Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.

Costs and outcomes of total hip and knee joint replacement for rheumatoid arthritis.

The objective of the study was to ascertain costs and outcomes of total joint replacement surgery for rheumatoid arthritis (RA) in Australia from the patients' perspective and to explore whether costs were affected by health status pre- or postsurgery. RA patients, scheduled for primary unilateral total knee replacement (TKR) or total hip replacement (THR) surgery at five Sydney hospitals, were approached. Preoperatively, patients retrospectively recorded expenses incurred over the previous 3 months and the health assessment questionnaire (HAQ). Postoperatively, patients completed detailed prospective cost diaries, short form (SF) 36, and HAQ every 3 months during the first postoperative year. In addition, patients were asked to complete a visual analogue measure for pain at 12 months postsurgery. Arthritis-specific cost information included prescription and nonprescription medication, visits to health professionals, tests, special equipment, alterations to the house, and use of private or community services. Thirty-one TKR and 11 THR patients provided cost data for the first postoperative year. Out-of-pocket costs and service utilization decreased over the first postoperative year for both TKR and THR patients. In addition, there was an improvement in the health status as measured by SF-36 but not the HAQ at 3 and 12 months postoperatively. The small sample size of this analysis is reflective of the current national trends of RA joint replacement surgery. Despite the low incidence of RA joint replacement surgery, it was substantiated that patients consider the positive impact on health outcomes and costs important. The generic SF-36 detected improvements in the health status of these RA patients, while total HAQ scores failed to do so. HAQ was found to be insensitive in reflecting improvements following lower limb replacement surgery. Patient out-of-pocket costs significantly decreased postoperatively; however, these costs remain substantial compared to osteoarthritis total joint replacement patients.

Osteochondritis dissecans of the knee; long-term clinical outcome following arthroscopic debridement.

We reviewed 32 knees in 26 patients who had previously undergone arthroscopic debridement for symptomatic osteochondritis dissecans (OCD) of the knee. The patients were followed up at a minimum of 11 years following surgery and were evaluated clinically using the American Knee Society Clinical Rating Score. Additional evaluation was performed using the Hughston Scale to include radiographic assessment. The mean American Knee Society Score was 179 (out of 200), indicating good clinical function. Radiographically, however, only 29% scored excellent or good on the Hughston Scale. Younger patients with a small, stable (and therefore preserved), medial femoral condyle lesion had the best prognosis. Whilst more novel and complex options such as chondrocyte implantation are being assessed for the treatment of OCD, it is clear that within this study group careful debridement with removal of loose tissue can achieve good clinical results in the long term. There was however radiographic evidence of early degenerative joint disease in 17/24 (71%) of patients reviewed. Patients undergoing excision of OCD fragments did worse than those in whom the fragment was preserved, however the risk of further surgery is raised if a fragment is left in situ at initial surgery.

Five- to 12-year follow-up of a hydroxyapatite-coated, cementless total knee replacement in young, active patients.

We carried out a prospective study of 118 hydroxyapatite-coated, cementless total knee replacements in patients who were

A comparison of bilateral uncemented total knee arthroplasty: simultaneous or staged?

In a series of 1304 patients (1867 knees), the results of simultaneous and staged bilateral total knee arthroplasty were compared with each other and with unilateral total knee arthroplasty. The bilateral procedures had a significantly higher rate of complications than unilateral procedures, almost entirely because of thromboembolic problems. However, this did not correspond to an increase in mortality. If a bilateral procedure was indicated, then a simultaneous procedure had no increased risk over a staged procedure. There was no increase in cardiovascular complications, the rate of deep-vein thrombosis or pulmonary embolism or mortality. The rate of infection was lower with a bilateral procedure and the overall revision rate was less than 1% in all groups. The prosthesis functioned as well in all groups in the medium and longer term periods. We feel that simultaneous bilateral total knee arthroplasty is a safe and successful procedure when compared with a staged bilateral procedure. It also has the added benefit of single anaesthetic, reduced costs and decreased total recovery time when compared to a staged bilateral procedure. For these reasons it should be considered as an option in the presence of bilateral knee joint disease.

Results of open arthrolysis for the treatment of stiffness after total knee replacement.

Stiffness is an uncommon but potentially debilitating complication following total knee replacement (TKR). The treatment of this condition remains difficult and controversial. We present the results of 13 patients who underwent open arthrolysis for stiffness. The mean time between TKR and arthrolysis was 14 months. The mean follow-up was 7.2 years (2 to 10). The mean range of movement prior to arthrolysis was 55 degrees . This increased to 91 degrees , six months after arthrolysis (p < 0.005). The improved range of movement was maintained during the follow-up period. No patient has required revision of their components. We have found arthrolysis to be a useful and successful approach to post-TKR stiffness.

A hydroxyapatite-coated total knee replacement: prospective analysis of 1000 patients.

We prospectively reviewed 1000 consecutive patients who underwent a cementless, hydroxyapatite-coated, stemless, total knee replacement over a period of nine years. Regular post-operative clinical follow-up was performed using the Knee Society score. The mean pre-operative score was 96, improving to 182 and 180 at five and ten years, respectively. To date, there have been seven (0.5%) cases which required revision, primarily for septic loosening (four cases), with low rates of other post-operative complications. The cumulative survival at ten years with revision as the end-point, was 99.14% (95% confidence interval 92.5 to 99.8). These results support the use of hydroxyapatite in a cementless total knee replacement since it can give reliable fixation with an excellent clinical and functional outcome.

Two knees or not two knees? Patient costs and outcomes following bilateral and unilateral total knee joint replacement surgery for OA.

AIMS: This study aims to address medical and non-medical direct costs and health outcomes of bilateral and unilateral total knee replacement from the patients' perspective during the first year post-surgery. METHODS: Osteoarthritis patients undergoing primary unilateral total knee or bilateral total knee replacement (TKR) surgery at three Sydney hospitals were eligible. Patients completed questionnaires pre-operatively to record expenses during the previous three months and health status immediately prior to surgery. Patients then maintained detailed prospective cost diaries and completed SF-36 and WOMAC Index each three months for the first post-operative year. RESULTS: Pre-operatively, no significant differences in health status were found between patients undergoing unilateral TKR and bilateral TKR. Both unilateral and bilateral TKR patients showed improvements in pain, stiffness and function from pre-surgery to 12 months post-surgery. Patients who had bilateral TKR spent an average of 12.3 days in acute hospital and patients who had unilateral TKR 13.6 days. Totally uncemented prostheses were used in 6% of unilateral replacements and 48% of bilateral replacements. In hospital, patients who had bilateral TKR experienced significantly more complications, mainly thromboembolic, than patients who had unilateral TKR. Regression analysis showed that for every one point increase in the pre-operative SF-36 physical score (i.e. improving physical status) out-of-pocket costs decreased by 94%. Out-of-pocket costs for female patients were 3.3 times greater than for males. CONCLUSION: Patients undergoing bilateral TKR and unilateral TKR had a similar length of stay in hospital and similar out-of-pocket expenditures. Bilateral replacement patients reported better physical function and general health with fewer health care visits one year post procedure. Patients requiring bilateral TKR have some additional information to aid their decision making. While their risk of peri-operative complications is higher, they have an excellent chance of good health outcomes at 12 months and are not going to be doubly "out-of-pocket" for the experience.

Hydroxyapatite-coated, cementless total knee replacement in patients aged 75 years and over.

We have carried out a prospective study comparing the results at five years in patients older than 75 years of age undergoing hydroxyapatite-coated, cementless total knee replacement (TKR) with those who were younger. The Knee Society clinical rating scores were recorded before and after operation. Of 559 patients undergoing TKR, 135 were in the elderly age group. The knee scores at five years or more showed comparable results, with patients under 75 years of age reaching a score of 183 and those aged 75 years or over reaching 174. These differences were predominantly due to the functional component of the score. We conclude that elderly patients do just as well as the younger group using this prosthesis.

Arthroscopic debridement in the treatment of the infected total knee replacement.

Infection is a potentially disastrous complication of total knee replacement (TKR). Retention of the prosthesis has been associated with high rates of persistent infection. Our study shows that in selected situations, arthroscopic debridement may allow retention of the prosthesis and eradication of the infection. However, the prosthesis must be stable, the surgical technique must be meticulous and specific antibiotics must be taken for a lengthy period. Arthroscopic debridement should be considered as an alternative to an open technique, or revision, for the infected TKR.

Ability to kneel after total knee replacement.

We have investigated the ability to kneel after total knee replacement. We asked 75 patients (100 knees) at least six months after routine uncemented primary total knee replacement, to comment on and to demonstrate their ability to kneel. Differences between the perceived and actual ability to kneel were noted. In 32 knees patients stated that they could kneel without significant discomfort. In 54 knees patients avoided kneeling because of uncertainties or recommendations from third parties (doctors, nursing staff, friends, etc). A total of 64 patients was actually able to kneel without discomfort or with mild discomfort only and 12 of the remainder were unable to kneel because of problems which were not related to the knee. Twenty-four patients therefore were unable to kneel because of discomfort in the knee. There was no difference between the 'kneelers' and 'non-kneelers' with regard to overall knee score, range of movement and the presence of patellar resurfacing.

"Silent" transverse patellar fracture following anterior cruciate ligament reconstruction.

Patellar fracture is a rare but specific complication of anterior cruciate ligament reconstruction using bone-patellar tendon-bone autograft. When this complication occurs, early internal fixation is recommended and need not compromise the outcome. We report 2 cases of displaced transverse patellar fracture occurring after reconstruction but which were not diagnosed and presented with late sequelae.

The meniscal "pseudocyst." A clinical sign of a torn meniscus.

We report a study of 636 patients requiring knee surgery, all of whom underwent detailed preoperative assessment. Fifty-eight patients had a clinical sign of a lump on the joint line when the knee was examined at 45 degrees of flexion, which has been thought to indicate a meniscal cyst. Of these 58 patients, however, only 30 patients had a meniscal cyst demonstrated at surgery. The remaining 28 patients had a meniscal tear without a cyst. In these 28 cases, the clinical sign of a lump protruding from the joint line was termed a "pseudocyst." This new clinical sign is important because of its frequency of occurrence and the complete correlation with meniscal tears requiring surgical intervention.

A comparison of outcomes in osteoarthritis patients undergoing total hip and knee replacement surgery.

OBJECTIVE: The aims of this study were to assess changes in physical function and quality of life with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the instrument of the Medical Outcomes Study SF-36 Health Survey (MOS SF-36), respectively, in patients undergoing hip anf knee joint replacement surgery and to compare the responsiveness of these two outcome measures 1 year after surgery. DESIGN: One hundred and ninety-four patients with osteoarthritis (OA knee 108, OA hip 86) admitted to four hospitals in Sydney were followed over a period of 1 year at 3 monthly intervals. RESULTS: WOMAC measures improved significantly after 1 year for OA hip and OA knee: there was reduction in pain of 71% and 53%, reduction of stiffness of 55% and 43% and improvement in physical function of 68% and 43%, respectively. MOS SF-36 measures in those having hip surgery improved significantly for pain (222%), physical function (247%), physical role functioning (402%), general health (110%), vitality (143%0, social functioning (169%) and mental health (114%). For those in the knee surgery group, significant improvement was seen for pain (175%), physical function (197%), physical role functioning (275%), vitality (125%) and social functioning (119%). The WOMAC was a more responsive measure than the MOS SF-36. CONCLUSION: WOMAC and MOS SF-36 detect significant and clinically meaningful changes in outcome after hip and knee replacement. WOMAC requires a smaller sample size and is more responsive in the short term. For a follow-up longer than 6 months MOS SF-36 provides additional information. The improvement in outcomes following hip joint surgery were significantly greater than those following knee surgery.

FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition.

Angiogenic growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs) are currently targets of intense efforts to inhibit deregulated blood vessel formation in diseases such as cancer. FGFs and VEGFs exert their effects via specific binding to cell surface-expressed receptors equipped with tyrosine kinase activity. Activation of the receptor kinase activity allows coupling to downstream signal transduction pathways that regulate proliferation, migration and differentiation of endothelial cells. Inhibitors of FGF and VEGF signalling are currently in clinical trials. In this article, the current knowledge of FGF- and VEGF-induced signal transduction that leads to specific biological responses will be summarized. Furthermore, the manner in which this knowledge is being exploited to regulate angiogenesis will be discussed.

Determinants of willingness to pay for hip and knee joint replacement surgery for osteoarthritis.

OBJECTIVES: To determine whether patients with osteoarthritis (OA) would be willing to pay for joint replacement and whether patient characteristics or health outcomes, including pain, physical function and health-related quality of life, were related to willingness to pay (WTP). METHODS: Patients who had undergone primary total hip replacement (THR) or total knee replacement (TKR) for OA completed a disease-specific questionnaire (Western Ontario and McMaster: WOMAC index), a generic measure of health status (Medical Outcome Study Short Form-36: SF-36) and an Evaluation Questionnaire to measure WTP and satisfaction with the replacement. RESULTS: Responses were obtained from 109 (77%) THR patients and 129 (72%) TKR patients. Mean age of respondents was 67 yr for THR (47% female) and 73 yr for TKR (60% female). Overall, 85% of patients responded to the WTP question. Of the THR patients, 71% were willing to pay something, 11% were not willing to pay anything and 18% did not answer the question. For TKR patients these figures were 70, 16 and 14% respectively. However, of those who responded to the WTP question, only 25% of the THR patients and 18% of the TKR patients indicated they would be willing to pay the actual current average cost of the operation in Australia (>/= A$15 000). A lower postoperative pain score (as measured by the WOMAC index) was a significant predictor of WTP for both THR and TKR patients. Income also significantly predicted WTP in THR patients but not in TKR patients. The other significant predictors for TKR patients were older age, having private health insurance and willingness to recommend joint replacement to others. CONCLUSIONS: Willingness to pay was a measure that was understandable and acceptable to patients, most of whom were willing to pay something. There was a high correlation between WTP, good health outcomes and patient satisfaction, pain relief being the dominant determinant.

G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and Galpha(i) signals.

G protein-coupled receptors (GPCRs) have been shown to stimulate extracellular regulated kinases (ERKs) through a number of linear pathways that are initiated by G(q/11) or G(i) proteins. We studied signaling to the ERK cascade by receptors that simultaneously activate both G protein subfamilies. In HEK293T cells, bradykinin B(2) receptor (B(2)R)-induced stimulation of ERK2 and transcriptional activity of Elk1 are dependent on Galpha(q)-mediated protein kinase C (PKC) and on Galpha(i)-induced Ras activation, while they are independent of Gbetagamma subunits, phosphatidylinositol 3-kinase, and tyrosine kinases. Similar results were obtained with m(1) and m(3) muscarinic receptors in HEK293T cells and with the B(2)R in human and mouse fibroblasts, indicating a general mechanism in signaling toward the ERK cascade. Furthermore, the bradykinin-induced activation of ERK is strongly reduced in Galpha(q/11)-deficient fibroblasts. In addition, we found that constitutively active mutants of Galpha(q/11) or Galpha(i) proteins alone poorly stimulate ERK2, whereas a combination of both led to synergistic effects. We conclude that dually coupled GPCRs require a cooperation of Galpha(i)- and G(q/11)-mediated pathways for efficient stimulation of the ERK cascade. Cooperative signaling by multiple G proteins thus might represent a novel concept implicated in the regulation of cellular responses by GPCRs.

Subareolar injection is a better technique for sentinel lymph node biopsy.

BACKGROUND: Numerous techniques and materials show accuracy in localizing the sentinel lymph node (SLN). We hypothesized that subareolar injection of material would localize the SLN as effectively as peritumoral injection. METHODS: Thirty-eight patients were injected with technetium-99 sulfur colloid either peritumorally or subareolarly in addition to the injection of blue dye around the tumor. Radioactive SLNs were localized using a hand-held gamma probe. RESULTS: Nineteen patients were included in each of the two groups, peritumoral and subareolar. SLNs were found in all patients injected subareolarly and in 18 of 19 injected peritumorally. The false-negative rate was 20% for peritumoral injection and 0% for subareolar injection. CONCLUSION: The results suggest that subareolar injection was as accurate, if not more accurate, than peritumoral injection for localizing the SLN. This technique is simpler than peritumoral injection and does not require injection under image guidance for nonpalpable lesions.

Outcomes after hip or knee replacement surgery for osteoarthritis. A prospective cohort study comparing patients' quality of life before and after surgery with age-related population norms.

OBJECTIVE: To compare the health-related quality of life of people with osteoarthritis before and after primary total hip and knee replacement surgery with that of the general Australian population. DESIGN: A prospective cohort study. SETTING: Three Sydney hospitals, public and private. PARTICIPANTS: Patients with osteoarthritis undergoing primary total hip (n = 59) and knee (n = 92) joint replacement surgery. MAIN OUTCOME MEASURE: Medical Outcomes Study Short Form (SF-36) scores before and 12 months after joint replacement surgery (compared with population norms). RESULTS: Patients in each age group showed a significant improvement in health-related quality of life after joint replacement surgery in most scales of the SF-36, particularly physical function, role physical and bodily pain. SF-36 scores for the 42 hip-replacement patients aged 55-74 years improved to equal or exceed the population norm on all scales. SF-36 scores of the 52 knee replacement patients aged 55-74 years improved, but physical function and bodily pain scores remained significantly worse than the population norm. SF-36 scores for both hip (n = 17) and knee (n = 40) replacement patients aged 75 years and over improved significantly, becoming similar to population norms for this age group. CONCLUSIONS: Total hip or knee replacement for osteoarthritis significantly improves patient health and well-being at 12 months after surgery. Age alone should not be a barrier to surgery.

The intercruciate band of the human knee. An anatomical and histological study.

Thirty cruciate ligaments were retrieved from either cadavers or limbs which had been amputated. Each specimen was sectioned and stained to demonstrate the presence of collagen, nerves and vessels. All 30 specimens contained an interconnecting band of collagen fibres between the anterior and posterior cruciate ligaments. Vascular structures were present in all specimens and nerve fibres were identified in 26 (86%). We have called this structure the 'intercruciate band'. The anterior and posterior cruciate ligaments should no longer be thought of in isolation, but together as a 'cruciate complex'.