Genetics of hemochromatosis.
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Biomedical subjects
Publications and source records attributed to M Simon.
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To determine whether a correlation exists between the biochemical expression of hemochromatosis and the HLA genotype, we studied 174 family members of 32 persons with the disease. Persons who shared both HLA haplotypes with the proband (and presumably having two hemochromatosis alleles) differed significantly from those who shared only one haplotype (and presumably having one hemochromatosis allele) in terms of serum iron (P less than 0.001 for both sexes), unsaturated iron-binding capacity (P less than 0.01 for female and P less than 0.0001 for male subjects) and serum ferritin (P less than 0.0001 for female and P less than 0.00001 for male subjects). The only significant difference between relatives having one hemochromatosis allele and age and sex-matched controls was related to serum ferritin values in male subjects (P less than 0.05, despite considerable overlap). In our hands, serum ferritin was the best indicator of disordered iron metabolism and was elevated among most homozygous but among few heterozygous family members.
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Inflammation is characterized by the combined reaction of living tissue of the target organ and various types of white blood cells recruited from the circulation and platelets, which tend to eliminate the injurious agent and to repair the damaged tissue. Much of the current knowledge of the functions and characteristics of human white blood cells has been derived from studies of lymphoid cells from patients with various diseases. The results of recent studies (17, 19, 28) have pointed to the diagnostic importance of the immunocompetent cells. The various characteristics of cells involved in immune mediated reactions of various organs and in circulation in man may lead to a better understanding of immune reactions and finally to effective therapeutic modalities.
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The basic disorder of iron metabolism in idiopathic haemochromatosis finds expression on at least two levels: the intestinal mucosa (increased iron absorption) and the liver. Its exact nature, however, remains obscure. The role of iron overload in the pathogenesis of the disorder seems clear. Lysosome disruption has recently been proposed as a possible pathogenic factor. Phenotypic family studies have lent considerable weight to the hypothesis of a recessive transmission of idiopathic haemochromatosis. Demonstration of a close link between the disease and the HLA antigen A3 and haplotype A3, B14 has made it possible: to remove all doubt as to the hereditary nature of the disease; identify the underlying gene as located on chromosome 6 near the A locus of the HLA system; demonstrate a recessive mode of transmission; and achieve the early detection of individuals at risk in the family of a patient with the disease. Thanks to this possibility of early detection, the feasability of preventive measures is greatly enhanced.
Over the last few years the study of idiopathic haemochromatosis has not brought to light any basic change in the overall pattern of organic and metabolic damage produced by the disease and comprising altered skin pigmentation, liver disease, diabete mellitus, heart disease, endocrine dysfunction, bone and joint disease. Nevertheless, certain facets of the clinical picture have been described and progress has been made in understanding the signs of the disease. Although the desferrioxamine test is no without merit, especially if performed after vitamin C administration, for measuring the extent of iron overload, two methods seem better equipped: serum ferritin radioimmunoassay and measurement of iron concentration in a liver biopsy specimen. The HLA antigen A3 and, more especially, haplotype A3, B14, are markers for the genetic basis of the disease. Repeated phlebotomy therapy generally brings about symptomatic improvement and a significant increase in survival.
We studied iron overloading and HLA genotype in two families with overt forms of idiopathic haemochromatosis in two successive generations. In each family the spouse of the patient with overt haemochromatosis in the first generation had clinical and laboratory signs of moderate iron overload and a HLA haplotype A3, B14 and A3, B7 respectively--which is frequently associated with the haemochromatosis gene. This specific HLA haplotype had been transmitted to the second generation patient with overt disease, which thus could be considered as having received a haemochromatosis gene from each parent. Although the finding of cases of overt disease in successive generation firstly suggests a dominant transmission the genetical analysis of these families lead to further strong argument in favour of recessive inheritance of idiopathic haemochromatosis.
Antimicrobial effectiveness of alcoformol two agents (AF 8.85 and AF 3.5) was studied in a clinical trial by means of bacteriologic examination of the root canals. After the initial culture was taken, one of the disinfectants was sealed in the pulp chamber for one week. At the second visit, the root canal was reamed and a second culture was taken. It was found that AF containing 3.5 percent formaldehyde is a satisfactory disinfectant for root canals of vital teeth. A concentration of 8.75 percent was needed for disinfection of teeth with necrotic pulps.
Antimicrobial effectiveness of two alcoformol agents (AF 8.75 and AF 3.5) was studied in a clinical trial by means of bacteriologic examination of the root canals. After the initial culture was taken, the root canal was reamed and a second culture was taken. One of the disinfectants was sealed in the pulp chamber for one week. At the second visit, a third culture was taken. No statistically significant differences were found between the effectiveness of the disinfectants; the cumulative effect of mechanical preparation and disinfection was such that initially positive teeth did not differ significantly from initially negative teeth when treated by this procedure.
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The alternative expression of Salmonella genes H1 and H2, which specify different flagellar antigens, results in the oscillation of phenotype known as phase variation. This alternation is controlled by the inversion of an 800-base-pair sequence of DNA adjacent to, or including part of, the H2 gene. The invertable region was presumed to regulate the function of a promoter and to include specific sites at which a recombinational event, resulting in the inversion, could occur. Here we report genetic manipulations of hybrid lambda phage carrying the H2 gene that were used to define the H2 promoter region and the recombinational sites. The H2 gene fragment was inserted on a hybrid lambda phage next to the cheW gene, which lacked a promoter element. In the resulting fusion, cheW gene activity was restored, the expression of the H2 and cheW genes was controlled coordinately by the inversion, and the polarity of transcription and location of the H2 gene could be determined. Evidence from this type of gene fusion suggested that the H2 gene promoter is included in the inversion region. Hybrid H2 phage were constructed that contained substitutions for regions of the H2 gene. In contrast to hybrid lambda containing the H2 gene, which alternate between "on" and "off" states, several substituted lambdaH2 were fixed in the "on" state. A site necessary for the recombinational event must have been removed in these fixed lambdaH2.
A method for monitoring therapeutic levels of the beta-blocking and antiarrhythmic drug propranolol in serum has been developed as a high performance liquid chromatography technique using bonded nitrile columns in a reverse phase mode with an aqueous methanol mobile phase containing acetate as a counterion. The performance characteristics of eight different types of reverse phase columns are discussed with evaluation for use in the method. The present method combines basic organic (cyclohexane) extraction with fluorescence detection of the chromatographic effluent to provide a specific, rapid, precise, and reliable technique that has been successfully used to monitor propranolol metabolites or other drugs. The method is shown to compare well with other methods and is suitable for therapeutic drug monitoring by routine clinical laboratories.
HLA-A and B antigens were defined in 154 unrelated idiopathic hemochromatosis patients. The study confirmed the highly significant positive association with HLA antigens A3 (corrected P less than 10(-10)) and B14 (corrected P less than 10(-9)). HLA-DR typing showed increased frequency of the specificity DRw6, which was frequently associated with the phenotype A3, B14 and antigen B14, suggesting linkage disequilibrium. This was borne out by PLT data.
Computerized Language Information Processing (CLIP) is a system of radiologic reporting in which the user interacts with a computer keyboard and cathode-ray tube terminal to generate coded reports. The hierarchical medical classification on which the code is based permits rapid on-line compilation of reports of any degree of complexity. The system provides organized sets of pre-assembled statements that are rapidly accessed and modified for each examination. Although the reports are printed in English, they are held in the computer as a succinct code that is eminently suited for permanent storage and rapid retrieval.
A modification in the introduction of the Kimray-Greenfield filter is described. Rather than advancing the stylet toward the Luer-lok assembly and thereby discharging the filter, the authors propose positioning the carrier containing the closed filter farther into the inferior vena cava, then withdrawing the catheter and carriage while holding the stylet in place. This method reduces the chance for damaging the caval wall.