Combined corticosteroid and aspirin treatment for the high risk lupus pregnancy.
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Antiphospholipid Syndrome↗
Biomedical subjects
R A Stuart
Publications and source records attributed to R A Stuart.
Transport of proteins into the various subcompartments of mitochondria.
The import of proteins into mitochondria is an intricate process comprised of multiple steps. The first step involves the sorting of cytosolically synthesized precursor proteins to the mitochondrial surface. There precursor proteins are recognized by specific receptors which deliver them to the general import site present in the outer membrane. The second stage of import involves a series of complex intraorganelle sorting events which results in the delivery of the proteins to one of the four possible submitochondrial destinations, namely the outer and inner membranes, the matrix and intermembrane space. Here in this review, we discuss the current knowledge on these intramitochondrial sorting events. We especially focus on targeting of proteins to the intermembrane space. Sorting to the intermembrane space represents a particularly interesting situation, as at least three separate targeting pathways to this subcompartment are known to exist.
Biological Transport↗
Import of cytochrome c heme lyase into mitochondria: a novel pathway into the intermembrane space.
Cytochrome c heme lyase (CCHL) catalyses the covalent attachment of the heme group to apocytochrome c during its import into mitochondria. The enzyme is membrane-associated and is located within the intermembrane space. The precursor of CCHL synthesized in vitro was efficiently translocated into isolated mitochondria from Neurospora crassa. The imported CCHL, like the native protein, was correctly localized to the intermembrane space, where it was membrane-bound. As with the majority of mitochondrial precursor proteins, CCHL uses the MOM19-GIP receptor complex in the outer membrane for import. In contrast to proteins taking the general import route, CCHL was imported independently of both ATP-hydrolysis and an electrochemical potential as external energy sources. CCHL which lacks a cleavable signal sequence apparently does not traverse the inner membrane to reach the intermembrane space; rather, it translocates through the outer membrane only. Thus, CCHL represents an example of a novel, 'non-conservative' import pathway into the intermembrane space, thereby also showing that the import apparatus in the outer membrane acts separately from the import machinery in the inner membrane.
Adenosine Triphosphate↗
A survey of current prescribing practices of antiinflammatory and urate-lowering drugs in gouty arthritis.
OBJECTIVE: to assess the prescribing habits in late 1988 of rheumatologists (NZR) and a random sample of general practitioners (NZGP) managing gout and hyperuricaemia. DESIGN: self administered questionnaires containing two demographic questions and 24 items probing the selection and prescription of antirheumatic drugs in patients with acute gout, chronic tophaceous gout and asymptomatic hyperuricaemia were sent to every rheumatologist and a 10% random sample of general practitioners in active practice. RESULTS: replies were received from 26 of 27 (96%) rheumatologists and 163 of 207 (79%) of general practitioners Rheumatologists were more likely to use indomethacin as the preferred drug for acute gout, and colchicine either alone or as adjunctive therapy for prophylaxis in chronic gout to prevent acute attacks occurring following the introduction of urate lowering agents, although nonsteroidal antiinflammatory drugs (NSAIDs) were more commonly used for this purpose by both groups. Prior to prescribing urate lowering therapy general practitioners were more likely to attempt control of alcohol intake, and rheumatologists more likely to avoid concomitant low dose salicylates. Allopurinol was the preferred hypouricaemic drug, with rheumatologists more likely to prescribe an initial dose of 100 mg daily, and gradually increase the dose according to the serum urate (SeUa). Although a minority of respondents prescribed allopurinol for asymptomatic hyperuricaemia, general practitioners were more likely to do so at a lower level of serum urate. CONCLUSION: there was a high level of adherence to what is considered optimal contemporary practice, with a number of differences in prescribing habits probably reflecting differences in case selection between patients attending rheumatologists and general practitioners. The data indicates a continuing need for education programmes for both specialists and general practitioners.
Acute Disease↗
Atlantoaxial subluxation in a patient with mixed connective tissue disease.
We describe a 55-year-old woman with an 8-year history of mixed connective tissue disease (MCTD). Her condition was characterized by severe Raynaud's, swollen fingers, digital ulceration and gangrene, esophagitis, polyarthropathy, myositis and restrictive lung function. She consistently had antibodies to U1-RNP. Rheumatoid factor was present in low titer. She developed atlantoaxial subluxation, a feature seen commonly in rheumatoid arthritis, reported in spondyloarthropathy and a small number of patients with systemic lupus erythematosus but not described in MCTD.
Antibodies↗
Hydroxyapatite crystals are a frequent finding in osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or interleukin 1 beta.
Synovial fluid (SF) was obtained from 40 patients with varying grades of osteoarthritis (OA) of the knee and examined by transmission electron microscopy to ascertain how frequently hydroxyapatite crystals (HA) were present and whether they were related to disease severity or putative markers or promoters of cartilage resorption. HA crystals were conspicuous and abundant in specimens from 21 of the 40 patients studied. Patients in whom HA was present had significantly larger effusions (13.0 +/- 8.9 vs 8.7 +/- 6.1 ml, p less than 0.05). They also tended to have radiologically more severe disease (radiological grade: 2.91 +/- 0.92 vs 2.39 +/- 0.85, p = 0.056). No difference in keratan sulfate (KS) concentrations was observed. Moreover, despite the presence in some specimens of numerous free histiocytes which were actively phagocytosing HA aggregates, the concentrations of interleukin 1 beta (IL-1 beta), a monocyte product with cartilage and bone resorbing activity, were below the limit of detection (20 pg/ml). Our results confirm that HA crystals are a common finding in patients with OA of the knee and show that HA is associated with larger effusions, but not increased SF concentrations of cartilage proteoglycan substituents (KS) or IL-1 beta.
Aged↗
Import of apocytochrome c into the mitochondrial intermembrane space along a cytochrome c1 sorting pathway.
The question of whether cytochrome c could be functionally sorted to the mitochondrial intermembrane space along a "conservative sorting" pathway was investigated using a fusion protein termed pLc1-c. pLc1-c contains 3-fold targeting information, namely, the complete bipartite presequence of the cytochrome c1 precursor joined to the amino terminus of apocytochrome c. pLc1-c could be selectively imported into the intermembrane space either directly across the outer membrane along a cytochrome c import route or along a cytochrome c1 route via the matrix. Thus, apocytochrome c could be sorted along a conservative sorting pathway; however, following reexport from the matrix, apo-Lc1-c could not be converted to its holo counterpart. Despite the apparent similarity of structure and functional location of the heme lyases and similarity of the heme binding regions in their respective apoproteins, cytochrome c heme lyase and cytochrome c1 heme lyase apparently have different and nonoverlapping substrate specificities.
Amino Acid Sequence↗
Early steps in mitochondrial protein import: receptor functions can be substituted by the membrane insertion activity of apocytochrome c.
The process of insertion of precursor proteins into mitochondrial membranes was investigated using a hybrid protein (pSc1-c) that contains dual targeting information and, at the same time, membrane insertion activity. pSc1-c is composed of the matrix-targeting domain of the cytochrome c1 presequence joined to the amino terminus of apocytochrome c. It can be selectively imported along either a cytochrome c1 route into the mitochondrial matrix or via the cytochrome c route into the intermembrane space. In contrast to cytochrome c1, pSc1-c does not require the receptor system/GIP for entry into the matrix. The apocytochrome c in the pSc1-c fusion protein appears to exert its membrane insertion activity in such a manner that the matrix-targeting sequence gains direct access to the membrane potential-dependent step. These results attribute an essential function to the receptor system in facilitating the initial insertion of precursors into the mitochondrial membranes.
Adenosine Triphosphate↗
Temporary artery biopsy in suspected temporal arteritis: a five year survey.
A retrospective five year review of 75 patients hospitalised in Middlemore Hospital, Auckland, who underwent temporal artery biopsy shows that the procedure was performed without complications and that the result could significantly alter patient management. Patients biopsied were all 50 years or older, predominantly female (77%) and caucasian (90%). Biopsies were positive in 14 patients (18.7%). Polymyalgia was present in 64% in both biopsy positive and negative groups. Visual disturbance was more frequent in the biopsy positive group (43% versus 21%) but not statistically significant. Jaw claudication and abnormalities of the temporal artery on examination were significantly more frequent in the biopsy positive group. Final diagnoses included 16 with temporal inflammatory polyarthritis, and 4 with malignant disease. As a result of a negative biopsy corticosteroids were stopped in 13 patients, reduced in dose in 5 patients, and begun in low dose in 7 patients.
Adrenal Cortex Hormones↗
Biogenesis of cytochrome c1. Role of cytochrome c1 heme lyase and of the two proteolytic processing steps during import into mitochondria.
The biogenesis of cytochrome c1 involves a number of steps including: synthesis as a precursor with a bipartite signal sequence, transfer across the outer and inner mitochondrial membranes, removal of the first part of the presequence in the matrix, reexport to the outer surface of the inner membrane, covalent addition of heme, and removal of the remainder of the presequence. In this report we have focused on the steps of heme addition, catalyzed by cytochrome c1 heme lyase, and of proteolytic processing during cytochrome c1 import into mitochondria. Following translocation from the matrix side to the intermembrane-space side of the inner membrane, apocytochrome c1 forms a complex with cytochrome c1 heme lyase, and then holocytochrome c1 formation occurs. Holocytochrome c1 formation can also be observed in detergent-solubilized preparations of mitochondria, but only after apocytochrome c1 has first interacted with cytochrome c1 heme lyase to produce this complex. Heme linkage takes place on the intermembrane-space side of the inner mitochondrial membrane and is dependent on NADH plus a cytosolic cofactor that can be replaced by flavin nucleotides. NADH and FMN appear to be necessary for reduction of heme prior to its linkage to apocytochrome c1. The second proteolytic processing of cytochrome c1 does not take place unless the covalent linkage of heme to apocytochrome c1 precedes it. On the other hand, the cytochrome c1 heme lyase reaction itself does not require that processing of the cytochrome c1 precursor to intermediate size cytochrome c1 takes place first. In conclusion, cytochrome c1 heme lyase catalyzes an essential step in the import pathway of cytochrome c1, but it is not involved in the transmembrane movement of the precursor polypeptide. This is in contrast to the case for cytochrome c in which heme addition is coupled to its transport directly across the outer membrane into the intermembrane space.
Chromatography, High Pressure Liquid↗
Paraparesis due to extruded thoracic disc for 25 years.
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Female↗
Biogenesis of mitochondrial proteins.
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DNA, Mitochondrial↗
Deficiency in mRNA splicing in a cytochrome c mutant of neurospora crassa: importance of carboxy terminus for import of apocytochrome c into mitochondria.
Molecular cloning and characterization of cytochrome c cDNA clones of Neurospora crassa wild-type (74A) and a cytochrome c-deficient mutant (cyc1-1) are described. Southern blot analysis of genomic DNA indicates that only one cytochrome c gene exists in the N. crassa genome. The cDNA sequence of the wild-type cytochrome c confirmed the previously determined protein sequence. Sequence analysis of the cyc1-1 cDNA for cytochrome c revealed the presence of a larger open reading frame, owing to the presence of an unspliced intron in the 3' end of the coding region. Splicing of this intron is obviously prevented due to the presence of two base exchanges in the highly conserved intron consensus sequences. Consequently, cyc1-1 synthesizes apocytochrome c with an altered carboxy terminus, 19 amino acids longer than the wild-type cytochrome c, with the final 27 amino acids being of an unrelated sequence. This alteration in the carboxy terminus renders the apocytochrome c incompetent for binding to mitochondria and, consequently, import into mitochondria. Thus, unlike other mitochondrial precursor proteins, where it has been demonstrated that the amino terminus alone is sufficient to target the protein to the mitochondria, an intact carboxy terminus is required for efficient import of apocytochrome c into mitochondria. This is independent confirmation for the view that the import pathway of cytochrome c is unique with respect to all other mitochondrial proteins studied to date.
Amino Acid Sequence↗
Three uncommon complications of chronic granulocytic leukaemia (CGL)
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Bone Neoplasms↗
A comprehensive analysis of renal DTPA studies. III. Renal artery stenosis.
Renal DTPA studies were analysed to produce numerical data of renal function (blood flow, glomerular filtration, and excretion), and this was used as an adjunct to the routine imaging information in a study of renal artery stenosis (RAS). The results show an overall accuracy of 81%, with a sensitivity of 96% and a specificity of 61%. In patients with RAS, beta-blocking drugs reduced the difference between the two kidneys. ACE-inhibiting drugs appeared to preserve renal blood flow but also to cause a deterioration in the glomerular filtration rate of kidneys with RAS. An explanation is proposed, in which renal capillary pressure is more important for function than is renal blood flow.
Adrenergic beta-Antagonists↗
Apocytochrome c: an exceptional mitochondrial precursor protein using an exceptional import pathway.
The cytochrome c import pathway differs markedly from the general route taken by the majority of other imported proteins, which is characterized by the import involvement of namely, surface receptors, the general insertion protein (GIP), contact sites and by the requirement of a membrane potential (delta psi). Unique features of both the cytochrome c precursor (apocytochrome c) and of the mechanism that transports it into mitochondria, have contributed to the evolution of a distinct import pathway that is not shared by any other mitochondrial protein analysed thus far. The cytochrome c pathway is particularly unique because i) apocytochrome c appears to have spontaneous membrane insertion-activity; ii) cytochrome c heme lyase seems to act as a specific binding site in lieu of a surface receptor and; iii) covalent heme addition and the associated refolding of the polypeptide appears to provide the free energy for the translocation of the cytochrome c polypeptide across the outer mitochondrial membrane.
Apoproteins↗
Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders.
OBJECTIVE: It is well established that connective tissue diseases such as systemic lupus erythematosus (SLE) are associated with a weak or absent acute phase response, although elevated serum interleukin 6 levels have been described. In this study, we have sought to correlate serum levels of IL-6 with standard laboratory and clinical assessments of disease activity in two connective tissue diseases, namely SLE and systemic sclerosis (SSc), and, for comparative purposes, rheumatoid arthritis (RA). METHODS: Serum IL-6 levels were determined by bioassay and also, in some sera, by immunoradiometric assay. They were compared with two inflammatory parameters, serum C-reactive protein (CRP) and plasma viscosity (PV), and with appropriate clinical measurements in the various patient groups, including BILAG in SLE, the skin score in SSc, and the Ritchie index in RA. RESULTS: Serum IL-6 (SeIL-6) levels were elevated in active SLE, SSc, and RA. This was poorly correlated with the acute phase response in SLE and SSc, but there was a strong relationship of SeIL-6 to disease activity in these conditions. In SLE, the BILAG disease activity index correlated best with SeIL-6 levels while there was only a weak relationship between CRP and IL-6, and no relationship between CRP and disease activity. In SSc there was a relationship of disease activity to SeIL-6 but not between SeIL-6 and either CRP or PV. In a small RA group there was a much stronger relationship of SeIL-6 to CRP and PV, as has been previously described. CONCLUSION: The determination of SeIL-6 may be a useful indicator of disease activity in those patients groups, including SLE and SSc, in which a normal acute phase response by the liver is often lacking. The mechanism underlying this hepatic impairment requires further investigation, but is clearly not due to a failure to generate the appropriate cytokine signal. Excessive local or systemic production of IL-6 in connective tissue diseases could play an important pathogenic role in these conditions, for example through stimulating autoantibody synthesis.
Arthritis, Rheumatoid↗