Quantitative studies of sulphate uptake by the cells of human cartilage (McElligott and Collins, 1960) have shown that chondrocyte activity increases in articular cartilage as age advances, while it decreases in costal cartilage. A considerably enhanced activity of articular over costal cartilage cells was recorded in cases where there was nakedeye evidence of destruction and fibrillation of the articular cartilage. We postulated a possible relationship between the increased sulphate utilization of ageing articular cartilage, the degree of osteo-arthritis, and the peculiar rearrangement and grouping of chondrocytes that are known to occur in these conditions. In order to investigate this, a large number of autoradiographs of cartilage incubated with labelled sulphate have been prepared and studied side by side with parallel sections stained by various methods including those that demonstrate mucopolysaccharides. It is the results of these studies that we now report. Material and MethodsA patella was removed at each of 34 necropsies from persons ranging in age from 4 to 83 years. Specimens were processed as soon as possible after removal and in all cases within 2 hours. During this delay the specimens were stored at 40 C. in the incubation medium, a procedure that reduces the rate of loss of chondrocyte activity. The intervals between death and autopsy and between the collection of the specimen and its processing were carefully noted.Preparation of Specimens. The patellae were inspected and changes of osteo-arthritis, if present, were graded 0-4 according to the classification proposed by Collins (1949, p. 76). Blocks of cartilage down to the bone were removed from the complete transverse diameter of the patellae and processed for quantitative measurement of sulphate fixation in 31 cases, as previously described (McElligott and Collins, 1960).Another block of cartilage with its subjacent bone was then cut from the specimen; this second block of cartilage adjoining that removed for radiochemical assay was used for the histological procedures to be described. The cut surfaces of the cartilage were then shaved with a razor so as to produce a block of the complete depth of the articular cartilage 1 mm. or less in thickness resting on a broader supporting block of the underlying bone, since thicknesses of cartilage greater than 1 mm. impair the uptake of "5SO4 (Bostrom and MaInsson, 1953). Incubation Medium.-The medium used for incubating the specimens and in which they were transported was that described by Kodicek and Loewi (1955 Layton (1950) reports that higher uptake of radioactive sulphate occurs where carrier is omitted.Radiochemical Technique.-The quantitative procedure, based on the methods fully set out by Layton (1949Layton ( , 1950 and by Kodicek and Loewi (1955), has been previously described (McElligott and Collins, 1960). In the preparation of autoradiographs the blocks of cartilage and bone were incubated in 10 ml. medium at 37°C. in a water bath, in flasks mounted in a mechanical rocker. Approxima...

Samples of paraquat dichloride and paraquat dimethosulphate are equitoxic when the LD50 is expressed as mg. paraquat ion/kg. body-weight. There are wide species variations in the LD5o and, of course, variations according to the route of administration in a single species.The pathological lesions attributable to paraquat are described in some detail. Among the most unusual is a peculiar proliferative condition in the lungs, which in an extreme case and in many parts can hardly be recognized as consisting of pulmonary tissue. With slight variations, the same microscopical picture may be seen in the rat, mouse, dog, and man, and less often in the rabbit. The experimental evidence suggests that once the condition is initiated it often proceeds in the absence of further exposure to paraquat until it becomes lethal.There is evidence that much of the mortality resulting from dermal application of paraquat in the rabbit is caused not by percutaneous absorption but by oral contamination from the stratum corneum. This leads to glossitis and oesophagitis and an inability or unwillingness to eat.In this paper we report the effects of paraquat administered to laboratory animals as the dichloride or dimethosulphate, either as a single dose by one or other route, or over a short term of repeated doses. Observations made by others on the effects of very exceptional cases of poisoning in man, arising from accidental imbibition of a solution of the substance rather than from its use in the field, suggest that similar pathological changes may be expected in human beings. Chemical Constitution and UsesParaquat is a dipyridylium compound. The formula and chemical nomenclature of the dichloride are given below.

Acetaminophen-induced (750 mg per kg p.o.) hepatotoxicity in mice is characterized by hepatomegaly and massive centrilobular congestion which precede the appearance of necrosis. The vascular changes are correlated with the morphologic features using liver hemoglobin content to quantitate erythrocyte sequestration, and hematocrit measurements and 125I-albumin injections to determine plasma and blood volume. The initial increase in liver size was a result of plasma accumulation due to endocytic vacuolation of hepatocytes and Disse space enlargement in centrilobular regions. Further increases in liver size after 3 hr were a consequence of erythrocyte and additional plasma sequestration within the damaged liver. These events occurred without any increase in intrahepatic or portal venous pressure. Hepatic hemoglobin and plasma levels increased 10- and 5-fold, respectively, by 4.5 to 6 hr after administration of acetaminophen. There are two major consequences of acetaminophen-induced hepatotoxic congestion. First, blood and plasma volumes fell significantly, and we suggest that hypovolemic shock contributes to early mortality after acetaminophen. Second, impaired circulation within the congested liver, as manifested by reduced 125I-albumin entry into the liver when 125I-albumin was injected after congestion had developed, probably aggravates the initial injury. Early lesions were always evenly distributed around central veins. However, the pattern of damage at 24 hr could be variable. Occasional large confluent areas of necrosis were always congested, which is consistent with the concept that secondary ischemic damage can develop. Congestion and hypovolemia are reversible and can be largely prevented by administration of the protective compound N-acetylcysteine (1,200 mg per kg p.o.) 3 hr after acetaminophen.

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.