Thorotrast, a colloidal suspension of the long-lived radionuclide, thorium-232, was widely used as a radiographic contrast medium for several decades. Due to the poor excretion of the sol, however, Thorotrast would deposit in the liver, bone marrow and other tissue, and patients would receive alpha-particle irradiation for life. To gauge the cumulative genetic damage to hematopoietic stem cells due to chronic exposure to alpha particles, we conducted a multi-end-point evaluation in a 72-year-old man who had been administered a 32-ml bolus of Thorotrast during cerebral angiography performed over 40 years ago in 1950. Peripheral T lymphocytes were cultured to quantify the frequencies and cellular distributions of asymmetrical and symmetrical types of chromosome aberrations in first-division metaphases and micronuclei in cytokinesis-arrested interphase II cells. Aberrations were scored using classical chromosome group analysis methods and chromosome painting techniques. Assays of glycophorin-A (GPA) mutations in red blood cells were also performed to obtain a relative measurement of damage sustained by the erythroid stem cell population. Results revealed that approximately 30% of the lymphocytes in this patient contained one or more chromosome aberrations, the majority of which were of the "stable" type. About one-third of the lymphocytes with chromosome damage carried multiple aberrations, suggesting that significant numbers of stem cells survive exposures to alpha-particle radiation that induce complex genomic alterations. Increased frequencies of GPA mutations were observed, demonstrating that genomic damage is also induced in erythroid progenitors. The numbers of micronuclei in lymphocytes were only moderately increased compared to expected values for persons of comparable age, and thus this end point was not useful for quantifying exposure level. Despite the relatively severe burden of somatic cell damage induced by 40 years of internal alpha-particle irradiation, the patient remains surprisingly free of any serious illness.
Nephronophthisis (previously described as familial juvenile nephronophthisis and medullary cystic disease) is characterized by insidious renal failure, its main features being increased urinary sodium loss, pitressin-resistant hypotonic polyuria, polydipsia, normal urine sediment and absence of hypertension. Renal function and histologic studies were performed in a family in which two siblings had this disorder, while the parents and two other siblings appeared clinically normal. Both parents demonstrated a moderate impairment of maximum urinary concentration. The values for tubular free water reabsorption (TcH2O) were relatively normal in the parents and the healthy siblings. One of the index patients showed only minimal sodium wasting even though he had hyposthenuria, thus suggesting an involvement of the collecting ducts in the early stage of nephronophthisis. No evidence of proximal tubular dysfunction was found. Although the light-microscopic examination of renal biopsies from the parents and the healthy siblings was unremarkable, electron microscopy revealed probable abnormalities in all four. An autosomal recessive mode of inheritance is, therefore, suggested in this family. The etiology of nephronophthisis is obscure but a likely possibility is that the renal damage results from an inborn metabolic error.
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