Biomedical subjects
Publications and source records attributed to J V Frei.
Some genes such as those for histones and RNAs are conserved unchanged through much of evolution and have numerous tandem repeat copies in the genome. It is proposed that as yet undetected 'polystrand' enzymes use such multiple copies as a means of conserving their sequence by comparing the copies and eliminating errors.
The relationship between iron absorption and hepatic iron was studied in 21 patients with hemochromatosis. Iron absorption was studied using 59Fe and total body counting and hepatic iron was measured by atomic absorption spectrophotometry. Iron absorption was inversely related to hepatic iron concentration (r = -0.51, p = 0.009) in this patient population. This observation suggests that iron absorption is regulated by body iron stores even in hemochromatosis, and does not support the hypothesis that the primary metabolic defect in hemochromatosis is a deregulation of iron absorption in relation to iron stores.
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Focal nodular hyperplasia (FNH) is a lesion of the liver in which a large anomalous artery is located within a region of hyperplastic hepatic parenchyma. Patients with FNH commonly have other lesions, often vascular in nature, in the liver or other organs. We have noted that these associated lesions almost always occur in patients with multiple FNH. We therefore studied 27 autopsied patients with FNH. All 13 with multiple FNH had other lesions such as hemangioma of liver, meningioma, astrocytoma, telangiectasis of the brain, berry aneurysm, dysplastic systemic arteries, and portal vein atresia. One patient had several of these lesions including multiple FNH, meningioma, astrocytoma, vascular malformation of the brain stem, and hemangioma of the liver. In contrast, among the 14 patients with solitary FNH there were no associated lesions, except for hepatic hemangioma in one patient. The prevalence of this syndrome was estimated by examination of 2500 serial autopsies and autopsies with various components of the syndrome. On review of 73 consecutive autopsies with meningioma, three had multiple FNH, compared with seven of 2500 consecutive adult autopsies (P less than 0.001). Multiple FNH was found in two of 83 autopsies with astrocytoma (P less than 0.05) and in one of 139 autopsies with berry aneurysm (not significant). We describe a telangiectatic subtype of FNH which occurs in this syndrome as well as in a minority of patients with solitary FNH. The existence and character of this syndrome suggest that there may be an underlying systemic abnormality in some patients having components of the syndrome. Investigation of patients with multiple FNH lesions may reveal significant treatable lesions.
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The effects of dietary fat on experimental mammary cancer have typically been observed in relatively young animals. However, in human populations, breast cancer incidence and mortality are highest in postmenopausal women. To develop an animal model that stimulates the human situation more closely, female Sprague-Dawley rats were given a relatively small dose (1.5 mg) of 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age while on a semipurified diet containing 3% sunflower-seed oil. One week later, half of the 70 rats were transferred to a diet containing 20% sunflower-seed oil. Very few mammary lesions appeared until about 35 weeks after administration of DMBA, at which time palpable mammary nodules began to appear in many of the animals on the high-fat diet. More than half of the animals in this group had developed nodules by Week 41, whereas the other half of the animals on the low-fat diet developed nodules by Week 46. Rats on the high-fat diet gradually became much more obese than those on the low-fat diet and were significantly heavier at the time they developed lesions. The incidence of nodules continued to increase in both groups and reached 100% in the group fed the high-fat diet by Week 55, with a 70% incidence of adenocarcinomas. At this time, 79% of the animals on the low-fat diet had palpable nodules without a plateau in incidence being reached. On autopsy, adenocarcinomas were found in 57% of animals on the low-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Wilson's disease is a rare inherited disorder of copper (Cu) metabolism characterized by the deposition of Cu in the liver, brain, and cornea. The levels of metallothionein (MT), Cu, and zinc (Zn) in the livers of two Wilson's disease patients were analyzed in this study. About 50-fold increase in the Cu levels above normal controls was observed in both patients (160 and 298 micrograms/g of wet tissue). About 73% of subcellular Cu was present in the cytoplasmic fraction and most of it was in association with MT. Analysis of hepatic MT levels showed a 3-fold increase (863 micrograms/g of wet tissue) over control human levels (321 micrograms/g of wet tissue). The two forms of MT (MT-I and MT-II) were isolated from one liver sample. Both forms contained high amounts of Cu (11 to 12 g atoms/mole), indicating saturation of MT which had only 2 to 3 g atoms of zinc. The distribution of MT in the hepatocytes was investigated using an immunohistochemical method. In tissue sections with minimal tissue damage, there was intense cytoplasmic staining for MT in hepatocytes whereas both nuclear and cytoplasmic staining was found in tissue sections with extensive necrosis and fibrosis. These results suggest that MT is the major hepatic Cu-binding protein in Wilson's disease, that it is present in a form saturated with Cu, and that only in degenerating hepatocytes is it found in the nucleus as well as the cytoplasm.
Under normal conditions, vitamin D absorbed from the diet or synthesized in the skin is transported to the liver where it undergoes hydroxylation. The purpose of this study was to determine whether excess hepatic iron affects this process and the subsequent production of 1,25-dihydroxyvitamin D (1,25-[OH]2D) in the kidney. Mean serum 25-hydroxyvitamin D (25-OHD) concentrations in untreated hereditary hemochromatosis were 13 +/- 6 (SD) in 9 patients with cirrhosis, 13 +/- 6 in 5 patients with hepatic fibrosis, and 22 +/- 6 in 10 patients with normal hepatic architecture aside from siderosis and were significantly lower than the levels found in 24 controls matched for age, sex, and season, p less than 0.05. The mean serum 25-OHD levels in the two groups with hemochromatosis and hepatic damage were significantly lower than the value in the group with normal hepatic architecture, p less than 0.05. Serum 25-OHD levels in individual patients were inversely related to the size of body iron stores as measured by exchangeable body iron, r = -0.64, or serum ferritin, r = -0.47, p less than 0.05. In 15 patients removal of excess body iron by venesection therapy produced a significant increase in the mean serum 25-OHD from 20 ng/ml to 30 ng/ml, p less than 0.05. In contrast, mean serum 1,25-[OH]2D levels were similar in iron-loaded and control subjects, indicating that the regulation of this metabolite was intact in patients with hemochromatosis. The results reveal that the low serum 25-OHD concentration in patients with hemochromatosis is directly related to the extent of iron loading and it is improved by venesection therapy.
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Eighteen large bowel adenomas with invasion of the head or the stalk were removed by endoscopic polypectomy or by segmental resection at University Hospital, London, Ontario between 1973 and 1982. All were completely removed by histological criteria. All the patients were traced for an average follow-up period of 4.6 years. None had developed disseminated large bowel cancer. Adding these results to those in the literature, it appears that, provided there is not a high degree of anaplasia of the tumor or lymphatic or venous invasion, endoscopic polypectomy is adequate therapy for such adenomas. An endoscopic recheck of the site of removal after approximately 2 months may be worthwhile as a few local recurrences of benign tumor were reported, although not in the present series. The patients should be followed for life.
Concern for the late formation of strictures at the site of an endoscopic sphincterotomy has delayed the acceptance of this procedure as treatment for choledocholithiasis in otherwise healthy patients. The authors addressed this issue by comparing the biochemical and histologic sequelae of sphincterotomy in 23 dogs with those in 10 sham-operated controls. Twenty-four hours after sphincterotomy, hemorrhagic, edematous mucosa surrounded the incision. Microscopically, there was an acute inflammatory exudate bridging the mucosal surfaces. Mucosal regeneration was sufficient after 1 week to cover the defect caused by the cautery, although some inflammatory changes were still evident. A widely patent sphincterotomy orifice was seen in 15 dogs followed up for 10 weeks. In three dogs, the fibres of the papilla had reunited below the incision, resulting in a choledochoduodenal fistula. Histologically, complete healing of the mucosal surface had occurred with no evidence of scar formation or chronic inflammation. Serum bilirubin and liver enzyme measurements did not show evidence of biliary obstruction due to the sphincterotomy. From the results of our study, there is no evidence to suggest that an endoscopic sphincterotomy is predisposed to late stenosis.
The records of the rectal biopsy diagnoses of ulcerative colitis and Crohn's disease in the Department of Pathology, St Mark's Hospital, London, were reviewed. The biopsy diagnoses were compared to subsequent resection diagnoses on the same patients, and annual and seasonal variations in the frequency of these and related diagnoses were studied. The accuracy rate for the biopsy diagnosis of ulcerative colitis was about 70% and for Crohn's disease about 40% each time a biopsy was read. The low figure for the accuracy rate for Crohn's disease could be attributed to sampling error inherent in the diagnosis of a disease which is essentially patchy, showing discontinuous pathology. Also, many patients with Crohn's disease have a normal rectum which is biopsied to demonstrate the distinction from ulcerative colitis. In practical terms therefore a 40% accuracy rate in Crohn's disease is probably adequate. The rate of "false-positive" diagnoses was about 5%. There was a seasonal variation in the frequency of these two diagnoses, but no variation attributable to changes in observers, as pathology trainees in the Department change regularly. The frequency of diagnoses of non-specific inflammation and of normal colon did show such non-random variations.
Chromosome complements of murine thymic lymphomas induced by an alkylating agent N-methyl-N-nitrosourea (MNUA) were analyzed microscopically and karyotypically using the Q-banding technique. The chemical carcinogen was injected intraperitoneally into either neonatal or 7-week-old CFW/D mice. In addition, thymic lymphomas induced in 7-week-old AKR mice and thymic lymphomas developed spontaneously in this strain were also examined. All six lymphomas induced in neonatal CFW/D had hyperdiploid cell lines that accounted for 90% of the cells analyzed. Chromosome analysis of lymphomas induced in adult DFW/D mice showed that only out of nine lymphomas had predominantly hyperdiploid cell lines. The remaining five lymphomas had diploid modal chromosome number although they also carried a variant line characterized by 41 chromosomes. All eight lymphomas induced in adult AKR mice and six out of seven spontaneous AKR lymphomas showed predominantly diploid modal line. The remaining spontaneous lymphoma had a hyperdiploid stem line of 41 chromosomes. Microscopic and karyotypic analysis further identified trisomy 15 as the regular chromosome abnormality in the hyperdiploid cells in lymphomas of each group, whereas cells with diploid chromosome number had no detectable chromosome abnormality. Additional trisomies were also found, but their appearance was restricted to individual tumors. Thus, the incidence of trisomy 15 in lymphomas induced by MNUA in adult CFW/D and AKR mice, as well as in the spontaneous AKR lymphomas, is significantly lower than that in lymphomas induced in neonatal mice by the same carcinogen.
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Induction of thymomas by methylnitrosourea in many strains of mice requires 3 "hits". AKR mice develop thymomas spontaneously late in life, probably because of their large load of viral leukemia oncogenes. It was expected therefore, and so found, that methylnitrosourea induces thymomas in AKR mice with only 1 or 2 "hits". The viral oncogene therefore appears to function as a dominant "hit" gene cooperating with the chemical carcinogen.
Specific-pathogen-free inbred C57BL/Cbi mice (adult virgin females) were given single sublethal doses of N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea and were studied for a lifetime for the development of thymomas. A fatal lymphocytic lymphoma with a "starry sky" pattern due to the presence of macrophages was induced in the thymuses of treated mice within 250 days of treatment. Control and low-dose treatment groups had up to 70% incidence of a histiocytic lymphoma that was usually primary in mesenteric lymph nodes and nearly always occurred later than 250 days after treatment. A "one-hit" linear relationship existed between the time of appearance of induced thymic lymphomas and the log fraction of non-tumor-bearing mice. The absolute latency period of these tumors was constant and independent of dose. The effect of dose was an exponential increase of the total incidence of induced thymic lymphomas. By mathematical analysis, the best estimate of the exponent from the results was 2 or 3, indicating that the development of these induced tumors may be produced by 2 or 3 "events" in the target cell. Possible candidates for these events are premutagenic alkylation of DNA, inactivation of DNA repair, oncovirus activation, regenerative hyperplasia, development of trisomy No 15, and inhibited immunosurveillance.
1-(2-Hydroxyethyl)-1-nitrosourea (HNU) was prepared by the action of nitrosyl chloride on (2-hydroxyethyl)urea. Attempts to synthesize HNU by an earlier described method were unsuccessful and led to the formation of the cyclized derivative 1-nitroso-2-oxazolidone. In addition, the spectral data that we obtained for HNU differed from those reported earlier. Female C57BL/Cbl mice were treated with single ip doses of HNU to determine its median lethal dose (LD50) and its ability to induce lymphocytic thymic lymphomas in these mice. The results showed that the LD50 was the same as that for 1-ethyl-1-nitrosourea (ENU) and that its was slightly more potent than ENU as a carcinogen in this system.
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