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Biomedical subjects

H R Gralnick

Publications and source records attributed to H R Gralnick.

At least 109 records · Page 6Linked to original sources
PubMed1983

Danazol increases factor VIII and factor IX in classic hemophilia and Christmas disease.

We gave danazol (600 mg per day orally for 14 days), an attenuated androgen, to four adults with classic hemophilia and one adult with Christmas disease. The levels of factor VIII in the patients with classic hemophilia ranged from 1 to 3 per cent before treatment and rose to 3 to 8 per cent during the treatment period. The level of factor IX in the patient with Christmas disease rose from 5 to 14 per cent. The rise in clotting-factor activity was usually observed within five to six days after the initiation of therapy and peaked between 7 and 13 days. The drug had no untoward effects. During the 70 patient-days of therapy, only two patients required plasma products, each on one occasion. These data suggest that danazol therapy may decrease the hemorrhagic tendency and reduce the need for transfusions of plasma products in classic hemophilia and Christmas disease. Controlled clinical trials will be required to establish its value in these applications.

Adult↗
PubMed1983

Noncardiovascular findings associated with heart disease in the idiopathic hypereosinophilic syndrome.

Heart disease characterized by endomyocardial fibrosis is one of the major causes of morbidity and mortality in the idiopathic hypereosinophilic syndrome. From our series of 50 patients with idiopathic hypereosinophilia, we defined the noncardiovascular characteristics that distinguish patients at risk of developing endomyocardial fibrosis from those who remain free of heart disease. These groups did not differ with respect to the extent of eosinophilia or the duration of disease. Patients with clinically overt heart disease were more likely (p less than 0.05) to be male and HLA-Bw44 positive and have splenomegaly, thrombocytopenia, elevated serum levels of vitamin B12, and hypogranular or vacuolated eosinophils and abnormal early myeloid precursors in the peripheral blood. These idiopathic hypereosinophilic patients with heart disease were also more likely to have fibrosis and decreased megakaryocytes in the bone marrow. In contrast, those who remained free of heart disease tended to be female and have angioedema, hypergammaglobulinemia, elevated serum levels of immunoglobulin E (IgE), and circulating immune complexes. Therefore, in the idiopathic hypereosinophilic syndrome, male patients with a myeloproliferative type disorder and the HLA-Bw44 haplotype were at a much increased risk for the development of endomyocardial fibrosis. However, those patients with a hypersensitivity-like illness and angioedema who were female did not develop heart disease. Appreciation of this relative degree of risk for the major complication of the idiopathic hypereosinophilic syndrome should prove useful in the early identification and appropriate treatment of patients in whom endomyocardial fibrosis might develop.

Adult↗
PubMed1983

Role of carbohydrate in multimeric structure of factor VIII/von Willebrand factor protein.

The carbohydrate moiety of the factor VIII/von Willebrand (vW) factor protein is important in the expression of vW factor activity and the intravascular survival of the protein. Studies of normal human factor VIII/vW factor protein indicate that there is a requirement of a full complement of penultimate galactose for the maintenance of a normal multimeric structure. Release of penultimate galactose by beta-galactosidase or modification by galactose oxidase results in loss of the largest molecular weight multimers and increased numbers of intermediate and smaller multimers. In contrast, terminal galactose on the factor VIII/vW factor protein does not appear to play a significant role in the maintenance of the multimer organization. The abnormalities in multimeric structure and molecular size were demonstrated by NaDodSO4/polyacrylamide/agarose gel electrophoresis, NaDodSO4/glyoxyl-agarose electrophoresis, and sucrose density ultracentrifugation. These studies indicate that the penultimate galactose plays a role in the maintenance of the largest multimers of the factor VIII/vW factor protein. This may explain why, in some patients with variant forms of vW disease, a carbohydrate abnormality also may affect the multimeric structure of the plasma factor VIII/vW factor protein.

Blood Coagulation Factors↗
PubMed1983

Treatment of polyneuropathy in Waldenström's macroglobulinemia: role of paraproteinemia and immunologic studies.

A patient with polyneuropathy due to Waldenström's macroglobulinemia (WM) was treated successfully with chlorambucil and prednisone. Before therapy, 60% of peripheral lymphocytes were B cells, the nerve had IgM-bearing B-cell infiltrates, and the circulating IgM had antibody-binding activity to autologous and homologous nerves. Neurologic improvement, sustained for 4 years, began 3 months after therapy and coincided with the return to normal of bone marrow and circulating B cells. Binding of IgM to autologous and homologous nerves persisted after therapy, suggesting that not the IgM alone but other B-cell factors, possibly complexed to IgM, may have been responsible for the nerve damage.

B-Lymphocytes↗
PubMed1982

The identification and functional significance of factor VIII components on normal platelets.

Factor VIII-related antigen (VIII R:Ag) has previously been identified on human platelets by fluorescein-labelled heterologous antibodies to factor VIII. However, it is not known whether these antibodies identify only VIII R:Ag or whether antigens associated with factor VIII coagulant activity (VIII:C Ag) are also present. The current studies utilize specific antibodies and their Fab' fragments to evaluate the presence of both VIII R:Ag and VIII:C Ag on human platelets and to study the functional role of the platelet-associated VIII R:Ag on ristocetin-induced platelet agglutination. Immunofluorescent studies demonstrate the presence of VIII R:Ag, but do not identify VIII:C Ag on platelets. The functional studies reveal that after incubation with either of the Fab' fragments, platelets retain their reactivity in the ristocetin cofactor assay. These results indicate that this population of VIII R:Ag is not essential for the ristocetin aggregation reaction and that no antigenic determinants for factor VIII coagulant activity (VIII:C) are detectable on human platelets by immunofluorescence.

Antigens↗
PubMed1982

NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations.

The idiopathic hypereosinophilic syndrome (HES) represents a heterogeneous group of disorders with the common features of prolonged eosinophilia of an undetectable cause and organ system dysfunction. Fifty patients with the idiopathic HES were studied over 11 years of the National Institutes of Health. Multiple organ systems were involved; bone marrow hypereosinophilia was common to all patients, but the most severe clinicopathologic involvement was of the heart and nervous system. Postmortem gross pathologic examination of the hearts of patients with idiopathic and nonidiopathic HES suggested that the common mechanism of cardiac disease is the eosinophilia. Endomyocardial biopsy findings showed that the endothelial cells in the endocardium and of the microvasculature were the primary targets of the tissue damage. This damage initiates thrombosis; endocardial fibrosis and restrictive endomyocardopathy may follow. In-vitro culture of circulating eosinophil colony-forming units showed some normal studies, some studies showing increased progenitor cells committed to eosinophil development, and others showing an excess production of eosinophil colony-stimulating factor. Chemotherapy to lower the eosinophil counts has resulted in marked improvement of HES prognosis, as have agressive medical and surgical approaches to cardiovascular complications.

Cardiomyopathies↗
PubMed1982

Characterization of the defect of the factor VIII/von Willebrand factor protein in von Willebrand's disease.

The factor VIII/von Willebrand factor (f.VIII/vWf) protein was purified from the plasma of a patient with von Willebrand's disease (vWd). The patient had all of the classic laboratory findings of vWd except for the ristocetin-induced platelet aggregation of his own platelet-rich plasma. The disease has been documented in three generations. Comparison of the purified normal and vWd f.VIIi/vWf protein revealed several abnormalities, including decreased concentration of f.VIII/vWf antigen; decreased specific vWf activity; absence of the larger molecular forms of the f.VIII/vWf protein; carbohydrate deficiencies affecting the sialic acid, penultimate galactose and N-acetylglucosamine moieties; and decreased binding of the f.VIII/vWf protein to its platelet receptor. These studies indicate the multiplicity of biochemical and functional abnormalities associated with the f.VIII/vWf protein in vWd. f.VIII/vWf protein to normal f.VIII/vWf protein that had been treated with 2-mercaptoethanol (2-ME) to reduce the multimer size and then treated with specific exoglycosidases to remove the sialic acid and penultimate galactose residues revealed similar biologic properties.

Acetylglucosamine↗
PubMed1982

Factor VIII/von Willebrand factor protein: sensitivity of periodic acid Schiff stain to carbohydrate deficiency.

We have investigated the periodic acid Schiff (PAS) Coomassie staining ratio of the human factor VIII/von Willebrand factor (fVIII/vWf) protein. The PAS-Coomassie staining ratio is consistent over 8 days. The PAS-Coomassie ratio of fVIII/vWf protein purified from different starting materials does not appear to be significantly different. The PAS stain can detect as little as 300 ng of carbohydrate in the fVIII/vWf protein. Desialation did not affect the PAS-Coomassie ratio, while removal of penultimate galactose resulted in a marked reduction in the PAS-Coomassie ratio. This reduction was further accentuated with the removal of N-acetylglucosamine. The smaller multimers of the fVIII/vWf protein have a reduced sialic acid and PAS-Coomassie staining ratio. This difference does not appear to be related to the sialic acid deficiency but may be related to the distribution or organization of the carbohydrate moieties on the smaller fVIII/vWf multimers.

Blood Coagulation Factors↗
PubMed1982

Factor VIII/von Willebrand factor binding to von Willebrand's disease platelets.

A form of von Willebrand's disease has been described with enhanced ristocetin-induced platelet aggregation and anodal migration of the factor VIII/von Willebrand factor protein (type IIb). We studied two families with this form of von Willebrand's disease and macrothrombocytopenia. We have found that these platelets bind more of the normal and intermediate-sized multimers of the factor VIII/von Willebrand factor than normal platelets. Analysis of the binding data show an increased affinity of these vWd platelets for the factor VIII/von Willebrand factor. These findings are consistent with an increased number of platelet receptors, which, either by their native topography or migration on the platelet surface, bind factor VIII/von Willebrand factor protein with greater affinity than normal platelets, platelets of other vWd patients, and large platelets of other etiologies.

Adolescent↗
PubMed1982

Proposals for the classification of the myelodysplastic syndromes.

New diagnostic criteria for the diagnosis of the various myelodysplastic syndromes (MDS) are proposed, and a detailed description is given of the features that may help define MDS. Five MDS are described: (1) refractory anaemia (RA), (2) RA with ring sideroblasts, (3) RA with excess of blasts (RAEB), (4) chronic myelomonocytic leukaemia (CMML), and (5) RAEB 'in transformation'. One of the main distinguishing features of these conditions is the proportion of blast cells in the peripheral blood (PB) and/or bone marrow (BM). The morphological features of the blast cells that are of diagnostic importance have been redefined. In RA, with or without ringed sideroblasts, there are fewer than 1% of blasts in the PB and fewer than 5% in the BM; RAEB is defined as having between 5% and 20% of blasts in the BM and fewer than 5% in the PB; RAEB in transformation (a newly defined category) will be considered when any of the following features is present: (i) more than 5% of blasts in the PB, (ii) 20-30% in the BM, and (iii) the presence of Auer rods in granulocyte precursors in BM or PB. In accordance with these newly defined criteria, it is now proposed that over 30% of bone marrow blasts will suffice for the diagnosis of acute myeloid leukaemia (AML) in any of its forms (M1-M6). The proposed descriptions of the MDS should facilitate the interpretation of data emerging from cytogenetic and bone marrow culture studies and the search for features of possible prognostic significance. Recognition of the new category, RAEB in transformation, may throw light on the pathogenesis of AML.

Anemia, Aplastic↗
PubMed1982

Cold-induced contact surface activation of the prothrombin time in whole blood.

Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

Blood Coagulation Factors↗
PubMed1982

Quantification of acute phase reactants after muscle biopsy.

Blood concentrations of six acute phase reactants (ESR, neutrophil count, fibrinogen, haptoglobin, alpha 1-antitrypsin, and ferritin), parameters of muscle necrosis (myoglobin, CK, ALT, and AST) as well as hemopexin, iron, and TIBC were determined before and for 7 consecutive days after muscle biopsy in patients and in a control group. A muscle biopsy was chosen as a standardized surgical procedure that induces a mild transient inflammatory response. After muscle biopsy, a significant increase occurred in five (ESR, neutrophil count, fibrinogen, haptoglobin, and alpha 1-antitrypsin) of the six acute phase reactants. The concentration of serum ferritin did not show a significant change. A significant decrease was noted in the serum iron concentration and a significant increase occurred with CK and myoglobin secondary to the muscle biopsy. Thus the inflammation of a muscle biopsy produces a significant acute phase reaction.

Adult↗
PubMed1981

The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations.

The degree of concordance in the morphological classification of ALL was assessed by the FAB group after two successive reviews of 200 and 100 slides respectively. As a result, a simple scoring system for types L1 and L2 is proposed based on the following four features: (1) nuclear cytoplasmic ratio, (2) presence, prominence and frequency of nucleoli, (3) regularity of nuclear membrane outline, and (4) cell size. By this method, the overall concordance by seven observers (agreement of 7:0 or 6:1 only) increased from 63% to 84%. A significant difference in the incidence of the ALL morphological types in children (less than or equal to 15 years) and adults (greater than 15 years) was found: 74% of L1 cases were children while 66% of L2 cases were adults (P less than 0.001). No significant differences were observed in the incidence of L3 in children and adults or between L1 and L2 according to the membrane phenotype of the blast cells. All L3 cases had B-cell characteristics. A better prognosis for L1 and a higher relapse rate for L2 has been found in several recent reports; The present study may facilitate the morphological analysis of ongoing clinical trials in ALL by improving the reproducibility of the FAB classification.

Acute Disease↗
PubMed1981

Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets.

The characteristics of the intact factor VIII/von Willebrand factor protein binding to human platelets was compared to 2-mercaptoethanol-treated factor VIII/von Willebrand factor protein and to fractions of plasma factor VIII/von Willebrand factor protein that elute after the void volume. These studies indicate that the factor VIII/von Willebrand factor protein larger size oligomers bind preferentially with high affinity to low capacity sites on human platelets. The intermediate and smaller size oligomers bind with intermediate or low affinity to sites with a much greater capacity. The results from binding analysis are also paralleled by the competitive inhibition of the intact factor VIII/von Willebrand factor protein by the various 2-mercaptoethanol-treated materials. These studies indicate that the two classes of binding sites seen in previous reports of factor VII/von Willebrand factor binding reflect heterogeneity in the oligomer size of the factor VIII/von Willebrand factor protein used in these assays. This study provides a model for understanding some of the normal structure-function relationships of the normal factor VIII/von Willebrand factor protein and the defect(s) in a variant form of von Willebrand's disease. In this form of the disease, decreased factor VIII/von Willebrand factor binding to platelets is reflected in decreased von Willebrand factor activity but coagulant and/or antigen levels are normal or only slightly decreased.

Animals↗
PubMed1981

A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. I. Hematologic manifestations.

A retrospective blind study of 32 patients with the hypereosinophilic syndrome was undertaken utilizing a hematologic scoring system that was based on peripheral blood and bone marrow findings, cytogenetics B12 levels, and leukocyte alkaline phosphatase determinations. In addition to the grading system, which allowed formulation of a hematologic score, the date could also be normalized for individuals who did not have all tests performed by use of the hematologic quotient. This study clearly defined two groups of patients within the idiopathic hypereosinophilic syndrome. One group were those individuals with low hematologic scores and quotients who did not require therapy or who responded to prednisone therapy, while the second group of patients required cytotoxic therapy. These patients had significantly higher hematologic scores and quotients and a significant number of abnormalities similar to those seen in myeloproliferative syndromes, such as myelofibrosis and cytogenetic abnormalities. This type of hematologic scoring seems useful in predicting therapy and/or evaluating individuals or groups of patients with the hypereosinophilic syndrome.

Bone Marrow↗
PubMed1981

A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations.

The idiopathic hypereosinophilic syndrome, a disorder characterized by peripheral blood and bone marrow eosinophilia associated with single or multiple organ system dysfunction attributable to tissue invasion by eosinophils has, in the past, been associated with an extremely poor prognosis. Recently, we reported the favorable impact of a therapeutic protocol consisting of prednisone and/or hydroxyurea on the morbidity and mortality of this syndrome. We have reviewed the clinical and hematologic features upon admission and the subsequent clinical courses of 32 patients with this disease referred to the NIH between 1965 and 1979 in an effort to determine which features suggest a more rapidly progressive course. A grading system based on 22 clinical features involving the 8 organ systems commonly affected by the illness was devised. The disease followed a more aggressive course in patients with evidence of cardiac or neurologic dysfunction at the time of initial NIH evaluation. Although splenomegaly, in and of itself, caused little morbidity, splenic enlargement at presentation appeared to be a predictor of a more aggressive course. The clinical grading system accurately predicted which patients would require no specific antihypereosinophilic therapy, which patients would respond adequately to corticosteroids, and which patients would require therapy with cytotoxic agents. It is proposed that this clinical grading system, and the hematologic grading system outlined in the accompanying report be used as aids in the selection of initial therapy in this group of patients.

Adolescent↗