Novel kinase platform for the validation of the anti-tubercular activities of Pelargonium sidoides (Geraniaceae).

BACKGROUND: Pelargonium sidoides is an important traditional medicine in South Africa with a well-defined history of both traditional and documented use of an aqueous-ethanolic formulation of the roots of P. sidoides (EPs 7630), which is successfully employed for the treatment of respiratory tract infections. There is also historical evidence of use in the treatment of tuberculosis. The aim of this study was to develop a platform of Mycobacterium tuberculosis (Mtb) kinase enzymes that may be used for the identification of therapeutically relevant ethnobotanical extracts that will allow drug target identification, as well as the subsequent isolation of the active compounds. RESULTS: Mtb kinases, Nucleoside diphosphokinase, Homoserine kinase, Acetate kinase, Glycerol kinase, Thiamine monophosphate kinase, Ribokinase, Aspartokinase and Shikimate kinase were cloned, produced in Escherichia coli and characterized. HPLC-based assays were used to determine the enzyme activities and subsequently the inhibitory potentials of varying concentrations of a P. sidoides extract against the produced enzymes. The enzyme activity assays indicated that these enzymes were active at low ATP concentrations. The 50% inhibitory concentration (IC50) of an aqueous root extract of P. sidoides against the kinases indicated SK has an IC50 of 1.2 µg/ml and GK 1.4 µg/ml. These enzyme targets were further assessed for compound identification from the P. sidoides literature. CONCLUSION: This study suggests P. sidoides is potentially a source of anti-tubercular compounds and the Mtb kinase platform has significant potential as a tool for the subsequent screening of P. sidoides extracts and plant extracts in general, for compound identification and elaboration by selected extract target inhibitor profiling.

Outcomes of outpatient ureteral stenting without fluoroscopy at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Ureteral stenting is generally a theatre-based procedure that requires a multidisciplinary team and on-table imaging. Limited hospital bed numbers and theatre time in our centre in Cape Town, South Africa, have led us to explore an alternative approach. OBJECTIVES: To see whether outpatient insertion of ureteric stents under local anaesthesia without fluoroscopy was a possible and acceptable alternative to theatre-based ureteral stenting. METHODS: Ureteral stenting (double-J stents and ureteric catheters) was performed with flexible cystoscopy under local anaesthesia and chemoprophylaxis, but without fluoroscopic guidance, in an outpatient setting. Every patient had an abdominal radiograph and an ultrasound scan of the kidney after the procedure to confirm stent position. RESULTS: Three hundred and sixteen procedures (276 double-J stents and 40 ureteric catheters) were performed in 161 men and 155 women. The overall success rate for the procedures was 85.4%, independent of gender (p=0.87), age (p=0.13), type of device inserted (p=0.81) or unilateral/bilateral nature of the procedure (p=1.0). Procedures with a successful outcome were performed in a significantly (p<0.0001) shorter median time (10 minutes (interquartile range (IQR) 5 - 15)) than failed procedures (20 minutes (IQR 10 - 30)). Patients with a pain score of >5 experienced a significantly (p=0.02) greater proportion of failure (27.3%) than patients with a pain score of ≤5 (12.5%). Difficulties were encountered in 23.7% of procedures, with a significantly higher proportion being registered in failed interventions compared with successful ones (82.6% v. 13.7%; p<0.0001). CONCLUSIONS: The procedure was easily mastered and technically simple, and represents savings in cost, time and human resources in our setting.

Investigating racial differences in clinical and pathological features of prostate cancer in South African men.

BACKGROUND: Men with West African ancestry living in Europe and North America are at higher risk of being diagnosed with prostate cancer, are diagnosed at a younger age, and have more severe disease characteristics. Published reports present a conflicting picture of the disease in sub-Saharan Africa. We aimed to study the clinical and pathological features of men undergoing prostate biopsy from different racial backgrounds in South Africa in an attempt to characterise the disease locally. Our hypothesis was that black African men presenting to our service had more severe disease characteristics than other patients. METHODS: All patients who underwent a prostate biopsy at Groote Schuur Hospital, Cape Town from July 2008 to July 2014 were studied. For each patient, data were collected on age, self-assigned race, presenting symptoms, prostate-specific antigen (PSA) level, prostate volume, and histological diagnosis. RESULTS: A total of 1016 patients were studied. 162 (15.9%) were black and 854 (84.1%) were coloured (mixed ancestry), white, or Asian. Black patients were compared as a group to the coloured, white and Asian patients. The black patients in the series had higher PSA values (mean 167.8 vs 47.7, median 16.4 vs 10.9, p < 0.001), were more likely to be diagnosed with cancer (57.4% vs 44.5%, p = 0.003), were more likely to present with locally advanced cancer (T3/4 16.1% vs 8.9%, p = 0.028), and were more likely to have high grade disease (Gleason ≥ 8 45.2% vs 30.5%, p = 0.011). There was no difference in age, presenting symptoms, or prostate volume. CONCLUSION: The black men diagnosed with prostate cancer at Groote Schuur Hospital had significantly worse clinical and pathological characteristics than the non-black men. Interpreting these differences as representative of a more common or aggressive disease among black men is not possible due to study limitations.

Investigating racial differences in clinical and pathological features of prostate cancer in South African men

Introduction: Men with West African ancestry living in Europe and North America are at higher risk of being diagnosed with prostate cancer, are diagnosed at a younger age, and have more severe disease characteristics. Published reports present a conflicting picture of the disease in sub-Saharan Africa. We aimed to study the clinical and pathological features of men undergoing prostate biopsy from different racial backgrounds in South Africa in an attempt to characterise the disease locally. Our hypothesis was that black African men presenting to our service had more severe disease characteristics than other patients. Methods: All patients who underwent a prostate biopsy at Groote Schuur Hospital, Cape Town from July 2008 to July 2014 were studied. For each patient, data were collected on age, self-assigned race, presenting symptoms, prostate-specific antigen (PSA) level, prostate volume, and histological diagnosis. Results: A total of 1016 patients were studied. 162 (15.9%) were black and 854 (84.1%) were coloured (mixed ancestry), white, or Asian. Black patients were compared as a group to the coloured, white and Asian patients. The black patients in the series had higher PSA values (mean 167.8 vs 47.7, median 16.4 vs 10.9, p < 0.001), were more likely to be diagnosed with cancer (57.4% vs 44.5%, p = 0.003), were more likely to present with locally advanced cancer (T3/4 16.1% vs 8.9%, p = 0.028), and were more likely to have high grade disease (Gleason ≥ 8 45.2% vs 30.5%, p = 0.011). There was no difference in age, presenting symptoms, or prostate volume. Conclusion: The black men diagnosed with prostate cancer at Groote Schuur Hospital had significantly worse clinical and pathological characteristics than the non-black men. Interpreting these differences as representative of a more common or aggressive disease among black men is not possible due to study limitations

Effect of amputation level on the stress transferred to the femur by an artificial limb directly attached to the bone.

Attachment of an artificial limb directly to the skeleton has a number of potential benefits and the technique has been implemented for several amputation sites. In this paper the transfer of stress from an external, transfemoral prosthesis to the femur during normal walking activity is investigated. The stress distribution in the femur and at the implant-bone interface is calculated using finite element analysis for the 3D geometry and inhomogeneous, anisotropic material properties obtained from a CT scan of a healthy femur. Attachment of the prosthetic leg at three different levels of amputation is considered. Stress concentrations are found at the distal end of the bone and adjacent to the implant tip and stress shielding is observed adjacent to the implant. It is found that the stress distribution in the femur distal to the epiphysis, where the femur geometry is close to cylindrical, can be predicted from a cylindrical finite element model, using the correct choice of bone diameter as measured from a radiograph. Proximal to the lesser trochanter the stress decreases as the femur geometry diverges significantly from a cylinder. The stress concentration at the distal, resected end of the bone is removed when a collared implant is employed. These findings form the basis for appropriate settings of an external fail-safe device to protect the bone from excessive stress in the event of an undue load.

Spatiotemporal multi-resolution approximation of the Amari type neural field model.

Neural fields are spatially continuous state variables described by integro-differential equations, which are well suited to describe the spatiotemporal evolution of cortical activations on multiple scales. Here we develop a multi-resolution approximation (MRA) framework for the integro-difference equation (IDE) neural field model based on semi-orthogonal cardinal B-spline wavelets. In this way, a flexible framework is created, whereby both macroscopic and microscopic behavior of the system can be represented simultaneously. State and parameter estimation is performed using the expectation maximization (EM) algorithm. A synthetic example is provided to demonstrate the framework.

A data-driven framework for neural field modeling.

This paper presents a framework for creating neural field models from electrophysiological data. The Wilson and Cowan or Amari style neural field equations are used to form a parametric model, where the parameters are estimated from data. To illustrate the estimation framework, data is generated using the neural field equations incorporating modeled sensors enabling a comparison between the estimated and true parameters. To facilitate state and parameter estimation, we introduce a method to reduce the continuum neural field model using a basis function decomposition to form a finite-dimensional state-space model. Spatial frequency analysis methods are introduced that systematically specify the basis function configuration required to capture the dominant characteristics of the neural field. The estimation procedure consists of a two-stage iterative algorithm incorporating the unscented Rauch-Tung-Striebel smoother for state estimation and a least squares algorithm for parameter estimation. The results show that it is theoretically possible to reconstruct the neural field and estimate intracortical connectivity structure and synaptic dynamics with the proposed framework.

Proteasome inhibition causes regression of leukemia and abrogates BCR-ABL-induced evasion of apoptosis in part through regulation of forkhead tumor suppressors.

BCR-ABL plays an essential role in the pathogenesis of chronic myeloid leukemia (CML) and some cases of acute lymphocytic leukemia (ALL). Although ABL kinase inhibitors have shown great promise in the treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR-ABL. Here, we show that BCR-ABL stimulates the proteasome-dependent degradation of members of the forkhead family of tumor suppressors in vitro, in an in vivo animal model, and in samples from patients with BCR-ABL-positive CML or ALL. As several downstream mediators of BCR-ABL are regulated by the proteasome degradation pathway, we also show that inhibition of this pathway, using bortezomib, causes regression of CML-like disease. Bortezomib treatment led to inhibition of BCR-ABL-induced suppression of FoxO proteins and their proapoptotic targets, tumor necrosis factor-related apoptosis-inducing ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy. We additionally show sensitivity of imatinib-resistant BCR-ABL T315I cells to bortezomib. Our data delineate the involvement of FoxO proteins in BCR-ABL-induced evasion of apoptosis and provide evidence that bortezomib is a candidate therapeutic in the treatment of BCR-ABL-induced leukemia.

The effect of design variables of condylar total knees on the joint forces in step climbing based on a computer model.

The ability to climb a steep step or rise from a low chair after total knee replacement may be enhanced if the required force in the quadriceps muscle is reduced. This can potentially be achieved if the total knee produces a large lever arm measured from the femoral-tibial contact point to the patellar ligament. A reduced quadriceps force would also reduce the patello-femoral force and the femoral-tibial contact force. The contact point location is likely to be a function of the geometry of the femoral and tibial components in the sagittal plane, including the relative distal and posterior radii of the femoral profile, the location of the bottom-of-the-dish of the tibial surface, the radius of the tibial surface, and the presence or absence of the posterior cruciate ligament. A three-dimensional model of the knee was developed including the quadriceps and various ligaments. In the study, the motion was confined to flexion extension and displacement in the sagittal plane. The quadriceps was assumed to be the only muscle acting. A standard software package (Pro/Mechanica) was used for the analysis. For a femoral component with a smaller distal radius, there was 12% reduction in the quadriceps muscle force and up to 11% reduction in the patello-femoral force from about 100 up to 60 degrees flexion. However, apart from that, there were less than 10% differences in all the forces as a function of all of the design variables studied. This was attributed to the relatively small changes in the lever arm of the patella tendon, since the tendon moves in an anterior-posterior direction along with the femur. An additional factor explaining the results was the change in the anterior-posterior contact point as controlled by the forces in the patella tendon and in the soft tissues. The results imply that for a standard condylar replacement knee, the muscle and contact forces are not greatly affected by the geometrical design variables.

Single-clamp technique does not protect against cerebrovascular accident in coronary artery bypass grafting.

OBJECTIVES: By potentially avoiding the embolic consequences of a side-biting aortic clamp, the single-clamp technique may decrease cerebrovascular accidents in coronary artery bypass grafting. However, this theoretical superiority in stroke prevention has not been conclusively demonstrated and use of this technique may lead to adverse myocardial effects due to longer cross-clamp times. In this study, we sought to determine if the single-clamp technique prevents postoperative stroke in clinical practice. METHODS: Of 607 consecutive isolated coronary bypass operations completed over a 3 year period, 301 (50%) were performed by one surgeon using exclusively the single-clamp technique and 306 (50%) were performed by a second surgeon using exclusively the two-clamp technique. Postoperative adverse events were retrospectively compared between these two groups. RESULTS: There were no differences between groups in terms of postoperative stroke (1.7% single-clamp vs. 2.0% two-clamp, P=0.78), hospital mortality (2.7% single-clamp vs. 1.6% two-clamp, P=0.38), or perioperative myocardial infarction (2.6% single-clamp vs. 0.7% two-clamp, P=0.052). The two-clamp technique was not a significant predictor of stroke by logistic regression analysis (P=0.72). CONCLUSIONS: We conclude that there are no statistically significant differences between clamp techniques with regard to stroke prevention or myocardial protection. We find no compelling evidence for surgeons successfully utilizing one technique to change to the other.

Comparison of Pulmicort pMDI plus Nebuhaler and Pulmicort Turbuhaler in asthmatic patients with dysphonia.

BACKGROUND: Dysphonia is a known local adverse effect of inhaled corticosteroids. This symptom was investigated by laryngoscopy and assessment in a voice laboratory. The effects of changing the treatment of patients with dysphonia, reported whilst using the pMDI, to pMDI plus Nebuhaler or Tubuhaler was also assessed. METHODS: Seventy-two patients reporting dysphonia and taking inhaled steroids from a pMDI entered a 12-week, open, parallel group study. Fifty-one completed the study per protocol; 26 in the Nebuhaler group [21 female, mean age 57 years (22-77)] and 25 in the Turbuhaler group [18 female, mean age 58 years (21-81)]. A dysphonia diary card was completed weekly. Voice laboratory assessments and laryngoscopy were performed on entry and at 12 weeks. RESULTS: There were no differences in voice laboratory data, laryngoscopic evidence of disordered glottic closure and diary data between the two groups at 12 weeks. At study entry laryngoscopic appearances were normal in almost half the patients. Vocal cord bowing was rarely seen. Glottic closure changed in nine patients during the study period, but there was no correlation with voice symptoms. The trend of symptomatic improvement of voice status in the Turbuhaler group did not correlate with voice laboratory assessments and laryngoscopic evidence of disordered glottic closure. After 4 weeks, 40% of patients using Turbuhaler and 8% in the Nebuhaler group scored their voice status as better (P < 0.02) but there was no significant difference between the two groups at 12 weeks (Turbuhaler 52%, Nebuhaler 23%, P=0.08). CONCLUSION: This study does not support the view that dysphonia in asthmatics inhaling corticosteroids is usually caused by myopathic bowing of the vocal cord muscles.

Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB. METHODS AND RESULTS: A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0. 05) in patients who received 1 or 2 mg/kg. CONCLUSIONS: A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.

Peak inspiratory flow through Turbuhaler in chronic obstructive airways disease.

Many patients with chronic obstructive airways disease (COAD) receive therapy by the inhaled route. This study was performed to assess whether patients with severe COAD could generate sufficient peak inspiratory flow (PIF) through Turbuhaler (Astra, Sodertalje) to operate it effectively. One hundred patients (45 men, 55 women, mean age 69.1 years) with COAD (mean (SD) duration 17.7 (16.3) years) and peak expiratory flow (PEF) < or = 200 l min-1 or forced expiratory volume in 1 sec (FEV1) < or = 1 litre were studied. A series of randomly assigned inspiratory and expiratory lung function tests were contiguously performed, using portable spirometers, within 48 h of a screening visit. An empty Turbuhaler was used in the study. The patients' normal medication was not restricted. Sixty-six patients were previous smokers, eight occasional smokers, 19 habitual smokers and seven had never smoked. Mean (SD) FEV1 was 0.7 (0.2) 1 and mean PEF was 182 (68) l min-1. All patients were able to generate PIF through Turbuhaler (PIF-T) of 28 l min-1 (mean 53; range 28-78 l min-1). Eighty-three patients generated PIF-T of > or = 40 l min-1. PIF-T correlated with PIF without Turbuhaler (r = 0.35), PEF (r = 0.3), FEV1 (r = 0.2) and forced vital capacity (FVC) (r = 0.23) although the relationships were too weak to be used to predict PIF-T. The results suggest that patients with severely limited lung function caused by COAD can operate Turbuhaler effectively.

Anticoagulation is unnecessary after biological aortic valve replacement.

BACKGROUND: Opinion differs as to whether anticoagulation is beneficial in preventing ischemic stroke in the early postoperative period after biological aortic valve replacement (AVR). The purpose of this study was to determine whether early anticoagulation with heparin and warfarin confers any significant advantage for patients undergoing such replacement. METHODS AND RESULTS: Patients undergoing biological AVR between 1987 and 1996 were divided retrospectively into 2 groups based on their postoperative anticoagulation. Group A (109 patients) received heparin followed by warfarin for 3 months (prothrombin time, 20 to 25 seconds). Group B (76 patients) received no postoperative anticoagulation. Patients were followed for cerebral ischemic events, bleeding, repeat operation, hospital stay, and survival. There were 5 (4.6%), 3 (2.8%), and 12 (11%) postoperative cerebral ischemic events for group A at time points of < 24 hours, 24 hours to 3 months, and > 3 months, respectively; for group B patients, 3 (3.9%), 2 (2.6%), and 9 (11.8%) events were seen during the same respective time periods. There were no statistically significant differences for ischemic events during any of these time periods for the 2 groups. Bleeding complications occurred in 10 (9.2%) group A and 7 (9.2%) group B patients. Mean hospital stay was 12 days for both groups. Repeat operative AVR was required in 6 (5.5%) group A and 7 (9.2%) group B patients. A comparison of Kaplan-Meier survival rates between groups A and B (mean follow-up, 47 +/- 26 and 59 +/- 30 months, for groups A and B, respectively) was not statistically significant (P = 0.60). Survival rates were 93%, 84%, and 62% at 1, 5, and 7 years for group A and 87%, 74%, and 67% for group B, respectively. CONCLUSIONS: Early anticoagulation after AVR confers no advantage in the prevention of early cerebral ischemic events after biological AVR. No disadvantage in terms of bleeding or prolonged hospital stay was incurred by early anticoagulation. Long-term valve function and survival were not adversely affected by withholding early anticoagulation. We conclude that early anticoagulation after biological AVR is unnecessary.

Free radial artery grafts: surgical technique and results.

In the search for alternative conduits, the use of radial artery (RA) grafts has found renewed interest. This study sought to evaluate prospectively the perioperative morbidity, including the postoperative complications in the donor forearm, and mortality in the routine use of RA grafts in coronary artery bypass surgery. Data were obtained prospectively on 200 consecutive patients who underwent coronary revascularization using at least one RA graft from January 1995 to April 1997. The mean age of the patents was 61.9+/-10.5 years (mean+/-standard deviation [SD]). The RA was obtained from one forearm in 197 patients and both forearms in 3 patients. Two patients (1%) required exploration for donor site hematomas, 4 patients (2%) had temporary perioperative dysesthesias in the region of the lateral cutaneous nerve of the forearm, and none had donor site wound infection. Two patients (1%) had a myocardial infarction with electrocardiographic changes in the areas grafted by the RA in the immediate postoperative period, indicating graft failure. The two deaths in the series were due to comorbid factors. Our data suggest that the RA is a safe and suitable conduit for coronary revascularization, and it provides good clinical results. Long-term follow-up of these patients is necessary to confirm the patency of RA conduits. Free RA grafts have the potential for use in other areas of surgery where a conduit is necessary for revascularization procedures.

Blood utilization in hip and knee arthroplasty: a cost-minimization study.

The non-utilization of crossmatched blood is an expensive waste of resources. We have audited blood utilization for all primary total hip and knee arthroplasty patients. We compared routine pre-operative crossmatching (Phase 1) with a policy of group, screen and save (G & S) only (Phase 2). The patient groups were similar in both phases. Pre- and post-operative haemoglobin results were not significantly different between Phase 1 and 2. No adverse transfusion reactions occurred. In Phase 1, 213 units were crossmatched pre-operatively, but only 127 (60%) were transfused. In Phase 2, 117 units were requested and all transfused. The G & S only policy proved to be a safe and practical option which improved the efficiency and cost-effectiveness of blood ordering. Based on a handling charge of 37.50 Pounds per unit of blood by the Regional Transfusion Centre, an estimated annual saving of over 8000 Pounds can be made in our directorate.

Comparative efficacy and potency of ipratropium via Turbuhaler and pressurized metered-dose inhaler in reversible airflow obstruction.

Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p<0.05). In conclusion, the efficacy study showed that maximum FEV1 occurred at low doses of IB, negating any opportunity to identify differences between devices. The potency study indicated that the 10 microg dose via TH was of similar efficacy to the 20 microg dose via pMDI, confirming an efficacy ratio of 1.5-2.0:1 for the TH device.

A knee simulating machine for performance evaluation of total knee replacements.

A knee simulating machine is required for the design and evaluation of total knee replacements, the kinematics and the long-term wear being aspects of particular importance. There are no generally agreed design criteria, such that existing designs of simulator have a wide variety of input and constraint conditions. In this study, it was postulated that in order to reproduce physiological wear patterns, the correct kinematics is required, on the basis that the wear will be a direct function of the sliding, rolling and tractive rolling conditions at the joint surfaces. In turn, the correct kinematics would only be achieved by the input of physiological forces, by the appropriate constraints on the fixtures holding the components, and by simulating the soft tissue restraints. A knee simulating machine based on these principles was constructed, and used to test the kinematics of a range of contemporary condylar replacement knees. The displacements and rotations varied over a range of almost two times, even with the soft tissue restraints. Without the restraints, the low constraint designs would have dislocated or moved unrealistically. It was concluded that a simulating machine should be based on the input of forces and moments, rather than on displacements and rotations, in order to provide data of kinematics and wear.