Dina Meytes

Serological and molecular survey for HTLV-I infection in a high-risk Middle Eastern group

To define the extent of human T-cell leukaemia virus (HTLV-I) infection among a group of Jewish immigrants to Israel with an increased frequency of adult T-cell leukaemia, various serological and molecular screening methods, including enzyme-linked immunosorbent assay (ELISA) for anti-HTLV-I, ELISA for antibody to recombinant HTLV-I p40tax protein, and molecular detection of infection by polymerase chain reaction (PCR) amplification of HTLV-I proviral DNA from peripheral blood mononuclear cell DNA, were used. By HTLV-I ELISA the overall rate of infection was 12% (24 of 208) among immigrants from Khurusan, northeastern Iran; no HTLV-I carriers were detected among 111 unselected Jewish immigrants from other parts of Iran. There was unexplained clustering of HTLV-I infection within a cohort of 32 elderly women of similar geographic origin in a home for old people--14 were seropositive by ELISA and 19 of 29 were positive by PCR. The findings in this newly identified high-risk population suggest that in addition to ELISA, other screening techniques may be required to detect all carriers in high-risk populations.

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.

Increased number of peripheral blood CD34+ cells in lithium-treated patients

Eight adult patients with bipolar disorder were prospectively examined to find whether lithium carbonate increased their peripheral blood CD34+ haemopoietic stem cells. Following lithium therapy for 3–4 weeks their neutrophil counts increased by a mean of 88% (from 4625 ± 1350 × 109/l, mean ± SD pretreatment, to a peak of 8300 ± 3910 × 109/l). Concommitantly, there was a significant increment in their CD34+ cells (from 0.11 ± 0.01% to a peak of 0.18 ± 0.08%). There was a significant correlation between the rise in neutrophil count and that of the CD34+ cells (r = 0.795, P = 0.019). Lithium therapy may be used to mobilize peripheral blood CD34+ cells for marrow transplantation.

Adult T-cell lymphoma in Israeli patients of Iranian origin.

The clinical and laboratory features of four Israeli patients with adult T‐cell lymphoma‐leukemia (ATL) are presented. In three of them evidence for human T‐cell lymphotropic leukemia virus (HTLV‐I) infection was obtained. Interestingly, all of the patients immigrated to Israel from the same regions in Iran. Except for lack of skin involvement, the clinical course was typical for ATL as described worldwide. This is the first report of ATL in an Iranian cohort. This observation suggests that Iranian patients with ATL‐like illness should be studied for the presence of HTLV‐I infection.

Reduced production of tumor necrosis factor by mononuclear cells in hairy cell leukemia patients and improvement following interferon therapy.

In 16 patients with hairy cell leukemia (HCL) there was a marked reduction in the production of cytotoxins (CTXs) by peripheral blood mononuclear leukocytes in response to stimulation in vitro by phytohemagglutinin (PHA), 4β‐phorbol‐12‐myristate‐13‐acetate (PMA), or Sendai virus. CTX yields of 23.5 ± 21.5 U/ml, 15 ± 18 U/ml, and 12.1 ± 12.1 U/ml were obtained in response to PHA, PMA, and Sendai virus, respectively, as compared with corresponding yields of 207.3 ± 93.1, 154 ± 37.4, and 205.2 ± 62.4 in healthy controls. The extent of reduced production of CTXs appeared to be correlated with the severity of the disease. Systemic interferon (IFN) administered to four patients caused CTX production to improve in response to PHA (147.5 ± 55.1 U/ml compared with pretreatment values of 14.1 ± 6 U/ml, P < 0.05). However, CTX production in response to Sendai virus remained low. The extent to which CTX production by hairy cell leukemia mononuclear cells was reduced was proportionate to the observed decrease in monocyte counts. However, the degree to which CTX production improved after IFN treatment was significantly greater than the observed increase in monocyte counts. The major CTX induced by PHA in mononuclear cells of healthy donors and of IFN‐treated HCL patients was identified as tumor necrosis factor‐α.

Monitoring oral anticoagulant therapy by telephone communication

The number of patients who need supervision during oral anticoagulant treatment is growing constantly. We have presently enrolled 156 patients who were referred to our anticoagulant clinic and who were taking sodium warfarin with target International Normalized Ratios (INR) of low (2–3), intermediate (2.5–3.5) and high (3–4) range. Patients performed the tests in laboratories situated in locations at their convenience and received further instructions from a specialist via telephone communication. A total of 8758 prothrombin times (5214, 1947 and 1597 tests for individuals in the low, intermediate and high range, respectively) were performed over the period of 3.16 ± 2.6 years (range, 6 months–9.5 years) and reported to the specialist. It was found that in the aforementioned three groups of intensity 63.3, 57.0 and 47.7% of the INRs were within the target range, the respective percentages for the expanded (± 0.5) target INR being 92.8, 87.8 and 78.5%. The INTERDAY software was used to calculate the number and proportion of days within the target INR range, the respective results being 71.0, 64.0 and 51.6% and 96.2, 93.2, 86.4% for the expanded range. The number and percentage of bleeding and embolic complications’ referrals to the emergency room and hospitalizations were similar to those reported for anticoagulant clinics in which patients have to actually pay a personal visit in order to receive instructions. Our study is significant in that it documents that trans-telephonic communication is feasible safe and cost-effective and that the clinical results are at least as good as those obtained by traditional consultation.

Effect of Excess Parathyroid Hormone on Human Bone Marrow Fibroblasts

Patients with uremia have excess levels of parathyroid hormone (PTH). It has been reported that excess PTH is associated with bone marrow fibrosis. The present study was undertaken to examine the in vitro effect of intact 1-34 PTH and the active 1-34 N-terminal fragment on human bone-marrow-derived fibroblasts. Proliferation of fibroblasts was not stimulated by PTH in concentrations present in uremia (5-30 U/ml) nor by uremic sera which contained either high or low PTH levels. The lack of stimulation contrasted with the activity of both PTH preparations in other systems, i.e., inhibitory to erythroid colonies and stimulatory to heart muscle cells.

Recombinant interferon alpha-C for advanced hairy cell leukemia. An Israeli multicenter study.

Thirteen patients with advanced hairy cell leukemia were treated with a new subspecies of interferon (IFN): recombinant IFN (rIFN)‐alpha‐C. The timing of the peripheral hematologic remission of individual blood elements was similar to that reported for other interferons, and 60% of patients attained a complete peripheral hematologic remission at 9 months. Two patients relapsed despite a good initial response to IFN. No anti‐IFN antibodies could be detected in their sera. in vitro studies of colony formation from the peripheral blood of all responding patients showed that rIFN‐alpha‐C did not inhibit the growth of colonies but favorably affected the maturation of their elements towards monocytes, granulocytes, and erythroid elements. The relapsing patient examined initially experienced a similar beneficial in vitro response which paralleled his in vivo improvement. During relapse, rIFN‐alpha‐C inhibited both the colony formation and the myelomonocytic differentiation in the in vitro cultures. These findings may suggest that the acquired resistance to IFN in our patient could be due either to an acquired stem cell maturation arrest in response to IFN or to emergence of a new clone indifferent to IFN‐alpha‐C differentiation effect.

Improved survival and marrow engraftment of mice transplanted with bone marrow of GM‐CSF‐treated donors

Abstract: Recombinant granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) administered to bone marrow (BM) transplant recipients is associated with earlier recovery. We have investigated the possibility of stimulating normal donor mice in vivo with GM‐CSF. Donor balb/c mice were injected i.p. with GM‐CSF (5000 u) or saline. Seventy‐two hours later 5 × 105 BM cells from either GM‐CSF‐treated or control donors were infused into lethally irradiated (850 R) recipients. In the recipients of BM from GM‐CSF‐treated donors, significantly higher CFU‐S and significantly higher survival rate (57% [n = 65]; vs. 30% [n = 63]; p<0.05) were noted. Donor mice of the GM‐CSF group did not differ in bone‐marrow cellularity and composition from their controls. However, recipients of BM from GM‐CSF‐treated mice had higher blood counts of haemoglobin, leukocytes and platelets compared to controls. These data demonstrate that pretreatment of BM donors with GM‐CSF may be of benefit in improving survival and marrow engraftment in mice.

Chemotherapy Related Leukemogenesis

Administration of aggressive chemotherapy to patients with cancer has considerably improved their outlook for effective palliation or cure. However, a hitherto unappreciated complication consisting of a secondary malignancy, in particular acute leukemia, has emerged. Prolonged therapy with alkylating agents and chemotherapy plus radiotherapy are associated with an increased risk of this complication. The disease evolves through a preleukemic phase of pancytopenia and sideroblastic refractory anemia. The median onset from the initiation of chemotherapy is about 5 years with an increasing incidence with time. Myelomonocytic, monocytic and erythroleukemia with atypical features and resistance to conventional therapy predominate. Hyploidy and aberrations involving chromosomes 5 and 7 are frequent. Alkylating agents are carcinogenic in laboratory animals. Although the pathway to leukemogenesis in humans is unknown, a multistep evolution is envisaged. This involves: 1) initiation through induction of errors in DNA, 2) promotion related to stem cell replication following chemotherapy-induced aplasia and 3) propagation related to immunosuppression. It is possible that, as in myeloproliferative disorders, an underlying tendency for leukemia is present in patients with cancer. This may be accentuated by chemotherapy, and more frequently observed due to the longer survival of such patients. The crucial role of chemotherapy in leukemogenesis is evident from data accumulated in non-malignant conditions such as rheumatoid arthritis.