Changes in aggrecan populations in experimental osteoarthritis

Adult articular cartilage contains at least two distinct populations of aggrecan: one is larger and richer in chondroitin sulfate (CS), while the other is smaller with less CS. The smaller form is thought to be derived from the larger. The amount of CS in cartilage decreases with maturation and aging, mainly because of a decrease in the proportion of the larger of these two proteoglycans. In early osteoarthritis (OA) the amount and concentration of CS in cartilage increases. To test the hypothesis that an increase in the more CS-rich form of aggrecan contributes to the increase in CS in cartilage in OA, experimental OA was induced in dogs by transection of the anterior cruciate ligament, with sacrifice at various times between 2 days and 64 weeks after the operation. Proteoglycans were extracted from the articular cartilage of eight areas of the joint, fractionated, and CS was quantified by measuring hexuronate. Aggrecan populations were assessed by composite agarose-polyacrylamide gel electrophoresis. The proportion of the more CS-rich form of aggrecan increased with time after operation in all areas of the joint. This increase correlated with increases in tissue mass and hexuronate, showing that the increase in the larger, CS-rich form of aggrecan contributes to the increase in CS in the tissue. It seems paradoxical that this form of aggrecan accumulates in the tissue despite the fact that increased protease activity has been demonstrated in experimental OA.     

Endoscopic Carpal Tunnel Release

On the basis of clinical outcome measures, endoscopic carpal tunnel release is an effective operation for treating idiopathic carpal tunnel syndrome. Patients who have undergone bilateral carpal tunnel operations have routinely preferred endoscopic release over the open release. An endoscopic release allows many patients to return to work sooner. However, the benefits of more rapid functional recovery and return to work are tempered by the increased cost and higher complication rate of the procedure. Endoscopic carpal tunnel release is a technically demanding procedure with low tolerances for error. Despite its widespread use, its role is not yet clearly defined.     

Standardized lifetime risk

The authors propose the use of two new standardized measures of risk, the standardized lifetime risk and the standardized number of years of life lost. These measures maintain the advantages of standardized rates but are more readily understood without special training. In this paper, standardizing weights based on 1992 data from England and Wales are provided, and the new measures are illustrated with a variety of examples. The new standardized rates are useful for examining trends over time; for comparing the impact of various diseases on public health; and for comparing rates of a given disease in several different countries. The authors think it is far more informative to say that 41 out of every 1,000 women die of breast cancer than to say that the standardized mortality rate is 51 per 100,000 women per year.     

Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor

Isoniazid (INH), a widely used drug in the prophylaxis and treatment of tuberculosis, is associated with a 1 to 2% risk of severe and potentially fatal hepatotoxicity. There is evidence that the INH metabolite hydrazine plays an important role in the mechanism of this toxicity. Metabolism of INH leads to the production of hydrazine via both direct and indirect pathways. In both cases, the activity of an INH amidase is required to hydrolyze an amide bond. In the present study, using a model of INH-induced hepatotoxicity in rabbits, pretreatment of rabbits with the amidase inhibitor bis-p-nitrophenyl phosphate 30 min before injection of INH inhibited the formation of INH-derived hydrazine and decreased measures of hepatocellular damage, hepatic triglyceride accumulation, and hypertriglyceridemia. Bis-p-nitrophenyl phosphate also potently inhibited the production of hydrazine from INH in in vitro microsomal incubations (IC50 2 microM). Although hepatic glutathione stores are decreased, they are not depleted in animals with INH-induced hepatotoxicity. Significant effects on hepatic microsomal cytochrome P-450 1A1/2 and cytochrome P-450 2E1 activities suggest that these isozymes may be involved in the mechanism of the toxicity. In conclusion, this study demonstrates the importance of amidase activity in this rabbit model of hepatotoxicity and provides additional evidence in support of the role of hydrazine in the mechanism of INH-induced hepatotoxicity.