INFLAMMATION 264 knee stability by recording anterioposterior tibial force versus displacement and varus-valgus moment versus angulation during manipulation of the knee (M73). Joint stiffness and laxity were also measured with knee muscles relaxed and tensed. A new knee goniometer was described which was designed to quantify the total relative motion of the lower leg relative to the upper leg (T80). Sagittal instability of the knee joint indicates injury to the cruciate ligaments, and also implies damage to the medial collateral ligament and joint capsule. An interesting radiologic method was developed which appears to separate most patients with tom anterior cruciate ligaments from individuals with normal ligaments (L82). Evidence was developed indicating that in the human knee, the menisci bear a substantial portion of the total joint load throughout flexion and extension (S192). Varus stress applied to moving rabbit knee joints led to degenerative changes confined to the medial tibial and femoral articular surfaces (015). Duration of stress appeared to be more important than the actual magnitude of stress in determining severity of cartilage damage. A technique for the study of contact between visco-elastic bodies was developed and applied to the patellofemoral joint (S142). Radiographic study of the wrist in flexion and extension defined the contribution of the radiocarpal and midcarpal joints, and analyzed the angular relationships of the radiocarpal components (S35). Kinematic investigation of the normal metacarpophalangeal joint demonstrated that functionally it is equivalent to a universal joint with 2" of freedom and negligible axial rotation (Y17). Biomechanical characteristics of the metacarpophalangeal joint were the subject of several investigations (B117, P7). The synergistic patterns of muscle mo- ments and energy flows during normal gait were analyzed, making it clear that forces of gravitation, muscle action, and knee joint acceleration act synergistically during both acceleration and deceleration (W162). Patterns of generation, absorption, and transfer of mechanical energy at joints during walking were described, and the unwary were cautioned concerning extrapolating from simple biomechanical experiments which may generate information not likely to apply to natural movements. Gait evaluation includes kinematic (displacement) and kinetic (force) parameters which may be useful in evaluating pathologic processes or the effects of treatment. In a study of the effects of walking velocity and age on hip kinematics and kinetics, it was shown that many of these parameters have a significant dependence on subject age and walking velocity (C228). While hip flexion-extension, stride length, hip resultant force, hip resultant moment, and hip contact force all increase with increasing velocity, only the hip resultant force was unaffected by the age of the subject. Clearly, then, the use of such parameters for clinical purposes requires appropriate correction for subject size, age, and walking velocity. The compliance of the human ankle joint was examined, and the dependence of the measured compliance on the mean joint angle was found primarily to be related to the passive properties of the joint and limb tissues (A25,G175). In a kinematic study, the shoulder complex was described as a 2-component system consisting first of the clavicle and scapula, with the second component composed of the scapula and humerus (D 159). Elevation of the arms was divided into 4 phases, and the importance of the serratus anterior as a prime mover of the shoulder girdle was emphasized. INFLAMMATION An outline of the history of inflammation was presented (R 106). The mediating systems participating in inflammatory disease, especially immunologic injury of the glomerulus, were discussed (C162). A concept of polyclonal activation as a form of primitive immunity, and its possible role in chronic inflammation, was presented ((2138). Mechanisms of interaction between the blood coagulation system and mediators of the inflam- matory response were described (Zl 1). The chemical aspects of inflammation were reviewed briefly (W 102). Thio complexes of monovalent copper were shown to be useful antiinflammatory agents in rats (W 103). Circulating copper levels rose significantly during inflammatory processes. Carrageenan-induced edema was significantly greater in copper deficient rats than in normal control animals (M231). INFLAMMATION The value and pitfalls of serum complement measurements in clinical medicine were reviewed (W96). Evidence was presented that antibody excess favors the complement activating effect of immune complexes (R1 1). The capacity of several agents to activate the complement system via the alternative pathway paralleled their ability to induce inflammatory responses in vivo (S100). A brief review of the role of complement in the pathogenesis of rheumatic diseases appeared (P 14). Soluble immune complexes did not cause release from platelets of serotonin, but conversion of soluble complexes to insoluble immune precipitates by rheumatoid factor induced serotonin release not associated with platelet aggregation or acid hydrolase release (Y 13). Horseradish peroxidase (HRP), a small protein antigen, was shown to pass from capillary lumen to joint space of rabbits (after intravenous or intraarticular injection) across fenestrated vessels (M268). Antigen localized to collagen fibers and synovial lining cells. Presence of fenestrated capillaries may render the synovium particularly vulnerable to antigen deposition. The possible role of synovial tissue cells and their products in degradation of joint structures was reviewed (D43). The interaction of circulating cells which enter sites of inflammation with resident tissue cells (e.g., synovial cells) was discussed, especially as the interaction relates to rheumatoid arthritis (D44). The relationship between cell mediated immunity and an inflammatory response was discussed (C176). The role played by suppressor cells (T and B cells and monocytes) in immunologic regulatory systems and abnormalities in disease was reviewed (W7). Responses of lymphocytes to antigens were compared in mother-neonate pairs and were found to be disparate (R176). The authors concluded that the relative resistance of the neonate to some infections does not depend on the transplacental passage of cellular immunity. The way in which immune thymus-derived lymphocytes (T cells) contribute to development or resolution of disease processes was considered (D121). It was shown that amethopterin-induced, lymphocyte-mediated inflammation in rats was blocked by hydrocortisone and nonsteroidal antiinflammatory agents (G 19). Persistent inflammatory responses induced by complete Freund’s adjuvant enhanced lymphocyte-mediated inflammation (G20). Modifications of the sponge implantation technique for inducing acute inflammation were described (F80). In the carrageenan-induced granuloma, it was observed that calcium ethylenediamine tetracetate treatment enhanced resorption of granulation tissue as a re- 265 sult of increased degradation of noncollagen protein (N10). Blood platelets were shown to accumulate early in development of carrageenan-induced paw edema and were considered to play an important role in initiation and perpetuation of the inflammatory response (V51). Lipid peroxidation in liver was found to be increased in rats with carrageenan-induced paw edema, and decreased in rats with adjuvant-induced arthritis (R96). The characteristics of acetic acid-induced pleural inflammation were outlined (C3). Evidence was presented that sensory nervous structures contribute to development of inflammatory responses through release of an active agent. Calcitonin was shown to inhibit the inflammation associated with adjuvant arthritis, nystatin edema, and the Arthus reaction (A7). Hydrocortisone, but not deoxycorticosterone, amplified PGEinduced increases in mast cell cyclic AMP and reduced histamine release (T70). It was shown that colchicine treatment of human leukocytes enhanced CAMP concentrations induced by compounds which stimulate adenylate cyclase (R 1?2). The authors suggested that cytoplasmic microtubules interact with the plasma membrane to impose constraints on the expression of hormone-sensitive adenylate cyclase. Chemotaxis One group used a new system in which cells can be viewed by phase microscopy as they are exposed to controlled concentrations and concentration gradients of chemotactic factors to investigate the ability of human and rabbit polymorphonuclear leukocytes (PMN) to orient along the direction of N-formylmethionyl chemotactic peptides (27). The early events in chemotaxis were viewed directly, and it was shown that PMN orientation depends upon mean concentration, as well as the concentration gradient of the chemotactic peptides. Cells were able to discriminate a 1%concentration difference. [An important advance in the study of PMN chemotaxis. Ed.] Colchicine (lo-’ M) was shown to inhibit random (chemokinesis) rather than directed or oriented (chemotaxis) locomotion of human PMN (V4). Thus the colchicine effect may be due to alteration in membrane transport of the signal for appropriate locomotion, rather than a microtubule effect. It was shown that human peripheral blood mononuclear cell chemotaxis, like PMN chemotaxis, is composed of a direct microtubule insensitive locomotion, and a leukocyte-induced microtubule dependent locomotion (S2 13). Phago- INFLAMMATION 266 cytosis-associated chemotaxis of these cells was not inhibited by antitubulin drugs, supporting the hypothesis of a tubulin insensitive chemotactic mechanism (R185). Preincubation of human PMN with a monosodium urate crystal-induced serum chemotactic factor was found to inhibit Con-A capping in colchicinetreated cells. It was proposed that the chemotactic factor might induce assembly of microtubules, thus preventing binding of colchicine to tubulin subunits (M49). Accumulation on a bottom filter of the Boyden chamber of PMN responding to casein measured mainly leukocyteinduced chemotaxis (B4). This locomotion was found to be antitubulin-sensitive. The antitubulin-induced inhibition was independent of the complement system. Soluble immune complexes, like insoluble complexes, can act on fresh normal guinea pig serum to induce chemoattractants for PMN. Chemotactic activity appeared due to serine esterases as well as complement activation (L81). Inhibition of rheumatoid but not healthy control leukocyte migration by IgG-IgG complexes was observed. That the inhibitory effect was mediated through the Fc region of the Ig implies some abnormality in Fc receptor function on rheumatoid cells (H19). Chemotactic factors (complement fragments and synthetic tripeptides) induced neutropenia when infused into rabbits (013). The neutropenia-inducing dose paralleled the chemotactic potency of the synthetic peptides. Neutropenia may have been due to leukocyte margination and/or agglutination. Tissue extracts from biopsies of acute skin inflammation induced on the backs of guinea pigs by dinitrochlorobenzene yielded a factor @robably a C3 cleavage product) chemotactic for PMN (at 12 hours) and an inhibitor of PMN chemotaxis (at 48 to 96 hours) (Bl). Thus another system for limiting acute inflammation has been uncovered. The effects of a variety of antiinflammatory drugs on granulocyte emigration in vivo in the rabbit skin collection chamber were examined (B202). Results after topical application of some agents correlated well with those obtained for oral treatment. The authors suggested that the technique may prove useful in screening antiinflammatory drugs. Phagocytosis Phagocytic cells, exemplified by macrophages and polymorphonuclear leukocytes were well studied: the role of macrophages in the rheumatic diseases was reviewed (S274), and the role of macrophage activation in chronic inflammation was discussed (A63). The in- volvement of PMN in inflammation and tissue damage was reviewed (B6). Leukocyte disappearance-probably due to aggregation of PMN and macrophageswas observed during acute nonimmune (e.g., powder glass-induced) inflammation (S409). The evidence was reviewed that phagocytosis results from enzymatic and mechanical interactions attributable to proteins exhibiting structural and functional properties established for actin and myosin of muscle (S387). Oxygen consumption by phagocytic leukocytes from patients with rheumatic diseases was shown to be less than in similar cells from normal controls (K188). The initial rate of particle uptake by PMN was accelerated in patients treated with penicillamine (H25). [Perhaps penicillamine therapy facilitates clearance by PMN of immune complexes. Ed.] Sera from pregnant women were found to contain a nondialyzable, heatstable factor which suppressed phagocytosis by human PMN (P93). The finding may help explain why pregnancy induces remission in rheumatoid arthritis (RA) patients. It was shown that compounds which increased cellular cyclic AMP reduced release of superoxide anion (02-) from human leukocytes engaged in phagocytosis (L62). The authors suggested that elevation of cyclic AMP could constitute a natural means of limiting inflammatory tissue damage. Lysosomes An elegant review of the role of lysosomes in rheumatoid joint inflammation appeared (W80). The actions of lysosomal enzymes on the degradation of cartilage components in relation to rheumatoid and osteoarthritis were outlined clearly and concisely (G71). The proteoglycan-degrading proteins of rabbit fibroblasts and leukocytes were described (W87). Soluble immune complexes (7S-22S), prepared in vitro or obtained from RA serum and synovial fluid, were fractionated into 3 pools, and their effect on provoking lysosomal enzyme release from human PMN was studied (M308). The 7 s pool (in vitro and synovial fluid) induced enzyme release. Interference with particle uptake and subsequent lysosomal enzyme release from guinea pig neutrophils by prostaglandins and several antiinflammatory agents were documented (S261). It was shown that extracts from human peripheral blood polymorphonuclear leukocytes and PMN granule lysates enhance immunoglobulin (Ig) synthesis by autologous peripheral blood lymphocytes (Y3). The effect was due to proteolytic enzymes, and the findings thus in- INFLAMMATION dicate another role for lysosomal enzymes in the pathogenesis of tissue injury. The action of the serine proteinase of human PMN on cartilage and tendon was investigated (S342). The molecular sequence of articular collagen degradation was determined. A serum activator that generates the chemotactic C5 fragment, C5a, is contained in specific granules of human PMN, whereas a C5a inactivator is restricted to azurophil granules. These molecules were found to be released at different times during phagocytosis, and may therefore contribute to local regulation of acute inflammatory responses (W194). Acute pleural exudates were produced in rats with calcium pyrophosphate dihydrate crystals (D76). Indiscriminate (nonselective) enzyme (lysosomal and cytoplasmic) release was not inhibited by intrapleural administration of cyclic AMP and theophylline. It was suggested that cyclic AMP is not important to regulation of PMN phagocytic and secretory functions. Mediators The mechanisms were reviewed whereby collagen breakdown is controlled. These events were related to cartilage degradation in RA (H63). The possible role of neutrophil proteinases in degradation of articular cartilage was reviewed (B46), as was the nature and regulation of neutral protease secretion by macrophages (G167). Human skin collagenase was purified, and its natural serum inhibitors were studied (W189). The activity of vertebrate collagenase was increased 3-fold by a heat and pH stable macromolecule found in normal human serum (S151). Latent collagenase released from rheumatoid synovial cells in culture was activated by plasminogen. Thus, rheumatoid synovium probably produces both latent collagenase and plasminogen activator (W88). It was shown that rheumatoid synovial cells in culture produce an inhibitor of collagenase as well as latent enzyme; the 2 probably exist in vitro as an enzyme-inhibitor complex (V33). Rheumatoid synovial cells that have been dissociated enzymatically from synovial tissue and are adherent to culture vessel surfaces are heterogeneous and include fibroblasts, macrophages, large rounded cells, and striking nonphagocytic “dendritic” or “stellate” cells with long radial extensions (W190). Immunofluorescence studies with a monospecific antibody to human collagenase localized the enzyme around these cytoplasmic extensions, suggesting that the dendritic cells secrete large quantities of active enzyme. 267 Collagenase has also been immunolocalized to the cartilage-pannus junction in tissue from patients with RA (W186). The observations supported the idea that synovial collagenase participates in cartilage erosion in RA. Greater collagenase activity was found in RA than degenerative joint disease synovial fluids (P69). Collangenase and elastase released from human neutrophils during phagocytosis formed complexes with serum a,-antitrypsin (021). Collagenase was found to be almost exclusively a component of specific granules in human PMN (M344). Human PMN collagenase attacked type I collagen preferentially (15 times greater activity) compared with type 111 collagen (H 187). It was shown that cathepsin B1 plays an important role in collagen breakdown and resorption of granulation tissue (N9). Collagenolytic cathepsin activity was detected in lysed rabbit peritoneal PMN (G78). Human PMN azurophil granules contain a neutral protease which can cleave IgG, producing a Fab-like piece (F73). Evidence was presented that antibodies directed at hidden antigenic sites in IgG revealed by endogenous proteolysis take part in the immune reaction and in the inflammation of rheumatoid joints (F22). A latent neutral proteinase was found in culture media of mouse bone explants (Vl). The latent enzyme was activated by treatments known to activate procollagenase. An aminopeptidase of human neutrophil lysosomes was partially purified and was found to amplify bradykinin-induced vascular permeability (P45). A new connective tissue activating peptide (CTAP) was described (C64). CTAP-111 is made in platelets. CTAP from lymphocytes (CTAP-I) and from platelets stimulated ”SO, incorporation into glycosaminoglycans in connective tissue cells in vitro (C65). Thymus-dependent lymphocytes challenged with specific antigen produced a factor(s) capable of causing dermal fibroblasts to undergo DNA and collagen synthesis (W4). Thus, fibroplasia and collagen deposition associated with chronic inflammatory disease may result from lymphocyte-mediated activation. Evidence was presented indicating that transformed lymphocytes produce a molecule which is a specific chemoattractant for lymphocytes (H193). It was shown that bradykinin-induced increases in cAMP in human synovial fibroblasts are due to activation of a phospholipase whose products (arachidonic acid, prostaglandins) stimulate adenylate cyclase (N43). The cAMP increments were inhibited by hydrocortisone and indomethacin. Only hydrocortisone prevented release of arachidonic acid. Rheumatoid syno- INFLAMMATION vial cells in culture secreted far less plasminogen activator than nonrheumatoid cells (B 1 11). Thus, rheumatoid cells may be defective in fibrinolysis capability. Polyethylene glycol was used to produce multinucleated cells in rabbit synovial fibroblast populations (B242). Collagenase in these cultures was increased 10fold over control cultures. On exposure to sucrose or neutral polysaccharides, cell cultures from human synovium exhibited ultrastructural changes similar to those described in rheumatoid synovium (L48). Changes were accompanied by increased intracellular lysosomal enzyme activity. An assay system was described that allows the presence of inflammatory factors in supernatants from stimulated human peripheral blood lymphocytes to be demonstrated by induction of an inflammatory exudate in mouse peritoneal cavity (W39). Prostaglandins A lucid, crisp review of the effects of prostaglandins on platelet aggregation appeared (N83). The evidence which led to the discovery that prostaglandins are mediators of inflammation was reviewed (F69). A commentary on the role of prostaglandins in chronic inflammation appeared (B 196). Most of the existing data were reviewed. The role of prostaglandins in inflammation was discussed (B195). The focus was on use of prostaglandin synthetase inhibitors in essential fatty acid deficient rats. The influence of prostaglandins on connective tissue cell growth and function was reviewed. PGE 1 was found to enhance glycosaminoglycan synthesis and reduce proliferation of cultured fibroblasts (P99). Endogenous prostaglandin production is markedly decreased in essential fatty acid deficient (EFAD) rats (P35). Collagen synthesis in granuloma induced by carrageenan-impregnated sponges was much greater in EFAD than in control rats, suggesting that prostaglandins may exert a negative feedback effect on collagen metabolism during proliferative inflammation. An ether-soluble, indomethacin-inhibitable activity [Presumably prostaglandins. Ed.] produced by rheumatoid synovium inhibited the metabolism of rabbit articular cartilage (L 153). The authors suggested this as a mechanism whereby prostaglandins may influence development of cartilaginous lesions in inflammatory arthritis. Human synovial fibroblasts in culture desensitized to PGE respond (increased cyclic AMP) to bradykinin, and those desensitized to bradykinin respond to PGE (F3). The bradykinin effect appeared to be mediated in part by prostaglandins. [These carefully done experiments emphasize the complex interaction which occur between mediators of inflammation in the rheumatoid joint. Ed.] Particulate materials added to sponges implanted in rats resulted in leukocyte migration and prostaglandin accumulation (F79). The 2 processes were not related. Naturally occurring antiiiammatory agents A summary of knowledge of rheumatoid synovial collagenase and its natural serum inhibitors, PIanticollagenase and a,-macroglobulin, in relation to cartilage collagen resorption was presented (W187). The role of endogenous antiinflammatory proteins was commented upon extensively (L106). Normal cartilage contains low molecular weight cationic protease inhibitors which inhibit collagenase. An analysis of how these molecules help prevent cartilage degradation was presented (K176). A radial diffusion assay for tissue collagenase was devised and used to examine known or potential inhibitors of collagenase (Y7). Thus, the procedure has potential for clinical determination of naturally occurring collagenase inhibitors. An assay was described for inhibitors of collagenase produced by rabbit bone, skin, and uterus in culture (M343). It was shown that the a m i t y of a,-macroglobulin for human granulocyte collagenase was about 10 times that of a,-antitrypsin, and the concentration of a,antitrypsin in blood exceeds that of a,-macroglobulin by about 12 times. Thus, the inhibitors appear equally important for defense against granulocyte collagenase (022). Human platelet factor 4 was shown to inhibit collagenase in addition to neutralizing heparin (H143). An inhibitor of kallekreins was obtained from rat kidney tubules (F121). Human chemotactic factor inhibitor (CFI) was shown to have antiinflammatory activity (J59). Small amounts of CFI suppressed the reversed passive Arthus reaction and immune complex-induced alveolitis.