Biomedical subjects
Publications and source records attributed to D K Kalousek.
We describe 2 children with a partial deletion of chromosome 18 and chronic arthritis. A boy with r(18)(p11.3; q23) lacked serum IgA and had arthritis affecting both knees. A girl with del (18)(q21.2; q22) had arthritis in 5 joints. Her serum IgA was normal. In both children, the arthritis responded to nonsteroidal antiinflammatory drugs.
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Detailed investigations were made on 150 fetuses with neural tube defects (NTD). After eliminating those with recognised causes, the rest were found to consist of fetuses with both isolated NTD and NTD with other developmental abnormalities. On evaluation of reproductive history, type and frequencies of NTD in pregnancies before conception, and sex of the fetuses involved, no demonstrable difference between these two types of NTD was found. Secondly, in those with additional developmental abnormalities, a significant clustering of developmental defects rather than a uniform distribution throughout abnormalities were found predominantly in cases of total craniorachischisis and upper thoracic spina bifida, less often in anencephaly and thoraco-lumbar spina bifida, and never in lumbo-sacral spina bifida. Thus it appears that there is not a random concurrence of other developmental abnormalities with NTD but a definite pattern. We suggest that this implies a connection between the developmental abnormality and the NTD and that the additional abnormalities arise due to mechanical induction by the particular specific disturbance of the neural tube and its surrounding tissues. The most important difference between isolated NTD and those with other associated abnormalities is that the disruption in development at neurulation is more far reaching in the latter than in the former.
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Previous studies have shown that Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia (CML) results from the abnormal expansion at the pluripotent stem cell level of a single clone of hemopoietic cells. Although it seems likely that this is related to the heightened proliferative activity characteristic of primitive CML progenitor cell types, the underlying mechanism is unknown. In this report we show that either normal or CML peripheral blood progenitors can be maintained on preestablished normal marrow adherent layers for periods of 1-2 months. Under these conditions numbers of both normal and neoplastic progenitors are usually higher in the adherent layer than in the nonadherent fraction. Moreover, the number of primitive progenitors of high proliferative potential present in the adherent layer is sufficient to allow their cycling status to be determined. Such measurements demonstrate that primitive normal progenitors of blood origin, when cultured in the presence of a preestablished adherent marrow feeder layer, go in and out of cycle after each medium change but in the absence of a feeder layer remain continuously in cycle. In contrast, primitive CML progenitors of either blood or marrow origin cycle continuously regardless of the presence or absence of an adherent feeder layer. We suggest that early expansion of the CML clone is related to an ability of the neoplastic stem cells to ignore or overcome a negative regulatory signal produced by nonneoplastic adherent marrow cells whose normal function is to maintain the stem cell reserve in a quiescent state.
We report the clinical and cytogenetic findings in a family in which a balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 5 is segregating together with Huntington disease in 2 generations. In situ hybridization studies revealed that the linked human DNA marker is located on the short arm of the normal and translocated chromosome 4 in the region 4p16. The association between Huntington disease and the translocation in this family may represent a chance occurrence. However, it is also possible that there is an undetected rearrangement of DNA on chromosome 4 involving the gene for Huntington disease but not affecting the site of the linked marker. Finally, the likelihood that this represents heterogeneity cannot be excluded.
Four cases of T cell neoplasia are reported: three presenting as T cell acute lymphoblastic leukemia and one presenting in the leukemic phase of a T cell lymphoma. In all cases, the cells of the leukemic clone were characterized by an identical cytogenetic abnormality. This abnormality was a unique reciprocal translocation involving chromosomes 10 and 14. The breakpoint in chromosome 14 was in band q11, coincident with the assigned locus of the alpha-chain gene of the T cell antigen receptor. The breakpoint in chromosome 10 was in band q24, a region reported to include the locus of the terminal deoxynucleotidyltransferase (TdT) gene. Our observations suggest that translocation t(10;14)(q24;q11) is specific for T cell neoplasia and that a gene in chromosomal band 10q24, possibly the TdT gene, plays an important role in T cell neoplasia when its expression or coding sequence is altered by aberrant recombination involving a T cell antigen receptor gene.
We studied G-banded chromosome complements on 318 couples with 2 or more spontaneous abortions. Seven chromosome abnormalities were detected. Three women and one man were identified as carriers of balanced Robertsonian translocations, t(13;14), t(13;14), t(13;21), and t(14;22), respectively. Aneuploidy: 47,XXX; 47,XX, + marker; and 45,X/46,XX/47,XXX were found in the other 3 women. The overall aberration frequency was 2.2% of couples. When a stringent criterion of greater than or equal to 3 consecutive spontaneous abortions was used, the frequency was 4.2%. In this series no chromosome aberrations were identified in couples with 2 spontaneous abortions and a live-born child with congenital anomalies; 1 of 22 couples with 2 spontaneous abortions and a still-born infant showed a chromosomal abnormality. Findings from the recent literature are compared with those from this study.
We have cytogenetically analysed individual haemopoietic colonies to investigate the level and extent of normal stem cell suppression that occurs in patients with Philadelphia chromosome (Ph1)-positive CML. Seventeen patients were studied at diagnosis prior to the initiation of chemotherapy and five of these were studied again 1-16 months later. Another nine patients were studied for the first time 2-96 months after diagnosis and initiation of chemotherapy. No chromosomally normal metaphases were found in either direct marrow preparations or in haemopoietic colonies obtained from simultaneous assays of marrow and/or blood samples from 20 of the 26 patients studied. In the other six, chromosomally normal haemopoietic progenitors (BFU-E, CFU-C and CFU-G/E) were readily demonstrable even though in five of these patients all dividing cells in the bone marrow appeared to belong to the Ph1-positive clone at the time of study. These results indicate that the suppressive effects of clonal expansion on normal haemopoiesis are more pronounced, and apparent sooner, in the more differentiated compartments. In addition, they support the view that the original population of normal stem cells does not disappear rapidly, although their numbers may be diluted to undetectable levels depending upon the extent of clonal expansion at the stem cell level by the time of diagnosis.
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We recently showed that long-term marrow cultures can be used to demonstrate the presence of Philadelphia (Ph1) negative progenitors in patients with newly diagnosed Ph1-positive chronic myeloid leukemia (CML). We now report results for 6 chronic phase patients studied 5-83 mo postdiagnosis and an additional 3 newly diagnosed patients. Marrow metaphases were exclusively Ph1-positive. Clonogenic assays revealed a minor population of Ph1-negative progenitors in 3 cases (1 treated, 2 untreated). Long-term marrow culture adherent layers contained Ph1-negative progenitors in 6 cases (3 treated, 3 untreated). Whenever this occurred, the Ph1-negative population had become the only one detectable within 3-4 wk, and this was always associated with a rapid decline of the Ph1-positive population. For 2 of the 3 cases where Ph1-negative progenitors were not detected, there was a similar rapid decline in the Ph1-positive population in culture. In the other case, Ph1-positive progenitors were maintained at levels typically seen in normal long-term marrow cultures. These results suggest that chromosomally normal stem cells may persist for a considerable period in the marrow of some, but perhaps not all, patients with CML, even in the face of maintenance chemotherapy. In addition, they provide new evidence of heterogeneity in this disease, as shown by the variable ability of Ph1-positive progenitor populations to be maintained in vitro.
We have investigated the clonality of Ph1-negative hemopoietic progenitor cells appearing in long-term marrow cultures established with cells from a mosaic Turner syndrome patient (46,XX/45,X) with Ph1-positive chronic myeloid leukemia (CML). The Ph1-positive clone had been shown previously to have arisen from a cell of the 45,X lineage. At the time of the present study, the patient was five years post-diagnosis and had been off chemotherapy for two months following a year of treatment for lymphoid blast crisis. All analyzed unstimulated marrow metaphases and each of 23 individually analyzed erythroid and granulocyte colonies produced in assays of the starting marrow were 45,X,Ph1. Pooled granulocyte colonies from the same assays yielded four metaphases that were 45,X,Ph1 and one that was 46,XX. Very few hemopoietic progenitors were detected in long-term cultures at any time; however, all of four individually analyzed large granulocyte colonies and a pooled granulocyte colony preparation obtained from assays of 4- to 6-week-old adherent layers yielded exclusively 46,XX metaphases. These results provide evidence that non-clonal progenitors can persist in patients with CML, even after the onset and treatment of blast crisis, and that the long-term marrow culture system provides a sensitive method for detecting such cells.
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Between 1971 and 1981, 58 (2.8%) of 2037 amniocenteses performed in Vancouver revealed chromosome abnormalities, 25 of which were trisomy 21. Of the 58 referrals that yielded abnormalities, 37 (63.8%) were for a maternal age of 38 years or more. The rates of detection of such abnormalities for single-year intervals of maternal age beyond 35 years were comparable to those calculated from pooled data obtained in multicentre studies in the United States, Canada and Europe.
Placental and fetal tissues from 46 human pregnancies were cultured and cytogenetically analyzed in an attempt to document the existence of chromosomal mosaicism confined strictly to tissues of extraembryonic origin. In two gestations in which chromosomal mosaicism was found, it was expressed exclusively in placental chorionic cells and was not detected in cells derived from the embryo proper. This demonstration of confined chorionic mosaicism may have implications for the understanding of the fetoplacental unit and for prenatal diagnosis.
We found that when marrow cells from four patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia were maintained in culture for two to four weeks, a previously undetectable population of chromosomally normal hematopoietic cells (including erythroid, granulopoietic, and pluripotent progenitors) became readily demonstrable in three cases. Time-course studies showed that in such cultures the dominant Philadelphia chromosome-positive population rapidly disappeared, in contrast to coexisting chromosomally normal progenitors, which remained detectable for periods of two to three months. Long-term marrow cultures thus offer a new approach to the assessment of a suppressed but functionally intact population of chromosomally normal hematopoietic stem cells in patients with chronic myelogenous leukemia.
A white female neonate with clinical manifestations of Down's syndrome was found to have a peripheral white count of 74,000/mm3 with 65% blast forms. Bone marrow aspirate revealed 36% blasts. On chromosomal analysis of bone marrow and peripheral blood, two cell lines were found, one with trisomy 21 and another with pentasomy 21. Colony cultures on the patient's bone marrow cells revealed an adequate growth pattern of CFU/GM. Cells were reactive with myeloblast alloantisera. At the age of 3 weeks, peripheral counts were within normal limits as was morphology of the repeat bone marrow aspirate. Chromosome analysis at that time showed complete absence of pentasomy 21 cell line, and repeat cell colony studies revealed normal growth, differentiation, and maturation of CFU/GM. Maternal serum totally inhibited colony growth of the patient's remission marrow and allogeneic blast cells. This serum inhibitor actually disappeared 1 month postpartum. The patient has had no recurrence of blast cells up to the present age of 3 years.
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