Suggestions for new international editors network.
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International Cooperation↗
Biomedical subjects
J V Frei
Publications and source records attributed to J V Frei.
Stable and unstable genes: distribution among species and range of mutations.
An expansion of the 'stable' gene hypothesis proposed previously is the hypothesis that there is a range of genes, some proto-oncogenes and some not, varying from those with multiple copies in the genome, wide distribution among species, and limited mutability because of a specific protective stabilizing mechanism of such genes, to those that are in single copies in the genome, unprotected, unique to one species, and highly mutable along their entire length.
Animals↗
Macroscopic healing of esophagitis does not improve esophageal motility.
The purpose of the present study was to prospectively determine if healing of esophagitis as assessed by endoscopy results in improved esophageal motility. Thirty-one patients with erosive esophagitis who were randomized to receive either omeprazole 20 mg once daily or placebo completed the double-blind study. All patients underwent endoscopy and esophageal motility before treatment and at four weeks after treatment. Twenty-two healthy volunteers underwent esophageal manometry and served as normal controls. Manometric tracings were coded, randomized, and analyzed blindly. Compared to normal controls, patients with esophagitis had significantly lower LESP, decreased amplitude of peristaltic contractions, and increased occurrence of abnormal contractions. Omeprazole was superior to placebo in healing of esophagitis. However, healing of esophagitis was not associated with any improvement in esophageal motility. The manometric data suggest that the motility disturbance seen in esophagitis is not secondary to the esophagitis but rather a primary phenomenon. The lack of improvement of esophageal motility with healing may explain the high recurrence of esophagitis in clinical trials following discontinuation of omeprazole.
Double-Blind Method↗
Proliferative cell indices measured by DNA flow cytometry in node-negative adenocarcinomas of breast: accuracy and significance in cytokeratin-stained archival specimens.
Proliferative rates of 73 node-negative adenocarcinomas of breast with 5-year or greater follow-up were studied using cytokeratin staining in two-parameter DNA flow cytometry of archival specimens. Quality control data of accuracy of the measurements were determined and all analyses were compared with single-parameter results of the same specimens, using demarcated tumor areas, quadruple analyses, and computerized nonspecific staining subtraction. Mitotic rates of the same samples correlated highly significantly with the S-phase fractions and proliferative index (S + G2 + M phases), especially for the cytokeratin data. The predictive value of mitotic rates was found significant, but that of the DNA flow-cytometry-obtained indices was not, probably because of low numbers of deaths in this study. The cytokeratin method identified heteroploid tumors containing a diploid cell population not identifiable by single-parameter analysis. In conclusion, cytokeratin staining can be reliably applied to DNA flow cytometry of archival specimens giving accurate ploidy, S-phase fractions, and proliferative index data limited almost exclusively to neoplastic cell populations. This will permit large-scale retrospective studies aimed at establishing the usefulness of DNA flow cytometry for clinical decisions on therapy of surgically removed node-negative adenocarcinomas of breast.
Adenocarcinoma↗
Hepatic iron and zinc concentrations after portacaval shunting for nonalcoholic cirrhosis.
Hepatic iron and zinc concentrations were determined in 26 consecutive nonalcoholic cirrhotic patients who had previously undergone portacaval shunting and then liver transplantation and 37 control patients. Stainable iron was graded on a scale of 0 to 4; 11 shunt patients and 3 control patients had grade 2 to 4 iron staining. Mean hepatic iron concentration was significantly increased (20.1 +/- 4.1 mumol/gm) in the shunt group compared with the control group (9.1 +/- 2.3 mumol/gm) (normal value, < 35 mumol/gm) (p = .015, Student's t test). Mean hepatic iron index (hepatic iron/age) was 0.5 +/- 0.10 in the shunt group and 0.19 +/- 0.04 in the control group (p = 0.002). One shunt patient had a hepatic iron index of greater than 2. Hepatic zinc was not significantly different between the shunt group (2.42 +/- 0.18 mumol/gm) and the control group (2.56 +/- 0.14 mumol/gm). Serial biopsy specimens were analyzed in 17 cases (6 shunt, 11 controls), and the mean annual rate of iron accumulation was significantly greater in shunt patients (4.75 mumol/gm/yr) than in control cases (0.93 mumol/gm/yr, p = 0.037). Although increased stainable iron was common after portacaval shunting, quantitative iron analysis demonstrated increased hepatic iron concentrations in only 6 of 26 shunt patients and 3 of 37 control patients (p = 0.14, chi 2 test). Quantitative hepatic iron analysis demonstrated in this study that portacaval shunt patients have far less accumulated iron than hemochromatosis patients and are unlikely to have tissue injury resulting from iron overload.
Adult↗
DNA flow cytometry of fresh and paraffin-embedded tissue using cytokeratin staining.
DNA flow cytometry measurements were performed using cytokeratin as a second parameter to identify epithelial cells selectively in fresh and in archival paraffin samples of normal and adenocarcinoma tissues from breast and colon. Fresh specimens consisted of 22 adenocarcinomas of breast, 20 adenocarcinomas of colon, 16 control breast samples, and 13 control colon samples. Paraffin block specimens consisted of 22 adenocarcinomas of breast (the same as fresh samples), 20 adenocarcinomas of colon (the same as fresh samples), 37 control breast samples and 34 control colon samples. The average proportion of cytokeratin-positive cells per group ranged from 31 to 55% for fresh samples and from 14 to 34% for paraffin samples. For aneuploid cells populations of adenocarcinomas, which consist only of epithelial cells, the average percentage of cytokeratin-positive cells ranged from 60 to 72%. The technique gave satisfactory measurements of ploidy and of cell cycle data in both types of samples. Cell cycle measurements were less accurate than ploidy measurements in both types of samples, and multiple sampling will be required for adequate accuracy. The average S-phase fraction of cytokeratin-positive cells ranged from 6 to 15% for fresh specimens and from 11 to 20% for paraffin samples. Similar data were obtained for the proliferative index (G1 + S + G2 + M phases). The coefficients of variation were smaller for proliferative index than for S-phase fraction data, indicating greater accuracy. Paraffin data give higher cycling cell measurements than corresponding fresh data, so separate standardization of measurements may be required for fresh and for paraffin data.
Adenocarcinoma↗
Metallothionein as an epithelial proliferative compartment marker for DNA flow cytometry.
The antibody to the metal-binding low molecular weight protein metallothionein (MT) stains preferentially the proliferative edge of epithelial tumors in paraffin sections. The present report demonstrates its usefulness as an epithelial cell marker in DNA flow cytometry of archival specimens. Nine control breast (mammoplasty) specimens, 10 control colonic specimens (resection edges), 12 adenocarcinomas of breast, and 13 adenocarcinomas of colon were analyzed by DNA flow cytometry after MT and DNA staining. The average percentage of cells stained by MT ranged from 12% to 27% in these groups of specimens, which contain epithelial as well as stromal and inflammatory cells. Comparing cell turnover, measured as S-phase fraction (SPF) in unstained and MT-stained preparations, it was 10% and 20%, respectively, in control tissues and 10% and 30%, respectively, in adenocarcinomas. The SPF is lower in unstained preparations because of dilution by noncycling inflammatory and stromal cells. Immunohistochemical staining of various tissues for MT showed specific staining of epithelial cells. Evaluation of aneuploid malignant epithelial cells detected in six breast and eight colonic adenocarcinomas showed that on average, 47% of cells were stained with MT and that their SPF increased by about 50% when MT staining was compared with the unstained preparations. The results suggest that MT stains epithelial cells adequately for ploidy and cell cycle evaluation and that it may stain preferentially the proliferating cell compartment, which is considered to be an index of malignancy.
Adenocarcinoma↗
Hereditary nonpolyposis colorectal cancer (Lynch syndrome II). Diploid malignancies with prolonged survival.
DNA flow cytometry was performed on 44 paraffin blocks from 16 specimens of 11 lesions in five patients from two families identified as probably having the dominant gene of the Lynch Type II syndrome. All but one specimen showed diploidy, although two such specimens were metastases and one a recurrence. The one aneuploid gastric biopsy was followed by a resection with diploidy in all 13 blocks from the malignancy and may represent a superficial change without clinical significance. The prolonged survival after discovery of malignancy in such families may be explained in part by diploidy of the lesions.
Adult↗
Aneuploidy in nonneoplastic and benign melanocytic and breast lesions determined by DNA flow cytometry.
A total of ten of 60 nonneoplastic lesions and eight of 76 benign neoplasms of skin and breast showed an aneuploid peak in DNA flow cytometry profiles obtained from archival paraffin blocks. This confirms previous similar scattered reports and emphasizes that caution needs to be exercised in interpreting aneuploidy in DNA flow cytometry to mean preneoplasia, neoplasia, or malignancy.
Aneuploidy↗
Transplantation of a donor liver with haemochromatosis: evidence against an inherited intrahepatic defect.
An iron loaded liver from a 40 year old man with occult haemochromatosis was transplanted into a 19 year old woman with acute liver failure secondary to a paracetamol overdose. Increased parenchymal hepatic iron was found in a liver specimen at biopsy undertaken because of mild rejection 30 days after transplantation. After transplantation the patient had two episodes of liver rejection confirmed by biopsy. The hepatic iron concentration fell from 161 mumol/g on day 30 after transplant to 26.5 mumol/g (normal less than 40) on day 210. Iron absorption, measured 45 days after transplant, was in the normal range at 12.4%. The rapid fall in hepatic iron and the normal iron absorption study result suggest that the genetic defect of haemochromatosis is not exclusively an intrahepatic defect.
Adult↗
DNA flow cytometry of large-bowel biopsies showing that adenoma tissue predicts the ultimate nature of the lesions.
Ploidy of neoplastic large-bowel cells in lesions from which biopsies showed only adenoma tissue by histopathologic examination was investigated retrospectively by DNA flow cytometry. Biopsy and resected-specimen blocks gave interpretable ploidy profiles from 83 lesions. The expectation that adenomas will show diploidy in biopsies and that adenocarcinomas will show aneuploidy in biopsies was fulfilled in 80% of the lesions. In addition, four lesions with diploid biopsies were polyps with minimal invasion. Thus, diploidy would have correctly predicted that local resection was adequate treatment for 62 lesions and conversely that cancer resection was the appropriate treatment for 8 lesions, for an overall predictive success rate of 87%. In conjunction with endoscopic, radiologic and other data, DNA flow cytometry of biopsies from apparently benign large-bowel lesions could become a useful addition to therapeutic decision-making.
Adenocarcinoma↗
Granulomatous hepatitis and fever of unknown origin. An 11-year experience of 23 cases with three years' follow-up.
Granulomatous hepatitis is a common cause of fever of unknown origin in up to 13% of patients with prolonged fever. Attempts to define an exact etiology of the granulomatous hepatitis frequently does not yield a precise diagnosis, so that the physician must consider empiric treatment. In this paper we retrospectively review 23 patients in whom granulomatous hepatitis was found as part of the initial assessment of fever of unknown origin, and we report on their outcomes after an overall prospective follow-up of 37 months. In 26% a precise diagnosis was established at the time of assessment: Q-fever in three, mycobacterial disease in two, and histoplasmosis in one. In the remaining 74% no etiology was established after 44 months follow-up. Forty-one percent of the idiopathic group resolved spontaneously without therapy, and 18% received short-term prednisone or indomethacin with a favourable outcome. The remaining 41% required long-term prednisone therapy for a mean of 33.1 months, but all have remained afebrile and otherwise healthy after 59.6 months follow-up. We conclude that patients with fever of unknown origin who are diagnosed as having idiopathic granulomatous hepatitis have an excellent prognosis, even the minority who require long-term corticosteroids.
Adult↗
Hepatic zinc in hemochromatosis.
Since an intestinal absorptive interaction between iron and zinc has been described in animals and humans, the possibility of increased accumulation of zinc as well as iron in the liver was studied in patients with hereditary hemochromatosis. Hepatic zinc was determined by atomic absorption spectrophotometry in liver biopsy specimens from 21 homozygotes for hemochromatosis, 21 normal liver samples from autopsies, and 15 cases of cirrhosis unrelated to iron overload. Mean hepatic zinc concentrations in the three groups were compared by one-way analysis of variance. Hemochromatosis patients had hepatic iron determinations by atomic absorption spectrophotometry, and iron absorption studies using 59Fe and total body counting had been previously documented in 18 of the 21 hemochromatosis patients. The mean hepatic zinc was significantly increased at 25.9 +/- 26.7 mumol/g (dry weight) in the hemochromatosis patients, as compared to 4.99 +/- 1.51 mumol/g in the control patients (p less than 0.05), and 2.13 +/- 1.13 mumol/g in the cirrhosis patients without iron overload (p less than 0.05). Hepatic zinc concentration was elevated in hemochromatosis patients who had either normal histology, fibrosis, and cirrhosis. Hepatic zinc concentration was not directly related to patient age, hepatic iron concentration, or iron absorption. In conclusion, hepatic zinc was increased approximately fivefold in patients with hemochromatosis. This finding suggests the concomitant hepatic accumulation of zinc as well as iron in this disorder, possibly by means of increased intestinal absorption of zinc and hepatic sequestration.
Adult↗
Stable genes.
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.
Animals↗
Hepatic iron and iron absorption in hemochromatosis.
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.
Absorption↗
Use of OKT3 in liver transplant patients.
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Antibodies, Monoclonal↗
Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome.
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.
Adolescent↗