Microbiological and pharmacokinetic studies of acyl demycinosyltylosin and related tylosin derivatives

A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compounds were more active in vitro than the tylosins. Two tetraacylated DMTs, Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 micrograms.hour ml) and A-56268 (21.6 micrograms.hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (11.8 micrograms.hour/ml) and erythromycin (1.5 micrograms.hour/ml) had lower levels. In mice administered 200 mg/kg orally, Sch 37644 (AUC, 19.4 micrograms.hour/ml) and Sch 38646 (15.4 micrograms.hour/ml) had higher serum levels than erythromycin (5.7 micrograms.hour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50S) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin.     

A method to differentiate between anti-C1q antibodies and C1q-binding immune complexes using collagenase-digested solid phase C1q.

A method for the detection of circulating immune complexes in the presence of autoantibodies to C1q is described. Solid phase C1q-digestion with bacterial collagenase results in the elimination of the collagen-like region of C1q. Binding of model immune complexes to this modified solid phase C1q is practically unaltered, while reactivity of anti-C1q antibodies is abolished by this procedure. In conjunction with an ELISA using the collagen-like region of C1q as antigen this modified C1q solid phase assay may be used to determine immune complexes and anti-C1q antibodies in the sera of patients with autoimmune rheumatic diseases.     

Scintigraphic evaluation of hepatic blood flow after intrahepatic portosystemic shunt (TIPS)

In patients with liver cirrhosis a transjugularly placed intrahepatic portocaval shunt (TIPS) is a non-surgical portosystemic device which aims to reduce portal venons pressure. In comparison with Doppler sonography, we evaluated in 28 patients the diagnostic impact of liver perfusion scintigraphy (with technetium-99m diethylene triamine penta-acetic acid) in the assessment of changes in the hepatic blood flow after TIPS shunting. The arterial and portal contributions to hepatic flow were calculated from the areas under the biphasic timeactivity curve. In the course of TIPS shunting, patency is threatened by reocclusion. Angiography is the gold standard for TIPS shunt reassessment. However, there is a need for a less invasive diagnostic procedure, such as scintigraphy or Doppler sonography, for the early detection of shunt insufficiency. Scintigraphy demonstrated that prior to TIPS shunting the portal venons contribution to hepatic perfusion was reduced to 29.2%, this reduction being due to portal hypertension. After TIPS placement a significant increase in portal venous perfusion was observed (38.2%;P<0.02). TIPS shunt occlusion was identified in patients by a significant reduction in the scintigraphically measured portal venons contribution to hepatic blood flow. Hepatic perfusion scintigraphy appears to be a valuable method to determine the immediate effect of TIPS on hepatic blood flow. Post-TIPS follow-up studies of hepatic haemodynamics by liver perfusion scintigraphy appear able to contribute to the detection of TIPS shunt occlusion before the clinical consequences of this complication have become apparent.     

Binding affinity of ibuprofen to collagen and other connective tissue components

In vitro binding of ibuprofen to various tissue components was studied to explain differences in tissue concentration after local application of ibuprofen cream (Dolgit Creme). Radioactive ibuprofen was incubated with human Collagen Type I to V, Elastine, bovine, Mouse-Laminin, and Matrigel of the mouse, respectively. In low concentrations--similar to plasmaconcentrations after percutaneous application of ibuprofen--a specific binding especially to Laminin and Collagen Type IV could be found. This finding possibly explains previous autoradiographic results, which showed higher concentrations of ibuprofen in connective tissue compared with fat and other surrounding tissues.     

Mobilization and evolutionary history of miniature inverted-repeat transposable elements (MITEs) in Beta vulgaris L.

We have identified three families of miniature inverted-repeat transposable elements (VulMITEs) in the genome of sugar beet (Beta vulgaris L.), evidently derived from a member of the Vulmar family of mariner transposons. While VulMITEs I are typical stowaway-like MITEs, VulMITEs II and VulMITEs III are rearranged stowaway elements of increased size. The integration of divergent moderately and highly repetitive sequences into VulMITEs II and, in particular in VulMITEs III, respectively, shows that amplification of repetitive DNA by MITEs contribute to the increase of genome size with possible implications for plant genome evolution. Fluorescent in-situ hybridization (FISH), for the first time visualizing stowaway MITE distribution on plant chromosomes, revealed a dispersed localization of VulMITEs along all B. vulgaris chromosomes. Analysis of the flanking sequences identified a dispersed repeat as target site for the integration of the stowaway element VulMITE I. Recent transposition of VulMITE I, which most likely occurred during the domestication of cultivated beets, was concluded from insertional polymorphisms between different B. vulgaris cultivars and species. ^†Sequence data from this article have been deposited in the EMBL/GenBank Data Library under the accession nos. AM231630-AM231653 and AM259123-AM259125.     

Rate of nitrous oxide exchange across the middle ear mucosa in monkeys before and after blockage of the mastoid antrum.

OBJECTIVES: We tested the hypothesis that mastoid volume buffers the rate of change in middle ear pressure caused by transmucosal, inert gas exchange. STUDY DESIGN: Twelve monkeys were randomly assigned to group 1 or group 2. Right ears of group 1 had sham surgery and of group 2 had obstruction of the mastoid antrum. Before and after surgery, the time constant for transmucosal N(2)O exchange was estimated from N(2)O breathing experiments. The hypothesis predicts that the postoperative time constant measured for right ears of group 2 but not group 1 is greater than that measured before surgery. RESULTS: Mastoid antrum block significantly decreased right middle ear volume but did not affect the time constant for transmucosal N(2)O exchange. CONCLUSION: A mastoid gas-reserve function is not supported by the experimental data. SIGNIFICANCE: These results for monkeys and the theory developed to explain the effect of mastoid volume on transmucosal inert gas exchange suggest that the results for previous experiments in humans interpreted as evidencing a mastoid gas-reserve function are consistent with alternative explanations.