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We report the case of a 13-year-old boy with acetylcholinesterase deficiency, a congenital myasthenic syndrome, who developed sleep hypoventilation syndrome during a period of rapid growth. His symptoms were insidious and life-threatening despite changes in strength or lung volume measurements that were not marked. He responded well to noninvasive nocturnal ventilation, with reversal of symptoms and normalization of blood gases. His lung volumes, but not motor function, improved after treatment.

Neonatal alloimmune thrombocytopenia (NAIT) most commonly involves antibodies directed against the PlA1 antigen, but other platelet specific alloantigens have been associated with it. We describe the case of a mother whose first three infants developed NAIT secondary to anti-Bak(a) antibodies, while her fourth infant did not. The three affected infants were treated postnatally with platelet transfusions. The fourth infant was treated antenatally with one dose of intravenous immunoglobulin (IVIg) given to the mother. Postpartum analysis revealed the infant's platelets to be Bak(a)-positive but negative for elevated IgG. Maternal serum reacted with neonatal platelets in vitro, but cord serum was negative for antiplatelet antibodies. These clinical observations do not prove the efficacy of IVIg; however, they raise several questions: Why wasn't this infant thrombocytopenic? Why didn't the umbilical cord contain maternal antibody? Was the single dose of IVIg responsible for preventing NAIT? IVIg is currently under investigation in a clinical trial evaluating its effectiveness in preventing NAIT in mothers with anti-PlA1 antibodies, where it has shown some success. There have been no reports of the use against anti-Bak(a) antibodies. We suggest that a weekly dose schedule may not be necessary for all affected pregnancies, and antibodies with specificity other than anti-PlA1 may require less vigorous therapy.

Somatic cutaneous small sensory fiber neuropathy (SSFN) can be an early manifestation of impaired glucose tolerance and diabetes mellitus and/or insulin resistance among obese subjects and is often associated with pain, wound occurrence and impaired wound healing. It is yet unclear as to whether SSFN is prevalent among obese individuals without glucose and/or insulin dysregulation despite abundant evidence of delayed wound healing. To observe whether there is hypofunctioning of stimulated capsaicin-sensitive cutaneous nerves (small sensory fibers) in obese subjects with/without hyperglycemia and hyperinsulinemia. Fifty-eight morbidly obese and 15 lean subjects were recruited for small fiber testing of the forearm in a cross-sectional study. Hyperglycemia was observed in 35 obese subjects. Of 25 obese subjects, hyperinsulinemia was noted in 15, 14 of which were hyperglycemic. No subjects demonstrated symptoms/signs of neuropathy over the hairy skin of the forearm. In fact, a neurological examination revealed that 37 subjects were asymptomatic in the legs and only four complained of a neuropathic pain in the foot. Virtually all subjects were exposed to a set of capsaicin-sensitive tests and measures which were identified by capsaicin desensitization procedures. These tests, conducted while in a supine position in bed at the Banner Good Samaritan Medical Center, Phoenix, examined the two principle roles of cutaneous SSFs, namely conveying pain signals to the CNS and controlling local neurogenic vasodilatation (flare; axon-reflex). Heat-induced pain was assessed by verbal reports of sensation after accommodation and heat-, capsaicin-, and transcutneous stimulation- induced blood flow was measured by laser Doppler flowmetry with probes placed at the site of stimulation and 1 cm remote from the site, the latter to evaluate flare latency and intensity of flare. Significant depression of pain and flare responses were observed in the obese subjects in all but one test. Decreased pain and flare responses were noted in all subjects without hyperglycemia and hyperinsulinemia. Age negatively correlated with capsaicin-induced flare in both the obese and normal groups. SSFN was prevalent in the cohort of morbidly obese subjects in a skin area without neurological symptoms or signs and in subjects with/without hyperglycemia and hyperinsulinemia. SSFN may be a serious factor in observations of impaired wound healing among obese subjects, a particularly worrisome problem in an obese aging population given the propensity for small fiber impairment in aging subjects. Small fiber impairment in the younger obese population may signal an early aging phenomenon.

We report the case of a 13-year-old boy with acetylcholinesterase deficiency, a congenital myasthenic syndrome, who developed sleep hypoventilation syndrome during a period of rapid growth. His symptoms were insidious and life-threatening despite changes in strength or lung volume measurements that were not marked. He responded well to noninvasive nocturnal ventilation, with reversal of symptoms and normalization of blood gases. His lung volumes, but not motor function, improved after treatment.

Previous reports have suggested that antibodies reactive with neutrophils (ARN) are frequently detectable in patients undergoing bone marrow or blood stem cell transplantation (BMT), and that such antibodies result in steroid-responsive delayed neutrophil engraftment or steroid-responsive post-engraftment neutropenia in some patients. However, the true incidence and significance of ARN in the BMT setting remain poorly established because most of the published data are in the form of retrospective case reports. Therefore, we prospectively studied the incidence of ARN, the rate of neutrophil engraftment, and the incidence of post-engraftment neutropenia in a cohort of 40 BMT candidates. Sixteen of the 36 evaluable patients (44%) had detectable ARN following transplant vs none of 25 concurrently studied healthy controls (P0.0001). Patients with detectable ARN in the post-transplant period recovered to an absolute neutrophil count (ANC) of 500 x 10(9)/l a median of 3.5 days later than patients without detectable ARN; multivariate analysis controlling for the potential effects of diagnosis, conditioning regimen, amount of prior therapy, and other factors revealed that only the administration of hematopoietic growth factors (P = 0.008) and the presence of ARN in the post-transplant period (P = 0.016) were independently predictive of the rate of neutrophil engraftment following BMT. Four of the 16 patients with detectable ARN (25%) satisfied previously published criteria for post-engraftment neutropenia, ie a fall in the ANC to less than 500 x 10(9)/l for at least 2 consecutive days, following initial engraftment to an ANC of at least 1000 x 10(9)/l for at least 2 consecutive days. In contrast, none of the 20 patients without detectable post-transplant ARN developed post-engraftment neutropenia. Multivariate analysis revealed that only the presence of ARN in the post-transplant period (P = 0.022) was independently predictive of post-engraftment neutropenia. All four patients with ARN-associated post-engraftment neutropenia responded to steroid-based therapy. These prospectively gathered data support previously published primarily case report data suggesting that ARN occur frequently following BMT and are associated with an increased incidence of delayed neutrophil engraftment and post-engraftment neutropenia. As is the case in the non-transplant setting, ARN-associated neutropenia occurring following BMT may respond to steroid-based therapy.

We studied 526 consecutive post-transplant platelet transfusions to determine the factors associated with response to platelet transfusion in the BMT setting. Poor responses to platelet transfusions occurred frequently, with 310 of the 484 evaluable transfusions (64%) resulting in post-infusion corrected count increments of less than 7500. Factors associated with poor response to platelet transfusion by both univariate and multivariate analysis included, (1) presence of serum lymphocytotoxic antibodies; (2) male sex; (3) body surface area greater than 1.7 m2; (4) transfusion of red cells on the day of the platelet infusion; (5) concurrent administration of steroids; (6) major ABO mismatch between the recipient and the platelet product; and (7) (among women) a history of one or more pregnancies prior to transplant. Paradoxically, a history of greater than 25 blood product exposures prior to transplant, and evidence of prior CMV infection in either the bone marrow donor or recipient were associated with higher CCIs by both univariate and multivariate analysis. Factors that showed little correlation with response to platelet transfusion included, (1) age of the infused platelet product; (2) concurrent fever; (3) recent administration of intravenous immunoglobulin; and (4) absolute neutrophil count at the time of the infusion. The factors associated with response to platelet transfusion in BMT patients appear to be different from those observed in the non-transplant setting.

Many clinical situations involve the platelet transfusion support of patients with thrombocytopenia. Among these are patients with leukemia, oncology patients receiving chemotherapy, patients undergoing bone marrow transplantation, patients with idiopathic thrombocytopenia purpura (ITP), and the acute trauma patient. The Transfusion Medicine service plays a key role in the care of patients in that they are expected to provide quality blood products and aid in clinical decision making. Issues often encountered are the effectiveness, efficiency, and appropriateness of the products being given. This review covers the clinical consequences of thrombocytopenia, the relationship between platelet count and hemorrhage, the impact of platelet transfusion on hemostasis, the "optimal" dosage of platelets, and the importance of individualizing dosage in various common clinical scenarios.

Recombinant myeloid growth factors have been increasingly used in recent years to combat induced and disease associated neutropenia. Their application in the management of Felty's syndrome with intercurrent infection has raised concern that resultant neutrophilia and activation of a diverse array of polymorphonuclear cell functions may have an adverse effect on the rheumatoid disease process. We describe a patient with Felty's syndrome receiving short term treatment with recombinant human granulocyte colony stimulating factor (GCSF), who then developed acute renal failure in conjunction with leukocytoclastic vasculitis and presumptive gout. We address the issue of "adding fuel to the fire" and review reported implications of GCSF in induction of vasculitis.

Antibody directed against the platelet-specific alloantigen, PlAl, is the most frequently reported cause of two syndromes, post-transfusion purpura (PTP), and neonatal alloimmune thrombocytopenia (NAIT). Numerous reports have indicated that anti-PlAl also has the ability to block certain responses of platelets to stimulation, including fibrinogen binding, platelet aggregation, and serotonin release. Because the PlAl epitope is located on platelet membrane glycoprotein (GP) IIb/IIIa that also contains the fibrinogen receptor, these effects may be mediated by antibody binding at or near the fibrinogen receptor site. This study examines the capacity of anti-PlAl from patients with PTP and from mothers of infants affected by the NAIT to block the binding of radio-labeled fibrinogen to washed human platelets stimulated by ADP and epinephrine. In six of the seven PTP patients, there was inhibition of fibrinogen binding, ranging from 28% to 84% inhibition. In contrast, all anti-PlAl sera from nine mothers of infants with NAIT, including four with intracranial hemorrhage, failed to inhibit fibrinogen binding. Despite the generally higher anti-PlAl titers of the PTP sera, the ability to inhibit fibrinogen binding did not appear attributable to antibody titers. These results suggest that interference with fibrinogen binding to platelets by maternal anti-PlAl does not underlie the increased risk of bleeding in NAIT, whereas inhibitory activity directed against fibrinogen binding appears to be a characteristic feature of the sera from PTP patients.

To study the in vitro effect of therapeutic levels of select nonsteroidal antiinflammatory drugs (NSAID) on prosthesis associated pseudomembrane induced bone resorption and cytokine and prostanoid synthesis using tissue obtained from osteoarthritic patients undergoing revision of cemented implants.Pseudomembranes were cultured in the presence and absence of therapeutic levels of select NSAID: Processed conditioned media were evaluated for bone resorbing capacity by assessing murine neonatal limb rudiment release of 45Ca. Interleukin 1 (IL-1) and tumor necrosis factor (TNF) were analyzed by bioassay and prostaglandin E2 (PGE2) by radioimmunoassay.Piroxicam, in contrast to indomethacin and sodium salicylate, significantly decreased membrane associated bone resorption. The NSAID effect correlated more consistently with piroxicam downregulation of TNF synthesis than that of IL-1. Consistent drug associated suppression of PGE2 synthesis did not enable differentiation of NSAID effectiveness in suppressing pseudomembrane induced bone resorption.Results provide a rational basis for design of animal models and/or further human studies to test the hypothesis that the prophylactic administration of an NSAID can potentially retard the pseudomembrane effected bone resorptive process associated with aseptic cemented prosthesis failure.

We report a case of unexplained graft failure in a 33-year-old man who received an allogeneic bone marrow graft that contained a donor-recipient mismatch involving the highly immunogenic NA1 neutrophil-specific alloantigen system. Laboratory and clinical data suggest that an alloimmune process related to the neutrophil alloantigen mismatch played a role in the development of the graft failure.

Select classes of nonsteroidal antiinflammatory drugs (NSAID), independent of their cyclooxygenase suppressing property, may potentially regulate pathophysiologic mechanisms operative in accelerated cartilage catabolism occurring in osteoarthritis (OA). Piroxicam has been shown to downregulate the expression of interleukin 1 (IL-1) associated chondrocyte enzyme inducing activity (catabolin) produced by OA synovium. In situ membrane synthesis of catabolin/IL-1 inhibitors functioning at various levels in thymocyte and catabolin bioassay systems is currently shown. The piroxicam effect appears due to a selective increase in production of a naturally occurring inhibitor(s) and/or induction of new inhibitor formation acting on chondrocytes at a post-IL-1 receptor level.

Few advances in our understanding of the polychondritic disease process have been made within the past year. Clinical studies have emphasized pulmonary manifestations and newer means of evaluation of functional and anatomic upper and lower airway disease. Esophageal dysfunction has been described. Further associations have been established with Sjögren's syndrome and with malignancy. Active disease during pregnancy was not associated with neonatal transmission. Although lacking diagnostic specificity, preliminary studies suggest that serum quantitation of a noncollagenous cartilage matrix protein may correlate with disease activity. Differential diagnosis must now include a recently described form of hereditary chondropathy. Segmental tracheal resection and splinting techniques including use of stents have been advocated for therapeutic management of severe tracheobronchial disease.

In a placebo-controlled, randomized blinded study, we evaluated the efficacy of intravenous gammaglobulin (IV-IgG) in alloimmunized thrombocytopenic patients. IV-IgG was administered at a dose of 400 mg/kg for 5 days. An incompatible platelet transfusion from the same donor was used before and after treatment. Seven patients received IV-IgG and five patients received placebo. Although platelet recovery in 1 to 6 hours was satisfactory in five patients after IV-IgG treatment, 24-hour survival was not improved in most patients. None of the patients receiving the placebo achieved satisfactory 1-hour platelet-corrected count increments (CCIs). By t test, the posttreatment mean values 1 hour after transfusion CCIs in the IV-IgG group were significantly greater than in the control group (8,413 v 1,050, P less than .007). Using a regression model to adjust for any distributional assumptions of the study population, the parameter estimate for IV-IgG treatment was positive, indicating that IV-IgG treatment is associated with higher CCIs. Although IV-IgG may improve 1-hour platelet recovery, clinical benefit was not demonstrated since 24-hour survival was not improved. IV-IgG treatment before unmatched platelet transfusions should not be considered as a replacement for HLA-compatible platelets in alloimmunized patients.

Baka is a platelet alloantigen whose putative allele, Bakb, has not been identified previously. By using a serum, “Har,” obtained from a patient with posttransfusion purpura, we describe the platelet alloantigen Bakb. The Har serum reacted with an NP-40-extractable platelet membrane protein of 142 kd with mobility similar to platelet glycoprotein IIb alpha. We found that the antigen recognized by the Har serum is inherited in an autosomal dominant mode with an apparent gene frequency of .39. Chi-square analysis of observed and expected phenotype frequencies indicated that serum Har recognizes Bakb, the anticipated allele of Baka. Our findings provide new evidence for polymorphism of glycoprotein IIb and for the association of posttransfusion purpura with alloimmunization to determinants on this glycoprotein.

A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

Posttransfusion purpura typically occurs in PLA1 negative blood recipients who have been previously immunized to the PLA1 antigen. Following transfusion, severe thrombocytopenia develops with the formation of anti-PLA1. Since the patients' platelets lack the PLA1 antigen, one would not expect this antibody to destroy autologous platelets. In this study we show that PLA1 antigen exists in stored blood and can absorb to PLA1 negative platelets making them PLA1 reactive. Incubating PLA1 (-) platelets with ultracentrifuged plasma from PLA1 (+) blood donors allowed anti-PLA1 to bind to PLA1 (-) platelets. Control plasma from PLA1 (-) blood donors did not lead to anti-PLA1 binding. Using an inhibition assay, we showed that stored blood contains PLA1 material that was not removed by ultracentrifugation. The material absorbing to PLA1 (-) platelets represented the PLA1 antigen, which was confirmed by Western blotting. After incubating plasma containing PLA1 antigen with PLA1 (-) platelets, reactivity at 95,000 D was observed. Native PLA1 (+) platelets showed a similar band. When PLA1 (-) platelets were incubated with plasma from a PLA1 (-) donor, this band was not present. These studies show that a soluble form of PLA1 antigen exists in stored blood that can absorb to PLA1 (-) platelets. Consequently, anti-PLA1 can bind to these platelets leading to thrombocytopenia. These observations may explain the autologous destruction of platelets in posttransfusion purpura.

The use of platelet transfusions to stop or to prevent bleeding in patients with thrombocytopenia or platelet dysfunction has accelerated in the past decade. Platelet counts and bleeding times, performed in conjunction with careful clinical evaluation of the patient, are appropriate guides in assessing the need for platelet transfusion. Complications of platelet transfusions are similar to those of red cell transfusions, with some additional concerns. Pooled random donor or single-donor apheresis concentrates, either randomly or selectively matched, are the major platelet products available. In most cases, transfusion requirements can be satisfied by use of random donor units. Proper evaluation of the effectiveness of transfused platelets is essential in determining the dose and frequency of future platelet transfusions. Refractoriness to random donor platelets eventually occurs in many recipients. This is most commonly associated with alloimmunization to histocompatibility antigens, but other platelet alloantigens may play a role. Many in vitro tests for platelet antibodies have been developed, and the clinical utility of these assays in selecting compatible platelets is now under evaluation. Strategies and different approaches to the management of thrombocytopenic patients with hypoplastic bone marrow states are also reviewed.

In studies designed to establish the safety and efficacy of laser treatment of arthritis, the in vitro effect of Nd:YAG laser radiation on normal, osteoarthritic and rheumatoid synovial tissue and synovial fibroblast metabolism has been addressed. Defined energy levels of normal pulsed radiation (TEMoo mode) consistently up-regulated synovial tissue explant culture hyaluronic acid and protein synthesis. In contrast, high intensity Q-switched delivery down-regulated the response. The application of normal pulsed radiation had a variable effect on synovial fibroblast synthesis but the response of any given cell isolate was consistent. DNA synthesis and cell viability were not affected.

A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

The multiple cholesterol emboli syndrome associated with severe atherosclerotic vascular disease may clinically simulate systemic necrotizing vasculitis. Widespread visceral infarctions in conjunction with potential leukocytosis, eosinophilia, thrombocytopenia, hypocomplementemia and an elevated sedimentation rate may be present. It frequently occurs after intraarterial procedures such as cardiac catheterization and aortography. Diagnosis is made by biopsy of involved tissue. It is essential to establish a proper diagnosis to avoid inappropriate use of steroid and cytotoxic treatment measures.

A variety of space traveling tubes and amplifiers have been developed and manufactured from 10 through 60 GHz. The tubes, which employ either a helix or coupled cavity slow-wave structure, provide output power of 1 to 100 W or more in some cases. High-efficiency, lightweight power supplies have been provided with certain amplifiers. Phase and gain performance characteristics are presented which demonstrate applicability to communications systems. Prospects for future increases in power and efficiency offer expanding horizons to the system engineer.

Studies were undertaken to define more fully the antigenic properties of human articular cartilage proteoglycans, in anticipation of its potential contribution to alterations arising in diseased states and following cartilage transplantation. Proteoglycans, extracted from normal, adult articular cartilage by dissociative measures, were subjected to purification by cesium density gradient ultracentrifugation, under conditions facilitating both molecular aggregation and dissociation. A polydisperse population of reactive determinants was observed in immunodiffusion and hemagglutination inhibition systems, employing proteoglycan specific antisera on gradient fractions. Highly aggregated proteoglycan species appeared to contain potentially masked antigenic determinants, which were revealed after guanidine dissociation but not hyaluronidase digestion. Polyacrilamide disc gel electrophoresis in sodium dodecyl sulfate, in conjunction with disc elution experiments, confirmed proteoglycan antigenic polydispersity.

Previous investigations of ribonucleotide binding activity in the sera of patients with connective tissue diseases unexpectedly identified binding to the single stranded nucleotide polyadenylic acid (Poly [A]) in osteoarthritic patients serving as control subjects. The basis for this response and the nature of the binding factor(s) were not evaluated. Hypothesizing that such activity may originate from diseased joint tissue and that its measurement would provide a valuable parameter to assess active cartilage catabolism, the present study examined the Poly (A) binding affinity of cartilage isolates. It was shown that low buoyant density associative cesium chloride gradient fractions of guanidine extracts of cartilage could bind to Poly (A). Activity appeared to be largely masked in native proteoglycan aggregates but could be identified in low buoyant density dissociative cesium chloride gradient fractions of aggregates. Chondroitin sulfate, hyaluronic acid and native and denatured cartilage collagen had a minimal binding affinity. By nucleotide absorption, a purine ring specificity was shown for the active binding factor. Using polyacrylamide slab gel elution and Poly (A) affinity chromatography, activity was localized to a 57 KDa protein.

Previous investigations assessing ribonucleotide binding in the sera of patients with diverse forms of connective tissue disease unexpectedly identified positive responses in control osteoarthritic subjects. The current study, using a radiolabelled assay, confirms the presence of a polyadenylic acid (Poly [A] binding factor(s) in the sera of a group of 50 well-characterized patients having primary or secondary forms of this disease process as contrasted with matched control subjects. The significance of such binding activity is unknown. No significantly meaningful correlation could be established between serum Poly (A) binding levels and clinical or x-ray parameters of disease.

Conditioned media derived from explant cultures of human osteoarthritic synovial tissue have been shown to contain preformed and newly synthesized factors of variable molecular weight which are capable on a concentration dependent basis of modulating cartilage proteoglycan metabolism. Anabolic inhibitory and stimulatory activity often appeared to coexist, a reversible down-regulation usually dominating in unfractionated preparations. The size of newly synthesized proteoglycan aggregates and monomers and the length of glycosaminoglycan chains produced in the presence of conditioned media were normal. The pattern of anabolic response did not necessarily correlate with the presence of catabolic inducing activity.

Non-enzymatic factors produced by synovial tissue can potentially mediate cartilage destruction by inducing the synthesis and release of matrix-degrading proteinases from chondrocytes. Pharmacologic control of this process is of potential clinical relevance. The in vitro effect of therapeutic concentrations of select nonsteroidal antiinflammatory drugs on the synthesis and activity of catabolism-inducing cytokines produced by 6-day explant cultures of osteoarthritic and rheumatoid synovial tissue was studied. Piroxicam regularly suppressed such factor synthesis by both types of tissue without significantly affecting total protein synthesis. This did not occur using sodium salicylate or indomethacin in osteoarthritis tissue cultures and was observed only occasionally in rheumatoid arthritis cultures. None of the nonsteroidal antiinflammatory drugs studied consistently blocked catabolism-inducing activity in osteoarthritis tissue, whereas piroxicam more consistently inhibited activity produced by rheumatoid arthritis tissue. Results suggest that the catabolism-inducing factors produced by the 2 tissue sources may differ.

The issue of selecting nonsteroidal anti-inflammatory drugs (NSAIDs) for the management of osteoarthritis based upon their direct effect on normal cartilage metabolism and their ability to modulate mechanisms that disturb such metabolism is addressed. This article provides an overview of the anatomic and biochemical changes that occur in diseased synovial tissue and cartilage, and the pathophysiologic mechanisms presumed to function in the induction and perpetuation of cartilage failure. Studies using experimental animal models of osteoarthritis are reviewed to evaluate the natural history of the disease, as well as the direct effect of NSAIDs on anabolic and catabolic cartilage function. Experimental evidence strongly indicates that NSAIDs of different classes, as well as members within a given class, function differently and manifest activity in addition to cyclo-oxygenase inhibition.

The in vitro effect of piroxicam, a newer nonsteroidal antiinflammatory drug (NSAID), on normal cartilage metabolism has been studied and response contrasted to indomethacin and sodium salicylate. Therapeutic levels of piroxicam has no effect on cartilage glycosaminoglycan (GAG), collagen or noncollagen protein synthesis by porcine weight bearing articular cartilage explants. Salicylate consistently suppressed GAG and protein synthesis, whereas indomethacin had no consistent effect on GAG production but suppressed protein synthesis. NSAID studied had no effect on proteoglycan catabolism. The potential significance of the effect of NSAID on cartilage metabolism is discussed and placed in perspective as regards selection of these agents for human use.

Investigations were performed to determine the potential of an immunologically-mediated basis underlying development of severe bilateral knee chondrolysis arising over a 2-yr period in a 29-yr-old man. Humoral and cell-mediated immune responses to autologous and homologous articular cartilage proteoglycan and collagen rich fractions were identified in sequential studies. Employing gradient derived peripheral blood mononuclear cells there was demonstration of spontaneous, T cell mitogen augmented and autologous cartilage antigen-induced release of factors capable of degrading articular cartilage proteoglycans and inhibiting chondrocyte glycosaminoglycan synthesis. Evidence has thus been provided incriminating immunologic events, likely functioning in a perpetuant manner, in the pathogenesis of this chondrolytic process.

Results of clinical, serologic and histologic studies documenting an association between hereditary C6 deficiency and a connective tissue disease are provided. The propositus had systemic lupus erythematosus with prominent discoid features, Sjögren's syndrome and hyperthyroidism. Serum C6 was undetectable by radial immunodiffusion and hemolytic assays. Serologic and typing studies performed on 9 family members suggested an autosomal codominant transmission. No correlation with a specific HLA phenotype was established.

The lysosomal endopeptidase cathepsin D is the most abundant proteinase in chondrocytes. Its significance in the pathogenesis of cartilage matrix proteoglycan (PG) degradation in osteoarthritis (OA) is unclear. The extracellular localization of cathepsin D and its potential spatial relationship to areas of PG depletion has been studied in human femoral head OA cartilage. Enzyme was identified by indirect immunofluorescence using rabbit antisera developed against a highly purified cathepsin D preparation. PG distribution was assessed in parallel sections by safranin O staining. Specimens were selected to include regions of cartilage having minimal structural and cellular alterations, severe reduction in thickness, hypocellularity, multicellular chondrocyte clusters and varying degrees of PG loss. Cathepsin D was identified in chondrocytes. When overlying fibrous connective tissue pannus was present, extracellular enzyme was predominantly localized to the cartilage-pannus interface. Cathepsin D could not be demonstrated extracellularly in areas of cartilage that were partially or totally devoid of PG. Chondrocytes in damaged regions, particularly in the superficial and upper transitional zones showing diffuse hypercellularity and/or "brood" clusters, contained increased enzyme staining. Results fail to support a role for cathepsin D in extracellular matrix PG degradation. The potential significance of this enzyme in the pathogenesis of OA would appear relegated to intracellular catabolism. Its intracellular increase at pathologic sites is consistent with enhanced catabolic activity in such regions.

Laser therapy is being increasingly applied in the treatment of diverse forms of arthritis without a firm scientific basis for its safety or efficacy. Our study in part addresses this issue by assessing the in vitro effect of Nd:YAG laser radiation on mature normal bovine articular cartilage metabolism. Normal pulsed mode delivery of defined energy levels could be shown to consistently upregulate cartilage proteoglycan, collagen, noncollagen protein and DNA synthesis in the absence of histologic or biochemical evidence of enhanced matrix catabolism. Laser induced repair could be shown biochemically in in vitro model systems of enzymatically mediated cartilage matrix depletion. Results suggest that Nd:YAG radiation applied directly at surgery or via arthroscopy may provide a potential means of effecting cartilage healing. Further studies are necessary to substantiate such usage.

Nutriment replenished conditioned media derived from cultures of osteoarthritic and rheumatoid synovial tissue contain factors of variable molecular weight, independent of prostaglandin activity, which are capable of reversibly down-regulating cartilage matrix proteoglycan synthesis. Piroxicam significantly reduced anabolic suppressant factor production on an apparent selective basis. It could be shown to partially modify the chromatographic profile of newly synthesized osteoarthritic synovial tissue protein fractions containing suppressant activity. Dependent on experimental design, piroxicam also partially blocked inhibitory activity at a chondrocyte level. Indomethacin and sodium salicylate were essentially without effect.