.

A patient with acute hyperleukocytotic myelogenous leukemia who presented with acute respiratory distress is reported. Clinical manifestations included dyspnea, tachypnea, hyperventilation, and cyanosis. Blood gas analysis revealed hypoxemia, hypocapnia, and metabolic acidosis. Chest X-ray and perfusion lung scanning were normal. Pulmonary leukostasis syndrome (PLS) was later confirmed at autopsy. In a patient with hyperleukocytosic from acute nonlymphocytic leukemia and respiratory distress, a normal perfusion lung scintigraph should make one consider the PLS.

Acute Disease↗
PubMed1988

Cerebral thrombosis in a newborn with a congenital deficiency of antithrombin III.

An Israeli Arab family with type I antithrombin III (AT-III) deficiency with several affected symptomatic members in three generations is reported. The propositus presented with deep vein thrombosis and pulmonary emboli associated with gestation. The propositus infant presented at the age of 2 weeks with superior sagittal and rectus sinus thrombosis. Hereditary AT-III deficiency should be considered in infants with cerebral thrombosis, especially if they have a family history of thromboembolism. The role of prophylactic therapy by AT-III concentrates in these infants should be further assessed.

Adult↗
PubMed1988

Recurrent spontaneous bacterial peritonitis in a patient with polycythemia vera.

Spontaneous bacterial peritonitis (SBP) is an infectious process that usually occurs in patients with cirrhosis. There are few reports of SBP in patients with other pathologies such as nephrotic syndrome, acute and chronic hepatitis, cardiac ascites, and ascites secondary to neoplastic disease. We report a patient with polycythemia vera in whom recurrent episodes of SBP occurred 8 months following a portacaval shunt operation for Budd-Chiari syndrome. Conceivably, the polycythemia vera (PV) complicated by hepatic vein thrombosis and portacaval shunt resulted in significant loss of hepatic reticuloendothelial system function and predisposed the patient to bacterial peritonitis.

Budd-Chiari Syndrome↗
PubMed1988

Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction.

The effect of Ca2+ upon the rate constant of force redevelopment following a period of isotonic shortening with immediate restretch to the starting sarcomere length was studied in rabbit psoas fibers at 5 degrees C. Control experiments support the assumption that the rate constant of force redevelopment represents isometric cross-bridge turnover kinetics (fapp + gapp), where fapp and gapp are the rate constants characterizing the transitions from the non-force-generating states to the force-generating states and back to the non-force-generating states, respectively. Parallel measurements of the rate constant of force redevelopment and of force, stiffness, and fiber ATPase during isometric contraction allow the effect of Ca2+ upon fapp and gapp to be determined. Analysis reveals that Ca2+ has a marked effect upon fapp, while gapp remains approximately unchanged. Furthermore, in the range above 25-30% of maximum Ca2+ activation, regulation of force, stiffness, and ATPase is mediated through changes in fapp. Below this range, however, it cannot be ruled out that, in addition, cross-bridges are also switched in and out of the turnover process ("recruitment"). As a consequence of regulation through turnover kinetics, both Ca2+ sensitivity and the slope of force-pCa (-log[Ca2+]) relations are shown to be affected by the ratio fapp/gapp, which may represent an important mechanism of modulation of contractile function in addition to modulation through changes within the regulatory protein system.

Adenosine Triphosphatases↗
PubMed1988

Adult hemolytic uremic syndrome associated with nonimmune deposit crescentic glomerulonephritis and alveolar hemorrhage.

An 18-year-old girl presented with anuric rapidly progressive glomerulonephritis associated with hypoxemic respiratory failure due to diffuse lung hemorrhage. The course of the kidney disease terminated in end-stage renal failure. The patient had been on permanent hemodialysis since her first admission; episodes of lung hemorrhage recurred five times over a follow-up period of 8 months. Two months after her first admission, the patient manifested features suggestive of the hemolytic uremic syndrome, namely, microangiopathic hemolytic anemia, thrombocytopenia, and excessive hypertension complicated by hypertensive encephalopathy. Based on the sequence of events in the course of this patient's disease, the authors believe that the hematological abnormalities were superimposed on the glomerular disease rather than being a primary disorder. Possible mechanisms for the association of the two disorders are discussed.

Adolescent↗
PubMed1988

IIB von Willebrand's disease: pathogenetic and therapeutic studies.

Infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) into patients with IIB von Willebrand's disease (vWD) has been reported to induce thrombocytopenia. In some families with this disorder thrombocytopenia is present even in the resting state. We have investigated the basis of this chronic thrombocytopenia in one such patient by performing platelet recovery and survival studies. Increased platelet consumption was suggested by a decrease in platelet recovery (40.5%, normal 45%) and mean platelet survival (112 h, normal range 144-224 h). In addition, we have administered test infusions of DDAVP and observed the effect on bleeding time and platelet count. DDAVP caused a decrease in the median platelet count from 86 x 10(9)/l (range 30-221) to 60 x 10(9)/l (range 5-144), the individual decline in the nine subjects ranging from 12% to 84% compared to the pretreatment values. Formation of platelet aggregates was observed in all patients following DDAVP. The bleeding time was prolonged before DDAVP in all patients and lengthened further in two after the infusion. However, partial correction of the bleeding time was seen in three and normalization in one patient following DDAVP infusion. Two IIB vWD patients were treated with virus-inactivated cryoprecipitate (Ristofact). Infusion of cryoprecipitate was followed by rapid appearance of all but the largest vWF multimers in plasma and did not affect the platelet count. The bleeding time was normalized in one patient but remained prolonged in the other. In conclusion, in IIB vWD patients virus-inactivated cryoprecipitate is the treatment of choice in the case of bleeding. Infusion of DDAVP might be effective in a subset of IIB vWD patients that has yet to be characterized.

Bleeding Time↗