Biomedical subjects
Publications and source records attributed to J R Mann.
Twenty-seven children with unilateral proptosis were investigated over a period of 8 1/2 years. Seventeen (63%) of them had local or disseminated malignancy, a higher proportion than in earlier reports. The frequency of inflammatory lesions, particularly ethmoiditis progressing to proptosis, appeared to have decreased, probably because of the liberal use of antibiotics for upper respiratory tract infections.
Ninety-six Birmingham children with sickle cell disease were studied prospectively between 1969 and 1979. Thirty-five were homozygotes for HbS (SS), 12 had sickle thalassaemia (S thal), and 23 were double heterozygotes for HbS and C (SC). Twenty-six whose family studies were incomplete were classified as SS or S thal although most were thought to be SS. The average length of follow-up was 5.1 years. Four SS children and 1 SC child died, the annual mortality rates being 1.3% for SS and presumed SS, 0% for S thal, and 0.9% for SC children. The incidence of pulmonary illnesses and anaemic crises was greater than reported from Jamaica, while leg ulceration described there and in New York was not observed in Birmingham. Severe infections were less common than in the series reported from New York and no case of salmonella osteomyelitis was observed in Birmingham. In general the S thal and SC children had milder illnesses than the SS, and the SS children often showed impairment of growth and sexual maturation.
A child receiving busulphan treatment for adult-type chronic myeloid leukaemia responded well for four years before the onset of complications leading to "busulphan lung'. Pulmonary function tests (PFT) were useful in monitoring the development of this condition and we recommended regular PFT for patient receiving busulphan treatment.
Jaundice and hepatomegaly developed in a boy with Fanconi anemia after he had undergone treatment with oxymetholone for nine years. A liver scan showed patchy uptake consistent with the presence of space-occupying lesions. After oxymetholone treatment was stopped, the jaundice resolved, the liver size decreased, and the filling defects were no longer detectable on the liver scan. A year later, 5% of his white blood cells showed a consistent chromosomal abnormality. His leukocyte count increased and 85% of these cells showed the same chromosomal abnormality. The rapid replication of this abnormal clone suggests that it was leukemic. The significance of oxymetholone therapy and the occurrence of hepatic tumors and leukemia is discussed.
Decreased placental transfer of 64Cu into both Mobr/Y and Mobr/+ foetuses was apparent after its administration to pregnant Mobr/+ mice. The severity of impairment and the degree of retention and accumulation of 64Cu in the placenta was not as great as has been previously observed in the gut of the suckling Mobr/Y mice.
During 1968-1978, 68 children presented in six centres in the United Kingdom with lymphoblastic mediastinal masses. The disease was classified as acute lymphoblastic leukaemia (ALL) in 49 children whose bone marrow aspirates contained > 20% lymphoblasts, and as lymphoma (Sternberg lymphosarcoma - LS) in 19 with < 20% marrow infiltration. Male predominated in both groups, and children with ALL had more visceromegaly and lymphadenopathy, lower haemoglobin levels and platelet counts, and higher white cell counts. The most common chest x-ray finding in both groups was a nonspecific anterior mediastinal mass, but the appearances varied considerably and could be classified into three categories, which are illustrated. Pleural effusions were present in 44%. Cell surface-marker studies showed T cell characteristics in 14 of the 17 patients tested. Response to treatment and complications, such as central nervous system (CNS) and testicular relapse, were similar in ALL and LS, and were related to the size of the initial tumour load. Median remission lengths were 37 weeks for ALL and 89 weeks for LS patients. Leukaemic transformation occurred in 47% of LS children. Compared with the outcome in ALL children without mediastinal mass, the results of treatment were poor, regardless of the protocol used, and prophylactic therapy to the CNS reduced the frequency of, but did not eliminate, CNS disease.
Of 95 boys treated for acute lymphoblastic leukaemia 25 have developed leukaemic infiltration of the testes. In 15 children relapse was apparently confined to the testes, and since treatment 7 of these boys remain in remission. The median duration of remission after testicular relapse was 72 weeks, considerably longer than that reported after other forms of leukaemic relapse.
The copper content of various organs of ;brindled' female heterozygotes and male mice affected by this X-linked mutation are documented at the last day of intrauterine development, at 1 day after birth and at 11 days of age. The findings indicate defective placental transfer of copper in utero, and an even more marked defect in intestinal absorption of copper after birth. In addition there is an abnormal distribution of copper among the tissues of the body once it is absorbed. The mutation produces abnormal accumulation of copper in kidney, in gut mucosa and in testis, whereas liver, brain, plasma and most other organs show diminished copper concentrations. The intestinal malabsorption of copper is accompanied by accumulation of abnormal amounts of the metal in the intestinal-mucosa cells. Copper concentrations in both mucosa and luminal contents rise progressively from duodenum to ileum. Defective upper-intestinal absorption, consequent progressive increase in luminal copper concentration and pinocytosis in the ileum would seem to explain the findings. Radioisotopic studies eliminated the possibility of excessive excretion of copper in bile or across the intestinal mucosa. Detailed comparison with findings in humans with Menkes' syndrome is difficult because of the different stages of development at which the studies have been performed, but the results seem in general to conform very satisfactorily. Those differences seen are probably explicable by known species differences. All the findings are in accord with a hypothesis that the basic defect involves accumulation and retention of copper in the cells of affected tissues such as kidney, gut mucosa and placenta.
Copper therapy was applied to brindled mouse mutants, which suffer from lethal hypocupraemia, by using cuprous and cupric solutions. The method of treatment was a single subcutaneous injection of 50 microgram of copper at 7 days of age. Early effects of the dose were: prevention of the tremors and spasms seen in untreated mutants, raising to normal and near-normal of caeruloplasmin oxidase and lysyl oxidase activities and pigmentation of skin and fur. Growth of mutants was retarded up to 23 days of age, but thereafter they rapidly gained weight to be nearly normal by 60 days of age. At 3 days after injection, copper concentrations in previously deficient mutant organs apart from liver were at least as much as those of treated normals, which had remained unchanged. Copper in mutant livers had increased only slightly in comparison with the normal control. A state of copper deficiency recurred in mutant tissues by 25 days after injection. A solution of Cu+, retained as such by an alkyl polyether, and sebacic acid resulted in greater growth rates after 23 days than did three other copper treatments. Cu+ may have resulted in an improved growth response owing to it being more readily metabolized than C12+. Delayed release of copper from the site of injection may have played an important role.
1. Duodenal injection of 64Cu in treated adult mutant mice (Mobr/y) revealed severe malabsorption of copper. In suckling mutants, malabsorption was less severe, owing to delayed absorption between 2 and 5 h after injection. Pinocytosis at the distal small intestine seems the likely explanation for this difference, and this is supported by results of ileal injection of radioisotope in the suckling mice. 2. The distribution of 64 Cu in various organs was measured in suckling normal, mutant and heterozygote mice and in adult normal and mutant mice during 48 h after intracardiac injection. Excessive accumulation of radioisotope was observed in most extrahepatic organs of mutant and heterozygote mice and was most pronounced in kidney. This could not be explained by initial copper deficiency. The livers of suckling mutant and heterozygote mice lost radioisotope rapidly after normal initial uptake. This pattern was not seen in adult mutants.
Two neck tumours in young children with similar clinical features were compared using light and electron microscopy. Both tumours consisted of uniform sheets of epithelial-like cells and there were scattered stromal elements in one. Tonofilaments in sheets or bundles reminiscent of squamous epithelium were striking in the epithelial cells. Intercellular junctions were frequent but true desmosomes were not seen. Most cells contained a few secretory droplets. Occasional secretory cells, foam cells and cilia were observed. Since these tumours were not sited superficially they are unlikely to have been derived from skin epithelium. An origin in branchial sinus remnants capable of differentiation towards squamous and ciliated epithelia is suggested.
Twenty-two patients with rhabdomyosarcoma have presented in the years 1970--1977. Of 8 patients who had inadequate postoperative chemotherapy and radiotherapy, or none at all, only 2 patients with small completely resectable tumors are alive and well at 6 and 4 yr after surgery. Fourteen patients had intensive combination chemotherapy in addition to appropriate surgery and radiotherapy. Five have died and the remaining nine are well and free of disease at follow up ranging from 9 mo to over 5 yr. A continued place in the treatment regime is advocated for early surgery aimed at total excision of the primary tumor where this is feasible.
Ligation of the rat pancreatic duct produced degeneration of the exocrine acinar tissue, inflammatory cell infiltration and fibrosis. The injection of methyl prednisolone for 5 days following duct ligation produced a marked reduction in the inflammatory-cell infiltrate whereas the administration of glucagon or a combination of glucagon and methyl prednisolone produced only a mild reduction in acinar degeneration. Administration of the drugs for 5 days after duct ligation and examination of the pancreas after 3 months showed no differences in the degree of cellular infiltration and acinar degeneration between controls and those that had received glucagon or glucagon and methyl prednisolone. However, those rats that had received only methyl prednisolone showed fibrosis, a minimal inflammatory-cell infiltrate and a considerable reduction in exocrine tissue. Mild degranulation of the islets of Langerhans was observed in those rats that received methyl prednisolone, alone or in combination with glucagon, and at 3 months the islets appeared normal. The implications for pancreatic transplantation are discussed.
Four children who had acurate lymphoblastic leukaemia in remission and developed pneumonia were studied. Investigations including electron microscopy and immunofluorescence of lung biopsy material disclosed measles, although there was no clinical evidence of the disease. Despite an identical presentation, two types of illness developed: two children died of giant-cell pneumonia, while the other two developed pneumonia indistinguishable from that associated with methotrexate treatment, recovering when treated with steroids and gammaglobulin. Measles infection is easily overlooked in the absence of rash. The diagnosis may be suggested by clinical and radiological features and confirmed by specific immunofluorescence staining of lung biopsy tissue.
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A study was carried out on serum carcinoembryonic antigen (CEA) and alpha-feto-protein (AFP) levels, both measured by radioimmunoassay, in 88 children with malignant solid tumours and in 26 children with nonmalignant disorders, who presented during the years 1973-77. Slightly or moderately raised CEA levels were found at presentation in 11 of 66 children with malignant tumours, in 2 others with recurrent tumours, and in 4 children with nonmalignant disorders. Raised CEA levels generally indicated advanced malignant disease, often affecting the liver, or other hepatic disorders, but were not associated with a specific tumour type. Except in the first months of life, significantly raised AFP levels were detected only in 11 patients with yolk sac-derived tumours, or hepatomas, and in one child with tyrosinosis who later developed a malignant hepatoma. Serial measurements of AFP accurately reflected the clinical response to treatment and in 2 patients indicated recurrence before this could be detected clinically.
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