Early detection of arthrotic changes in animal experiments and clinical medicine

With arthroscopy cartilage changes are being detected more and more frequently which must be classified as early arthrosis. Similar changes (stage II) could be induced in 17 rabbits 6 weeks after lateral meniscectomy. Extraction (4M-GuHcl) and gel chromatography (Sepharose 2B) of 35S-proteoglycans resulted in typical elution profiles. Aggregates were remarkably, monomers slightly reduced, and a third population of nonaggregated proteoglycans increased. In 81 patients undergoing knee arthroscopy 98 small cartilage biopsies were taken from standardized regions and analysed biochemically. Elution profiles were correlated to anamnestic and clinical data (Wilcoxon-test, cluster analyses). Irrespective of the grade of osteoarthrosis (OA) the ratio of aggregated and nonaggregated 35S-proteoglycans varied. Almost half of the samples from macroscopically "normal" cartilage revealed a depression of aggregates. No correlation to anamnestic or clinical data was found. The profiles probably represent different metabolic stages in developing OA. By analysis of 35S-proteoglycans in cartilage biopsies it seems possible to detect early metabolic changes at the onset of osteoarthrosis.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Accumulation of organic contaminants in sentinel mallards utilizing confined disposal facilities at Hamilton Harbour,Lake Ontario,Canada

Organochlorine analysis was performed on adult and juvenile farm-raised mallards (Anas platyrhynchos) released and collected at three experimental sites in southern Ontario: Hamilton Harbour Confined Disposal Facility (CDF); Winona Sewage Lagoons (SL); and Big Creek Marsh, Canada. Collections were scheduled at 10, 30, and 70 days after release. Hamilton Harbour CDF and Winona SL are known to be contaminated whereas Big Creek Marsh is a relatively clean, natural site. All sites are important resting and feeding areas for migratory and resident waterfowl. Breast muscle concentrations of polychlorobiphenyls (PCBs) in ducks collected 10 days after release (160.8 g/kg, wet wt) at Hamilton Harbour CDF were more than 5300 times greater than day 0 birds (0.03 g/kg). All ducks collected from Hamilton Harbour CDF had PCB concentrations exceeding Health and Welfare Canada and United States Food and Drug Administration (FDA) guidelines for edible poultry. Concentrations of DDE (216.9 g/kg), hexachlorobenzene (0.9 g/kg), dieldrin (1.9 g/kg), and 1,2,4,5,-tetrachlorobenzene (24.9 g/kg) were significantly elevated in ducks utilizing Winona SL. Concentrations of 1,2,3,4-tetrachlorobenzene, mirex, and photomirex were elevated at one or more of the sites. Ducks from Big Creek Marsh had lower contaminant concentrations than ducks from the other study sites. It is not clear whether bioaccumulation of organochlorines at these sites would pose a potential hazard to migratory and resident mallards; however, other duck species such as diving ducks that have more contact with sediments and sediment-derived foods would probably be at much higher risk.     

Hypertension secondary to progressive vascular neurofibromatosis

A 4 year old girl with neurofibromatosis type 1 (NF1) was referred for hypertension. An aortogram showed narrowing of the left main renal artery. An angiogram three and a half years later showed coarctation of the abdominal aorta. She underwent aortoplasty but the stenosis recurred. Vascular involvement in NF1 may be progressive and requires long term follow up.     

Paradoxical embolization via a patent foramen ovale following acute pulmonary embolism

The foramen ovale is usually obliterated following establishment of the adult circulation but remains patent in 25% of individuals. This potential communication between the venous and arterial circulations can allow thromboembolic material to bypass the lungs and enter the systemic circulation. We report two cases of paradoxical embolization through a patent foramen ovale following acute large pulmonary embolism (PE) and discuss the factors that predispose to paradoxical embolization following PE.     

Metabolic activation of chondrocytes in human osteoarthritis. Expression of type II collagen]

OBJECTIVE/METHODS: Type II collagen is the dominating collagen in articular cartilage. It is essential for the structural integrity and the biomechanical properties of cartilage. Using immunohistology and in situ hybridization we systematically analyzed the protein and mRNA-expression of type II collagen in cartilage/bone sections without any signs of osteoarthritis and osteoarthritic samples with various degrees of osteoarthritis. RESULTS: In normal articular cartilage without any histologic signs of osteoarthritis type II collagen was distributed homogeneously. An expression of the type II collagen-mRNA was not detectable in any of these samples. In cartilage sections with a roughening of the cartilage surface and a superficial loss of the safranin O staining as early histologic signs of osteoarthritis the immunohistologic staining for type II collagen was reduced in the deep cartilage zone. An expression of the type II collagen-mRNA was found in 19 of 35 preparations. This expression, however, was restricted to the middle and deep zone of cartilage. A good and reproducible correlation of the specific gene and protein expression was found in samples with more severe osteoarthritic lesions. CONCLUSIONS: Detailed information on metabolic changes and the activation of chondrocytes in osteoarthritic cartilage are important to characterize certain stages of osteoarthritis and thus identify new prognostic factors. Increasing knowledge of the factors regulating the matrix synthesis and degradation in cartilage will provide the basis for new disease modifying therapies in osteoarthritis.     

Heart Rate Variability Predicts Severe Hypotension after Spinal Anesthesia

Background: Hypotension due to vasodilatation after spinal anesthesia (SA) may be harmful. Heart rate variability, an indirect measure of autonomic control, may predict hypotension.

Methods: One hundred patients were studied. Retrospectively, heart rate variability was analyzed in 30 patients, classified depending on the lowest systolic blood pressure (SBP) after SA. Seventy patients were studied prospectively, assigned to one of two groups by their low to high frequency ratio (LF/HF) before SA. Sensitivity and specificity of LF/HF for prediction of decrease of SBP greater 20% of baseline were tested.

Results: Retrospective analysis showed differences of LF/HF depending on the degree of hypotension after SA. Prospective analysis demonstrated significant differences of SBP after SA depending on baseline LF/HF (mean +/- SD): low LF/HF (1.3 +/- 0.7) = > SBP: 91 +/- 8% of baseline versus high LF/HF (5.5 +/- 2.4) = > SBP: 66 +/- 10% of baseline (P < 0.05). Baseline LF/HF as well as high frequency and proportional decrease of SBP after SA correlated significantly, in contrast to baseline hemodynamic parameters heart rate and SBP. A receiver operator curve characteristic analysis showed a sensitivity and specificity of LF/HF > 2.5 of 85% to predict SBP decrease of greater than 20% of baseline after SA.