Sweat gland function in Sjögren's syndrome.
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Adult↗
Biomedical subjects
D Caspi
Publications and source records attributed to D Caspi.
Is the serum amyloid A protein in acute phase plasma high density lipoprotein the precursor of AA amyloid fibrils?
Serum amyloid A protein (SAA), an apolipoprotein of high density lipoprotein (HDL), is generally considered to be the precursor of AA protein, which forms the fibrils in reactive systemic amyloidosis in man and animals. This view is based on amino acid sequence identity between AA and the amino-terminal portion of SAA. However, in extensive and well-controlled studies of experimentally induced murine AA amyloidosis, we were unable to demonstrate a direct precursor-product relationship between SAA, in SAA-rich HDL preparations from acute phase or amyloidotic mouse or human serum, and AA protein in the amyloid deposits. This raises the possibility that SAA in its usual form, as an apolipoprotein of HDL synthesized during the acute phase response, may not be the major precursor of AA fibrils. The amyloidogenic forms of circulating SAA molecules may not be isolated during the preparation of HDL. Alternatively, particularly in the light of recent evidence that SAA mRNA is expressed in many different tissues throughout the body of appropriately stimulated animals, amyloidogenic SAA may be derived from sources other than the liver cells in which SAA-rich HDL is synthesized.
Acute-Phase Reaction↗
Secondary structure prediction of human SAA1. Presumptive identification of calcium and lipid binding sites.
Serum amyloid A protein (SAA), an apolipoprotein of high density lipoprotein (HDL), is an acute phase protein thought to be the precursor of amyloid fibrils in reactive systemic (AA) amyloidosis. A prediction of the secondary structure of the human serum amyloid protein SAA1(alpha) is presented. The prediction was based upon one-dimensional Fourier analysis of the amino acid sequence together with sequence matching to known structural motifs. The results were compared with those from prediction algorithms based upon statistical techniques. Our findings are consistent with available experimental data. They include the putative identification of the amino-terminal 11 residues as the functionally important lipid-binding site of SAA and of a likely, neutral, calcium-binding sequence: Gly48-Pro49-Gly50-Gly51. Sequence comparisons between SAA and protein tyrosine kinases, phospholipases A2 and delta-crystallin, all of which bind both calcium and phospholipid, revealed significant homologies that support our proposals concerning structure-function relationships in SAA.
Animals↗
X-ray scattering and diffraction by wet gels of AA amyloid fibrils.
Systemic amyloidosis is characterized by the extracellular accumulation of protein fibrils with typical ultrastructural morphology. The persistence in vivo of amyloid fibrils, which is responsible for their serious clinical effects, has been thought to reflect the particular, specific conformation of peptide chains constituting the fibrils. On the basis of earlier structural studies this conformation is generally considered to be almost exclusively anti-parallel beta-sheets. We have re-examined X-ray scattering by human amyloid A protein (AA) amyloid fibrils, with careful attention to the state of hydration of the preparations. We show that a stack of anti-parallel sheets is not consistent with the details of the X-ray pattern, which contains diffracted intensities that can be indexed on a 33A X 33A lattice. A structural model for the AA fibre consistent with the X-ray data is presented. The model takes account of the prediction of the secondary structure of the AA precursor SAA1(alpha) presented in our accompanying paper, and has the AA monomers arranged on a primitive lattice, with two unique molecules per unit cell.
Amyloidosis↗
Circulating serum amyloid P component is the precursor of amyloid P component in tissue amyloid deposits.
Intravenous administration of 125I-labelled isolated mouse serum amyloid P component (SAP) to mice with systemic amyloidosis was followed by specific deposition of the labelled protein in amyloidotic organs. Although only a small proportion of the total injected dose became localized in this way, the amount correlated with the quantity of amyloid present in different organs and was greatest in the spleen. No such localization was detected in the organs of control, untreated mice or animals which had received inflammatory stimuli but did not have amyloidosis. The labelled SAP was found by autoradiography to be present in the same distribution within the tissues as the Congophilic amyloid deposits. These observations establish directly, for the first time, that circulating SAP is the precursor of the amyloid P component (AP) in systemic amyloidosis. They were confirmed by the further finding that intravenous injection into amyloidotic mice of human SAP, either in whole human serum or in isolated pure form, was followed by appearance of the human SAP in the mouse amyloid deposits. In addition to elucidating one aspect of the pathogenesis of amyloid deposition and strengthening the homology of functional behaviour between SAP of different species, the present results suggest a means for selective targeting of diagnostic tracers and/or effector agents to amyloid deposits in vivo.
Amyloidosis↗
C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy.
C-reactive protein levels were measured in sera of 111 patients with rheumatoid arthritis and were compared with erythrocyte sedimentation rate. The patients were divided into six groups according to drug therapy. Comparison between the groups suggests that CRP correlates best with ESR in patients treated with penicillamine and in patients in clinical remission. Patients treated with gold, NSAID or methotrexate have a weaker correlation between the two parameters, while steroid therapy yields the poorest correlation which is not statistically significant. Our data suggest that although CRP is a sensitive index of disease activity, the specific drug taken by the patient must be considered before interpreting the results.
Adult↗
A comparison of the erythrocyte sedimentation rate and serum C-reactive protein concentration in elderly patients.
Fifty-five consecutive admissions to an acute geriatric unit were studied prospectively. Individuals were classified according to the obvious presence or absence of an active disease process on admission and their serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured then and five days later. There was no significant difference between the ESR values in the two groups either on admission or at day 5, nor was there any significant change between admission and day 5. In contrast, CRP values were very significantly higher in the active than in the non-active group and there were marked changes over the 5-day period corresponding to changes in clinical condition. These results indicate that the serum CRP concentration is superior to the ESR as an objective, non-specific marker for disease activity in the elderly.
Aged↗
Specific chemical dissociation of fibrillar and non-fibrillar components of amyloid deposits.
In systemic amyloidosis, a fatal disorder for which there is no effective treatment, the extracellular protein deposits are composed of amyloid fibrils together with a non-fibrillar glycoprotein, amyloid P component (AP). Methyl 4,6-O-(1-carboxyethylidene)-beta-D-galactopyranoside (MO beta DG), a recently identified ligand for AP, was tested for its ability to produce in-vitro elution of AP which had been laid down with amyloid fibrils in vivo. Millimolar concentrations of MO beta DG completely dissociated AP from human and murine splenic amyloid deposits. Availability of this material thus provides for the first time the opportunity for specific molecular dissection of amyloid deposits. If MO beta DG or a related substance were effective in vivo it might be of therapeutic importance.
Amyloid↗
Binding specificity of serum amyloid P component for the pyruvate acetal of galactose.
Serum amyloid P component (SAP) is a normal plasma protein that is of interest because of its presence in amyloid deposits, its presence in normal human glomerular basement membrane, and its stable evolutionary conservation. It has calcium-dependent ligand-binding specificity for amyloid fibrils, fibronectin (Fn), C4-binding protein (C4bp), and agarose. Although the binding to agarose, a linear galactan hydrocolloid derived from some marine algae, is unlikely per se to be related to the physiological function of SAP, it does provide a model system in which to explore the precise ligand requirements of SAP. We report here that the amount of SAP from human, mouse, and plaice (Pleuronectes platessa L.) serum able to bind to agarose from different sources reflect precisely their pyruvate content. Methylation with diazomethane of the carboxyl groups in the pyruvate moiety of agarose completely abolishes SAP binding to agarose. The pyruvate in agarose exists as the 4,6-pyruvate acetal of beta-D-galactopyranose. We have therefore synthesized this galactoside, using a novel procedure, established its structure by analysis of its nuclear magnetic resonance spectra, and shown that it completely inhibits all known calcium-dependent binding reactions of SAP. The R isomer of the cyclic acetal, methyl 4,6-O-(1-carboxyethylidene)-beta-D-galactopyranoside (MO beta DG) was effective at millimolar concentration and was more potent than its noncyclic analogue, while pyruvate, D-galactose, and methyl beta-D-galactopyranoside were without effect. The autologous protein ligands of SAP presumably, therefore express a structural determinant(s) that stereochemically resembles MO beta DG. Availability of this specific, well-characterized, low molecular weight ligand for SAP should facilitate further investigation of the function of SAP and its role in physiological and pathophysiological processes.
Amyloid↗
Acute phase protein response to infection in elderly patients.
The presence of infection is often difficult to diagnose in elderly patients. In view of this, laboratory markers of infection are of great clinical importance. The pattern of change in acute phase proteins has not hitherto been studied in elderly patients. In a prospective series of 114 acute elderly admissions to a Geriatric Unit there was a significant change with infection in all proteins studied, but C-reactive protein was the most sensitive marker of the presence and severity of infection and the response to antimicrobial therapy. The best pair of acute phase proteins in the prediction of infection were alpha 1-acid glycoprotein and C-reactive protein whilst albumin and alpha 1-acid glycoprotein together contributed significantly to the prediction of outcome.
Aged↗
'Amyloid degrading activity' of human serum, an in vitro clearing effect which does not involve degradation of amyloid fibrils.
Clearing of turbid amyloid A fibril containing agarose gels by human serum has been ascribed to 'amyloid degrading activity'. We report here that this optical phenomenon is not due to an enzymatic reaction, does not involve proteolysis of the fibril subunits and is not inhibited by sera of patients with AA amyloidosis. The extent of clearing correlates closely with the serum albumin concentration and, as previously reported by others, serum albumin itself causes clearing comparable to that of whole serum. Furthermore addition of albumin solutions to turbid aqueous suspensions of AA amyloid fibrils causes immediate clearing. Serum albumin is known to clarify turbid non-amyloid fibril containing gels and is used commercially to improve the optical properties of radial immunodiffusion plates. We therefore propose that this property of albumin, the mechanism of which is not yet understood, underlies the so called 'amyloid degrading activity' of human serum and the latter is not therefore likely to be of in vivo biological or clinical significance.
Amyloid↗
The failure of ascorbic acid therapy to alter the induction or remission of murine amyloidosis.
It has been claimed that ascorbic acid enhances the in vitro degradation of AA amyloid fibrils. This raises the possibility that ascorbic acid may be of benefit in systemic AA amyloidosis, a condition with serious morbidity and mortality for which there is as yet no specific treatment. The effect was therefore tested of oral or injected supplements of ascorbic acid on the induction of AA amyloidosis in mice. Amyloid was induced either by repeated injections of casein or by injection of 'amyloid enhancing factor' and silver nitrate. Mice with established amyloidosis were also treated with additional ascorbic acid. Despite the fact that plasma ascorbic acid levels were significantly higher in orally supplemented mice than in controls there was no demonstrable effect on the induction, the extent and distribution or the progression of amyloidosis.
Amyloid↗
Isolation and characterization of C-reactive protein from the dog.
Using calcium-dependent affinity chromatography on Sepharose-bearing, covalently-coupled pneumococcal C-polysaccharide, a protein was isolated from the serum of dogs that had undergone general anaesthesia and major surgery. This protein was confirmed as the canine analogue of C-reactive protein (CRP) in other species by virtue of its electron microscopic appearance, subunit composition and behaviour as an acute phase reactant. Dog CRP had an apparent molecular weight of approximately 100,000 and was composed of five subunits of approximately 20,000 MW each. Two of the five subunits in each molecule were glycosylated. Negatively stained preparations had the typical cyclic pentameric disc-like structure of proteins of the pentraxin family, and in some preparations had a tendency to form stacks. Serum from normal healthy dogs of various strains usually contained less than 5 mg/l of CRP but, following the stimulus of major surgery, an increase in the CRP concentration was first detected at 4 hr.
Animals↗
[Hypnosis for acute emotional reactions in Sjögren's syndrome].
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Adult↗
[Pemphigus folliaceous following D-penicillamine in rheumatoid arthritis].
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Arthritis, Rheumatoid↗
Serum lipids and lipoprotein concentrations in women with rheumatoid arthritis.
Serum lipid and lipoprotein concentrations were measured in 51 women with rheumatoid arthritis treated with both nonsteroidal and steroidal drugs and compared to a group of women with rheumatoid arthritis not receiving anti-inflammatory drugs and to a healthy control group. Significantly lower concentrations of total cholesterol and low density lipoprotein cholesterol were found in the rheumatoid patients on nonsteroidal or steroidal anti-inflammatory drugs, while no difference was found in high density lipoprotein cholesterol and triglycerides. In the group of rheumatoid patients who received no nonsteroidal or steroidal anti-inflammatory drugs, the triglyceride level was higher than in the control group, and that of HDL-C was lower. Total cholesterol and LDL-C levels were higher in the patients not on anti-inflammatory drugs than in patients receiving anti-inflammatory drugs. The results of this study suggest that hyperlipidemia is not one of the predisposing factors for coronary disease in patients with rheumatoid arthritis receiving anti-inflammatory therapy. Anti-inflammatory drugs may play a role in the regulation of serum lipids in patients with rheumatoid arthritis.
Adult↗
Reiter's syndrome complicating dysentery epidemic in a small military unit: case reports.
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Adult↗