Age-related morphometry of equine calcified cartilage.

Although there are many studies in the equine literature focused on articular diseases and the aetiology of osteoarthritis, few have concentrated on normal articular structures and how they change with age. The objective of this investigation was to study the thickness and morphology of the calcified cartilage layer of the distal metacarpus over a range of ages. A parasagittal slab of bone was sectioned from the region of sesamoid contact on the medial condyle of the metacarpi from 34 horses. The slab of bone was preserved, dehydrated and embedded, undecalcified, in methylmethacrylate and then stained with toluidine blue. Six repeatable fields of interest from the distal aspect of each metacarpus were digitised and examined to determine the morphology of the calcified cartilage layer. The thickness of the calcified cartilage, range 88-426 microm, was estimated using a method of integration. The results indicate an age-related influence on the thickness of the calcified cartilage layer, generally increased in older horses. While this finding is significant, perhaps more importantly a positional relationship was also identified, indicating that pressures endured by different regions within a joint may dictate morphological development of the tissues. This study has begun to lay the groundwork to determine whether the calcified layer of the hyaline cartilage could be involved in the development of osteoarthritis.

Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.

Synthesis and biological evaluation of cryptophycin analogs with substitution at C-6 (fragment C region).

Analogs of the antitumor agents cryptophycins 1 and 8 with dialkyl substitution at C-6 (fragment C) were synthesized and evaluated for in vitro cytotoxicity against human leukemia cells (CCRF-CEM). The activity of these analogs decreased as the size of the substituents at C-6 increased. The C-6 spirocylopropyl compound (2g) was highly potent in vitro and showed excellent antitumor activity in animal models.

Magnetic resonance imaging of the equine metacarpophalangeal joint: three-dimensional reconstruction and anatomic analysis.

Magnetic resonance imaging was used to examine the equine metacarpophalangeal joint. Thirty-two saggital images generated by partial volume imaging were transferred to a computer for three-dimensional reconstruction and analysis. All the tissues constituting the metacarpophalangeal joint were readily identified. The most significant increase finding regarded the soft tissues on the palmar aspect of the metacarpophalangeal joint and their interactions with the proximal sesamoid bones. The equine metacarpophalangeal joint has not previously been evaluated using 3-dimensional imaging software.

Correlation between anatomic features and low-field magnetic resonance imaging of the equine metacarpophalangeal joint.

OBJECTIVE: To expand our current knowledge and to establish limits of correlation between signal intensities of the magnetic resonance (MR) image and actual macroscopic and microscopic anatomic features of the imaged structures of the equine metacarpophalangeal joint (MCPJ). SAMPLE POPULATION: The right MCPJ was obtained from 4 adult horses that were euthanatized for reasons unrelated to the musculoskeletal system. PROCEDURE: The distal portion of the right forelimbs was collected from 4 equine cadavers. The bones were drilled to provide fixed reference points and examined by MR imaging. After imaging, the joints were sectioned for gross and histologic inspection. The MR images were aligned and correlated with digitized gross and histologic images to identify tissue types. RESULTS: Comparison of the images resulted in identification of different bone types, articular cartilage, and soft tissue structures of the equine MCPJ. CONCLUSION: Results provided relevant information regarding the appearance of the imaged tissues of the equine MCPJ. CLINICAL RELEVANCE: Although MR imaging does not have current clinical applications for equine practitioners, its wide acceptance as the imaging modality used for most human musculoskeletal derangements may aid in developing more realistic applications in equine medicine.

Amesergide and structurally related nor-D-ergolines: 5HT2 receptor interactions in the rat.

A series of tricyclic (nor-D) partial ergolines were synthesized via a highly convergent enantiospecific strategy, ultimately arising from a racemic tricyclic ketone. Michael addition to an acrylamide, followed by reductive methylation, afforded the key intermediate. Selective deprotection and oxidation provided the tricyclic ergoline. Vascular 5HT2 receptor interactions for the partial ergolines were dramatically reduced compared to the parent ergoline, amesergide, as determined in vivo by activation of a pressor response or blockade of 5HT-induced pressor responses in pithed rats. The desisopropyl tricyclic ergolines possessed some modest pressor activity that was unlikely to be related to 5HT2 receptor activation since these compounds did not inhibit the pressor response to serotonin. In contrast, the isopropyl tricyclic ergolines exhibited no agonist activity, but inhibited the pressor response to serotonin at 1 mg/kg i.v. The ergoline amesergide inhibited the pressor response to serotonin in doses of 0.01-0.1 mg/kg i.v. The homochiral isopropyl tricyclic ergoline was more potent as a 5HT2 receptor antagonist than the epimeric (unnatural stereochemistry) analogue. Thus, the isopropyl moiety on the indole nitrogen is important for vascular 5HT2 receptor affinity in the rat. Most importantly, these data suggest that conformational rigidity of the ergoline D-ring is required for optimal 5HT2 receptor interactions in the rat.

Characterization by photoaffinity labelling of the human platelet thromboxane A2/prostaglandin H2 receptor: evidence for N-linked glycosylation.

Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) are potent proaggregatory and vasoconstrictor lipids acting through a receptor referred to as the TXA2/PGH2 receptor. The receptor was purified using a modification of a previously described method from human platelet membranes solubilized using the detergent (3-[(3-cholamidopropyl)-dimethylammonio]-1-propane-sulfonate (CHAPS) and a combination of affinity chromatography and wheat germ lectin chromatography. This procedure resulted in a 1075 +/- 375-fold purification and a specific activity of 1.45 +/- 0.55 nmol/mg protein (n = 5). Repeating these chromatography steps on this partially purified receptor resulted in a preparation with a specific activity of 21 +/- 3 nmol/mg protein (n = 5). This represents the theoretical specific activity if one assumes a molecular weight of 50,000 for the receptor. The fold purification was 11,750 +/- 1250 based on crude membranes and an overall yield of 24%. To further the characterization of this receptor, we synthesized a new radioiodinated photoaffinity probe, 7-[(1R,2S,3S,5R)-6,6-dimethyl-3-(4-azido-3-iodobenzenesulfonylamino++ + )- bicyclo[3.1.1]hept-2-yl]-5(Z)-heptenoic acid (I-SAP-N3). [125I]l-SAP-N3 irreversibly incorporated into the purified receptor yielding a single band by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) autoradiography and indicated a molecular weight for the receptor of 50-51 kDa. The incorporation of the ligand could be inhibited by a variety of TXA2/PGH2 analogues. In addition, photoaffinity labelling was inhibited in a stereoselective manner as demonstrated by the pair of enantiomers (d)- and (l)-S145. Digestion of photoaffinity labelled receptor with N-glycosidase F demonstrated the presence of at least two N-linked glycosylation sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of angiographic center and local site analysis of PTCA results in a multicenter angioplasty-restenosis trial. The M Heart Group.

We compared three methods of coronary stenosis (S) sizing in a multihospital PTCA restenosis trial: visual analysis by independent observers, single point caliper measurements, and quantitative coronary angiography (QCA). Cine films from 50 patients were submitted from the clinical site to the quantitative angiographic center, where visual analysis and computer quantitation were performed. Regression analysis revealed a correlation coefficient of .857 for caliper vs. QCA (p less than .0001) and .876 for visual observation vs. QCA (p less than .0001). No significant differences were found between any of the 3 methods for pre- or post-PTCA stenosis values. However, QCA yielded smaller PTCA changes in stenosis severity than either caliper or visual observation (p less than .05). Both caliper and visual methods correlated well with QCA in assessing stenosis size pre- and post-PTCA. Trained observers can visually assess lesion severity with accuracy approaching QCA. QCA is likely to be less expensive when compared to visual analysis by three experienced observers and should be the method used for estimating the results of PTCA in clinical trials.