Biomedical subjects
Publications and source records attributed to B Lund.
Seven adults with the sequelae of Osgood-Schlatter's disease presented after experiencing symptoms for an average of eight years. In four cases a true joint had formed between an ossicle in the patellar ligament and a facet on the tibia. Surgical treatment produced good results in all of the patients. Treatment differs from that in children in whom the epiphyseal lines are open.
Escherichia coli strains associated with extra-intestinal infections frequently express carbohydrate binding adhesins which are present as minor components of pili. The adhesin protein, PapG, and at least two other minor pilus subunits, PapE and PapF, are associated with the tips of Gal alpha (1-4)Gal-binding Pap pili or P fimbriae of uropathogenic E. coli. The structural and antigenic variation of these tip-associated proteins is discussed and evidence is presented showing that serologically identical pili may contain antigenically distinct adhesins each capable of binding to a specific receptor. One approach to the purification of these tip-associated proteins is presented and involves complex formation with the periplasmic transport protein PapD.
Gentamicin-loaded bone cement is used with increasing frequency in primary and revision arthroplasty. Considering the high local concentration and the well-known toxic effect of gentamicin on the kidney, a similar inhibiting effect on bone tissue might be expected. In a series of in vitro studies using paired mouse calvaries cultured for 2 days, the authors found a dose-dependent decrease in the release of previously incorporated calcium-45 (45Ca) or tritiated proline and a decrease in alkaline phosphatase activity. In combination with methylmethacrylate, a small additional reduction in 45Ca release and a marked decrease in alkaline phosphatase activity were recorded. These results indicate that released gentamicin and monomer from antibiotic-supplemented bone cement depresses bone turnover and might thus play an important part in the pathogenesis of loosening.
Uropathogenic Escherichia coli frequently express P-pilus adhesins that recognize Gal alpha (1-4)Gal-containing glycoconjugates. The P-pilus adhesin of the E. coli isolate J96 is encoded by the pap gene cluster and has been shown to agglutinate P1-erythrocytes. We now describe a novel gene cluster from J96, prs, which is responsible for the agglutination of sheep erythrocytes. The structurally related gene clusters both expressed pili exhibiting the F13 antigen. Analysis of mutants of cloned prs sequences, together with trans-complementation of pap and prs genes, identified the sheep-specific adhesin as the 37-kD PrsG protein. The prsG gene occupies the equivalent position in prs as occupied by papG, which specifies the Gal alpha (1-4)Gal-specific adhesin of pap. PrsG was shown to be structurally distinct from PapG since PapG-specific antiserum did not cross-react with PrsG. Using a solid phase glycolipid receptor binding assay, PrsG was found to specify preferential binding to the Forssman antigen, a major constituent of sheep erythrocyte membranes. The binding epitope was identified as the GaINAc alpha (1-3)GaINAc moiety. This is the first direct evidence that serologically identical pili may present antigenically distinct adhesins, each capable of binding to a specific receptor.
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Pyelonephritogenic Escherichia coli frequently expresses pili which bind to Gal alpha (1-4)Gal receptors present on the uroepithelium. Binding of these pili is mediated by a pilus-associated adhesin, PapG, and not by the major subunit which constitutes the bulk of the pilus structure. The adhesin and two pilinlike proteins, PapE and PapF, are present in only a few copies each at the pilus tip. Surface exposure of both PapF and PapG is required to achieve receptor-specific binding. The nucleotide sequences for the genes encoding the tip-associated proteins PapE, PapF, and PapG were determined for two E. coli clones expressing P pili of serotypes F11 and F7(2) and compared with the corresponding sequences established for proteins of F13 pili. Specific antisera were used to study the cross-reactivity between the F13 tip proteins and the equivalent proteins in F11 and F7(2) pili. We present data showing that, like the major pilus subunit, PapE varies its structure and antigenic properties among pili of different serotypes. In contrast, the PapF protein was highly conserved, and PapF-specific antisera raised against serotype F13 cross-reacted with the PapF proteins of both F11 and F7(2) serotypes. The PapG adhesin protein from F11 and F7(2) pili differed by only five amino acids out of 316 residues. However, the F13 adhesin showed only 45% amino acid homology with the other two variants.
The elderly rheumatic patients and 7 healthy young persons received naproxen (Naprosyn, Syntex) 500 mg orally twice a day for 4 weeks. The serum concentrations were determined using mass fragmentography. After an initial 1,000-mg dose, no significant differences were found between the two groups in peak serum concentration, time to peak serum concentration, area below the serum concentration-time curve, volume of distribution, elimination half-life, or total body clearance of naproxen. At steady state, the median total through naproxen concentration was 50.5 mg/l in the elderly and 62.7 in the young (p = 0.08); the unbound concentration was 58 micrograms/l and 44 micrograms/l, respectively (p = 0.06). There was a significant inverse correlation between serum albumin and the free fraction of naproxen (R = -0.58, p = 0.01). The hepatic extraction ratio of naproxen is relatively low and it is suggested that the reduced protein binding in the elderly may conceal the age-related reduction in cellular activity. An estimated value of intrinsic clearance was reduced by 37% in the elderly patients. It is suggested to start naproxen at the lower end of its dose range in the elderly.
Timegadine is a tri-substituted guanidine derivative which inhibits both arachidonate cyclo-oxygenase and lipoxygenase activity. In a 24-week randomized double-blind controlled trial, timegadine 500 mg/day was compared with naproxen 750 mg/day in two groups of 20 patients with active rheumatoid arthritis. In the timegadine group, significant improvements were seen in both biochemical and clinical markers of disease activity, i.e. ESR, serum IgG and IgM, leukocyte and platelet counts, duration of morning stiffness, Ritchie index, number of swollen joints, pain, and general condition. In the naproxen group, only the Ritchie index improved. Differences between treatments, when present, were always in favour of timegadine. Serum alkaline phosphatase rose during the first 8 weeks of treatment in the timegadine group. A transient rise was also seen in the naproxen group. The side effects reported were mainly gastrointestinal and allergic, the latter being more frequently found in the timegadine group. Timegadine is superior to naproxen in controlling disease activity in rheumatoid arthritis, and appears to possess disease-modifying properties.
The effect of early initiation of auranofin (AF) therapy on outcome measures was studied in a controlled 24-month double blind trial in 138 patients with early rheumatoid arthritis (RA) using an intent to treat approach. Patients were randomized to AF or placebo but in case of insufficient effect or intolerable adverse events, they switched to open disease modifying antirheumatic drug therapy. Patients who started AF fared significantly better in improved joint swelling. Stanford Health Assessment Questionnaire index, Keitel functional test, and mental depression, and furthermore, radiologic progression was significantly retarded. Our results support a disease modifying beneficial effect of AF in early active RA.se
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Conventional glucocorticoids exert a negative influence on calcium balance, and long-term treatment with these agents leads to osteopenia. Deflazacort is an oxazoline derivative of prednisolone with documented calcium-sparing properties when compared to prednisone on a weight basis. The purpose of the present study was to determine the relative antiinflammatory potency of deflazacort and prednisone. In a randomized, cross-over, double-blind trial, 11 patients, all suffering from polymyalgia rheumatica, and all on a stable maintenance dose of prednisone, were treated with equimolar doses of prednisone and deflazacort (i.e., weight ratio 1:1.2) for two consecutive 2-week periods. Following deflazacort treatment, significant rises compared with initial values were seen in erythrocyte sedimentation rate (ESR), plasma fibrinogen, serum alkaline phosphatase, and general pain and tenderness. No changes were seen following prednisone treatment. Subsequently, in a similar regimen, prednisone was compared with deflazacort at a weight ratio of 1:1.2 in 10 patients, 1:1.5 in another 10 patients, and 1:1.8 in still another 10 patients for purposes of dose titration. Again, significant rises were seen in ESR, plasma fibrinogen, and serum alkaline phosphatase following the lowest dose of deflazacort, whereas no changes were seen following the higher doses of deflazacort or prednisone. In conclusion, the relative antiinflammatory potency of deflazacort and prednisone lies between 0.83 and 0.66 on a weight basis (1.02 and 0.82 on a molar basis) as evaluated by clinical and biochemical parameters reflecting disease activity in polymyalgia. This disease appears to represent a sensitive, reliable and reproducible clinical model for assessment of the relative antiinflammatory potency of glucocorticoids.
Six previously untreated poor prognosis patients and eight previously treated patients with small cell lung cancer (SCC) were treated with 1,2,4-triglycidylurazol (TGU, NSC-332488) 800 and 650 mg/m2 every 4 weeks, respectively. No responses were observed. The survival time of the previously untreated patients was short, a median of 7 weeks (range 5-10 weeks). Myelosuppression was severe and prolonged with white blood count, WHO grade 3-4, in four previously untreated patients and in two previously patients, and with platelets, WHO grade 3-4, in both four previously untreated and in four previously treated patients. Gastrointestinal toxicity was mild to moderate. It is concluded that TGU is inactive in SCC.
Bone mineral density (BMD, g/cm2) was measured using dual-photon absorptiometry (DPA) in selected areas of the proximal tibia following uncemented PCA knee prosthesis. In nine patients with 14 alloplastic operations, measurements were taken at 3-6-month intervals for the first 3 1/2 years after operation. There was a significant increase in BMD of about 15% during the first 6 months after operation. The following year it remained increased, although not significantly, compared with the initial values, then gradually diminished. Increased bone density after arthroplasty may be explained mainly by stimulation of bone formation from weight bearing due to improved walking ability. Stress shielding of the proximal part of the supporting tibial bone did not seem to occur.
Uropathogenic Escherichia coli adhere to uroepithelial cells by their digalactoside alpha-D-galactopyranosyl-(1----4)-beta-D-galactopyranose [alpha-D-Galp-(1----4)-beta-D-Galp or Gal alpha (1----4)Gal]-binding pili, which are composed of repeating identical subunits. The major subunit (PapA) of these pili is not required for binding, but the papF and papG gene products are essential for adhesion. Transcomplementation analysis between the pap gene cluster and a related gene cluster encoding a different binding specificity showed that PapG and not PapF is the Gal alpha (1----4)Gal-specific adhesin. Antibodies against PapG were obtained upon immunizing with whole Pap pili, showing that the adhesin is a pilus component. Antisera specific for different Pap proteins were used to demonstrate that a pilin protein, either PapA or PapE, together with both PapG and PapF, must be exposed on the cell surface to allow E. coli to bind. The DNA sequence of the papG gene is presented, and the deduced primary structure showed similarities both to the B-chain sequence of the digalactoside-binding Shigella toxin and to established amino acid sequences of pilins.
A human interferon-alpha 2 gene variant was expressed in Escherichia coli under the control of the tryptophan operon promoter and of a series of synthetic partially overlapping ribosomal binding sites, which control initiation of translation. Variation in the distance between the start codon and such a set of ribosomal binding sites affected the level of interferon expression much less than previously described for single ribosomal binding sites.
The vitamin D status was investigated in 94 geriatric patients in a Danish long-stay ward. The influence of mobility and thus possibility of outdoor activity was studied as well as the influence of regular vitamin D intake. Serum levels of 25-hydroxyvitamin D (25-OHD) were significantly reduced in all groups compared with age-matched controls. In 50% of the patients hypocalcaemia and elevated levels of alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) were found in combination with severely reduced serum 25-OHD values (less than 5 ng/ml) indicating the presence of osteomalacia. Supplementation with 400 IU vitamin D daily in the winter months resulted in significantly higher 25-OHD levels and normocalcaemia while slightly elevated levels of alkaline phosphatase and iPTH persisted. The serum concentrations of 25-OHD were highest in the subjects who were not confined to bed. In these patients the biochemical parameters reflecting osteomalacia were normal. Low serum 1,25-dihydroxyvitamin D levels were found in the patients with low 25-OHD while 24,25-dihydroxyvitamin D levels were within the normal range in all groups and correlated with 25-OHD. Daily vitamin D supplementation appears to be indicated for geriatric patients, especially when bedridden, even in countries where the nutritional vitamin D intake is high.
The long-acting antiphlogistics tenoxicam (Ro 12-0068, Tilcotil) and piroxicam in single daily oral doses of 20 mg are compared in a double-blind, group-comparative, randomised trial planned to last for five years. Results of 12 months' treatment of 108 patients with osteoarthritis of the hip or knee have been reported. This interim analysis focuses mainly on the 12 to 24 month interval. The clinical improvements obtained within the first 12 months persisted during the second year in the 55 patients remaining on treatment. After 24 months, 53 patients had been withdrawn prematurely, three-quarters because of inefficacy or intolerance. Only six patients were withdrawn between 12 and 24 months, three for lack of efficacy, two for side-effects and one for reasons unrelated to therapy. There was no difference between the treatment groups with regard to incidence, time or reason for withdrawal, and only small, insignificant differences in efficacy and tolerability. This trial shows that long-term treatment of osteoarthritis with tenoxicam and with piroxicam is beneficial. Once efficacy and tolerability have been established, maintenance of therapy is feasible.