Ian H. Porter

Clinical Aspects of Congenital Heart Disease in Mongolism

Abstract The clinical course of 39 children with mongolism and congenital heart disease is presented. In all the diagnosis was confirmed by cardiac catheterization, angiocardiography and chromosomal studies. Patients were classified into 3 groups according to the hemodynamic findings as follows: group I, 6 patients with right ventricular outflow tract obstruction; group II, 22 patients with pulmonary hypertension at systemic levels; and group III, 11 patients with normal or slightly increased pulmonary vascular resistance. The underlying cardiac pathologic findings in these 3 groups are presented. In group I, the mortality rate was 33 percent, and hypoxia was the major problem. Recurrent chest infections and congestive heart failure developed in patients in group II, and the mortality rate was 36.5 percent. Eisenmengers reaction developed by age 3 years in the majority in this group. Patients in group III did extremely well, and most were asymptomatic.

Recent advances in molecular pathology: A review: Some Aspects of Chromosome Changes in Cancer

Abstract Chromosomal changes, numerical and/or structural are usually present in malignant cells. As far aswe can tell, chromosomal changes may predispose to cancer. Certain structural changes and/or numerical abnormalities may herald the invasive stage of cancer, with marker chromosomes such as the Ph 1 and the long acrocentric chromosomes possibly being particularly significant in malignant transformation. Chromosomal studies also provide evidence for clonal evolution from a single stem cell in tumor formation. Evolution implies selection and Lejeune (1965) has proposed some laws which govern this process: (1) duplication of normal or abnormal supernumerary chromosomes; (2) mechanisms involving self-recognition which, in most instances, would protect against neoplasia, but occasionally may induce malignant transformation by causing chromosomal changes which either promote mutational events, potentiate oncogenic agents, and/or confer a selective growth advantage on the cell involved; and (3) initiation of the neoplastic process may be produced by specific marker chromosomes. These are only suggestions: there is as yet no proof that the common pathway of oncogenic agents are chromosomal aberrations. We need to extend the types of studies we have described, with particular emphasis on the early and preinvasive stages of cancer and clearer morphologic studies of marker chromosomes using thymidine-labeled tritiated chromosomes. In addition, such elegant techniques as developed by Beerman (1964) to study the control of differentiation at the chromosomal level, the beautiful electromicroscopic work of Brinkley (1969) showing the ultrastructural changes of damaged chromosomes, and the ingenious studies by Weiss and Green (1967) and others to investigate the properties of somatic hybrid cell lines and SV40-transformed human cells may become of considerable help in the pursuit of the relationship between chromosome changes and neoplasia. The latter technique may be particularly valuable in providing information about the location of specific genes in the human karyotype which we so badly need in order to obtain a fuller understanding of the relationship between genetic alterations and the properties of neoplastic cells ( Littlefield, 1969 ).

THE CELL CYCLE AND CHROMOSOME ANOMALIES

Delayed growth, retarded intellect, premature senescence, shortened life expectancy, and other clinical signs which autosomal trisomy syndromes have in common and, perhaps, the increased susceptibility to malignancy, suggest a basic derangement of cellular regulation.As patients with Downs syndrome have a decreased rate of DNA synthesis both in fibroblasts and in lymphocytes and as patients with trisomy 13, 18 and 21 have less than normal numbers of cells in different organs, the question arises whether these findings may be related to alterations in the cell cycle. We measured the length of cell cycles in patients with abnormal chromosomal constitutions by pulse labeling cultured fibroblasts and counting the proportion of labeled metaphases every 3 hburs for 30 hours. Patients with trisomy 13, 18 and 21 and other chromosomal anomalies all demonstrated an increase in the total length of the cell cycle and particularly in the length of G1.Thus, it would appear that the addition of a particular chromosome has a general effect on the length of the cell cycle leading to slowing of the rate of cell proliferation and consequently to growth retardation and, perhaps, also a specific effect on the differential mitotic rate at certain developmental stages at times when increased activity of particular cells is required, leading to specific congenital anomalies.

SUCCESSFUL MARROW RE-TRANSPLANTATION FOLLOWING FAILURE OF FIRST TRANSPLANT FOR APLASTIC ANEMIA

An 11 year old girl with aplastic anemia of unknown etiology was transplanted with MLC and HLA identical sibling marrow following 4 doses of Cyclophosphamide (CY) 50 mg/kg. She had received multiple blood transfusions before transplantation (TP). Three weeks following TP the marrow was repopulating, but 4 weeks later the marrow was again aplastic. Immunosuppression with Procarbazine, anti-thymocyte globulin, and a repeat course of CY were given followed by a second TP from the same donor. A take of donor marrow cells now occurred and has persisted to the present (140 days after TP). No evidence of graftversus-host disease was seen; PHA responsive peripheral blood lymphocytes have remained predominantly of host type. The patient has remained in excellent clinical health. Her B cell function is normalizing, but her T cell function is as yet depressed.

SCREENING FOR ADA DEFICIENCY

Some forms of combined immunodeficiency (CID) have been shown to have deficient activity of the enzyme adenosine deaminase (ADA). Earlier detection of CID prior to infection, by ADA assay, would greatly benefit those patients, particularly if a histocompatible marrow donor were available. As the usual methods for measuring ADA are too laborious for large scale screening and require venous blood not readily available from newborns, we have developed a screening method using blood spotted on filter paper identical to the samples used in the Guthrie test for phenylketonuria. This method depends on pH reagents incorporated into a gel containing adenosine, which change color as ammonia is released in the presence of ADA. The method is about 97% accurate, and is simple to perform. The cost is about 1½ cents per sample. This technique has also been adapted for screening of serum, cultured fibroblasts, tissue hemogenates, and eluates from column chromatography with pH < 6.A pilot study using this method is at present underway at the PKU laboratory of the New York State Dept. of Health, Division of Labs, and Research, in Albany, N.Y., which analyzes blood from all newborns in the eastern half of New York State.