Ectopic medullary hematopoiesis as a cause of ascites in agnogenic myeloid metaplasia. Case report and review of the literature.

We report an unusual case of a 44-year-old female patient with 'malignant' ascites caused by ectopic foci of extramedullary hematopoiesis in the course of agnogenic myeloid metaplasia. The patient had suffered also from severe Coombs-positive acquired hemolytic anemia and had been splenectomized. Two years after splenectomy, ascites caused by peritoneal implants of hematopoietic tissue appeared. The ascites responded promptly to treatment with busulfan and hydroxyurea. The clinical picture, treatment and a review of the literature concerning the mechanisms of this uncommon evolution are discussed.

Hereditary nephritis, platelet disorders and deafness-Epstein's syndrome.

A 14-year-old boy with persistent proteinuria (1.6-4.0 g/day), microscopic haematuria, moderate hypertension, macrothrombocytopenia (giant platelets, platelet number 30 x 10(9)/l) and a familial sensorineural hearing loss (the father and the brother were also affected) was studied. Kidney biopsy revealed a diffuse mesangial proliferation, and a focal thickening of the glomerular basement membrane was seen on electron microscopy. A normal number of megakaryocytes was observed in bone marrow aspirates. The aggregation response of the platelets to collagen, epinephrine and adenosine diphosphate (ADP) was decreased. The platelet number was slightly diminished, platelets were of normal size in both parents and the brother, and showed a decreased aggregability in response to collagen, epinephrine and ADP in the brother and mother. No functional abnormality of the platelets was observed in the father. Urinalysis and kidney function were normal in the family members. This boy with nephritis, platelet disorders and hearing loss corresponds to Epstein's syndrome.

[Macrothrombopenia, nephritis and hearing loss--a new case of Epstein syndrome]. / Macrothrombopenia, nephritis és halláscsökkenés--egy új Epstein-syndromás eset.

A 14 years old boy with persistent proteinuria (1.6-4.0 g/day), microscopic haematuria, macrothrombocytopenia (giant platelets, platelet number 30 G/l), and a familial sensorineural hearing loss (the father and the brother were also affected) was studied. Kidney biopsy presented a diffuse mesangial proliferation, and a focal thickening of the glomerular basement membrane was seen on electron microscopy. With bone marrow aspiration normal number of megacaryocytes was observed. The aggregation response of the platelets was decreased on collagen, epinephrine and ADP but it was normal on aggristin. The presented case with nephritis, platelet disorders and hearing loss corresponds to Epstein syndrome, a variant of Alport's syndrome.

Danazol in non-splenectomized patients with refractory idiopathic thrombocytopenic purpura.

Seven non-splenectomized patients with chronic refractory idiopathic thrombocytopenic purpura were treated with danazol 800 mg daily. All were glucocorticoid failures and four were refractory to all additional previous therapy. Five patients benefited from danazol and in two sustained normal platelet counts, for over 44 and 51 months, were observed. We conclude that danazol is useful for long term management of otherwise refractory idiopathic thrombocytopenic purpura. The advantage of danazol over splenectomy as a first line treatment in steroid failure is suggested.

Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43.

Growth cones, the motile apparatus at the ends of elongating axons, are sites of extensive and dynamic membrane-cytoskeletal interaction and insertion of new membrane into the growing axon. One of the most abundant proteins in growth cone membranes is a protein designated GAP-43, whose synthesis increases dramatically in most neurons during periods of axon development or regeneration. We have begun to explore the role of GAP-43 in growth cone membrane functions by asking how the protein interacts with those membranes. Membrane-washing experiments indicate that mature GAP-43 is tightly bound to growth cone membranes, and partitioning of Triton X-114-solubilized GAP-43 between detergent-enriched and detergent-depleted phases indicates considerable hydrophobicity. The hydrophobic behavior of the protein is modulated by divalent cations, particularly zinc and calcium. In vivo labeling of GAP-43 in neonatal rat brain with [35S]methionine shows that GAP-43 is initially synthesized as a soluble protein that becomes attached to membranes posttranslationally. In tissue culture, both rat cerebral cortex cells and neuron-like PC12 cells actively incorporate [3H]palmitic acid into GAP-43. Isolated growth cones detached from their cell bodies also incorporate labeled fatty acid into GAP-43, suggesting active turnover of the fatty acid moieties on the mature protein. Hydrolysis of ester-like bonds with neutral hydroxylamine removes the bound fatty acid and exposes new thiol groups on GAP-43, suggesting that fatty acid is attached to the protein's only two cysteine residues, located in a short hydrophobic domain at the amino terminus. Modulation of the protein's hydrophobic behavior by divalent cations suggests that other domains, containing large numbers of negatively charged residues, might also contribute to GAP-43-membrane interactions. Our observations suggest a dynamic and reversible interaction of GAP-43 with growth cone membranes.

Chromosome examinations on a six-hour culture of unstimulated peripheral blood from a patient with childhood erythroleukaemia.

A six-hour culture of unstimulated peripheral blood from a patient with childhood erythroleukaemia was examined for chromosome karyotype. The characteristic chromosomal abnormalities of erythroleukaemia del (5q) and monosomy 7 were found in this case together with a marker chromosome and other chromosomal abnormalities. The results suggest the usefulness of this simple method in the cytogenetic diagnosis of some types of leukaemias.

Phytohemagglutinin-stimulated leukocyte-conditioned medium induces differentiation in acute promyelocytic leukemia cells in vitro.

Six-day cultures of FCS and PHA-LCM-stimulated whole blood from a patient with acute promyelocytic leukemia (APL) were examined for differential cell count and chromosome karyotypes. It was found that both FCS and PHA-LCM could induce partial leukemic cell differentiation and maturation to macrophage in vitro, while PHA-LCM caused lymphocyte proliferation too. The absolute number of atypical blasts and neutrophils decreased in all 6-day cultures. The majority of the dividing cells (81.4%) contained the characteristic translocation for APL, t(15; 17) (q22; q11). Thus, these were members of the leukemic myeloid lineage, whereas some cells contained normal karyotypes, which could be lymphocytes.

Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth.

Nerve regeneration and developmental outgrowth of axons are both correlated with increased synthesis of an axonal membrane protein designated GAP-43. Phosphorylation of an apparently identical protein, present at lower abundance in adult brains, has been correlated with long-term potentiation, a form of synaptic plasticity. We have now isolated a cDNA clone encoding GAP-43 from neonatal rat brain. The amino acid sequence is extremely hydrophilic, with no potential membrane-spanning domains and no sites for N-linked glycosylation, but with a short hydrophobic segment at the protein's amino terminus, consistent with a model in which GAP-43 extends from the cytoplasmic surface of growth cone and synaptic plasma membranes. Among several tissues and cells examined, GAP-43 mRNA is expressed only in neurons. Developmental and regeneration-associated changes in GAP-43 synthesis appear to be mediated largely at the level of transcription of a single gene.

Heparin-induced thrombocytopenia and recurrent thrombosis in pregnancy. A case report.

Heparin-induced thrombocytopenia with thromboembolism calls for an immediate substitution of the heparin with other potent anticoagulants, such as coumarin derivatives. The occurrence of this adverse effect in pregnancy poses an additional dilemma because the use of coumarin derivatives is not acceptable during pregnancy, while other medications may not be as effective. In a pregnant patient treated with mucous sodium heparin for deep vein thrombosis, recurrent heparin-induced thrombosis and disseminated intravascular coagulation (DIC) occurred. Replacing the heparin with a different brand of the same drug resulted in reversal of the DIC and in clinical improvement. If severe heparin-induced thrombosis occurs in a patient in whom anticoagulation with other drugs is contraindicated, substituting one brand of heparin for another could be of value.

Lymphocyte subsets in habitual abortion.

Lymphocyte subpopulations were characterized by means of monoclonal antibodies in 25 women with habitual abortion and 21 multiparous normal women. Compared to nonpregnant women (N = 8), pregnant normal women were associated with significantly lower helper-to-suppressor ratios (1.71 +/- 0.41 versus 2.37 +/- 0.66). In contrast in pregnant women with habitual abortion (N = 13) the ratio remained high (2.32 +/- 0.73). Failure to increase the number of suppressors and a significant rise in helpers caused this increased ratio. We discuss the possible mechanisms and etiological importance of this finding in habitual abortion.

A protein associated with axon growth, GAP-43, is widely distributed and developmentally regulated in rat CNS.

Development or regeneration of axons in several systems is accompanied by 20-100-fold increases in the synthesis of an acidic, axonally transported membrane protein with an apparent molecular weight of 43-50,000 (Benowitz and Lewis, 1983; Skene and Willard, 1981a, b), which we designate GAP-43. We have proposed that some step(s) in axon growth require production of GAP-43, and perhaps a small number of other "growth-associated proteins," at rates much higher than those typical of mature neurons. This hypothesis predicts that virtually all neurons synthesize GAP-43 at elevated levels during normal CNS development. Here we show that a protein similar to GAP-43 from regenerating toad nerves is prominent among the newly synthesized (35S-methionine-labeled) and total (Coomassie blue-stained) proteins in neonatal rat cerebral cortex and cerebellum, suggesting that synthesis of GAP-43 is indeed a common feature of many developing neurons. Synthesis and accumulation of the protein decline an order of magnitude as animals mature. Antibodies raised against the rat cortex GAP-43 also recognize electrophoretically similar proteins from regenerating toad optic nerves and from developing hamster sensorimotor cortex, indicating that structural features of GAP-43 are conserved in evolution. Cell-free translation of polyadenylated RNA from neonatal and adult cortex suggests that developmental regulation of GAP-43 synthesis is mediated largely through changes in mRNA abundance. These observations together suggest that developmental regulation of GAP-43 gene expression may be common to most vertebrate CNS neurons. GAP-43 remains detectable at a low level in adult rat cortex, and it co-migrates on two-dimensional gels with B-50, a synaptic membrane protein which is a preferred substrate for protein kinase C in adult brains. Phosphorylation of the protein by endogenous kinase(s) in vitro is 4-7-fold greater in growth cone membranes than in mature synaptic membranes, which raises the possibility that local modification of the protein in axon terminals may be synergistic with regulation of GAP-43 synthesis in the cell body.

[Results and problems in the treatment of childhood leukaemia (author's transl)]. / Ergebnisse und Probleme bei der Behandlung der kindlichen Leukämien in Ungarn.

391 children received complex chemotherapy according to uniform treatment schedules, proposed by the Hungarian Study Group for Childhood Leukaemia, which was established in 1971. Survival among the patients showed an increasing tendency: more than 50% of patients with ALL are stille alive 3 years after the beginning of treatment. One patient is in complete remission 9 3/4 years after the establishment of the diagnosis. Two types of maintenance therapy were investigated among the patients entered for this study in 1974. "Pulses" with Vincristine-Prednisolone every second month were found to be more optimal than monthly "pulses".

Prophylactic central nervous system therapy in childhood acute lymphatic leukemia. Effect of poor-risk patients on the results.

The results of treatment in a group of 50 children with acute lymphatic leukemia are summarized. A comparison was made between those who received prophylactic central nervous systen (CNS) therapy on attaining complete remission and those who did not. Although none of the prophylactically treated children developed CNS leukemia, the expected prolongation of median complete remission time was not achieved. It was found that there was a high percentage of poor-risk patients in the CNS-treated group, and these patients relapsed early in the course of the disease. The prevention of CNS leukemia, a late complication of the disease, did not change the natural course of the disease in poor-risk patients. A need exists for new treatment protocols aimed at better control of the disease in these poor-risk cases.

Therapeutic results: report of the Hungarian children's leukaemia study group.

In Hungary, the morbidity of leukaemia in children aged 0 to 15 years is 3.6/100,000. The rate of complete remission was 88.5% in ALL and 57.1% in AML. The most important factors limiting survival were infections acquired during induction therapy in 91.3% and during Co irradiation in 66.3% of the patients.