Niel Wald

Paternal Transmission of Maleness in XX Human Beings

Abstract Phenotypic maleness was observed in a 7 1/2-year-old child and his father with an XY karyotype. Two brothers and a paternal uncle were found to have an XX sex-chromosome constitution. The ...

Activation of the nitric oxide synthase 2 pathway in the response of bone marrow stromal cells to high doses of ionizing radiation.

Abstract Gorbunov, N. V., Pogue-Geile, K. L., Epperly, M. W., Bigbee, W. L., Draviam, R., Day, B. W., Wald, N., Watkins, S. C. and Greenberger, J. S. Activation of the Nitric Oxide Synthase 2 Pathway in the Response of Bone Marrow Stromal Cells to High Doses of Ionizing Radiation. Reverse transcription-polymerase chain reaction and immunofluorescence analysis of D2XRII murine bone marrow stromal cells showed that γ irradiation with doses of 2–50 Gy from 137Cs stimulated expression of nitric oxide synthase 2 (Nos2, also known as iNos). The activation of Nos2 was accompanied by an increase in the fluorescence of 4,5-diaminofluorescein diacetate, a nitric oxide trap, and accumulation of 3-nitrotyrosine within cellular proteins in a dose-dependent manner. These effects were inhibited by actinomycin D and by N-[3-(aminomethyl)benzyl]acetamidine dihydrochloride, a specific inhibitor of Nos2. The induction of Nos2 expression and Nos2-dependent release of nitric oxide in D2XRII cells was observed within 24 h after irradiation and was similar in magnitude to that observed in cultures incubated with Il1b and Tnf. We conducted (1) confocal fluorescence imaging of 3-nitrotyrosine in bone marrow cells of irradiated C57BL/6J mice and (2) 3-nitrotyrosine fluorescence imaging of FDC-P1JL26 hematopoietic cells that were cocultured with previously irradiated D2XRII bone marrow stromal cells. Exposure to ionizing radiation increased the production of 3-nitrotyrosine in irradiated bone marrow cells in vivo and in nonirradiated FDC-P1JL26 cells cocultured with irradiated D2XRII cells for 1 or 4 h. We suggest that nitrative/oxidative stress to the transplanted multilineage hematopoietic cells due to exposure to nitric oxide released by host bone marrow stromal cells may contribute to the genotoxic events associated with malignant alterations in bone marrow tissue of transplant recipients who are prepared for engraftment by total-body irradiation.

Induced acute non-lymphocytic leukemia following long-term chemotherapy. A study of 20 cases

Twenty individuals developed acute non‐lymphocytic leukemia (ANLL) following long‐term chemotherapy for other disorders. The primary disorders included non‐Hodgkins lymphoma (five), Hodgkins disease (five), carcinoma (four), multiple myeloma (three), chronic lymphocytic leukemia (two), and rheumatoid arthritis. Leukemia developed from 11–132 months (mean approximately 60 months) following institution of chemotherapy and all cases have occurred since 1974. Pre‐leukemic cytopenias were present in 15 individuals. Fifteen of the 20 patients had chromosome analyses and 14 were abnormal. The leukemia was invariably refractory to chemotherapy with a median survival of only two months. Of the patients autopsied, only one individual had any evidence of the primary malignancy. This study illustrates the need for surveillance for secondary ANLL following long‐term chemotherapy with/ without radiotherapy. Duration of optimal chemotherapy for the primary disease must be determined by control trials and weighed against the risk of developing a secondary leukemia.

Cytogenetic evidence concerning possible transplacental transfer of leukocytes in pregnant women

Abstract Chromosome analyses were performed on 5,490 leukocytes in metaphase which were obtained from the cord blood of 183 live newborn male infants. Of these, 5,474 cells contained XY chromosomes, 14 were XX, and 2 had XO sex patterns. The 16 cells with XX and XO chromosomes were derived from 2 infants who had developmental defects and died within 34 days of delivery. It is suggested that mitotically capable leukocytes do not cross the placentas of normal fetuses, and that transfer may occur if the fetus and placenta are developmentally defective.

On the estimation of the incubation period in malignant disease: The brief exposure case, leukemia☆

Abstract 1. 1. The incubation period of radiation-induced leukemia in adults is estimated to be about 5 years with 90 per cent of the cases occurring less than 10 years after exposure. 2. 2. Assuming genesis during gestation, there is a somewhat shorter incubation period for children. 3. 3. If one is willing to assume that the incubation period of leukemia induced by other means is approximately the same, there is now plain indication to search for other causes of leukemia up to 10 years before onset in adults, and during gestation or the first few weeks of postnatal life in the case of children. 4. 4. This approach to the estimation of the incubation period should prove profitable in other malignant diseases.

Radiation-Induced Mouse Leukemia: Consistent Occurrence of an Extra and a Marker Chromosome

Granulocytic leukemia, induced in the primary mouse by x-irradiation, was serially transmitted to RF/Up mice. An extra chromosome, as well as a morphologicaly unusual chromosome, was found in the bone marrow cells of all the leukemic mice that had been injected previously either with leukemic spleen cells or with cell-free ultracentrifugates. This suggests that the changes in the chromosomes are caused by a virus.

Acquired monosomy 7 in donor cells in a patient treated for acute lymphoblastic leukemia with bone marrow transplantation.

Two years after a bone marrow transplant (BMT) from his haploidentical mother, a 28-year-old male with a history of acute lymphoblastic leukemia (ALI.) developed myelodysplastic syndrome (MDS) with monosomy 7 in his female bone marrow cells. Follow-up cytogenetic studies, including fluorescence in situ hybridization (FISH) performed twenty-seven and thirty-one months post-BMT consistently showed a female chromosome pattern with monosomy 7. Thirty-six and thirty-nine months post-BMT, further clonal evolution occurred, with the appearance of a sideline of the female cells that first expressed a del(10)(p11.2) and then developed a translocation, t(10;21)(p11.2;q22), in addition to the monosomy 7. Cytogenetic monitoring of this male patient helped to reveal a rare case of early MDS in transplanted donor cells and evolution of the acquired abnormal clone by identifying chromosomal alterations in the donated female bone marrow cells.

An abnormal clone with monosomy 7 and trisomy 21 in the bone marrow of a child with congenital agranulocytosis (Kostmann disease) treated with granulocyte colony-stimulating factor : evolution towards myelodysplastic syndrome and acute basophilic leukemia

Cytogenetic analysis of bone marrow cells revealed an abnormal clone with monosomy 7 and trisomy 21 in a 12-year-old child with Kostmann disease (KD). The patient presented with anemia, thrombocytopenia, and splenomegaly after 5 years of treatment with granulocyte colony-stimulating factor (G-CSF). The bone marrow morphology was consistent with the diagnosis of myelodysplastic syndrome (MDS). Administration of G-CSF was discontinued at this point. Bone marrow studies 2 and 5 months later showed persistence of both myelodysplasia and the abnormal clone with monosomy 7 and trisomy 21. Monosomy 7 was also confirmed by fluorescence in situ hybridization (FISH). After 2 months of follow-up, the patient presented with acute basophilic leukemia, a very rare variant of acute myeloid leukemia (AML), expressing the same bone marrow chromosome abnormalities as observed earlier. This is a rare case of KD with prolonged survival and a cytogenetically abnormal clone evolving to MDS and acute basophilic leukemia. The significance of monosomy 7 and trisomy 21 in KD treated with G-CSF is discussed.

DOWNS SYNDROME AND EXPOSURE TO X-IRRADIATION*

The purpose of this paper is to consider the possibility that x-irradiation of individuals may increase, in some manner, the likelihood of their subsequent progeny having Down’s syndrome. The evaluation of present relevant information requires that we consider observations made in three research areas. These include epidemiologic studies, population cytogenetic investigations, and the results of some newer biological experiments.

A Near-Haploid Bone Marrow Karyotype in Systemic Mast Cell Disease: Is It Characteristic of the Disease or an Incidental Finding?

We present the case of a 40-year-old man with aggressive systemic mast cell disease. The patient had a predominant near-haploid clone in his bone marrow cells, detected by cytogenetic analysis performed at the time of diagnosis. The similarities between this case and a previously published case of near-haploidy in a patient with malignant mastocytosis suggest that near-haploidy may be a characteristic of aggressive systemic mast cell disease rather than an incidental finding.