Search

Osteoarthritis is a disease in which articular cartilage metabolism is altered, leading to cartilage destruction. As insulin-like growth factor-I (IGF-I) is the major anabolic mediator for articular cartilage, and the IGF-binding proteins (IGFBPs) are an integral part of the IGF axis, they may play a role in the pathophysiology of osteoarthritis. Chondrocytes isolated from fibrillated and normal appearing areas of osteoarthritic human cartilage and from normal cartilage were studied for IGF and IGFBP expression. IGF and IGFBP messenger ribonucleic acids were analyzed by a RT-quantitative PCR technique and Northern blotting. In osteoarthritic chondrocytes, IGF-I message was increased 3.5-fold, IGFBP-3 was increased 24-fold, and IGFBP-5 was increased 16-fold over normal chondrocytes. Chondrocytes from normal appearing areas of cartilage from osteoarthritic joints had intermediate levels. Message levels for beta-actin, IGF-II, and IGFBP-4 were unchanged between the cartilage types. IGF and IGFBP production were analyzed by Western ligand blots and RIAs of conditioned medium from cartilage cultured in serum-free conditions. IGF-I was undetectable in conditioned medium from normal cartilage and increased in that from osteoarthritic cartilage. Osteoarthritic cartilage samples produced IGFBP-2, -3, and -4; glycosylated IGFBP-4; and IGFBP-5. IGFBP-2, -3, and -5 production was increased in osteoarthritic cartilage. Proteases with activity against IGFBP-3 and -5 were also produced by osteoarthritic cartilage. The observation that IGFBP-3 and -5 expression and production are elevated in osteoarthritic cartilage suggests that they may be acting as a competitor for IGF-I in osteoarthritic cartilage, thus reducing the anabolic stimulation of this tissue and contributing to the net loss of cartilage in this disease.

This study tested the effects of hydrostatic pressure (10 MPa) on adult articular chondrocyte mRNA and extracellular matrix synthesis in vitro. High density primary cultures of bovine chondrocytes were exposed to hydrostatic pressure applied intermittently at 1 Hz or constantly for 4 hours in serum-free medium or in medium containing 1% fetal bovine serum. mRNAs for aggrecan, types I and II collagen, and beta-actin were analyzed by Northern blots and quantified by slot blots. Proteoglycan synthesis was quantified by 35SO4 uptake into cetylpyridinium chloride-precipitable glycosaminoglycans, and cell-associated aggrecan and type-II collagen were detected by immunohistochemical techniques. In serum-free medium, intermittent pressure increased aggrecan mRNA signal by 14% and constant pressure decreased type-II collagen mRNA signal by 16% (p < 0.05). In the presence of 1% fetal bovine serum, intermittent pressure increased aggrecan and type-II collagen mRNA signals by 31% (p < 0.01) and 36% (p < 0.001), respectively, whereas constant pressure had no effect on either mRNA. Intermittent and constant pressure stimulated glycosaminoglycan synthesis 65% (p < 0.001) and 32% (p < 0.05), respectively. Immunohistochemical detection of cell-associated aggrecan and type-II collagen was increased in response to both intermittent and constant pressure. These data support the hypothesis that physiologic hydrostatic pressure directly influences the extracellular matrix metabolism of articular chondrocytes.

This study tested the effect of fluid-induced shear on interleukin-6 expression in normal human articular chondrocytes in vitro. As determined by Northern blot analysis, interleukin-6 mRNA expression occurs in chondrocytes from osteoarthritic cartilage but not in normal chondrocytes. Applying fluid-induced shear stress to primary high density cultures of chondrocytes increased interleukin-6 mRNA signal 4-fold at 1 hour and 10 to 15-fold at 48 hours compared with unsheared control cultures. At 48 hours, fluid-induced shear stress increased interleukin-6 protein levels in the culture medium 9 to 10-fold compared with unsheared controls. mRNA signals for interleukin-1alpha, interleukin-1beta, and tumor necrosis factor-alpha in RNA from sheared or control chondrocytes were not detected by Northern blotting. Transforming growth factor-beta mRNA signal was detectable but was not affected by shear. In contrast, human lung fibroblasts (WI-38) responded to fluid-induced shear with increased signal for transforming growth factor-beta, but not interleukin-6, mRNA. Both cell types did respond to interleukin-1alpha with increased interleukin-6 mRNA signal. These data demonstrated that distortional forces, such as fluid-induced shear stress, alter interleukin-6 levels in normal chondrocytes in vitro and suggest that increased interleukin-6 expression in osteoarthritic cartilage may result, in part, from alterations in the mechanical loading of the tissue.

Laser energy stimulates articular cartilage repair when applied at low energy levels (Schultz et al., 1985; Borovoy et al., 1989). Tissue repair occurs through increased cartilage and synovial cell activity. We review here the organization and function of articular cartilage and summarize effects of laser energy on joint tissue as reported in the literature and from our experimental studies with the 2.1 μm holmium:YAG laser. Our studies showed that human articular cartilage responds to low levels of 2.1 μm holmium:YAG laser energy through cell proliferation (DNA synthesis) and increased proteoglycan synthesis (sulfate incorporation into glycosaminoglycan). At high levels of laser energy, cartilage cell metabolism was inhibited.

We report effects of applying variable doses of Holmium:YAG laser energy to bovine articular cartilage in vitro. The response of the cartilage to the Holmium:YAG laser energy was determined by quantification of cell proliferation and extracellular matrix glycosaminoglycan synthesis. This study demonstrates that articular cartilage cell metabolism was maintained at a normal level following treatment of cartilage at a dose of 0.6 joules/pulse. The laser energy was applied at 10 Hz for 10 seconds at 1 mm distance from the cartilage. Under these conditions and at a dose of 0.6 joules/pulse, the total energy density was calculated to be 240 joules/cm2, assuming minimal loss of energy due to water absorption. Energy levels grater than 0.8 joules/pulse corresponding to calculated energy densities greater than 320 joules/cm2 proved harmful to cartilage. Our data demonstrate that low levels of Holmium:YAG laser energy can be applied to articular cartilage under conditions that maintain and/or stimulate cell metabolism.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The authors have used computer modeling techniques to examine stress-related bone changes in the acetabular region. Using a previously developed theory for bone development and adaptation, the authors simulated the distribution of bone density in the natural pelvis as well as changes in bone density following total hip arthroplasty. The geometry of the finite element model was based on a two-dimensional slice through the pelvis. Starting from a solid, homogeneous structure, the computer simulations predicted the distribution of bone density throughout the natural pelvis. The predicted bone density distribution in this first simulation agreed well with the actual bone density distribution only when loads representing multiple activities were incorporated. Using the predicted density distribution as a starting point the authors modified the finite element models to study two designs of noncemented, metal-backed acetabular cups. The simulations with fully fixed bone-implant interfaces predicted extensive loss of bone density medial and inferior to the prosthetic components. The simulations with loose interfaces led to more moderate losses of bone density, indicating a load transfer more similar to that which occurs in the natural joint. The differences in simulated bone remodeling between the two component designs were quite minimal. These results indicate that acetabular components with full bony ingrowth may induce significant stress-related bone remodeling due to a nonphysiologic transfer of load.

This study analyzed processes underlying osteoporosis and osteoarthrosis after short-term immobilization of the right hind limb of postadolescent (2.8 kg) and mature (4.0 kg) rabbits. After 3 weeks, the lateral posterior aspect of the lateral tibial plateau and the lateral femoral condyle of the immobilized limb exhibited prominent subchondral vascular eruptions. Femoral metaphyseal bone density decreased 27 and 18% in the immobilized limbs of postadolescent and mature rabbits, respectively. Calcein green fluorescence increased 1.9-fold (p less than 0.001) in the metaphyseal trabeculae of immobilized femurs. With immobilization, sulfate incorporation into femoral cartilage glycosaminoglycan increased, although total cartilage glycosaminoglycan and hydroxyproline levels were unchanged. Thymidine incorporation into DNA increased four- to fivefold in tibial and femoral cartilage of the immobilized limb. In this study, bone loss and remodeling preceded erosive cartilage degradation.

Foreign body infection is a special clinical problem because with few exceptions standard treatment (debridement and antibiotics) normally effective for most bodily infections is ineffective. Prosthetic implants are common and infection is the second most common reason for failure. The reason that prosthetic infections fail to resolve with antibiotic therapy has remained a mystery, but new insights are beginning to penetrate this enigma. Antibiotics will not kill sensitive bacteria in a test tube when they are attached to an object in the test tube or the walls of the test tube. Evidence suggests that once attachment has taken place bacteria may proliferate in the presence of bactericidal antibiotic concentrations. The extracellular matrix of bacteria, glycocalyx, may in some instances, such as with Staphylococcus epidermidis, enhance survival of bacteria. Glycocalyx appears to promote rapid attachment to foreign bodies under some circumstances. Attachment itself seems to confer upon the bacteria the ability to survive normally lethal concentrations of antibiotics. Critical insights as to the mechanism for this invulnerability are likely to result from investigating genomic expression of the bacteria at the time of attachment.

Human articular cartilage released significantly increased levels of metal-dependent enzymes capable of degrading collagen, casein, and gelatin at a neutral pH following exposure to a sterile, purified fraction of Staphylococcus aureus culture medium. Neutral metalloprotease activity was determined by radiolabeled substrate assays and substrate gel analysis. The enzymes were activated with 4-aminophenylmercuric acetate and were inhibited by 1, 10-phenanthroline and ethylenediamine tetraacetic acid. Protein immunoblots demonstrated that type I collagenase and stromelysin (matrix metalloproteinase III) secretion was increased following staphylococcal medium challenge. The profile of enzymatic activity induced by staphylococcal medium was directly comparable to that observed with interleukin-1, which was used as a positive control. The staphylococcal medium had no inherent proteolytic activity. Increased production of the neutral metalloproteases collagenase and stromelysin may significantly contribute to the extensive cartilage destruction noted in staphylococcal septic arthritis.

Computer simulations of bone remodeling in response to mechanical stresses can be used to understand normal growth and development of the skeleton or to predict the remodeling of bone in response to prosthetic devices. Using a previously derived bone maintenance theory, a technique for computing bone density distributions was applied to the proximal femur and tibia using two-dimensional, multiple-loading finite element models. The models initially represented solid, homogeneous structures. Using an iterative bone remodeling technique that relates bone apparent density to loading history, the internal distributions of apparent density and elastic modulus for the normal bones were predicted. The finite element models were then modified to represent bones in which porous-coated femoral surface replacements and tibial tray components had been implanted. The same iterative remodeling method was then applied to predict the distribution of bone around these components. The predicted bone density distributions for the natural femur and tibia agree with previously documented normal bone morphology. The predicted bone density distributions around various implanted prostheses were characteristic of the component under investigation and were consistent with clinical and experimental findings of other investigators. In the femoral head, stress shielding occurred underneath the metal surface replacement cup, resulting in lower densities in the femoral head. The addition of a central femoral cup fixation peg caused bone hypertrophy around the peg. In the tibia, the stress concentrations around the pegs also resulted in denser bone, with a concomitant decrease in bone density at more peripheral locations underneath the prosthetic tray. This remodeling technique has the potential to be an important tool in predicting the possible remodeling consequences of new implant design features.

The relationship between adherence of bacteria to foreign bodies and their deposition of extracellular matrix was examined on glass and suture material. To quantitate bacterial adherence, uptake of ({sup 3}H)thymidine into bacterial DNA was analyzed. Corresponding amounts of extracellular matrix were measured by a new technique using ({sup 14}C)glucose incorporation. This study shows that ({sup 14}C)glucose preferentially labeled bacterial strains in proportion to biofilm production. The ratio of {sup 3}H{sup 14}C in high biofilm producers was 0.9 and in low producers it was 3.7. Radioactive identification of organisms as high and low producers was confirmed by electron microscopy. The results presented here show that production and accumulation of biofilm over time is a stable characteristic in different strains of S. epidermidis. The use of ratios reflecting radiolabeling of bacteria and biofilm by ({sup 3}H)thymidine and ({sup 14}C)glucose, respectively, is a quantitative yet simple technique to assess extracellular matrix of different strains of S. epidermidis.

The outcome of total joint arthroplasty is determined by biological events at the bone-implant interface. Macrophages phagocytose implant or wear debris at the interface and release proinflammatory mediators such as interleukins 1 and 6, tumor necrosis factor-alpha, and prostaglandin E2. These mediators are thought to contribute to the resorption of periprosthetic bone. Previous studies of tissues harvested from the bone-implant interface of failed orthopaedic implants demonstrated a possible role for two other cytokines, granulocyte-macrophage colony-stimulating factor and interleukin-4. The present study examined the effects of in vitro challenge with polymethylmethacrylate particles on the expression of granulocyte-macrophage colony-stimulating factor by primary human monocytes/macrophages and the role of interleukin-4 in regulating this expression. The polymethylmethacrylate particles caused a dose-dependent release of granulocyte-macrophage colony-stimulating factor at 48 hours. This release was accompanied by increased expression of interleukins 6 and 1beta and tumor necrosis factor-alpha. Release of the lysosomal enzyme hexosaminidase also increased in response to the particles. Interleukin-4 inhibited the expression of granulocyte-macrophage colony-stimulating factor, interleukin-6, and tumor necrosis factor-alpha at 48 hours in a dose-dependent manner. The data presented in this study confirm the hypothesis that interleukin-4 downregulates particle-induced activation of macrophages, as demonstrated by the decreased release of proinflammatory mediators.

Alterations in the location of the hip center may change the lengths and moment arms of the muscles, and thereby affect their capacity to generate force and moment about the hip. This study demonstrates some of the differences between compensating and not compensating for changes in muscle length that arise from displacement of the hip center. A computer model was developed to estimate the maximum isometric moment generating capacity of the hip muscles under two conditions. In the compensated condition, the hip center was displaced, but the muscles were restored to their original lengths and orientations by altering proximal femoral geometry. In the uncompensated condition, femoral geometry remained constant; thus, muscle lengths and orientations changed with displacement of the hip center. The computer simulations showed large differences between the two conditions. For example, a 2-cm superior displacement of the hip center decreased the moment generating capacity of the hip abductors 18% with compensation and 49% without compensation. Similarly, a 1-cm medial displacement of the hip center increased the moment generating capacity of the abductors 17% with compensation, but decreased it 4% without compensation. In contrast, a 1-cm inferior displacement decreased the moment generating capacity of flexors 6% with compensation, but increased it 12% without compensation. The results presented here demonstrate that compensating for changes in muscle length can be important in terms of preserving the moment generating capacity of the muscles when the hip center is displaced superiorly and medially, but not when the hip center is displaced in the inferior direction.

Cement removal in revision total hip arthroplasty can be technically challenging. Traditional methods involve using a combination of chisels, power burrs, and drills, as well as windowing the femoral cortex to gain access to cement distally. These methods can be associated with femoral fracture or uncontrolled cortical perforation and bone loss. A new technique had been developed that permits segmental extraction of bone cement from the femoral canal. Fresh cement is introduced into the old cement mantle and a threaded rod is placed into the wet cement and held in place while the cement hardens

Range of motion (ROM) after total knee arthroplasty (TKA) is an important variable in determining clinical outcome. Recent design modifications have been aimed at improving final motion. The posterior stabilized total knee prosthesis was introduced as a modification of the total condylar design, changing the center of curvature of the femoral component to allow greater ROM. In this study, all primary TKAs performed at the authors' institution from July 1982 until December 1986 were reviewed to determine the effect of this design modification on outcome. A total condylar (TC) group comprised 51 arthroplasties and was compared to 53 arthroplasties in a posterior stabilized (PSTC) group. the postoperative protocol was identical in both groups. The mean postoperative flexion was 11 better in the PSTC group; however, the mean preoperative flexion had initially been 10 degrees better in the PSTC group. The maximum flexion achieved by any patient in both groups was similar, but the TC group actually gained slightly more arc of motion. The better motion in the PSTC group may be secondary to better motion preoperatively and not implant design in this series. The more limited the preoperative ROM, the greater the quadriceps stiffness is likely to be, which is an important determinant of postoperative flexion. Review of the literature supports present observations that a group with less mean preoperative motion paradoxically gains a slightly greater increment of flexion. Differences in flexion after TKA are difficult to attribute to design in either the current study or by a review of the literature. This is because determinants of flexion after TKA are multifactorial and outcome data limited, notwithstanding the similarities among modern prostheses.

The roles of physical activity (both work and leisure time), obesity, and history of significant knee injury on the development of severe osteoarthrosis (OA) of the knee were evaluated. A case-control design compared 46 cases with a history of severe OA of the knee with 46 community controls matched for age and gender. Data were gathered with a self-administered questionnaire. The OA cases were 3.5 times more likely than controls to have been obese at 20 years of age, two to three times more likely than controls to have performed heavy work, and almost five times more likely than controls to have had a significant knee injury. In contrast, leisure-time physical activity was not significantly different in cases compared with controls. Obesity, significant knee injury, and long-term heavy physical activity are important risk factors for the development of OA of the knee.

Can patients treated with total hip arthroplasty (THA) receive high-quality inpatient care at less cost? In 1984, a group of orthopedic surgeons and nurses examined the use of resources for THA patients and changed certain clinical practices to promote more cost-effective hospital care. At the end of the two-year project, orders for complete blood counts fell 72% and mean operating room time dropped 47 minutes for the participating orthopedists. For all orthopedists in the division, average length of stay (ALOS) decreased from 13 to 11 days. By the end of the following year, when clinicians received quarterly length-of-stay (LOS) data, ALOS dropped further to 9.8 days. This significant ALOS reduction was not accompanied by an increase in hospital readmissions or nursing home placements. The ALOS reduction was also not seen in elective coronary artery bypass graft patients whose ALOS did not substantially change over the same period. Two years after the project, ALOS for THA patients remained at ten days or below. This reduction in LOS and in the use of other hospital services translated into a mean total hospital charge decrease of $2045 per THA patient.

All primary condylar total knee replacement arthroplasties (TKAs) performed from 1977 to 1984 at the authors' institution were divided into two groups based on the use of continuous passive motion (CPM) in the immediate postoperative period. The control group consisted of 73 patients who were treated with 95 TKAs without postoperative CPM. The average age was 65.4 years. The study group consisted of 38 patients who had 51 TKAs in which CPM was used postoperatively. The mean patient age was 62.8 years. The most common diagnoses in both groups were osteoarthritis and rheumatoid arthritis. Range of motion (ROM) was recorded preoperatively, at discharge, at three months, one year, two years, and at the last follow-up visit. There were no statistically significant differences in the ROM between the two groups at any of these time periods. At two years, the mean flexion and extension in the study group were 99 degrees and -4 degrees, respectively, compared to 103 degrees and -5 degrees in the control group. The average hospital stay was 11.2 days in the study group, whereas it was 15.1 days in control group. In the control group, there was one superficial infection, no deep infections, and four pulmonary emboli compared with three superficial infections, two deep infections, and no pulmonary emboli in the study group. There was no difference in the transfusion requirements between the two groups. CPM is advocated by the authors to help achieve discharge ROM earlier, but the protocol has been changed to begin CPM on the second postoperative day to allow the wound to stabilize.

UNLABELLED Using a standardized strain of Escherichia coli 06 and a rabbit knee-joint model, we determined the following values: (1) the effective concentrations of amikacin and carbenicillin in vitro against Escherichia coli 06 when used singly or in combination; (2) the levels of each of these antibiotics in serum and synovial fluid after an intramuscular injection; (3) the effectiveness of amikacin in preventing intra-articular infection when it is administered thirty minutes before and six hours after an intra-articular inoculation of the same strain of Escherichia coli; and (4) the synergistic effects of amikacin and carbenicillin in combination both in vitro and in vivo when used together as a single dose six hours after intra-articular bacterial inoculation. Amikacin was much more effective when administered before joint inoculation and the minimum effective (inhibitory) concentrations of amikacin in vitro and in vivo were approximately the same. A synergistic effect of amikacin and carbenicillin in combination was more clearly evident in vitro than in vivo. CLINICAL RELEVANCE In vitro tests such as determinations of the minimum inhibitory concentration and the minimum bactericidal concentration, and the serum bactericidal test, can provide valuable guides for the determination of minimum goals for antibiotic therapy. These in vitro tests were related to concentrations of antibiotics in tissue assessed by in vivo bacterial challenge tests and were found to be predictive of efficacy in vivo.

We calculated subchondral deformations and stresses in the femoral head and acetabulum during weight bearing using finite element models. Areas of high joint contact pressures on the femoral head were shown to correspond to high hydrostatic compression in subchondral bone. The magnitude of the subchondral bone compressive hydrostatic stress correlated with cartilage thickness and was highest in the superior femoral head and moderate at the acetabular roof. The seldom contacting surfaces of the medial-inferior and peripheral areas of the femoral head and the roof of the acetabulum had lower hydrostatic compression and significant subchondral bone tensile strains tangential to the joint surface. Initial cartilage fibrillation and osteophyte formation are often found in these areas. These findings suggest that fluctuating hydrostatic pressure inhibits vascular invasion and the degeneration and ossification of articular cartilage. The generation of tensile strain may promote the degenerative process by direct mechanical mechanisms. Additionally, since tensile strains are associated with a reduction in the compressive hydrostatic stresses in the cartilage and an increase in shear stresses, their presence may permit or promote vascular invasion, cartilage degeneration, and osteophyte formation. These mechanical principles in arthrosis are the same as those that have been previously demonstrated to guide the degeneration and ossification of the cartilage primordium during skeletal morphogenesis. In this sense, arthrosis may be viewed as the final stage in the degeneration and ossification of the cartilage anlage.

The purpose of this study was to compare the effects of human recombinant interleukin 1, alpha and beta, on articular cartilage. The effects of rIL-1 alpha and rIL-1 beta on proteoglycan degradation and synthesis following treatment of bovine articular cartilage in serum-free organ culture were quantified. Purified human IL-1 and both rIL-1 alpha and rIL-1 beta induced a two-fold or greater increase in glycosaminoglycan (GAG) release from cultured articular cartilage. Levels or rIL-1 alpha as low as 15 pM induced increased proteoglycan degradation whereas identical levels of rIL-1 beta did not. Killing of the cartilage cells abolished induced GAG release by all forms of IL-1. Analysis of proteoglycan size following IL-1 treatment showed limited degradation of material released into the culture medium or remaining within cartilage. Both forms of recombinant IL-1 inhibited GAG synthesis when continually present in the culture medium. Actinomycin D and cycloheximide inhibited IL-1 dependent cartilage destruction whereas indomethacin did not.

A single intravenous dose of one gram of cefazolin was administered prophylactically to forty-eight patients undergoing total joint replacement. The serum half-life of the antibiotic was 1.8 hours, the same value found in normal volunteers. The mean concentration in bone during surgery was 5.7 micrograms per gram of bone. The mean concentration in synovial fluid during surgery was 24.4 micrograms per milliliter of fluid.

Cefoxitin was administered to 47 patients on an orthopedic service; 1 or 2 g of the drug was given intravenously every 4-8 hr. Thirty-one evaluated patients with acute or chronic infections of bone, joint, or muscle and tendon had an overall rate of cure of 84%. Ten patients with spinal cord injuries who had urinary tract infections due to Serratia or indole-positive Proteus were treated, and all 10 were cured. Significant adverse effects of cefoxitin included one case of fever due to the drug and three cases of superinfection. Cefoxitin therapy was successful in a variety of difficult-to-treat infections, including some of polymicrobial etiology.

This article describes the macromolecular changes in keratan sulfate and proteoglycan that occur in rabbit articular cartilage during postnatal development. Articular cartilage glycosaminoglycans from femoral condyles and the tibial plateaus of rabbits at 8, 12, 18, and 26 weeks and 2 years of age were extracted, fractionated, and quantified. The predominant glycosaminoglycan present in articular cartilage at 8 weeks was chondroitin sulfate. During subsequent maturation the relative proportions of keratan sulfate and chondroitin sulfate varied inversely. The greatest increase in the amount of keratan sulfate present in cartilage was observed between 12 and 26 weeks of age. Hyaluronic acid content was measurable at 12 weeks; afterward the amount remained relatively constant with age. Proteoglycans, extracted from 6-, 12-, and 22-week-old rabbit femoral and tibial cartilage in the presence of protease inhibitors, were analyzed on columns of Sepharose CL-2B. Cartilage proteoglycans decreased in hydrodynamic size between 12 and 22 weeks, corresponding to the period of maximal change in content of keratan and chondroitin sulfate.

An understanding of the absorption of antibiotics from joints was investigated comparing intraarticular (i.a.) absorption with intramuscular (i.m.) absorption in a rabbit knee model. The antibiotics investigated were methicillin, cephalothin, cefazolin, cefoxitin, amikacin, neomycin, kanamycin, and gentamicin. Absorption was measured both in animals in which the knee joint was infected with Staphylococcus aureus and in normal animals. The pattern of absorption was similar among different antibiotics. On an average, antibiotics are absorbed from infected joints 37% slower than from an i.m. injection. In animals that are not infected i.a. antibiotics are actually absorbed 12% faster than i.m. antibiotics. Thus, i.a. antibiotics are absorbed rapidly and similarly to i.m. injection and should be included in total dose calculations for antibiotic regimens, especially with regard to their potential toxicity.

The effects of fixed axes of rotation on the varus-valgus and torsional load-displacement characteristics of the human knee have been determined. The location of the axes of varus-valgus and torsional rotations resulting in minimum resisting loads are also determined, and it is shown that they correspond to minimal coupled load levels. The coupled loads are seen to be sensitive to the location of the axis of rotation. The nonlinear load-displacement data is fitted with a four interval least-squares cubic spline with matching first and second derivatives at nodes. The data from two fresh human knees are presented.

Concentrations of cephalothin or cefamandole were measured in serum, bone, synovial fluid, and wound drainage fluid in fifty-seven patients undergoing total hip or knee replacement after a two-gram intravenous bolus injection. The concentrations were similar in serum and synovial fluid for both antibiotics; however, in bone and drainage fluid the concentration of cefamandole was higher by a factor of three. Concentrations of the same antibiotic at the hip and knee were not significantly different even though a tourniquet was used for the knee replacement procedures. Clinical Relevance: The antibiotics penetrate bone and enter synovial fluid so rapidly that it is unnecessary to administer prophylactic antibiotics prior to the time of surgery.

In joints with bacterial arthritis, continuing prolonged destruction of cartilage may occur in spite of prompt, effective antibiotic therapy. We measured the extent to which early antibiotic therapy with ceforanide altered the degradation of the cartilage after arthritis due to Staphylococcus aureus had been produced in the knee joint in rabbits. Degradation of the cartilage was quantified by analyses for glycosaminoglycan and collagen. Three weeks after the infection was produced, the cartilage had lost more than half of its glycosaminoglycan whether the antibiotic therapy had been started at one, two, or seven days after infection. Beginning the antibiotic treatment one day after infection reduced over-all loss of collagen by 37 per cent and decreased the area of erosion of the infected articular surfaces. When antibiotic treatment was begun at four, eight, or twelve hours after infection, the loss of glycosaminoglycan averaged 18 per cent. Prophylaxis with antibiotics completely prevented any degradation of the cartilage. Clinical relevance: The findings reported here show how rapidly cartilage loses glycosaminoglycan when it is involved by arthritis caused by staphylococci and how early treatment of the infection reduces the loss of collagen. There is less protection against loss of glycosaminoglycan. The results emphasize the need for early diagnosis and treatment of infectious synovitis and support the rationale for early administration of antibiotics without waiting for identification of the responsible bacteria.

Analytical and experimental studies were performed to examine some characteristics of poly(methyl methacrylate) bone cement in the context of total hip replacement. Proceeding from fundamental principles of balance of energy and heat conduction, three simulation models of total hip replacement, using the finite-element method of numerical analysis, were used to predict the temperature response in the femoral prosthesis, cement, cancellous bone, and bone-cement interface. When cement collars are a centimeter or less in thickness, the models predict little likelihood of permanent bone thermal necrosis. In addition, laboratory experimental results indicate that peak temperatures attained in Simplex-P and Palacos-R cement specimens are nearly identical and that adding 0.5 and 1.0 g of the antibiotic gentamicin to Palacos-R has negligible influence on peak temperature. Experimental results also indicate that cooling cement specimens to 8 degrees C extends the set time, which in turn could significantly increase the likelihood of stem-cement loosening during surgery.

Four in vitro human knee specimens have been loaded, two with varus-valgus femoral rotations and two with internal and external axial tibial rotations. Each specimen has been tested in full extension and in 30° of flexion. All orthogonal components of applied force and moment required to cause the rotations were measured as were all resultant orthogonal components of load on the femur. Curves fit to the data were studied to establish the portions of the applied load transmitted by each ligament.

Effects of Escherichia coli and Staphylococcus aureus on cartilage and chondrocytes in culture are reported. Under these conditions, bacterial effects on cartilage degradation and cell viability are measured in the absence of inflammation. E coli causes a 28% loss and S aureus an 83% loss of cartilage glycosaminoglycan within 48 hours. Collagen content is unchanged. Both bacterial species induce chondrocyte death in explants and in monolayers within 48 hours. Bacterial effects on glycosaminoglycans and cell viability do not result from depletion of nutrients from the culture medium. Serum in the culture media inhibits the bacterial effects on cartilage degradation but does not prevent cell death.

We report the effect of staphylococci on induction of proteoglycan release from cartilage in organ culture and document the presence of a staphylococcal proteoglycan-releasing factor in the bacterial growth medium. Staphylococci cocultured with cartilage increased release of proteoglycan 3-4-fold within 48 hours. Viable cartilage was essential for maximum loss of proteoglycan. Killed bacteria had no effect on proteoglycan release. Four Staphylococcus aureus strains yielded growth media preparations active in proteoglycan release. Analysis of the proteoglycan subunits released from cartilage showed only limited degradation, and glycosaminoglycan chain length was not significantly altered.

The purpose of this study was to test whether cartilage serves as the source or repository of antigenic components active in the stimulation of inflammation in rheumatoid arthritis through an analysis of peripheral blood lymphocyte proliferation. Articular cartilage samples were obtained from patients with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis undergoing joint replacement surgery. Each sample was homogenized and characterized biochemically with respect to the content of proteoglycan, collagen, and immunoglobulin. Proteoglycan content of rheumatoid cartilage was reduced by 71% when compared to osteoarthritic cartilage; the proteoglycan content of ankylosing spondylitis cartilage was reduced by 40% when compared to osteoarthritic cartilage. Immunoglobulins were detectable in all cartilage samples when analyzed by ELISA or end-plate titration. Lymphocyte proliferation, quantified by uptake of 3H-thymidine, was unaltered by addition of cartilage fragments, low (saline) and high salt extracts (2.0 M CaCl2), or cartilage residues. Both autologous and heterologous lymphocytes were tested against the cartilage samples with no difference in reactivity. Purified bovine articular proteoglycans and Type II collagen were also inactive. Although tetanus toxoid and phytohemagglutinin were effective stimulants of proliferation, lymphocytes from arthritis patients were suppressed relative to those of normal individuals. Analysis of arthritic articular cartilage by these techniques failed to demonstrate the presence of antigen(s) stimulating proliferation of peripheral blood lymphocytes.

An axisymmetric finite element code was used to predict stresses and displacements in the proximal tibia of the human knee. Joint geometries were determined from a midfrontal section of a normal lateral tibial plateau. Constitutive relations, tibiofemoral forces and joint contact areas were estimated from the literature. Fourier expansions were used to provide localized loading over the assumed contact region. The results emphasize that subchondral trabecular bone serves to transmit the large loads applied to the cartilage surface by gradually concentrating these loads into the compact bone of the tibial diaphysis. The model predicts a nearly hydrostatic stress state in articular cartilage within the contact region and high tensile principal strains at the edge of the contact region. For trabecular bone, the model predicts maximum compressive stresses beneath the center of the contact region and maximum shear stresses beneath the edge of the contact region. The predicted principal stress directions in the continuum representation for trabecular bone also bear a strong resemblance to the trabecular architecture of the lateral tibial plateau.

The evolution of endocrine systems has been intensively studied (for review see ref. 1). Recent findings indicate the existence of vertebrate-like hormones in primitive species including fungi and unicellular eukaryotes2–4. Although proteins that bind vertebrate steroids have been described in at least one lower organism5, the presence of recognition molecules analogous to hormone receptors in higher organisms has not previously been demonstrated. We have investigated Candida albicans and now report the existence of a receptor-like protein macromolecule in the cytosol of this simple yeast which binds vertebrate corticosteroids with high affinity, selectivity and stereospecificity. In addition, a lipid-extractable material present in the yeast cells and released into the chemically defined growth medium reversibly competes for 3H-corticosterone binding sites in yeast cytosol and may represent an endogenous ligand. Of interest is the finding that the yeast extract also competes for mammalian glucocorticoid receptors. The data suggest that the evolutionary origin of hormonal steroid systems may go back at least as far as simple unicellular eukaryotes. Furthermore, the demonstration of interactions between mammalian steroids and the yeast binder and between the yeast ligand and mammalian receptors suggests the possibility of important clinical consequences.

Fatigue tests to failure of compact bovine bone specimens were conducted at five stress amplitudes (65–108 MN/m2) and four temperature levels (21–45°C). The resulting relationships between fatigue life and stress amplitude, bone temperature, and bone density have been reported (Carter and Hayes, 1975). In the present study, the bone specimens were categorized into four microstructure groups based on the extent of secondary Harversian remodeling. A significant correlation (P < 0·001) between density and microstructure group was shown with primary bone specimens generally being more dense than secondary Haversian specimens. A positive correlation (P < 0·01) between fatigue life and density was revealed within each structural group. In addition, a negative correlation (P < 0·001) between fatigue life and the extent of Haversian remodeling was shown even after appropriate adjustments for density differences. These data suggest that Haversian remodeling of primary bovine bone reduces fatigue resistance not only by decreasing bone density, but also by creating an inherently weaker structure.