Effect of parathyroid hormone on erythropoiesis.

Inhibitors of erythropoiesis have been found in the blood of uremic patients but their nature has not been identified. These patients have excess blood levels of parathyroid hormone (PTH) and it is possible that PTH inhibits erythropoiesis. The present study was undertaken to examine the effect of intact PTH molecules and some of its fragments on human peripheral blood and mouse bone marrow burst-forming units-erythroid (BFU-E), on mouse bone marrow erythroid colony-forming unit (CFU-E), and granulocyte macrophage progenitors (CFU-GM), and evaluate the interaction between PTH and erythropoietin (Ep) on human BFU-E. Intact PTH (1-84 bPTH) in concentrations (7.5-30 U/ml;) comparable to those found in blood of uremic patients produced marked and significant (P less than 0.01) inhibition of BFU-E and mouse marrow GFU-GM, but not of mouse marrow CFU-E. Inactivation of 1-84 bPTH abolished its action on erythropoiesis. Increasing the concentration of Ep in the media from 0.67 to 1.9 U/ml overcame the inhibitory effect of 1-84 bPTH on BFU-E. The N-terminal fragment of PTH (1-34 bPTH) and 53-84 hPTH had no effect on BFU-E. The results demonstrate that (a) either the intact PTH molecule or a C-terminal fragment(s) bigger than 53-84 moiety exerts the inhibitory effect on erythropoiesis, and (b) adequate amounts of Ep can overcome this action of PTH. The data provide one possible pathway for the participation of excess PTH in the genesis of the anemia of uremia.

Significance of high HbA1 levels in normal glucose tolerance.

The significance of high hemoglobin A1 (HbA1) levels (greater than or equal to 8.0%) found in 12.1% of 648 individuals with normal glucose tolerance constituting a part of a representative population sample was examined. Measurement error in HbA1 and/or glucose-tolerance levels was precluded by HbA1 remaining in the same range over 3.5 yr in 89.7% of 29 individuals with initially high and 68.1% of 22 individuals with initially low (less than 6.5%) HbA1. Rate of deterioration to glucose intolerance (6.9%) in the high group during that period resembled the rate (11.8%) in a control group (n = 279). Fasting plasma glucose significantly accounted for only 2.4% of total HbA1-population variance. No correlation of HbA1 was found with other correlates of glucose tolerance or with daily caloric intake and physical activity. A small but significant increment in HbA1 was associated with smoking (7.1 vs. 6.8%, P less than .01) and with clinically overt atherosclerosis (7.3 vs. 6.9%, P less than .01). We conclude that factors unrelated to glucose metabolism are the main determinants of HbA1 level in normal glucose tolerance and play an important role in diabetes as well. These factors have bearing on evaluation of diabetic control by HbA1 and possibly on risk for diabetic complications.

Biological properties of a human urinary protein fraction with burst promoting activity.

Urinary proteins from patients with iron deficiency anemia and acquired aplastic anemia were fractionated by chromatography on QAE-Sephadex A-50 and Sephadex G-25. Fractions containing erythroid burst promoting activity (code named regulatory protein RP) were separated from erythropoietin. Mouse bone marrow cells were preincubated for one day in suspension culture, in the presence or absence of RP, transferred to a methylcellulose based system and incubated for six more days with erythropoietin (EPO). It was found that the presence of RP in the preincubation medium had a 2 to 4 fold enhancing effect on subsequent erythroid burst colony formation. However, when RP was added to methylcellulose based cultures simultaneously with EPO, the erythroid burst response was reduced or abolished. Addition of RP to marrow cell suspension cultures increased the number of self replicating, pluripotent (erythroid/granuloid, E/G ratio = 3) spleen colony forming units (CFU-S) found at the end of 2 days incubation 3-5 fold over their number in control cultures incubated without the factor. In marked contrast to this, addition of EPO to the cultures caused an increased persistence of CFU-S with a predominantly erythroid commitment (E/G ratio = 19) and a low self replicating ability, as measured by retransplantation of spleen cells into secondary recipients. These observations are compatible with the presence in RP of a factor, or factors, capable of maintaining the size of certain early precursor cell compartments.

Measurement of human erythroid burst-promoting activity by a specific cell culture assay.

A two-stage cell culture assay specific for human erythroid burst-promoting activity (BPA) is described. Human peripheral blood mononuclear cells were cultured in suspension with or without a BPA test sample for two days, then transferred to methylcellulose medium with added erythropoietin (EPO) and incubated for ten more days, and finally BFU-E-derived colonies were scored. An increase in number of colonies due to the presence of BPA was observed that was proportional to the concentration of BPA in the test sample. This response was linear with respect to number of cells plated between 2 and 5 X 10(5)/ml. The system was standardized with a partially purified human urinary BPA preparation. Dose responses to urinary protein preparations, plasma, and serum were parallel. The assay system was found to be nonresponsive to highly purified EPO and to bacterial endotoxin. It was determined that BPA action was confined to the suspension culture stage of the assay, while EPO presence was an absolute requirement during methylcellulose culture. In the two-stage assay optimal amounts of BPA caused up to 358% increases of BFU-E-derived colonies; the same amounts of BPA added to conventional methylcellulose cultures caused only up to 54% increases over the number of colonies obtained with EPO alone. Plasma and serum BPA levels of hematologically normal and abnormal individuals showed no correlation with EPO levels and hemoglobin (Hb) concentrations. This seems to rule out the possibility that BPA elaboration is regulated by oxygen availability or the amount of EPO circulating in an organism.

Constancy of erythroid burst forming unit (BFUE) levels in the blood of hematologically normal individuals.

Repeated determination of circulating blood BFUE levels in 7 hematologically normal individuals, during a 6 to 16 month period, showed their respective levels to be maintained within narrow limits (coefficient of variation did not exceed 15.1%). However, males differed from each other 3-fold and females as much as 12-fold in the number of BFUE/ml blood. These differences may reflect various sizes of the early erythroid progenitor compartment, which in the presence of different levels of humoral regulators of erythropoiesis are capable of maintaining a normal rate of red cell production. Our findings suggest that the observation of changes of the blood BFUE level of individuals, over a period of time, may be indicative of a change in their erythropoiesis and may shed some light on the physiological role of the peripheral blood BFUE.

Autoantibodies to DNA in multicase families with schizophrenia.

In an attempt to define the autoimmune status of members of multicase families with schizophrenia, sera of both patients and healthy relatives from 28 such cases were tested for antinuclear antibodies, anti-double-stranded DNA, and anti-single-stranded DNA autoantibodies. These autoantibodies were significantly more frequent in both schizophrenic patients and healthy relatives than in normal subjects. Immunoglobulin (Ig) M anti-DNA antibodies were more common in patients, whereas in healthy relatives, IgG anti-DNA antibodies were more common. No significant differences were found between schizophrenic patients and their healthy relatives. The data indicate that an autoimmune process may be involved in the etiology of a subset of patients with schizophrenia.

Expression of the mid-stage differentiation B-cell antigen GP-70 in patients with early and stable form of B-CLL.

The expression of B-cell surface markers SmIg and GP-70 was determined on the mononuclear cells from the peripheral blood of 25 patients with chronic lymphocytic leukemia (CLL), 10 patients with multiple myeloma (MM), 6 normal blood donors and in 3 cases of unexplained persistent lymphocytosis. GP-70 was expressed only in CLL patients whereas multiple myeloma patients, blood donors and patients with unexplained lymphocytosis were all negative to GP-70. SmIg was expressed in CLL patients and in some of the multiple myeloma patients. Subgrouping of CLL patients to "early", stable patients (10) and to more advanced CLL patients (15) revealed differential expression of GP-70 on CLL cells from patients with more advanced stage of disease rather than in the patients with the "early" stable clinical course of disease. SmIg, on the other hand, was expressed equally on both subgroups of CLL. Furthermore, in some cases (25%) where SmIg and the light chains of Ig were only weakly expressed or were absent, GP-70 was markedly expressed. These findings suggest that GP-70 can be used as a single laboratory determination to establish clonality of the B-lymphocyte proliferation in CLL. In addition, expression of GP-70 correlates with significant clinical parameters of the disease.

Platelet parameters and aggregation in essential and reactive thrombocytosis.

Platelet characteristics were assessed in 15 patients with essential thrombocytosis (ET), 89 patients with reactive thrombocytosis (RT), and 23 normal controls. A platelet volume distribution width (PDW) greater than or equal to 10.5 was found in 50%, 21%, and 14% of the three groups, respectively (P = 0.01 between patients with ET and patients with RT; P = 0.02 between patients with RT and controls), reflecting an excess of extreme values at both ends of the distribution. Compared with controls, the increase in platelet number in patients with RT was about twofold throughout the platelet volume range, whereas ET was characterized by a fivefold increase in small platelets less than 7.5 fL and threefold increase in larger size platelets. Mean platelet volume (MPV) was significantly lower in patients with ET versus patients with RT and in patients with RT versus controls (mean +/- SD 7.5 +/- 1.2 vs. 8.8 +/- 0.1 and 10.2 +/- 1.8 fL, respectively, P less than 0.01). Rate of in vitro platelet aggregation greater than or equal to 50% was significantly lower in patients with ET versus patients with RT and in patients with RT versus controls (0%, 23%, and 45%, respectively, P less than 0.01). Aggregation rate was positively correlated with MPV (r = 0.54; P less than 0.0001). Aggregation rate in patients with ET was significantly lower (P = 0.01) than expected from their reduced MPV alone. Despite these group differences, the overlap of individual platelet characteristics between the three groups precludes their usefulness for diagnostic purposes.

Acute lymphoblastic leukemia with a unique translocation in an adolescent boy.

We report a case of an adolescent boy with acute lymphoblastic leukemia whose blasts had three chromosomal abnormalities: trisomy 8, a t(5;15), and an extra "marker" chromosome. The patient presented with huge hepatosplenomegaly and pancytopenia. The response to treatment (ALL BFM 90 protocol) was very rapid, and the patient is in complete remission 1 year after diagnosis.

Translocation (1;20)(q32;q13.3) in myelofibrosis following polycythemia vera.

We report a novel chromosomal translocation (1;20)(q32;q13.3) in a patient with myelofibrosis following polycythemia vera. This 73-year-old woman developed myelofibrosis 6 years after the initial diagnosis of polycythemia vera (PV). The course of PV was uneventful. Subsequent to the diagnosis, the patient was treated with phlebotomy and low doses of hydroxyurea for 4 years. No therapy was delivered during the remaining 2 years. A bone-marrow biopsy and a karyotype analysis performed because of evolving anemia demonstrated myelofibrosis and a chromosomal aberration-t(1;20)(q32;q13.3). Aberrations in chromosomes 1 and 20 have been reported in myeloproliferative disorders, but a t(1;20) translocation has not been reported. Because a karyotype analysis was not performed at the time PV was diagnosed, whether this translocation is linked to the primary disease (PV) or to the transition to myelofibrosis is not known.

Deletion of the long arm of chromosome 7 in myelomonocytic leukemia with bone marrow eosinophilia.

We report a 62-year-old man with acute myelomonocytic leukemia with bone marrow eosinophilia (M4Eo), and a deletion of the long arm of chromosome 7. The patient presented with pancytopenia, which shortly after evolved to overt leukemia. There was no response to the daunorubicin-cytosine arabinoside (Ara-C) regimen, and a remission achieved with amsacrine (AMSA)-Ara-C lasted only for a short time. On relapse, a peculiar skin rash accompanied the hematologic picture. While ANLL with chromosome 7 abnormalities usually carries adverse prognosis, patients with M4Eo (which is usually associated with chromosome 16 abnormalities) do better. The patient described here examplifies that M4Eo may be associated with del(7)(q22), and that it is the chromosomal abnormality rather than the type of leukemia that might determine the clinical outcome.

Persistent abnormalities in red cell parameters following treatment of lymphoma.

Patients who have recovered from malignant lymphoma are at an increased risk of secondary acute leukemia (AL), and overt AL is frequently preceded by a myelodysplastic syndrome. Although the statistical risk is significant, only a minority of the patients will be so affected. We have reviewed peripheral blood counts of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) treated in the Departments of Hematology at the Edith Wolfson and Chaim Sheba Medical Centers, Israel. Included were only those who went into a complete remission and remained lymphoma free for extended periods. There were 85 patients with HD and 36 with NHL. In both groups peripheral blood counts at diagnosis were within the normal range. A prolonged follow-up (> 4 y), during which no further treatment was given, revealed a sustained increment over time of MCV (delta MCV) both in HD and NHL. A persistent monocytosis in HD patients was also evident. delta MCV was larger in HD. The difference at the end of the follow-up period was as follows: 10.1 fl + 11.8 in HD vs 5.0 fl + 6.2 in NHL, (P < 0.001). In addition, a significant loss of the normal correlation between the MCV and levels of hemoglobin was seen at the last follow-up. The change in MCV was present in all treatment groups, its magnitude increasing from radiotherapy to chemotherapy to combined radio chemotherapy. This trend is in analogy to the risk of secondary AL which is lower in NHL vs HD. Furthermore, it is lowest post radiotherapy and highest when both treatment modalities are used.(ABSTRACT TRUNCATED AT 250 WORDS)

Insect bite-like reaction in patients with hematologic malignant neoplasms.

BACKGROUND: Exaggerated reaction to insect bites, mainly to mosquitoes, is infrequently described in patients with chronic lymphocytic leukemia. Skin lesions usually appear months to years after the diagnosis of leukemia and are unrelated to laboratory findings, disease course, or therapy. OBSERVATIONS: We describe 8 patients with various hematologic disorders (chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, mantle-cell lymphoma, large-cell lymphoma, and myelofibrosis) who developed insect bite-like reaction. Although the clinical picture and the histological characteristics of the lesions were typical for insect bites, none of the patients actually had a history, course, or response to treatment suggestive of arthropod assaults. In 2 patients, the eruption preceded the diagnosis of the malignant neoplasm. The rash persisted for months to years and was resistant to therapies other than systemic corticosteroids. The 3 patients with chronic lymphocytic leukemia seemed to have a worse prognosis than expected for their disease. In 1, the polymerase chain reaction detected leukemic cells in the infiltrate. CONCLUSIONS: Insect bite-like reaction is an infrequent, disturbing, and difficult-to-treat nonspecific phenomenon in patients with hematologic malignant neoplasms. Since it may precede the hematologic disorder, oriented evaluation is warranted. We speculate that immunodeficiency plays a role in its pathogenesis; however, the exact pathogenesis and its prognostic implications await further studies.

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.

Autologous umbilical cord blood transfusion.

The purpose of this study was to examine some aspects of umbilical cord blood collection for autologous transfusion in premature infants. All 120 microbacterial cultures (aerobic and anaerobic) of cord blood samples as well as 30 cultures of mycoplasma were treated. Cord prothrombin fragment (F 1 + 2) concentrations were quantified at one and 10 minutes after clamping of the cord. F 1 + 2 concentrations assessed on 25 newborn infants were similar and no linear association with time of clamping could be drawn. This means that cord blood thrombosis is not activated for at least 10 minutes following clamping of the cord. As far as is known, the first newborn infant to benefit from this method of transfusion is reported here. The premature infant received two portions of autologous blood (on days 5 and 7). No untoward effects were noted. Blood, collected from the umbilical cord, is a safe source for autotransfusion, provided that bacteriological testing has been carried out.

Short note: the potential of umbilical cord blood to increase tissue oxygenation in adult respiratory distress syndrome.

Umbilical blood, consisting mainly of fetal haemoglobin, has an increased oxygen affinity. Adult respiratory distress syndrome may be caused by any acute, diffuse, infiltrative lung lesion of diverse aetiologies and is characterized by severe arterial hypoxia. Mechanical ventilation with high FIO2 and elevated pressures is used to improve tissue oxygenation in these patients. Nevertheless, adult respiratory distress syndrome may be fatal. Our hypothesis suggests that transfusion of umbilical cord blood to adult respiratory distress syndrome patients may facilitate oxygen transport by increasing oxygen binding in the erythrocytes passing through the damaged lungs. The local hypoxia and the accompanied acidosis in the periphery may accelerate the oxygen unload to the tissues, thus augmenting overall oxygen delivery. Studies with animals and humans show that left-shifted oxyhaemoglobin dissociated curve confers a degree of adaptation to low-oxygen tension ambient. Umbilical cord blood is available in every hospital, and there are no contraindications to its use.

High rate of asthma among immigrants.

Articles dealing with the epidemiological aspects of asthma were carefully reviewed in order to support or reject our clinical impression of increased rate of asthma among immigrants. Particular emphasis was put on data on very high or very low rates of asthma. The proposed theories to explain these differences were critically examined. The prevalence of asthma in China and in Africa is 1-2% and 0.5-5%, respectively. The prevalence of the disease in other indigenous populations ranges between 0.5% and 12%. On the other hand, asthma is much more frequently seen in Australia and in New Zealand (approximately 20-25%), where peoples' ancestors immigrated from distant areas. Statistical meta-analysis found a significant difference between the rates of asthma in the two groups of populations (P < 0.001). Immunoglobulin E levels of immigrants in Sweden are higher than those of native Swedes. Similarly, cord blood immunoglobulin E concentrations are more elevated in neonates whose mothers emigrated to Germany from Eastern countries than in those of native German mothers. There is an increased rate of IgE-mediated asthma among immigrant populations.

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.

[Remission of acute promyelocytic leukemia after all-trans-retinoic acid].

This is the first report in Israel of the successful treatment of acute promyelocytic leukemia (APL; M3) with an active metabolite of vitamin A. In a 42-year-old woman with APL all-trans-retinoic acid (ATRA; tretinoin), 45 mg/m2/day was given per os for 90 days. APL is associated with a distinct cytogenetic abnormality: translocation of a portion of the long arm chromosome 17 onto the long arm chromosome 15t (15; 17) with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha), playing a crucial role in the leukemogenesis of APL. In man, the drug induces myeloid and mainly promyelocytic leukemic cells to differentiate, without the development of bone marrow hypoplasia. In our patient it caused complete remission and the disappearance of intravascular disseminated coagulation. The only side-effects were a transient macular rash, gastrointestinal symptoms and mild hypertriglyceridemia. Other principal adverse effects reported in the literature are relatively not very serious and consist of dryness of the skin, occasional headaches and intracranial hypertension, nasal congestion, lymphadenopathy, respiratory distress with infiltrates in the lung, bone pain and increased hepatic aminotransferase. A hyperleukocytosis syndrome seems to be more problematic. ATRA appears to be superior to conventional chemotherapeutic regimens. It is safe and highly effective in inducing clinical, morphologic and karyotypic remission with a marked decrease in the expression of the abnormal RAR-message in APL. There is a possible molecular link between the pathogenesis and treatment of this severe and often fatal coagulopathic disease. This therapy of course does not eradicate the leukemic clone, and consolidation chemotherapy or bone marrow transplantation is necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

The long term risk of myelodysplastic syndromes among anemia patients: a population-based study.

We have utilized the computerized data of a nationwide health plan to elucidate several epidemiologic aspects and risk factor of myelodysplastic syndromes (MDS) in Israel. The annual incidence rate (IR) of reported MDS was of 3.32 per 100,000. Among anemic patients aged 40+, the risk of reported MDS was 56.7 per 100,000. Only 44% of the reported MDS cases had an indication of bone marrow examination. In a multivariable model, older age, hemoglobin level <9 g/dl, white blood cell count of less than 3500/mm(3), and platelet count of less than 100×10(9)/L were associated with a significantly higher risk of MDS. The mean lag period from the first demonstration of anemia to the final diagnosis of MDS was 3.5 years. Our study results could be helpful for improving the detection of patients with high MDS risk, therapeutic decision-making, and designing interventional trials in the future.