Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor.

Considerable evidence has associated the expression of matrix metalloproteinases (MMPs) with the degradation of cartilage and bone in chronic conditions such as arthritis. Direct evaluation of MMPs' role in vivo has awaited the development of MMP inhibitors with appropriate pharmacological properties. We have identified butanediamide, N4-hydroxy-2-(2-methylpropyl)-N1-[2-[[2-(morpholinyl)ethyl]-,[S- (R*,S*)] (GI168) as a potent MMP inhibitor with sufficient solubility and stability to permit evaluation in an experimental model of chronic destructive arthritis (adjuvant-induced arthritis) in rats. In this model, pronounced acute and chronic synovial inflammation, distal tibia and metatarsal marrow hyperplasia associated with osteoclasia, severe bone and cartilage destruction, and ectopic new bone growth are well developed by 3 wk after adjuvant injection. Rats were injected with Freund's adjuvant on day 0. GI168 was was administered systemically from days 8 to 21 by osmotic minipumps implanted subcutaneously. GI168 at 6, 12, and 25 mg/kg per d reduced ankle swelling in a dose-related fashion. Radiological and histological ankle joint evaluation on day 22 revealed a profound dose related inhibition of bone and cartilage destruction in treated rats relative to rats receiving vehicle alone. A significant reduction in edema, pannus formation, periosteal new bone growth and the numbers of adherent marrow osteoclasts was also noted. However, no significant decrease in polymorphonuclear and mononuclear leukocyte infiltration of synovium and marrow hematopoietic cellularity was seen. This unique profile of antiarthritic activity indicates that GI168 is osteo- and chondro-protective, and it supports a direct role for MMP in cartilage and bone damage and pannus formation in adjuvant-induced arthritis.

Effect of matrix metalloproteinase inhibitors on tumor growth and spontaneous metastasis.

Four potent, synthetic inhibitors of matrix metalloproteinases (MMPs) were assessed as inhibitors of tumor growth and spontaneous metastasis to the lung. Mat Ly Lu rat prostate tumor, LOX human melanoma and M27 murine Lewis lung tumor were implanted subcutaneously (s.c.) in mice and allowed to grow for 3-12 days. The lungs of the tumor-bearing mice were then removed and implanted s.c. into untreated mice, and the outgrowth of secondary tumors from the implanted lungs measured. The incidence and rate of outgrowth of secondary tumors increased with the length of primary tumor growth, validating these measurements as indices of spontaneous metastasis to the lung. Compounds were tested by s.c. implantation of minipumps which delivered compound throughout the period of primary tumor growth and spontaneous metastasis to the lung at steady-state drug concentrations orders of magnitude greater than the concentrations needed to either inhibit collagenase, gelatinase or stromelysin in vitro. Inhibitor treatment slowed the growth of primary s.c. Mat Ly Lu and LOX tumors by 40-60% but had no significant effect on the growth of primary M27 tumors. Surprisingly, inhibitor treatment had no significant effect on the ability of the lung to generate secondary tumors when reimplanted s.c. in untreated mice. Because of the possible importance of cathepsins B, H and L in tumor growth and metastasis, the irreversible inhibitor E-64 was also infused by s.c. minipump. E-64 had no effect on the growth or spontaneous metastasis of Mat Ly Lu or M27 tumors.

The sonographic evaluation of hydronephrosis with progressive ureteric obstruction. An experimental model.

An experimental animal model was set up to examine the interrelationship between urine flow and progressive ureteric stenosis in producing sonographically detectable hydronephrosis. In four rabbits with mild ureteric stenosis or no stenosis the renal pelvis showed little distension even with rapid diuresis. Progressively tighter ureteric stenoses resulted in progressive renal pelvic distension accentuated by diuresis. The implication is that the normal, unobstructed ureter in the rabbit is able to remove urine from the kidney as fast as it may be produced, even during conditions of maximal diuresis. Therefore, in the absence of any other factor that may contribute to overdistension of the upper urinary tract, a state of diuresis will not simulate hydronephrosis.

Patency evaluation of a LeVeen shunt using 99mTc-sulfur colloid.

The LeVeen shunt has proved valuable in relieving intractable ascites. It is however subject to failure in about 5--8% of cases. To our knowledge there are only three reports in the literature describing the use of nuclides to assess patency; two using 99mTc-sulfur colloid and one using 99mTc-albumin. The purpose of this paper is to add our experience to the data currently published and stress that late liver visualization may occur with an obstructed shunt.

Radionuclide brain scan findings in superior sagittal sinus thrombosis.

Superior sagittal sinus thrombosis is a serious condition requiring early diagnosis. This paper presents our experience with two cases and describes the findings. In one case radionuclide brain imaging was the first study performed. In the other, the diagnosis was made at arteriography with scanning used for follow-up.

Percentage agreement and phi: A conversion table.

STUDIES IN APPLIED BEHAVIOR ANALYSIS HAVE USED TWO EXPRESSIONS OF RELIABILITY FOR HUMAN OBSERVATIONS: percentage agreement (including percentage occurrence and percentage nonoccurrence agreement) and correlational techniques (including the phi coefficient). The formal relationship between these two expressions is demonstrated, and a table for converting percentage agreement to phi, or vice-versa, is presented. It is suggested that both expressions be reported in order to communicate reliability unambiguously and to facilitate comparison of the reliabilities from different studies.

Maslow's need hierarchy and Cattell's 16PF.

Canonical correlation analysis was used to investigate the overall relationship between the Sixteen Personality Factors Questionnaire (16PF) and the Work Motivation Inventory (WMI). The results indicated that the two instruments shared two independent components which accounted for 30% of their total variance. The results provide some support for the validity of both devices and provide a link between the factorially constructed 16PF and Maslow's personality theory.

An empirical comparison of Maslow's and Murray's needs systems.

The Work Motivation Inventory (WMI), a measure of Maslow's hierarchy of needs, and the Edwards Personal Preference Schedule (EPPS), a measure of Murray's manifest needs, were administered to 372 undergraduates. The two instruments were compared using canonical analysis. The analysis revealed three significant relationships between components of the two instruments. The first relationship supported Maslow's need hierarchy in general and its measurement by the WMI. The second suggested a fluctuating relationship between giving and receiving help and the levels of Maslow's hierarchy. The third relationship suggested that need for Achievement is associated with the intermediate levels of Maslow's hierarchy.

Subjective ratings of Cattell's 16 Personality Factors.

The Sixteen Personality Factors Questionnaire (16PF) was administered to 69 subjects. Each subject was asked to rate himself on the 16 personality factors on the 16PF. The 16PF scores and the self-ratings were compared by canonical analysis. Three significant relationships were identified. The relationships primarily involved indices of social interaction from the 16PF and indices of internal traits from the self-ratings.

MMPI Scales for measuring Eysenck's personality factors.

Four new MMPI Scales were constructed to identify Eysenck's personality factors of psychoticism, extraversion, and neuroticism as well as a lie score. The scales showed good construct validities against the Eysenck Personality Questionnaire and the Friedman Overlap Scales developed from items in the MMPI. The study also supported the construct validity of the Friedman overlap scales.

Sonography of experimental acute renal vein occlusion.

Complete occlusion of the renal vein in five rabbits with the kidney in its normal position was followed by high-resolution ultrasound. Early changes consisted of moderate renal enlargement and a diffuse increase in renal echogenicity with a fine echo pattern. On the average, renal length increased by only 13%. Delayed changes were a gradual reduction in renal echogenicity, falling to below baseline, with blurring of the corticomedullary boundary. Intrarenal hemorrhage alone occurred in only one kidney. Perirenal hematoma were seen in two other cases associated with localized intrarenal hemorrhage adjacent to the point of capsular rupture (overall renal morphology was preserved). The relative subtlety of the changes observed contrasts with previously reported data and is felt to preclude a specific diagnosis.

Sex-roles of ideal opposite sexed persons for college males and females.

Relationships between sex-roles as measured by the Bem Sex-Role Inventory (BSRI) and the ideal sex-role of persons of the opposite sex as measured by a modified BSRI were investigated for 169 college males and 204 college females. The distributions of sex-roles were different for men and women, as were the distributions of ideal sex-roles of opposite sexed persons. Androgynous (A), feminine (F) and masculine (M) men identified F women as ideal, while undifferentiated (U) men identified U women as ideal. M women preferred M men, and U women preferred U men. Effects of ideal sex-role of the two sexes on sexual attraction were discussed.

Drug attitude factors: comparisons of samples from 1985 and 1992.

The Stanislaus Chemical Effects Survey, which contains the names of twenty-four substances and asks subjects to rate the relative harm and benefit of each to society, was given to male and female undergraduates in 1985 and 1992. Factor analysis of the responses from each sample were done separately and then a comparison was made of the resulting factors. Fifteen of the twenty-four drugs retained their approximate same position in the structure of drug attitudes between the two samples. Attitudes about three substances, tobacco, oral contraceptives, and PCP, notably appeared to have undergone significant shifts. Discriminant analysis revealed significant differences between the two samples, between males and females regardless of year, and an interaction between year and gender. Findings suggest that attitudes remain conservative about drugs in general and that public policies may be contributing to the shifts in attitudes seen.