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Biomedical subjects

M Skinner

Publications and source records attributed to M Skinner.

At least 109 records · Page 6Linked to original sources
PubMed1992

Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent.

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited form of amyloidosis usually associated with an abnormal transthyretin (TTR), previously known as prealbumin. Several disease-related variants of the protein, each with a different amino acid substitution and correlating DNA point mutation, have been identified. The TTR gene from a patient suffering from this disorder was asymmetrically amplified and directly sequenced, revealing a cytosine for thymine substitution in the second base of codon 30 and the creation of a novel Cfo I restriction endonuclease site in exon 2. This mutation results in a previously undescribed substitution of an alanine for valine in the final TTR protein. Analysis of the amino acid mutation reveals it to be a hydrophilic substitution at a hydrophobic core position. Alanine at position 30 represents the second FAP-associated mutation at position 30 in TTR.

Adult↗
PubMed1991

A second transthyretin mutation at position 33 (Leu/Phe) associated with familial amyloidotic polyneuropathy.

Genomic DNA was isolated from peripheral blood lymphocytes of a patient with familial amyloidotic polyneuropathy (FAP) and the transthyretin (TTR) gene examined for sequence mutations. Polymerase chain reaction was used to asymmetrically amplify the TTR exons. Direct DNA sequencing of the PCR product revealed a C for T mutation at the first base of codon 33 located in exon 2 of one transthyretin gene. This resulted in a substitution of leucine for phenylalanine at position 33. Exons 3 and 4 were examined and found to be normal. The mutation creates a novel DdeI restriction site at the point of the mutation.

Amyloidosis↗
PubMed1991

Role of aspartate-37 in determining cofactor specificity and binding in rat liver dihydropteridine reductase.

Full-length rat dihydropteridine reductase (DHPR) cDNAs have been combined with a prokaryotic expression vector and introduced into Escherichia coli. Transformed bacteria express dihydropteridine reductase immunoreactive proteins and demonstrate conversion of quinonoid dihydropteridines to their tetrahydro forms. Several recombinant enzymes have been purified to homogeneity and biochemical studies have been carried out comparing their properties with those exhibited by the rat liver enzyme. The optimal reaction conditions, kinetic constants, and stability are similar for the recombinant and naturally occurring enzyme. The results indicate that the nonmutant recombinant rat DHPR is an authentic replica of the natural protein and that the characteristics of DHPR activity are determined by a single gene product and do not require specific modification via the eukaryotic cell. In addition to the wild type, three specific mutagenic forms of the reductase, A-6-V, W-104-F, and D-37-I, and an additional abbreviated structure have also been formed. Each of the products exhibits reductase activity, although they show varied affinities for their cofactor, NADH, and less stability to chromatography, dialysis, and concentration than the wild-type enzyme. The N-terminal sequence contains a classic NADH binding region between amino acids 9 and 36, and Asp 37 is essential for binding the cofactor as is shown by the approximately 20-fold increase in dissociation constant for the D-37-I mutant and diminished kcat (approximately 43 s-1 compared to 156 s-1 for the wild-type enzyme). The results indicate that the DHPR cofactor binding site is similar to typical dinucleotide requiring dehydrogenases such as lactic acid and liver alcohol dehydrogenase.

Amino Acid Sequence↗
PubMed1991

The predictive value of bone marrow morphologic characteristics and immunostaining in primary (AL) amyloidosis.

The authors previously demonstrated that bone marrow plasmacytosis in primary (AL) amyloidosis may be monoclonal or polyclonal. However, the clinical implications of the degree of plasmacytosis and its clonality have not been studied. The authors evaluated 62 patients with AL amyloidosis, 40 of whom had monoclonal medullary plasma cells. There was complete concordance between the light chain class of the plasma cells in the monoclonal cases and that of the circulating paraprotein in the 22 cases associated with a paraprotein. The remaining 22 patients had polyclonal plasma cells, although a paraprotein was detected in 6. The degree of plasmacytosis was significantly higher among patients with monoclonal plasma cells and correlated inversely with length of survival. The authors' findings indicate that the quantitation of bone marrow plasma cells in AL amyloidosis by immunoperoxidase studies may predict the clinical course.

Adult↗
PubMed1991

A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90.

A new transthyretin variant which lost an Sph I cleavage site within exon 3 has been characterized. A 260 bp sequence containing exon 3 was amplified using the polymerase chain reaction, and the variant was found to possess a Bsm I cleavage site not present in normal transthyretin. This led to the conclusion that the histidine at position 90 was replaced by asparagine, and amino acid analysis supported the conclusion. The discovery of this mutation suggests that intermolecular binding between hydrophobic polypeptide loops on the surface of transthyretin can lead to familial amyloidotic polyneuropathy.

Amino Acid Sequence↗
PubMed1991

Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is associated with the deposition of an abnormal transthyretin (TTR) molecule. We have studied DNA from a family of Greek descent with FAP. The proband's TTR gene was asymmetrically amplified by using PCR and then was sequenced directly, to reveal a cytosine-for-guanine substitution in codon 36. This substitution removes a recognition site for endonuclease Fnu4HI. Allele-specific PCR was employed for diagnosis of the mutation. The predicted amino acid change of alanine to proline at position 36 was confirmed by protein sequencing of the proband's plasma TTR.

Adult↗
PubMed1991

Individualization and enamel histology: a case report in forensic anthropology.

The cranium of a native Indian child about six years old was found in 1979 near Taseko River, British Columbia, Canada. While the remains matched the report of a child missing for eight years in terms of race, age at death, locale, and elapsed time since death, the cranium and dentition were basically unidentifiable because of the claimed lack of medical or dental history. There was no dental work, and the parents were unknown or dead. We report the presence, in the dental enamel of the primary and secondary dentition, of stress markers, termed striae of Retzius, whose locations correspond well with anecdotal reports and recently discovered medical records which describe the timing of specific episodes of stress. The enhanced probability of personal identification from dental histological stress markers is evaluated.

British Columbia↗
PubMed1991

The ins and outs of laboratory information systems. Combining the hospital and reference laboratory.

Regulatory and reimbursement pressure on laboratory and hospital organizations have led to diversified or hybrid combinations of hospital inpatient, outpatient, and reference laboratory operations. Laboratory information system (LIS) requirements to integrate these operations become more complex than for either operation alone, because inpatient and reference operations have different and sometime conflicting priorities. Careful attention to LIS requirements is necessary to implement hybrid laboratory operations systems successfully.

Appointments and Schedules↗
PubMed1990

Gadopentetate dimeglumine clearance in renal insufficiency in rabbits.

The total body clearance of gadopentetate dimeglumine (Gd-DTPA) was evaluated in 17 normal rabbits and 11 rabbits with renal insufficiency induced by angioinfarction. Serial measurements of the serum spin lattice relaxation rate (1/T1) were compared with actual gadolinium concentrations as determined by mass spectroscopy. Gadopentetate dimeglumine concentrations measured by both mass spectroscopy and magnetic resonance (MR) relaxometry decreased by two logs in both normals and rabbits with renal impairment by 24 hours and were highly correlated with each other (r = .98). The estimated total body clearance of gadopentetate dimeglumine was 14.1 +/- 0.56 cc/minute for the normal animals and 3.78 +/- 0.19 cc/minute for the impaired rabbits. These results indicate that gadopentetate dimeglumine is excreted rapidly, usually within 24 hours, even in the presence of renal insufficiency.

Animals↗
PubMed1990

Isolated ulnar shaft fractures. Retrospective study of 46 cases.

Retrospectively, we reviewed the treatment and outcome of 46 isolated fractures of the ulnar shaft. Of 18 fractures treated by immediate open reduction and internal fixation, one open fracture became infected and failed to unite. Of 28 fractures treated closed, seven failed to unite. The factors prognostic of nonunion in closed treated fractures were (1) fracture in the proximal third of the ulna and (2) displacement 5 mm or more. In such cases, we recommend internal fixation.

Adolescent↗
PubMed1990

Glycosaminoglycans of the hemodialysis-associated carpal synovial amyloid and of amyloid-rich tissues and fibrils of heart, liver, and spleen.

Significant amounts of glycosaminoglycans (GAGs) were found in amyloid fibril preparations. Using two-dimensional electrophoresis to fractionate GAG mixtures, we quantified and identified for the first time the GAGs of the fibrils from carpal synovium of patients with amyloid associated with chronic hemodialysis. The total GAG content was small, but the GAG distribution (high relative content of chondroitin sulfate and hyaluronic acid and lack of the other GAGs) was unique, unlike that for the other amyloid fibril preparations. The amyloid-rich heart, liver, and spleen tissues, as well as the fibrils isolated from these tissues of patients with systemic forms (primary amyloid and secondary amyloid) of amyloid disease, were also analyzed for GAGs. Fibrils from heart tissue of a patient with primary amyloidosis, now examined for the first time, contained four major GAGs (chondroitin sulfate, dermatan sulfate, hyaluronic acid, and heparan sulfate).

Amyloid↗
PubMed1989

A new mutation causing familial amyloidotic polyneuropathy.

The DNA from an individual with familial amyloidotic polyneuropathy was examined. It did not possess any of the mutations which have previously been associated with familial amyloidotic polyneuropathy. However, a novel 7.0 kb Sph I restriction fragment was discovered, and the mutation creating it was localized to exon 3 of the transthyretin gene. This mutation was inherited from a parent, and may result in an amino acid substitution for glu89, his90 or ala91. The patient's transthyretin has a lower pI than normal transthyretin.

Amino Acid Sequence↗
PubMed1989

Sensitivity, specificity, and predictive value of abdominal fat aspiration for the diagnosis of amyloidosis.

Samples of abdominal fat aspirates from 73 patients were sent to us for staining and interpretation. Ten samples were positive for amyloid. We calculated the sensitivity, specificity, and predictive value of the procedure based on the findings and the clinical information and other biopsy data about these patients. Using the results from more traditional biopsies as the "gold standard," sensitivity was 57%, specificity was 100%, and the predictive value was 100% for positive findings in the abdominal fat aspirate. Although the sample size in this study was relatively small, the procedure was found to be a minimally invasive test of high clinical utility.

Abdomen↗
PubMed1989

Lack of association of a restriction fragment length polymorphism for serum amyloid P gene with reactive amyloidosis.

The prevalence of a recently described restriction fragment length polymorphism using Msp I for the serum amyloid P gene was determined in 5 groups of patients. Patients with reactive (secondary) amyloidosis, juvenile rheumatoid arthritis, related inflammatory conditions, or juvenile rheumatoid arthritis with reactive amyloidosis, and healthy control subjects were found to be polymorphic for 8.8-kb and 5.6-kb gene fragments; they either had one or the other or both fragments. No significant differences were seen between these groups with relation to this polymorphism, and no correlation with the presence of reactive amyloidosis was observed.

Amyloidosis↗
PubMed1989

Hierarchy of cytotoxic T cell clones. I. Reversal of resistance to lysis and killing between anti-hapten cytotoxic T cells.

Cells from clones of anti-hapten cytotoxic T lymphocytes (CTL) can act as both effector cells and, when treated with the specific hapten, as target cells. Individual clones can kill haptenated cells only from other clones that are less efficient killers. Clones specific for both fluorescein and trinitrophenol could be ordered in a single hierarchy in which resistance to lysis correlated with lytic efficiency. When the killing efficiency was reduced with phorbol myristate acetate (PMA) or the colchicine analogue, Colcemid, the degree of resistance to lysis was also reduced. The use of PMA-treated fluoresceinated targets greatly enhanced intraclonal killing and similarly lead to a repositioning of clones within the hierarchy of normal cells. By the haptenation of appropriate clones, efficient CTL could kill cells from other clones in a direction apparently opposite to recognition. The results demonstrate that effects other than antigen recognition of the target cell may result in variations in the nature of T cell immune responses.

Animals↗