PubMed Health⌕ Search

Biomedical subjects

V J Marder

Publications and source records attributed to V J Marder.

At least 19 recordsLinked to original sources
PubMed1995

Current issues concerning thrombolytic therapy for acute myocardial infarction.

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States--tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)--all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by approximately 20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by approximately 23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive.(ABSTRACT TRUNCATED AT 250 WORDS)

Anistreplase↗
PubMed1993

E-selectin-dependent neutrophil adhesion to Rickettsia rickettsii-infected endothelial cells.

Increased neutrophil or HL60 cell adhesion to Rickettsia rickettsii-infected endothelial cells (ECs) was observed at 6 to 8 hours after the initiation of infection, diminishing by 24 hours. Similar increases were observed using formaldehyde-fixed neutrophils. Cellular association and likely the intracellular presence of rickettsiae was required for enhanced neutrophil adhesion, because culture medium conditioned by infected cells or rickettsiae rendered noninfective by pretreatment with tetracycline were ineffective at inducing neutrophil adhesion. Increases in neutrophil adhesion caused by infection were blocked by pretreatment of ECs with cycloheximide, suggesting the involvement of new protein synthesis in the cells' response. Flow cytometric analysis of infected cells showed increases in cell surface expression of E-selectin compared with uninfected control cells. Furthermore, incubation of 6- to 8-hour infected cells with a blocking monoclonal antibody against E-selectin (BB11) inhibited neutrophil adhesion an average of 61%. These results suggest the involvement of E-selectin in neutrophil adhesion to infected ECs occurring early in the course of the infection process. EC-initiated recruitment of neutrophil adhesion during rickettsiae infection could contribute to the pathologic changes associated with Rocky Mountain Spotted Fever.

Animals↗
PubMed1992

Plasma crosslinked fibrin polymers: quantitation based on tissue plasminogen activator conversion to D-dimer and measurement in normal and patients with acute thrombotic disorders.

Plasma crosslinked fibrin polymers (XLFP) are formed as a result of in vivo hemostatic activation and are elevated in thrombotic disease. We have investigated the plasmic degradation of plasma XLFP in vitro to provide information regarding the pattern of crosslinking and the composition of degradation products. Plasma XLFP were identified by sodium dodecyl sulfate (SDS)-agarose electrophoresis and Western blotting and quantitated by gel scanning. D-dimer was measured by enzyme-linked immunosorbent assay and the results were verified by SDS-polyacrylamide gel electrophoresis and Western blotting of the digests. Complete degradation of XLFP occurred only after supplementation of plasma with plasminogen (5 U/mL) and incubation with recombinant tissue plasminogen activator (rt-PA), indicating that the normal plasma plasminogen concentration limits plasmic degradation in vitro. Gel electrophoresis showed that the principal terminal degradation products of XLDP were fragments D, DD, and E, indicating that crosslinking occurred primarily through gamma chain dimers. After adding a low concentration of thrombin to plasma in vitro, XLFP increased progressively before clotting, and the concentration correlated with the increase in the D-dimer concentration after degradation (r = .98). Plasma XLFP and D-dimer concentrations in plasmic digests were significantly elevated in patients with stroke (150 +/- 83 micrograms/mL and 88 +/- 32 micrograms/mL), myocardial infarction (217 +/- 110 micrograms/mL and 84 +/- 30 micrograms/mL), and venous thrombosis (187 +/- 80 micrograms/mL and 86 +/- 19 micrograms/mL) compared with normals (28 +/- 12 micrograms/mL and 25 +/- 7 micrograms/mL). There was a strong correlation between the plasma concentration of XLFP and the D-dimer immunoreactivity of plasma after plasmic degradation (r = .87). The results indicate that XLFP in plasma are crosslinked primarily through gamma chains and degrade to fragment DD with plasminogen activation. Also, the immunoreactivity of in vitro plasmic digests of plasma reflects the concentration of XLFP and may provide a useful indirect measure of in vivo hemostatic activation in patients with thrombotic disease.

Acute Disease↗
PubMed1992

An animal model of fibrinolytic bleeding based on the rebleed phenomenon: application to a study of vulnerability of hemostatic plugs of different age.

The primary bleeding time is prolonged when tested during the infusion of both plasminogen activators and anticoagulants, and such sites frequently exhibit rebleeding after initial hemostatic control. This study describes an animal (rabbit) model which distinguishes fibrinolytic from anticoagulant hemorrhage and further applies the model to the study of hemostatic plugs of increasing age. In this model, rebleeding occurred from hemostatically-stable ear puncture sites induced prior to infusion of streptokinase (SK) or recombinant tissue-plasminogen activator (rt-PA), but not of heparin or hirudin. This distinction was apparent even for lesions induced only 15 minutes prior to the infusion and fibrinolytic bleeding was observed in such lesions induced up to 24 hours earlier. Post-infusion sites bled more quickly than did pre-infusion sites, and there was a gradual decrease in susceptibility of such prior trauma sites for rebleeding, evidenced not only by a lower proportion of sites that rebled, but also by a longer lag time after starting SK or rt-PA before such rebleeding occurred. At the dosages tested, SK showed a trend (not statistically significant) toward more sites that rebled, while rt-PA showed a trend towards a longer duration of rebleeding. Thus, this animal model of rebleeding appears to be unique for fibrinolytic agents and allows for more detailed study of the physiological mechanisms of such bleeding and for a multifaceted comparison of the bleeding potential of plasminogen activators.

Animals↗
PubMed1992

Comparison of warfarin and external pneumatic compression in prevention of venous thrombosis after total hip replacement.

OBJECTIVE: To compare the effectiveness and safety of warfarin and external pneumatic compression (EPC) in prevention of venous thrombosis after total hip replacement. DESIGN: Prospective, randomized trial in consecutive patients, with blinded assessment of the primary end point. SETTING: University medical center and large community hospital. PATIENTS: Patients over age 18 years scheduled for elective primary total hip replacement were eligible. Of 254 patients interviewed, 232 were randomized, 220 patients had surgery and received prophylaxis, and 201 had venography. INTERVENTIONS: Patients were randomly assigned to prophylaxis with a device providing bilateral sequential EPC to both the calf and thigh or to receive warfarin in a low-intensity regimen beginning 10 to 14 days preoperatively. Prophylaxis was continued until venography. MAIN OUTCOME MEASURES: Venous thrombosis was diagnosed by venography between postoperative days 6 and 8. Bleeding was assessed by surgical blood loss, transfusion requirements, changes in hematocrit, and clinically identified bleeding complications. RESULTS: The total incidence of venous thrombosis was virtually the same in the warfarin and EPC groups (31% vs 27%), but the distribution of thrombi was different. Proximal thrombosis occurred in 12% of patients in the EPC group compared with only 3% in the warfarin group (P = .012, 95% confidence interval for difference, 2% to 18%). In contrast, calf vein thrombosis was more frequent in the warfarin group (21%) than in the EPC group (12%) (P = .021, 95% confidence interval for difference, 0% to 18%). Most proximal thrombi in EPC-treated patients were located within 15 cm of the femoral head and were not continuous with thrombi in deep calf veins. The high incidence of proximal thrombosis in the EPC group resulted in termination of the study by the safety monitoring committee. Blood loss and bleeding complications were similar in the two groups. CONCLUSION: Warfarin therapy is significantly more effective than EPC in preventing serious proximal vein thrombosis after total hip replacement. The greater effectiveness of warfarin therapy in preventing proximal vein thrombi and of EPC in preventing thrombosis in the calf suggests that there are differences in the pathogenesis of thrombosis in these two locations.

Aged↗
PubMed1992

Lack of influence of pretreatment antistreptokinase antibody on efficacy in a multicenter patency comparison of intravenous streptokinase and anistreplase in acute myocardial infarction.

Antistreptokinase antibodies present in patients as a result of previous streptococcal infections might theoretically influence the thrombolytic response to streptokinase or anistreplase. The potential influence of antibody, measured as antigen binding to immunoglobulin G, was investigated in a randomized, double-blind, multicenter patency comparison of intravenous streptokinase (1.5 million units/60 minutes) and intravenous anistreplase (30 units/2 to 5 minutes) in patients with acute myocardial infarction. Antibody results were evaluated in 333 patients (from a total study population of 370 patients) less than 76 years of age with ECG evidence of ST segment elevation who could be treated within 4 hours of the onset of symptoms. Variations in pretreatment circulating levels of antibody did not influence angiographically defined early coronary patency rates (Thrombolysis in Myocardial Infarction grade 2 or 3 perfusion, measured at a mean of 140 minutes after therapy was begun) for either streptokinase or anistreplase. Similarly the lytic response represented by systemic plasminogen activation and measured as changes in plasma plasminogen and fibrinogen levels after dosing (at mean times of 90 minutes and 24 hours) was not correlated with baseline antibody levels. Furthermore, pretreatment antibody was not a risk factor for poor outcome in response to streptokinase or anistreplase (reocclusion within 24 hours, in-hospital death, or stroke) and did not correlate with hypotension or allergic-type reactions recorded as adverse events. In conclusion, within the population limits defined by the inclusion and exclusion criteria of the study (patients were excluded if they had received streptokinase or anistreplase within the previous 6 months), pretreatment antistreptokinase immunoglobulin G is not a significant determinant of the efficacy response to streptokinase or anistreplase.

Anistreplase↗
PubMed1992

Enhancement of fibrinolysis in vitro by ultrasound.

The effect of ultrasound on the rate of fibrinolysis has been investigated using an in vitro system. Plasma or blood clots containing a trace label of 125I fibrin were suspended in plasma containing plasminogen activator and intermittently exposed to continuous wave 1-MHz ultrasound at intensities up to 8 W/cm2. Plasma clot lysis at 1 h with 1 microgram/ml recombinant tissue plasminogen activator (rt-PA) was 12.8 +/- 1.2% without ultrasound and was significantly (P = 0.0001) increased by exposure to ultrasound with greater lysis at 1 W/cm2 (18.0 +/- 1.4%), 2 W/cm2 (19.3 +/- 0.7%), 4 W/cm2 (22.8 +/- 1.8%), and 8 W/cm2 (58.7 +/- 7.1%). Significant increases in lysis were also seen with urokinase at ultrasound intensities of 2 W/cm2 and above. Exposure of clots to ultrasound in the absence of plasminogen activator did not increase lysis. Ultrasound exposure resulted in a marked reduction in the rt-PA concentration required to achieve an equivalent degree of lysis to that seen without ultrasound. For example, 15% lysis occurred in 1 h at 1 microgram/ml rt-PA without ultrasound or with 0.2 microgram/ml with ultrasound, a five-fold reduction in concentration. Ultrasound at 1 W/cm2 and above also potentiated lysis of retracted whole blood clots mediated by rt-PA or urokinase. The maximum temperature increase of plasma clots exposed to 4 W/cm2 ultrasound was only 1.7 degrees C, which could not explain the enhancement of fibrinolysis. Ultrasound exposure did not cause mechanical fragmentation of the clot into sedimentable fragments, nor did it alter the sizes of plasmic derivatives as demonstrated by SDS polyacrylamide gel electrophoresis. We conclude that ultrasound at 1 MHz potentiates enzymatic fibrinolysis by a nonthermal mechanism at energies that can potentially be applied and tolerated in vivo to accelerate therapeutic fibrinolysis.

Fibrinolysis↗
PubMed1992

Effects of ionic and nonionic radiographic contrast agents on endothelial cells in vitro.

Intravenous administration of radiographic contrast agents results in the occasional occurrence of thrombotic complications, which are more common after the use of ionic agents than nonionic agents. To investigate the pathophysiologic basis of this thrombotic tendency, we compared the effects of ionic and nonionic contrast agents on endothelial cells in vitro. Exposure of cultured human umbilical vein endothelial cells to ionic contrast medium for 10 minutes resulted in lifting of 76% +/- 8% of cells, significantly greater than that after exposure to nonionic medium (6% +/- 4%; p less than 0.005). A modified Baumgartner chamber was used to evaluate the effects of contrast agents on adhesion of platelets in anticoagulated whole blood to everted segments of fresh or stored deendothelialized rabbit aorta segments. Exposure of fresh vessels to ionic contrast medium led to a significant increase in platelet adhesion (31% +/- 7%; p less than .01), whereas the increase was smaller after exposure to nonionic contrast medium (25% +/- 3%). Platelet adhesion to stored vessels (41% +/- 4%) was significantly greater than adhesion to fresh aorta segments (15% +/- 2%; p less than 0.001), and contrast agents did not further increase adhesion. Microscopic examination of perfused aorta segments exposed to ionic contrast medium showed platelet adherence to intact endothelial cells, a phenomenon that did not occur without prior exposure of fresh aorta segments to ionic contrast medium. These findings demonstrate that exposure of endothelial cells to ionic contrast medium results in marked changes in cell viability and adhesive properties that may contribute to their thrombotic potential.

Cell Survival↗
PubMed1992

Comparison of dosage schedules of rt-PA in the treatment of proximal deep vein thrombosis.

This study assessed the efficacy and safety of increasing durations of constant-dose intravenous recombinant tissue-type plasminogen activator (rt-PA) in the treatment of deep vein thrombosis. Patients with venogram-documented proximal lower limb (popliteal, iliofemoral) or upper limb (axillary, subclavian) thrombi were given an initial 2-hour rt-PA infusion at 4 micrograms/kg/min, followed by a maintenance infusion of 1 microgram/kg/min for an additional 4, 22, or 33 hours (mean total rt-PA dosages of 54, 127, and 185 mg). A new quantitative venogram scoring system was applied to the study, based on measurements of thrombus volume before and after completion of treatment. Whereas none of the seven patients given treatment for 6 hours and only one of four given treatment for 24 hours showed significant lysis, four of seven who received a prolonged infusion for 35 hours showed lysis of more than 40% of the original thrombus. Overall, the prolonged 35-hour infusion induced 51% lysis of original thrombus, representing a thrombus volume of 16.7 ml dissolved. Hemorrhagic complications were common in all three groups, with four of 18 patients having significant bleeding, including one massive gastrointestinal hemorrhage, two patients with a decrease in hematocrit of more than 10%, and one patient with an intracranial hemorrhage who recovered completely. Pharmacokinetics of the rt-PA showed a steady state antigen concentration of 240 ng/ml and activity of 200 IU/ml during the initial 2-hour infusion and a postinfusion half-life of 5 minutes. Plasma fibrinogen concentrations decreased to approximately 40% to 50% of initial values with all three treatment regimens, but the nadir fibrinogen concentrations did not correlate with either therapeutic efficacy or bleeding complications. One patient with systemic lupus erythematosus had an unusual allergic reaction that manifested primarily as angioedema. This study suggests that rt-PA infusion of 35 hours induces greater thrombolysis of deep vein thrombosis than does a shorter course of 6 or 24 hours, without an increase in hemorrhagic complications.

Adult↗
PubMed1992

Depletion of plasminogen in vitro or during thrombolytic therapy limits fibrinolytic potential.

Thrombolytic therapy frequently induces a "lytic state" associated with a decrease in plasma plasminogen concentration that could limit therapeutic efficacy. We therefore investigated the influence of soluble plasminogen concentration on in vitro lysis of retracted whole-blood clots in plasma from normal subjects and from patients undergoing thrombolytic therapy. With recombinant tissue plasminogen activator (1000 ng/ml) or two-chain urokinase plasminogen activator (250 U/ml), minimal clot lysis occurred in normal plasma depleted of plasminogen by lysine Sepharose chromatography. Clot lysis induced by two-chain urokinase plasminogen activator increased progressively in normal plasma at initial plasminogen concentrations between 0.06 to 6 U/ml, whereas maximum lysis with recombinant tissue plasminogen activator occurred between 0.5 U/ml and 1 U/ml and was less at lower and higher concentrations of plasminogen. Incubation of whole-blood clots in normal plasma with recombinant tissue plasminogen activator resulted in little change in plasminogen concentration during 6 hours, with a constant rate of clot lysis. Incubation with two-chain urokinase plasminogen activator, however, caused a rapid decrease in plasminogen concentration and a corresponding decrease in lysis rate; lysis rate was restored after repletion with purified plasminogen. The effect of in vivo activator-induced plasminogen depletion on in vitro clot lysis rates was tested with plasma obtained from patients 90 to 120 minutes after they had received 30 mg of acylated plasminogen-streptokinase activator complex that showed depletion of plasminogen to 14% +/- 2%. These plasma samples produced only 4% +/- 1% in vitro clot lysis during 4 hours but lysis increased progressively after repletion with 1, 2, and 4 U/ml plasminogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1991

Creation of the recombinant tissue plasminogen activator (rt-PA) image and its influence on practice habits.

American physicians have commonly practiced thrombolytic therapy for acute myocardial infarction with the recombinant form of tissue plasminogen activator (rt-PA), although its cost is much higher than that of streptokinase. The greater popularity of rt-PA is based on the belief that it is a more effective and a safer drug for achieving myocardial salvage and mortality reduction. However, a series of studies testing this assumption have not substantiated its greater efficacy or safety with respect to not only streptokinase but also urokinase and anisoylated plasminogen-streptokinase activator complex (APSAC). This editorial reviews the sequence of events that led to the creation of the rt-PA image, the mistaken premises on which it was based and the questions that need to be addressed if we are to strengthen the scientific method for evaluating similar types of drugs and its influence on practice habits including the costs to the health system.

Anistreplase↗
PubMed1991

Rickettsia rickettsii infection of cultured endothelial cells induces release of large von Willebrand factor multimers from Weibel-Palade bodies.

The clinical manifestations of Rocky Mountain spotted fever (RMSF) result from Rickettsia rickettsii (R rickettsii) infection of endothelial cells and are mediated by pathologic changes localized to the vessel, including in situ thrombosis and tissue ischemia. This study uses in vitro infection of cultured human umbilical vein endothelial cells with R rickettsii to test the hypothesis that such infection induces von Willebrand factor (vWF) release from Weibel-Palade bodies, a process that could contribute to thrombotic changes. At 24 hours postinfection, there was an increase in metabolically prelabeled large multimers of vWF in the culture medium, with a concomitant decrease of these forms in the cell lysate samples. This release reaction was specific for the large multimer pool of vWF, localized to Weibel-Palade bodies, because no change in the distribution of dimeric forms between cells and culture medium was detected. Double-label immunofluorescence staining showed an inverse correlation between the number of R rickettsii and the number of Weibel-Palade bodies in infected cells. Cell lysis was minimal at 24 hours postinfection, as no detectable intracellular precursor forms (molecular weight 260,000) of vWF were released into the culture medium, there was no decrease in cell viability as measured by trypan blue exclusion, and no increase in 51Cr-release into the culture medium was observed when compared with uninfected controls. Release was likely a direct effect of the intracellular presence of the organism, rather than due to a noxious soluble factor such as endotoxin, because culture medium conditioned by infected endothelial cells was ineffective at inducing release in uninfected endothelial cell cultures. In summary, in vitro infection of endothelial cells by R rickettsii induces release of Weibel-Palade body contents, a process that may contribute to the pathogenesis of RMSF.

Cell Survival↗
PubMed1991

Photosensitized release of von Willebrand factor from cultured human endothelial cells.

Cultured endothelial cells from the human umbilical vein were incubated with low concentrations (1 microgram/ml) of the photosensitizer Photofrin II. Following a sublethal light exposure, a light dose-dependent release of von Willebrand factor (vWf) into the culture medium was observed. Analysis of the multimeric composition of the released protein indicated that it originated from the intracellular pool of large vWf multimers stored in the Weibel-Palade bodies. This release was detected as early as 1 h postirradiation. Release was inhibited at low temperature and was dependent upon the presence of extracellular calcium. Photosensitization resulted in an influx of calcium whose time course paralleled vWf release from the cells. Since vWf mediates platelet adhesion to the vascular subendothelium, it is possible that its photochemically stimulated release in vivo could contribute to platelet thrombus formation observed in tissue following photodynamic therapy.

Cysteine↗
PubMed1991

Streptokinase and recombinant tissue plasminogen activator (rt-PA) are equally effective in treating acute myocardial infarction.

In recent trials, patients with myocardial infarction who received either recombinant tissue-type plasminogen activator (rt-PA) or streptokinase showed essentially no difference in the amount of myocardial salvage, in mortality reduction, or in the incidence of bleeding complications. These findings thus failed to fulfill the expectation that rt-PA would be twice as effective as streptokinase as a thrombolytic agent. The basis for this mistaken prediction was an unfortunate overemphasis on an inadequate surrogate endpoint, namely, the patency or reperfusion rate at 90 minutes after the start of therapy. Using the 90-minute patency or reperfusion rate as an endpoint has several serious limitations. First, it is an observation made at only one point in time during a dynamic process that may change even during the infusion proper. Second, a single view at 90 minutes completely disregards the possibility of subsequent reocclusion which often occurs within 1 hour after treatment. Third, an image at 90 minutes is more a reflection of the speed of thrombolysis than of whether lysis will eventually occur; the pace of clot lysis depends on both the agent used and the age of the thrombus. Fourth, lysis at 90 minutes is of minimal relevance for myocardial salvage unless observed within the time frame when infarction size can be limited significantly, which is generally less than 4 hours between symptom onset and the time that reperfusion is accomplished. Fifth, a stable state of vessel patency is meaningful for mortality reduction even if stabilization occurs after completion of the infarction. Such "late," but lasting, patency is a critical component of the "open vessel" principle and explains, at least in part, the survival benefit that accrues to patients treated even 24 hours after the onset of symptoms. There is currently no evidence that rt-PA has a more beneficial effect on survival or function than does streptokinase or any other plasminogen activator used in treating acute myocardial infarction; nor is there any evidence that patients who receive rt-PA therapy show a decreased incidence of bleeding complications compared with those who receive streptokinase, despite the relative fibrinogen-sparing attribute of rt-PA. Given the poor predictive value of the 90-minute angiogram for ultimate clinical advantage of one agent over another, studies that are limited to this endpoint are of marginal use in evaluating treatment regimens used in mortality studies. The best evidence to date indicates that streptokinase and rt-PA are of equivalent value for survival after acute myocardial infarction, a conclusion that can be justifiably challenged only with a valid mortality study.

Clinical Trials as Topic↗
PubMed1991

Developmental expression of mRNAs encoding platelet proteins in rat megakaryocytes.

The committed bone marrow megakaryocyte (MK) progenitor undergoes a series of highly regulated stages of development resulting in a large multi-nucleated platelet-producing cell. We studied the developmental expression of the mRNA for two alpha granule proteins, fibronectin (FN) and fibrinogen gamma chain (gamma-FIB), and a cytoskeletal protein, actin, in MKs from marrow of Sprague-Dawley rats. By the method of in situ RNA:RNA hybridization, we showed that mRNAs for the alpha granule proteins were expressed most abundantly in a population of 15-microns diameter promegakaryocytes and in cells as small as 10 microns whose identity as immature MKs was inferred by positive staining for platelet- and MK-specific markers. gamma-FIB and FN mRNAs were present in reduced abundance in a small proportion of intermediate MKs; however, little or no expression was seen in mature platelet-producing MKs. In contrast, high levels of actin mRNA were expressed predominantly in mature, multi-nucleated MKs, and less abundantly in the immature forms. These results suggest that FN and gamma-FIB are transcribed early in MK development to permit translation and packaging of the protein into alpha granules, after which transcription ceases. On the other hand, transcription of actin occurs continuously throughout development, with highest levels in mature platelet-producing MKs, in which actin is needed for shape changes and intracellular movement of organelles. Our data suggest that in situ RNA:RNA hybridization for platelet-specific markers will provide additional criteria by which to establish MK lineage in immature marrow progenitors.

Actins↗