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Biomedical subjects

M Skinner

Publications and source records attributed to M Skinner.

At least 163 records · Page 9Linked to original sources
PubMed1985

Lowered prealbumin levels in patients with familial amyloid polyneuropathy (FAP) and their non-affected but at risk relatives.

Amyloid fibrils in familial amyloid polyneuropathy, the familial (AF) form of systemic amyloidosis, are composed of the monomeric unit (14,000 MW) of prealbumin molecules. By radioimmunoassay, the serum level of prealbumin was measured in 25 patients from 12 different kinships with this dominantly inherited form of amyloidosis and 56 unaffected, but at risk, relatives from two of the kinships. Results were compared to prealbumin levels in normal individuals and patients with primary (AL) and secondary (AA) forms of systemic amyloidosis. Significantly lowered prealbumin levels were found in the AF patients (149.2 micrograms/ml) and their at risk relatives (169.0 micrograms/ml) when compared to normal individuals (232.9 micrograms/ml), AL patients (221.9 micrograms/ml) and AA patients (211.7 micrograms/ml). No abnormality was found in levels of retinol binding protein (RBP), which is carried by prealbumin, in the serum of either the AF patients or their relatives. The depressed prealbumin levels may indicate a structural variant molecular form, an extra hepatic synthesis or an abnormality in catabolism of this protein that is present prior to the clinical or histopathologic onset of the AF disease.

Amyloidosis↗
PubMed1985

Isolation and characterization of a kappa amyloid fibril protein.

The fibril in primary amyloidosis (AL) is composed of a monoclonal light chain or portions thereof. No unique primary structure has been identified that predisposes certain light chains to form amyloid fibrils. Currently, classification of amyloidosis is based on the biochemistry of the amyloid fibril. We determined the NH2-terminal sequence of an amyloid fibril and found it to be of the kappa I immunoglobulin subgroup. No structural alterations were detected to account for the conversion of the light-chain fragment to an amyloid fibril. Antiserum produced to the fibril protein did not react in immunodiffusion with purified LEP or MAG antigens, which are kappa I proteins. This antiserum may be directed to antigenic sites unique to the immunizing protein and is unable to recognize homologous proteins, rendering it unsuitable for immunochemical identification of amyloid deposits of light-chain origin. PAG represents the 10th reported variable kappa I amyloid fibril protein subjected to partial sequence analysis. Antisera that recognize antigenic determinants present in all members of an immunoglobulin subgroup need further development.

Amino Acid Sequence↗
PubMed1985

Histochemical and immunohistochemical characterization of amyloid associated with chronic hemodialysis as beta 2-microglobulin.

The carpal tunnel syndrome has been associated with amyloid deposits and is now regarded as a major complication in patients undergoing chronic hemodialysis. The hemodialysis-associated amyloidosis appears to have systemic rather than local involvement, although its full extent is yet to be determined. In an attempt to examine the chemical and immunologic nature of the amyloid, the authors carried out a series of histochemical and immunohistochemical studies with the following results. The amyloid was "sensitive" to the "permanganate treatment," suggesting it was the AA (secondary) type. On immunohistochemistry, however, anti-human AA did not give positive reaction with the amyloid deposits, suggesting that this would be a new form of amyloid. As reported elsewhere, the authors' preliminary results on the amino acid sequence analysis in one specimen have revealed homology of its amino terminal sequence to beta 2-microglobulin. In the present study, anti-beta 2-microglobulin did indeed react positively (with appropriate controls) with the amyloid deposits in the tissues collected from five different patients, confirming the beta 2-microglobulin-related nature of the amyloid. The present observations are significant in two points: (a) they confirm that hemodialysis-associated amyloid is of beta 2-microglobulin origin since it shares same antigenic determinant(s) with it and since the amino acid sequence is homologous; and (b) it adds what many have suspected, i.e., "permanganate-sensitive" amyloid is not specific for the AA type but includes AA and beta 2-microglobulin amyloid deposits at the minimum.

Amyloid↗
PubMed1985

Effect of colchicine on experimental amyloidosis in two CBA/J mouse models. Chronic inflammatory stimulation and administration of amyloid-enhancing factor during acute inflammation.

To investigate the mechanism of action of colchicine in blocking amyloid deposition, two model systems of amyloidosis in CBA/J mice were studied. In experimental chronic inflammation, daily injection of silver nitrate (AgNO3) resulted in the deposition of 667 +/- 68 ng of amyloid A protein (AA)/mg of spleen after 25 days. Treatment with 10 micrograms of colchicine daily decreased AgNO3-induced AA deposition to 12 +/- 1 ng of AA/mg of spleen (p less than 0.001). Colchicine diminished the acute phase serum amyloid A protein (SAA) response after 24 hours. Over a 25-day period, SAA concentrations declined and approached baseline both in colchicine-treated and (unexpectedly) in control mice. This suggested that suppression of SAA levels was not the primary event inhibiting amyloid deposition. In a model of accelerated amyloid deposition, injection of preformed amyloid-enhancing factor along with AgNO3 induced the deposition of 974 +/- 46 ng of AA/mg of spleen 48 hours later. Colchicine only partially decreased amyloid-enhancing factor-induced amyloid deposition to 578 +/- 91 ng of AA/mg of spleen, while blunting the acute phase SAA response. These results suggest that colchicine inhibits amyloidosis in the predeposition phase, possibly by blocking formation of amyloid-enhancing factor.

Amyloid↗
PubMed1985

Prostaglandin E1 inhibition of experimental amyloidosis in CBA/J mice.

The antiinflammatory activity of systemically administered prostaglandin E1 (PGE1) was studied in experimental CBA/J mouse amyloidosis induced by chronic stimulation with silver nitrate. PGE1 lowered splenic deposition of amyloid A protein (AA) (p = 0.035). Serum amyloid A protein (SAA) levels were not suppressed by PGE1 in the acute phase, while decreased SAA levels appeared to be an integral part of the chronic inflammatory phase, with or without PGE1 treatment. Accelerated amyloid deposition induced by amyloid-enhancing factor (AEF) was not blocked by PGE1. This suggests that PGE1 inhibits amyloidosis in the predeposition phase, possibly by preventing formation of AEF or other deposition factors.

Alprostadil↗
PubMed1984

Measurement of murine serum amyloid P component by rate nephelometry.

Murine serum amyloid P component (SAP) is an acute-phase protein that is increased 2-10-fold in concentration following appropriate inflammatory or infectious stimuli. Previous studies of the acute-phase SAP response have employed quantitative immunoelectrophoresis or radioimmunoassay to measure SAP concentration. A rate nephelometric procedure has been developed which measures SAP concentration rapidly and with equivalent or greater precision than the previously applied techniques. This simple method will facilitate experimental and clinical studies of the acute-phase response.

Acute-Phase Proteins↗
PubMed1984

T-cell development in the absence of a thymus: the number, the phenotype, and the functional capacity of T lymphocytes in nude mice.

A small but definite proportion of T-lymphocyte-like cells have been reported in nu/nu (nude) mouse spleen despite the congenital absence of a thymus in these animals. We have determined the number and the characteristics of such cells using flow cytometry. The level of T-like cells increased with age. In 4-month-old nu/nu CBA spleen, 14% of all cells expressed some Thy 1 antigen. However, only 4% expressed mature T-cell levels, and only the 2% with the highest Thy 1 also showed a normal distribution of Ly 1 and Ly 2 antigens. These T-like cells were slightly larger than normal nondividing T lymphocytes. We have assessed the total functional capacity of T-like cells in nu/nu CBA spleen using a high-cloning-efficiency limit-dilution culture system. Almost all precursor cells capable of forming clones when stimulated with concanavalin A in the presence of irradiated spleen cells and growth factors, and almost all precursors of those clones that were cytolytic in a lectin-mediated tumor-cell-lysis assay, were within this 2% subpopulation of nu/nu spleen cells with mature T-cell markers. Increased levels of purified interleukin 2 failed to induce further precursor function, indicating that maturation of pre-T cells was not obtained. However the nu/nu spleen cells bearing mature T-cell markers displayed only 10-30% of the cloning efficiency of normal splenic T cells. The majority of nu/nu spleen T-like cells, even within this phenotypically "normal" subset, appeared to be nonfunctional. We conclude that the absence of a thymus leads to qualitative, as well as quantitative, deficiencies in the T-cell population, and various interpretations are discussed.

Animals↗
PubMed1984

Regulation of cytotoxic lymphocyte precursors: I. Interactions between concanavalin A and T cell growth factors.

The induction of cytotoxic T lymphocytes by concanavalin A has been analyzed under conditions of limit dilution. The dose-response curves deviate from linearity in a way that has been interpreted as revealing successive zones of suppression as the cell concentration was increased. The magnitude of suppression was influenced by both the concentration of concanavalin A and the amount of T cell growth factors added to the culture. These regulatory events involve the cytotoxic T cell clones produced by (CBA X DBA)F1 spleen cells which are detected by DBA mastocytoma (P815) targets at a maximum detectable frequency of 1 in 2000 cells. Similar multiphase dose-response data were also obtained with syngeneic and allogeneic combinations with the same target cell. It is suggested that the successive zones of suppression and activation are a consequence of the relative frequencies of CTL-P, suppressive and helper cells, and the ease with which the cells are activated in limit dilution cultures. The experimental approach illustrates how CTL production can be manipulated to study the balance of signals required to control effector cell production.

Aging↗
PubMed1984

Quantitation of serum suppressor factor, related to the erythrocyte receptor of human peripheral blood T lymphocytes as measured by radioimmunoassay.

A solid phase radioimmunoassay for a serum suppressor factor has been developed. The factor was previously purified from malignant ascites fluids and shown to be related to the sheep erythrocyte receptor of human peripheral blood T lymphocytes. This humoral suppressor factor has been termed suppressive E-receptor factor. Using this assay, it was demonstrated that both ascites fluids and sera derived from patients with solid tumors contain elevated levels of this factor compared to similar specimens from patients with a variety of nonmalignant diseases. The concentration of this SER factor does not correlate with serum immunoglobulin G levels but it does correlate with the ability of sera from individual patients to inhibit phytohemagglutinin-induced DNA synthesis by normal human peripheral blood T lymphocytes. Kinetically, this suppressive E-receptor factor directly competes with monoclonal antibody directed to the sheep erythrocyte receptor of human peripheral T lymphocytes and exhibits noncompetitive-type inhibition of DNA synthesis induced by phytohemagglutinin.

Antibodies, Monoclonal↗
PubMed1984

Heterogeneous participation of the hepatocyte population in amyloid protein AA synthesis.

Amyloid protein AA is believed to be synthesized in the liver in a form of its precursor, the acute phase reactant, SAA. To identify precisely the cell involved in SAA biosynthesis, immunohistochemical reaction to anti-mouse AA was analysed on the liver sections from CBA/J mice which had received a single casein injection and were sacrificed at predetermined times up to 48 hours. Two different primary localizations of the reaction were revealed. One was in the cytoplasm of certain hepatocytes. This reaction peaked at 6-8 hours after the casein injection in the intensity of the reaction and in the number of the cells involved. The hepatocytes with positive cytoplasmic reaction were scattered over the lobule and even at the peak did not exceed 20% of the total hepatocyte population. The other localization of the reaction covered linearly the surface of the hepatocyte cords, and peaked at 12-16 hours after the casein injection.

Amyloid↗
PubMed1984

Acute-phase proteins or tumour markers: the role of SAA, SAP, CRP and CEA as indicators of metastasis in a broad spectrum of neoplastic diseases.

Two hundred and seventy-seven patients with a broad spectrum of neoplastic diseases, including 10 classes of solid tumours and three classes of haematologic malignancies, were retrospectively surveyed, and from the same sample of plasma or serum their concentrations of serum amyloid A (SAA), serum amyloid P component (SAP), C-reactive protein (CRP), and carcinoembryonic antigen (CEA) were measured. SAA levels varied from 105 ng/ml to 105,000 ng/ml, and mean SAA levels were higher in patients with metastatic tumours than in those with limited disease (P less than 0.001). Similarly, CRP levels varied from less than 8 micrograms/ml to 328 micrograms/ml and were significantly higher in the metastatic disease category. In contrast, SAP levels varied from 32 micrograms/ml to 120 micrograms/ml and showed no difference in patients with limited or metastatic disease, although an overall slight elevation was present. CEA levels were available in 150 patients and were significantly higher in patients with advanced lung or breast cancer than in patients with limited disease. The correlation between mean SAA and CRP levels was significant (r = 0.74, P less than 0.001), suggesting that SAA originates as an acute-phase protein rather than as a tumour cell product. However, the consistent elevation of SAA in all tumour types and the more marked elevation in metastatic disease may make its measurement useful in malignancy.

Acute Disease↗
PubMed1984

Serum amyloid A protein concentration in progressive systemic sclerosis (scleroderma).

Serum amyloid A protein (SAA) concentrations were determined in 62 patients with progressive systemic sclerosis (PSS). Forty-seven patients had normal or slightly elevated SAA levels (less than 1000 ng/ml = micrograms/l), while 15 patients had moderately to markedly elevated SAA levels, similar to those observed in active rheumatoid arthritis (RA) (greater than or equal to 1000 ng/ml = micrograms/l). Five patients with PSS had SAA levels corresponding to those observed in amyloidosis secondary to RA. High SAA was associated with more severe skin thickening and diminished cumulative survival at five years. The rarity of amyloidosis secondary to PSS is unlikely to be related to an intrinsic defect in SAA production.

Amyloid↗