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Biomedical subjects

M M Gordon

Publications and source records attributed to M M Gordon.

At least 19 recordsLinked to original sources
PubMed2003

Acute renal failure complicating HELLP syndrome, SLE and anti-phospholipid syndrome: successful outcome using plasma exchange therapy.

Renal disease is very common in patients with systemic lupus erythematosis (SLE) and it may emerge during pregnancy or the post-partum period. Patients with anti-phospholipid syndrome (APS)are also at risk of renal disease. We present a case of acute renal failure in the post-partum period in a patient with SLE and APS. This case illustrates the potential difficulties in reaching a diagnosis in such a patient. It also illustrates the complexities of management and the potential interactions between SLE, Haemolysis, elevated liver enzymes and low platelets syndrome, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome and APS. We also review the role of plasma exchange therapy in managing our patient.

Acute Kidney Injury↗
PubMed2001

Minocycline induced lupus: case series in the West of Scotland.

OBJECTIVE: To describe the clinical symptoms and serology of drug-induced lupus in patients treated with the semisynthetic tetracycline derivative, minocycline. METHODS: For a 5-year period, all consultant rheumatologists and dermatologists in the West of Scotland were asked to report any suspected cases of a lupus-like syndrome to one center. Twenty cases were identified on the basis of arthritis, positive antinuclear factor and at least one other extraarticular feature following treatment for acne with minocycline. Case histories were reviewed to determine any demographic, clinical, or serological correlations. RESULTS: Minocycline had been prescribed for a mean of 25 months for the 20 patients identified with drug-induced lupus; 15 were female, 5 were male with a mean age of 24 years. All patients had arthritis and most had at least one other extraarticular feature including lethargy, myalgia, fevers, Raynaud's phenomenon, abdominal pain, and butterfly rash. None had renal involvement. All symptoms resolved at a mean of 15.7 weeks after discontinuation of minocycline treatment. CONCLUSIONS: Minocycline is widely used in the treatment of acne and increasingly in the treatment of rheumatic diseases. Although the absolute risk of developing drug-induced lupus is relatively low, it has been estimated that current use of minocycline is associated with an 8.5 fold increased risk of developing a lupus-like syndrome. Prescribing physicians must be vigilant for any of the characteristic symptoms to avoid unnecessary morbidity, investigations, and therapy.

Acne Vulgaris↗
PubMed2000

Functional expression in Pichia pastoris of human and rat intrinsic factor.

Intrinsic factor (IF) has been expressed previously in Baculovirus with a yield (0.1-1 mg/l) that was inadequate for structural and metabolic studies. IF cDNAs were cloned into the shuttle vector pPIC9 of P. pastoris, and the proteins were induced and purified by cobalamin (Cbl) affinity chromatography. Expression of recombinant proteins revealed a major band of 49 kDa for both human and rat IF. Expression of human IF was achieved at 1040 mg/l, but of rat IF at only 1-2 mg/l. Reaction of human IF with a photo-activatable derivative of Cbl was demonstrated by Western blotting, and detection of IF fragments by anti-Cbl monoclonal antibody and by amino-terminal sequencing revealed at least three regions (residues 129-151, 234-254, and +294) linked to Cbl. Both recombinant human and rat [125I]IF-Cbl bound to rat and guinea pig brush border membranes with similar affinity, but the binding capacity of human IF for the rat receptor was only 10% compared with rat IF. All six amino acids within the previously identified N-terminal binding region of human IF were mutated to be identical to rat IF, but the resulting chimeric IF still bound poorly to rat membranes. Mutations of residues 26/27 (Glu26 to Asp and Asn27 to Gln) and 32/34 (Ser32 to Thr and Tyr34 to Arg) showed changes in both Ka and Vmax, with great effects on Vmax. In conclusion, P. pastoris is an expression system that produces functional human IF at a higher yield than in the baculovirus system. Cbl binding was directly demonstrated at multiple sites along the linear sequence of human IF. The receptor binding function of the amino terminal sequence 25 62 has been confirmed, but it is insufficient to reproduce all the features of IF-Cbl binding.

Animals↗
PubMed2000

Improved medical and surgical management of cervical spine disease in patients with rheumatoid arthritis over 10 years.

OBJECTIVES: (1) To compare clinical outcome and symptomatology of rheumatoid cervical myelopathy between patients managed conservatively and surgically. (2) To determine if surgical outcome has improved since the series published from this unit in 1987. (3) To examine the role of magnetic resonance imaging (MRI) in the diagnosis of cervical myelopathy. METHODS: Patients undergoing MRI of the cervical spine between 1991 and 1996 were identified. Case records were reviewed retrospectively. RESULTS: 111 patients with RA underwent 124 MRI scans. The median age at onset of cervical spine symptoms was 58 years (range 16-87) with median disease duration of 16 years (range 1-59). 18 (16%) required surgery immediately after MRI. 93 (84%) were managed conservatively, 9 of whom (10%) later required surgery. 2/7 deaths in the conservative group were directly related to cervical myelopathy. Patients requiring surgery were more likely to report paraesthesia, weakness, unsteadiness and to exhibit extensor plantar reflexes, gait disturbance, and reduced power. MRI findings did not correlate with clinical features. When compared with the 1974-82 cohort, fewer patients had severe myelopathy (Ranawat grade IIIB) before surgery (34% versus 7%). Early postoperative mortality improved from 9% to 0% and surgical complication rate fell from 50% to 22%. 89% of patients in the 1991-96 cohort reported subjective improvement in overall function. CONCLUSION: In this series surgical outcome has improved. The major factor in this more favourable outcome is probably that patients presenting with rheumatoid cervical myelopathy are now referred for surgery at an earlier stage of disease. Clinical findings correlate poorly with MRI findings, therefore clinical history should remain the key to determining the need for MRI.

Adult↗
PubMed2000

Production of gastric intrinsic factor, transcobalamin, and haptocorrin in opossum kidney cells.

Opossum kidney epithelial cells were shown previously to synthesize and secrete two cobalamin (Cbl)-binding proteins, presumed to be haptocorrin (Hc) and transcobalamin II (TCII). The present study examines the hypothesis that renal tubular cells also produce intrinsic factor (IF), and this production provides an explanation for the presence of IF in urine. By using antisera raised against human IF and against TCII, the presence of TCII was confirmed, and that of IF discovered in the media of opossum kidney (OK) cells in culture. The apparent molecular weight of IF and TCII was 68 and 43 kDa, respectively. Immunoreactivity on Western blot of the putative IF protein was blocked by recombinant human IF. When proteins secreted into the media were separated electrophoretically under nondenaturing conditions after binding with [(57)Co]Cbl, a broad major band migrated at a relative front independently of recombinant IF or TCII, and probably represents Hc, as the Cbl binding is blocked by cobinamide. Small amounts of bound [(57)Co]Cbl migrated in the position of both IF and TCII, when cobinamide was present. The presence of IF and TCII in OK cells was confirmed by immunohistology. Specific reactivity for IF (blocked by recombinant IF) was found in proximal tubules of opossum kidney, but not in other portions of the nephron, confirming the ability of anti-human IF antiserum to detect opossum IF. A 732-bp fragment of IF, nearly identical in sequence to rat IF, was isolated by RT-PCR from opossum kidney mRNA, and Western blot confirmed the presence of IF protein. The presence of IF was also documented in rat kidney by isolation of an RT-PCR fragment, immunocytochemistry, and Western blot. IF should be added to the list of renal (proximal) tubular antigens that are shared by other epithelia.

Animals↗
PubMed2000

Acquired C1q deficiency caused by monoclonal paraproteinaemia.

Acquired C1q deficiency secondary to anti C1q auto-antibodies may result in the hypocomplementaemic urticarial vasculitis syndrome and may also be seen in active systemic lupus erythematosus. Some patients with acquired C1 inhibitor deficiency are found to have an underlying malignancy, most commonly lymphoma. We report a case of a 40-year-old man presenting with a lupus-like illness with acquired C1q deficiency secondary to a monoclonal paraprotein in the presence of splenic lymphoma with villous lymphocytes. His clinical symptoms correlated with the presence of the paraprotein. Relapse coincided with a rise in the paraprotein and fall in C1q, C3 and C4. There was no improvement in his clinical condition following combination chemotherapy. He remains on oral prednisolone.

Adult↗
PubMed1999

Does sulphasalazine cause drug induced systemic lupus erythematosus? No effect evident in a prospective randomised trial of 200 rheumatoid patients treated with sulphasalazine or auranofin over five years.

BACKGROUND: Sulphasalazine (SSZ) has been reported to cause drug induced systemic lupus erythematosus (SLE), but diagnosis of this complication in the context of rheumatoid arthritis (RA) is difficult. OBJECTIVE: To determine prospectively: (1) if patients become seropositive for antinuclear antibodies (ANA) during prolonged treatment with SSZ without clinical evidence of SLE; (2) if ANA positive patients develop more adverse reactions than ANA negative patients; (3) if drug induced SLE was identified in this cohort. METHODS: 200 patients enrolled in a randomised prospective trial of SSZ and auranofin (AUR) were followed up for five years. Baseline and annual ANA results were collected along with information on drug toxicity and reasons for discontinuation of treatment. RESULTS: Over five years 24 patients stopped taking SSZ and 49 AUR because of side effects. Of the features common to SLE, rash developed in nine SSZ patients and 11 AUR treated patients and mouth ulcers in three and four patients respectively. Six SSZ treated patients and three treated with AUR developed leucopenia, which promptly resolved with drug withdrawal. No adverse event was ascribed to drug induced SLE. Of the 72 SSZ treated patients who were ANA negative or weakly positive at outset, 14 (19%) became strongly ANA positive compared with 11 (14%) of 80 AUR patients. Patients ANA positive at baseline or who became ANA positive were not more likely to develop drug toxicity or to withdraw from treatment than those ANA negative throughout. CONCLUSION: ANA positivity is common in patients with RA, but the presence or development of ANA did not increase the likelihood of withdrawing from treatment. No case of drug induced SLE was seen over five years in this study.

Antibodies, Antinuclear↗
PubMed1997

A receptor binding site on intrinsic factor is located between amino acids 25-44 and interacts with other parts of the protein.

A receptor-binding region of intrinsic factor (IF) has been localized to amino acid residues 25-44 by in vitro transcription/translation studies. To further define sites within the region that are necessary for binding, the effects on binding activity of brush border membranes were tested when peptides corresponding with residues 1-44 were added to normal IF and when point mutations were made between residues 25 and 44. Both human IF and IF-cobalamin (cbl) complex bound equally to membranes. None of the peptides tested inhibited human IF or IF-cbl complex binding. Both control rat IF and rat IF that was mutated to be like human IF in residues 25-44 bound to guinea pig and rat membranes; the mutant with altered charge showed 50- to 100-fold decreased affinity. Thus, the putative receptor binding region is important, but cannot alone account for all the physiologic parameters of IF binding. Conformational changes in IF are additionally important.

Amino Acids↗
PubMed1997

Comparison of the Amplicor HIV-1 monitor test and the nucleic acid sequence-based amplification assay for quantitation of human immunodeficiency virus RNA in plasma, serum, and plasma subjected to freeze-thaw cycles.

The Amplicor HIV-1 Monitor test was compared to the nucleic acid sequence-based amplification (Nasba) assay system for the quantitation of human immunodeficiency virus (HIV) RNA in three different types of clinical samples: plasma, serum, and plasma subjected to freeze-and-thaw cycles. Each assay detected HIV RNA in the same 73 (90%) of 81 samples tested, and the quantitative results obtained with the two assays were significantly correlated. Both assays detected higher RNA levels in patients with CD4+ cell counts lower than 200 cells/mm3 than in patients with CD4+ cell counts higher than 200 cells/mm3. In addition, RNA levels in plasma higher than 5 logs predicted higher numbers of clinical events than did RNA levels in plasma lower than 5 logs. Quantitation of HIV RNA in paired plasma and serum samples showed lower HIV RNA content in serum than in the paired plasma sample, with mean differences between HIV RNA contents of plasma and serum of 0.54 and 0.28 log RNA copy/ml by the Nasba assay and the Amplicor HIV-1 Monitor assay, respectively. No significant loss of HIV RNA was detected with either assay in plasma samples subjected to multiple freeze-and-thaw cycles. These studies demonstrate that the Nasba and Amplicor assays perform similarly with plasma and serum samples. Further, the results indicate that freeze-and-thaw cycles do not result in significant loss of detectable HIV RNA.

Evaluation Studies as Topic↗
PubMed1995

Cathepsin L mediates intracellular ileal digestion of gastric intrinsic factor.

Although acidic proteases of lysosomal origin are implicated in the degradation of intrinsic factor (IF) during cobalamin (cbl) transport across enterocytes and proximal renal tubule cell lines, the enzyme(s) involved in this process is not known. Recombinant (baculovirus-produced) rat 125I-labeled IF (125I-rIF), 43 kDa, added in vivo to the lumen of rat ileum was converted intracellularly to peptides of 33 and 26 kDa. In vitro rat 125I-rIF was degraded to peptides of 33 and 31 kDa by addition of cathepsin L; this conversion was fully inhibited by leupeptin. Western blot analysis using antiserum against denatured native rat IF identified additional cathepsin L degradation products in the 17- to 23-kDa range. In vitro the binding of cobalamin partially inhibited cathepsin L degradation of IF. Rat rIF produced from either insect (Sf9) or mammalian (CHO) cells and native rat IF were all degraded by cathepsin L, although the prominence of the various products differed in the recombinant preparations, being 33 and 36 kDa, respectively. Native rat IF was most sensitive to proteolysis, and no degradation products were identified. Rat 125I-rIF was taken up by LLC-PK1 cells, and 125I from degraded IF appeared abundantly on the basolateral side of cell monolayers by 1 h. The intracellular products of rat rIF in LLC-PK1 cells were the same size as those produced in vitro by the action of cathepsin L. Antiserum against a human kidney cDNA cathepsin L fusion protein easily demonstrated the protease in rat intestinal mucosa, as well as in all other tissues tested. These data suggest that cathepsin L is the protease responsible for the leupeptin-sensitive intracellular degradation of IF.

Animals↗
PubMed1992

The intrinsic factor (IF)-cobalamin receptor binding site is located in the amino-terminal portion of IF.

Intrinsic factor has two binding sites, one each for cobalamin and for the ileal receptor recognizing the intrinsic factor-cobalamin complex. To obtain initial functional mapping of these domains, cDNAs encoding intact rat and human intrinsic factor or fragments thereof were expressed transiently in COS-1 cells or in an in vitro transcription/translation system. Deletion of as little as 12% of the amino acids from the carboxyl terminus resulted in loss of cobalamin binding activity. On the other hand, the receptor binding region of intrinsic factor appears localized to a restricted region in the amino-terminal portion of the protein. Only those transcription/translation fragments of rat or human intrinsic factor tested that contained amino acid residues 25 to 62 (out of 399) showed calcium-dependent binding to isolated kidney brush borders, the shortest sequence corresponding with 20 consecutive amino acids. In contrast, a 232-amino acid carboxyl-terminal fragment of rat intrinsic factor and 243- and 338-amino acid carboxyl-terminal fragments of human intrinsic factor showed no receptor binding activity.

Animals↗
PubMed1991

Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11.

A human gastric intrinsic factor (IF) cDNA clone was isolated using a rat cDNA clone as a probe. Comparison of the predicted amino acid sequence revealed 80% identity of human IF with rat IF. These cDNA clones were used to isolate and map two overlapping clones encoding the human IF gene. The first exon of the cloned region (exon 2) contains 30 bp of the 5' untranslated region, the signal peptide, and the first 8 amino acids of the mature protein. Exons 3-10 encode the remainder of the coding and 3' noncoding regions. Southern analysis of genomic DNA indicated the presence of a single human IF gene and also revealed the presence of strong hybridizing sequences in genomic DNA from monkey, rat, mouse, cow, and human, suggesting that the IF gene is well conserved. The IF gene was localized to human chromosome 11 by concurrent cytogenetic and cDNA probe analysis of a panel of human X mouse somatic cell hybrids. Southern analysis of genomic DNA from patients with congenital pernicious anemia (lacking intrinsic factor) revealed normal restriction fragment patterns, suggesting that a sizable gene deletion was not responsible for the deficiency.

Amino Acid Sequence↗
PubMed1991

Glycosylation is not required for ligand or receptor binding by expressed rat intrinsic factor.

A cDNA clone encoding rat intrinsic factor (IF), pIFQ, has been inserted into the eukaryotic expression vector pSVL and used to transfect COS-1 cells. The IF produced by the transfected cells was secreted nearly exclusively into the medium at concentrations of 0.1-0.2 micrograms/ml. Tunicamycin treatment (1-10 micrograms/ml) completely blocked N-linked glycosylation but had no effect on IF secretion. The secreted glycosylated IF retained all the properties of native IF, i.e., high affinity for cobalamin (Cbl) and for the IF-Cbl receptor and relative resistance to low pH and to proteolysis. The nonglycosylated IF also retained these properties except that it was more protease sensitive. The protease degradation was prevented by the presence of the ligand Cbl. The presence of carbohydrate may play a role in protecting IF from digestion by pancreatic proteases in the intestinal lumen.

Animals↗