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Biomedical subjects

M D Benson

Publications and source records attributed to M D Benson.

At least 163 records · Page 9Linked to original sources
PubMed1986

Treatment of AL amyloidosis with melphalan, prednisone, and colchicine.

Seven patients with immunoglobulin type (AL) amyloidosis were treated with combination chemotherapy, including melphalan, prednisone, and colchicine. Two patients died within 5 months of the beginning of therapy. Both had amyloid cardiomyopathy. Five patients were alive 17-60 months after the start of therapy, and none had shown progression of disease. The most significant findings were the resolution of the nephrotic syndrome in 2 patients, and improvement of liver function, as demonstrated by excretion of indocyanine green, in 2 patients. These results are encouraging and support the need for further studies of this regimen of combination chemotherapy for patients with AL amyloidosis.

Aged↗
PubMed1986

DNA sequence evidence for polymorphic forms of human serum amyloid A (SAA).

Serum amyloid A (SAA) is an acute-phase reactant and precursor to amyloid A protein, the major constituent of the fibril deposits of reactive amyloidosis. The factors determining whether the 104-amino acid SAA molecule is converted into the 76-amino acid amyloid A protein and deposited as fibrils are not known. As an initial step toward investigating the possibility that a particular primary structure of SAA is involved in amyloid formation, we have cloned and determined the nucleotide sequence of human SAA-specific cDNAs. The first clone, selected using an oligonucleotide probe, was shown to encode the signal peptide and amino-terminal region of SAA. The cDNA of this clone served as probe in the selection of two distinct, full-length SAA cDNAs, initially differentiated by the presence (pSAA21) or absence (pSAA82) of a PstI site in the coding sequence. The complete nucleotide sequence of pSAA82 cDNA was determined. Since there appear to be multiple human SAA alleles, it is conceivable that their differential expression is important to amyloid formation.

Amino Acid Sequence↗
PubMed1986

Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis.

The tissue distribution of amyloid deposits was studied in 15 related Abyssinian cats with familial amyloidosis. There was interstitial medullary amyloidosis in the kidneys of all 15 cats but only 11 had detectable glomerular involvement. The thyroid glands, stomach and colon were affected in all cats examined. Most of the cats also had amyloid deposits in the small intestine, spleen, heart, adrenals, pancreas, liver, lymph nodes and bladder. In 50 per cent or fewer of the cats examined, there was involvement of the parathyroids, lung and gonads. The central nervous system was not involved in any of the 3 cats evaluated. In 8 of the cats, no concurrent inflammatory disease could be detected. The tissue distribution of amyloid deposits resembled that found in other breeds of domestic cats with systemic amyloidosis. Despite the wide tissue distribution of amyloid deposits, clinical signs were related to renal amyloidosis. Familial amyloidosis in the Abyssinian cat may represent a valuable spontaneous animal model for the study of Familial Mediterranean Fever in man and the pathogenesis of reactive amyloidosis in general.

Amyloid↗
PubMed1986

Polymorphism in a kappa I primary (AL) amyloid protein (BAN).

In an attempt to understand the relationship of amino acid sequence to the formation of primary or multiple myeloma-related amyloid (AL amyloid), we have determined the complete amino acid sequence of amyloid protein BAN. This protein belongs to the kappa I immunoglobulin light chain subgroup and has a polypeptide chain length of 126 amino acids. It encompasses the entire variable region, the joining segment and the first tryptic peptide of the constant region. This protein has two unique features. First, the molecule is glycosylated. At position 61 the usual arginine residue has been replaced by an asparagine with the generation of the signal sequence Asn-Phe-Thr, to which a glucosamine-containing carbohydrate unit is attached. Secondly, the protein is not monoclonal but consists of two chains which have the same variable region but different J-segments. Comparison of the BAN sequence with other amyloid and nonamyloid kappa I proteins reveals a systematic difference between the two groups. In the amyloid proteins, several hydrophilic framework residues have been replaced by hydrophobic residues. These substitutions may provide the nucleation sites for self-aggregation and fibril formation.

Adult↗
PubMed1986

Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant late-onset disorder characterized by the extracellular deposition of amyloid fibrils. In all cases studied these fibrils have been found to be composed of plasma prealbumin (transthyretin) containing a single amino acid substitution. Biochemical studies were conducted on amyloid from one patient and plasma prealbumin from his affected brother, both part of a large kindred from the Appalachian region of the United States. Sequence analysis of the amyloid subunit protein showed it to be prealbumin with about two-thirds of the molecules containing a substitution of alanine for threonine at position 60. Studies of the plasma prealbumin showed that the same substitution was present in 40-45% of the protein. Based on this substitution and the prealbumin cDNA sequence, a Pvu II restriction fragment length DNA polymorphism (RFLP) was predicted and demonstrated in DNA of both patients as well as other family members. This RFLP confirms the predicted DNA mutation responsible for the protein variant, and represents an accurate method for detection of this gene.

Aged↗
PubMed1986

Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss).

Amyloid fibrils were isolated from cardiac tissue of two brothers who died from familial amyloidotic polyneuropathy (FAP) type II. Sequence analysis on peptides derived from proteolytic cleavage with trypsin and fragmentation with cyanogen bromide reveal that the fibril subunit protein is derived from plasma transthyretin (prealbumin). About two-thirds of the fibril subunit protein was found to contain an amino acid substitution at position 84 where the normal isoleucine residue has been replaced by serine. Sequence analysis of the plasma transthyretin (prealbumin) from the two brothers as well as two clinically diagnosed FAP type II family members and two of four children of affected individuals showed the presence of serine at position 84. The presence of this substitution also correlates with low serum levels of retinol-binding protein and thus transthyretin (prealbumin) position 84 may be involved with the interaction of these two proteins.

Amino Acid Sequence↗
PubMed1986

Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy.

T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20% of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (Ka) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of Ka was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (+/- SD) values of 0.24 +/- 0.08 X 10(7) M-1 for type I and 0.26 +/- 0.10 X 10(7) M-1 for type II were significantly (P less than 0.0001) lower than those for normal relatives (1.39 +/- 0.30 X 10(7) M-1) or unrelated normal subjects (1.41 +/- 0.18 X 10(7) M-1). The mean Ka value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 +/- 0.11 X 10(7) M-1). There was no overlap of individual Ka values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the beta-structure which forms the presumed binding site, in agreement with our results of Ka measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.

Amyloidosis↗
PubMed1986

Relationship of migraine headache and stroke to oral contraceptive use.

Are oral contraceptive users who also suffer from migraine headaches at higher risk of having a cerebrovascular accident? The data are inconclusive in establishing that women who used the relatively higher-dose pills prescribed in the 1960s have a higher risk of either thrombotic or hemorrhagic stroke. Furthermore, a review of the literature does not support the belief that those women who use oral contraceptives have a higher incidence of migraine headache. The available data do not indicate that migraine headache is necessarily a contraindication to prescribing oral contraceptives.

Cerebral Hemorrhage↗
PubMed1986

Chemical classification of hereditary amyloidosis in Brazilian families and identification of gene carriers.

Plasma prealbumin was isolated from individuals in 3 kindreds from Brazil with biopsy proven heredofamilial amyloidosis as well as from a number of asymptomatic family members. The prealbumin samples were cleaved with cyanogen bromide and the resulting peptide mixtures separated by reverse phase high performance liquid chromatography. The peptide elution pattern seen for the individuals with confirmed amyloidosis is consistent for the presence of a prealbumin variant with a methionine for valine at position 30 of the molecule. Sequence analysis of the isolated peptides confirms this observation and shows that the 3 Brazilian families investigated in our study have the same prealbumin variant as individuals with amyloidosis of Swedish/American, Portuguese and Japanese origins.

Adult↗
PubMed1985

Localization of the human prealbumin gene to chromosome 18.

A human liver cDNA library was screened using an oligonucleotide probe based on the amino acid sequence of human prealbumin. The cDNA insert of one positive clone was sequenced and found to contain the entire coding sequence of human prealbumin plus untranslated 5' and 3' regions. This cDNA was used to probe DNA from a panel of mouse/human somatic cell hybrids. Only those hybrids containing human chromosome 18 showed the human-specific hybridization pattern, thereby localizing the human prealbumin gene to this chromosome.

Amino Acid Sequence↗
PubMed1985

Adult survival with intrahepatic portal venous gas secondary to acute gastric dilatation, with a review of portal venous gas.

The radiological observation of hepatic portal venous gas on plain abdominal radiography, ultrasonography or computed tomography is a highly significant finding. Its cause warrants urgent diagnosis and will usually require surgical management. Current overall mortality rate associated with this sign is 75%. A case of acute gastric dilatation with hepatic portal venous gas in an adult who survived without surgery is presented. Patients having this sign after double-contrast barium enemas with quiescent inflammatory bowel disease have also been reported to survive without surgery.

Acute Disease↗
PubMed1985

Amino acid sequence of a lambda VI primary (AL) amyloid protein (WLT).

It has been observed that monoclonal immunoglobulin proteins of the lambda VI subgroup have a high propensity to form amyloid deposits. To ascertain whether lambda VI proteins have unique structure determinants that would account for self association and resultant fibril formation, we have determined the complete amino acid sequence of the AL amyloid protein WLT. This protein, isolated from the spleen of a patient with AL amyloid, has 134 amino acid residues and contains the entire variable region, the joining segment, and the first tryptic peptide of the constant region. Comparison of the structure of this protein with the 3 completely sequenced lambda VI proteins reveals that they are highly homologous and contain a 2-residue insertion at positions 68 and 69. Phylogenetic comparisons of the variable domain of all lambda VI proteins reveal that the 3 amyloid proteins WLT, SUT, and AR are all more closely related to each other than to the myeloma protein NIG48. Separating the variable domains into framework (FR) and complementarity-determining regions (CD) and recalculating the phylogenetic comparisons, we identify major substitutions in the FR regions of NIG48 in relation to the amyloid proteins. This supports the hypothesis that the formation of AL amyloid is a result of the secondary structure of the FR regions of the precursor molecules.

Adult↗
PubMed1985

Cerebellar calcification and lead.

In elderly subjects who were brought up in a known high lead environment in Queensland, Australia, childhood residence and occupational status provide circumstantial evidence of a relationship between excessive lead intake and cerebellar calcification as seen on computed tomography. This supports experimental and neuropathological studies demonstrating an association between exposure to lead and perivascular cerebellar calcification.

Basal Ganglia Diseases↗
PubMed1985

Identification of carriers of a variant plasma prealbumin (transthyretin) associated with familial amyloidotic polyneuropathy type I.

A method is described for detecting carriers of a variant plasma prealbumin that is associated with familial amyloidotic polyneuropathy (FAP) type I. It is based on the finding of an extra methionine in the variant prealbumin, at position 30 from the amino terminals. Since normal prealbumin has only one methionine (position 13), treatment with cyanogen bromide (CNBr), which cleaves only at methionines, results in two peptides. CNBr treatment of the variant prealbumin gives three peptides. The extra can then be detected in two ways: by HPLC using a reverse phase C18 column, and by sequential Edman degradation. Each method can detect as little as 1% variant prealbumin in isolated plasma prealbumin, and therefore, can identify carriers of the gene for the variant protein. Since FAP type I usually is not manifest until after the childbearing years, this method to identify carriers of the gene offers a new approach for genetic counseling of families with this disease. To date, kindreds with hereditary amyloidosis that could benefit from these studies include those with FAP type I of Swedish, Japanese, and Portuguese origins.

Adult↗
PubMed1985

Identification and characterization of amyloid protein AA in spontaneous canine amyloidosis.

Amyloid fibrils were isolated from kidney tissue of a dog that presented with renal failure due to spontaneous amyloidosis. This fibril material was reduced, alkylated and chromatographed on a column of Sepharose CL6B. A major retarded fraction, when subjected to amino acid sequencing, demonstrated a blocked amino terminus. The isolated protein was then degraded with cyanogen bromide, and the resultant three peptides were isolated by high-pressure liquid chromatography. The amino acid sequence of one peptide corresponded to the sequence of human amyloid protein AA from position 17 to 23. A second peptide gave an amino acid sequence homologous to the published human protein AA sequence starting with position 24. Although a high degree of homology between canine and human AA is seen, the blocked amino terminus is similar to the AA protein of mink. These data show that spontaneous canine amyloid is analogous to human reactive (secondary) amyloid and, therefore, may aid in defining mechanisms of human amyloid pathogenesis.

Amino Acid Sequence↗