Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment.

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.

The discrepancy between patient expectations and actual outcome reduces at the first 6 months following total knee replacement surgery.

PURPOSE: Patients undergoing total knee arthroplasty often have unfulfilled expectations from the surgery that can lead to dissatisfaction. This study aimed to examine the discrepancy between patients' expectations and actual functional abilities prior to undergoing knee replacement surgery, and at 6 and 12 months following the surgery. METHODS: A survey was undertaken of patients before, and 6 and 12 months post-surgery. The survey included the Knee Surgery Perception Questionnaire (KSPQ) to assess patients' current perception of their level of function and pain, their desired outcomes, and the discrepancy between the two. Pain, function and quality of life were also assessed. Repeated measure ANOVAs were used to assess differences between pre- and post-surgery. RESULTS: A total of 176 patients were surveyed. Significant differences in the KSPQ discrepancy scores (subscale and total scores) were demonstrated between the three assessment point times (p < 0.01). Paired t tests identified significant differences between the pre-surgery and 6-month KSPQ discrepancy scores, (p < 0.01) indicative of substantial improvement in physical function and slight reduction in expectations. Overall significant improvement (p < 0.01) was reported over time across all measures: physical function, pain and stiffness and quality of life. CONCLUSION: The discrepancy between patients' current abilities and their expectation changes following surgery, especially in the first 6 months post-surgery. Patients' goals might change as their function and pain improve post-surgery. Combining education programmes and discussion with the treating orthopaedic surgeons pre-operatively is important for the development of realistic, achievable expectations. LEVEL OF EVIDENCE: III.

Pre-operative predictors of post-operative falls in people undergoing total hip and knee replacement surgery: a prospective study.

INTRODUCTION: Pain and disability often persist following hip (THR) and knee replacement (TKR) surgery predisposing patients to increased risk of falling. This study identified pre-operative predictors for post-operative falls in TKR and THR patients, and the incidence and circumstances of falls in the 12 months post-surgery. MATERIALS AND METHODS: A survey was undertaken of patients before THR and TKR, and was repeated 12 months post-operation. The survey included (1) medical history and medications usage, (2) pain and function, (3) health-related and physical activity and (4) fear of falls and history of falls questionnaires. Patients were classified as 'fallers' (≥1 fall) or 'non-fallers' based on prospectively documented falls in the 12 months post-surgery. Binary logistic regression was conducted to identify independent pre-operative predictors of incident falls status. RESULTS: Eighty-two of the 243 participants (33.7%) reported ≥1 fall in the 12 months post-operatively [60 (34.1%) patients following TKR and 22 (32.8%) following THR]. The logistic regression model was statistically significant, χ 2 = 24.731, p < 0.001, the model explaining 22% of the variance in falls, and correctly classifying 73.7% of cases as fallers or non-fallers. Reduced SF-36v2 general health sub-scale, increased planned physical activity and previous falls in the preceding year were predictors of falls. Those reporting ≥1 fall pre-operatively were three times more likely to fall post-operatively. CONCLUSION: People awaiting hip or knee joint replacement surgery might present with complex conditions that predispose them to greater risk of falling post-operation. Review of general health and history of falling is recommended pre-operatively to identify patients at risk.

Skeletal muscle vitamin D in patients with end stage osteoarthritis of the knee.

Muscle function is often impaired in patients with knee osteoarthritis (OA), with reduced strength and increased pain. The role of vitamin D and the vitamin D-endocrine pathway in muscle health has recently been placed in the spotlight, with various groups reporting positive effects on muscle development, function and health. Recently, it has been shown that uptake into muscle of the specialized vitamin D binding protein (DBP) is dependent on the endocytic receptor, megalin. Here we analyse circulating vitamin D, and muscle DBP, megalin and the cognate vitamin D receptor (VDR) in patients with knee OA and compare them to asymptomatic controls. Muscle and blood samples were collected from 19 patients with end-stage OA of the knee and 10 age-matched controls. Muscle biopsies from the OA group were performed during knee replacement surgery and a needle biopsy was used on control volunteers. Immunoblots performed with specific antibodies were used to detect the presence of DBP, megalin, VDR (using the specific D-6 antibody) and albumin in the muscle biopsies. Results were correlated with FoxO1, a key regulator of the ubiquitin-proteasome degradation pathway in muscle. There were no differences in circulating levels of 25 (OH) vitamin D3 between the groups, and no subjects were vitamin D deficient. We found increased VDR, DBP and albumin protein in the muscle from patients with OA compared to controls, with no change in muscle megalin expression. Furthermore, DBP levels in the muscle correlated with FoxO1, suggesting an association between muscle protein breakdown and the activation of the vitamin D-endocrine pathway in muscle surrounding an OA affected joint. We show, for the first time, that the factors involved in the vitamin D-endocrine-pathway are present at higher levels in muscles from OA patients compared to asymptomatic controls. This is despite no differences in circulating 25 (OH) vitamin D levels between the groups. These findings indicate the activation of vitamin D pathway in these muscles that may provide a beneficial compensatory stimulation of the repair process in muscles that are subject to inflammatory and proteolytic processes.

Development and validation of a questionnaire assessing discrepancy between patients' pre-surgery expectations and abilities and post-surgical outcomes following knee replacement surgery.

PURPOSE: The discrepancy between patient-desired outcomes and achievable functional outcomes is a source of patient dissatisfaction. This paper reports development and validation of a questionnaire to assess this discrepancy in patients undergoing knee replacement surgery. METHODS: The initial questionnaire (Knee Surgery Perception Questionnaire, KSPQ) comprised two parts. Part A, assessed patients' perception of their current level of function and pain, and Part B, assessed patients' desired outcomes of the surgery. Validation was carried out for Part A and then applied to Part B using a one-factor congeneric model and was tested in 185 patients preceding surgery. A discrepancy score between patients' expectations and desired outcome (Part B) and their perception of current function (Part A) was also calculated. Pearson correlations were used between the KSPQ total score and subscales and other knee-specific questionnaires to determine construct validity. RESULTS: The final best set of models included four items for each subscale with a Chi-square value of 7.3 (n.s). The subscales and the total KSPQ showed significant strong to moderate correlations with knee-specific questionnaires. The discrepancy score in each subscale and the overall score showed relatively large discrepancy between patients' expectations and their perception of current function; with higher discrepancy score reported for pain and walking. CONCLUSION: The KSPQ is a valid questionnaire to assess patients' expected and desired outcomes of knee replacement surgery and their perception of their current abilities and function, and discrepancy between these. The KSPQ now requires further investigation at different stages of recovery following surgery. LEVEL OF EVIDENCE: III.

The effects of osteoarthritis and age on skeletal muscle strength, Na+-K+-ATPase content, gene and isoform expression.

Knee osteoarthritis (OA) is a debilitating disorder prevalent in older populations that is accompanied by declines in muscle mass, strength, and physical activity. In skeletal muscle, the Na(+)-K(+) pump (NKA) is pivotal in ion homeostasis and excitability and is modulated by disuse and exercise training. This study examined the effects of OA and aging on muscle NKA in 36 older adults (range 55-81 yr), including 19 with OA (69.9 ± 6.5 yr, mean ± SD) and 17 asymptomatic controls (CON, 66.8 ± 6.4 yr). Participants completed knee extensor strength testing and a physical activity questionnaire. A vastus lateralis muscle biopsy was analyzed for NKA content ([(3)H]ouabain binding sites), α1-3- and ß1-3-isoform protein abundance (immunoblotting), and mRNA (real-time RT-PCR). The association between age and NKA content was investigated within the OA and CON groups and in pooled data. The NKA content was also contrasted between subgroups below and above the median age of 68.5 yr. OA had lower strength (-40.8%, P = 0.005), but higher NKA α2- (∼34%, P = 0.006) and α3-protein (100%, P = 0.016) abundance than CON and performed more incidental physical activity (P = 0.035). No differences were found between groups for NKA content, abundance of other NKA isoforms, or gene expression. There was a negative correlation between age and NKA content within OA (r = -0.63, P = 0.03) and with both groups combined (r = -0.47, P = 0.038). The NKA content was 25.5% lower in the older (69-81 yr) than in the younger (55-68 yr) subgroup. Hence older age, but not knee OA, was related to lowered muscle NKA content in older adults.

Lower limb biomechanics in individuals with knee osteoarthritis before and after total knee arthroplasty surgery.

We investigated the biomechanical changes that occur in the lower limb following total knee arthroplasty (TKA). Lower limb joint kinematics and kinetics were evaluated in 32 patients before and 12 months following TKA and 28 age-matched controls. Analysis of variance with Bonferroni-adjusted post-hoc tests showed no significant changes in knee joint kinematics and kinetics following TKA despite significant improvements in pain and function. Significant increases in peak ankle plantarflexion and dorsiflexion moments and ankle power generation were observed which may be a compensatory response to impaired knee function to allow sufficient power generation for propulsion. Differences in knee gait parameters may arise as a result of the presence of osteoarthritis and mechanical changes associated with TKA as well as retention of the pre-surgery gait pattern.

Dynamic foot function changes following total knee replacement surgery.

BACKGROUND: Individuals with knee osteoarthritis (OA) have flatter/more pronated feet than those without OA, but it is unclear whether altered foot posture and function are a cause or consequence of knee OA. The purpose of this study was to examine whether changes in foot posture and function occur after realignment of the knee following total knee replacement (TKR). MATERIALS AND METHODS: Nineteen patients with predominantly medial compartment knee OA were tested prior to and 12 months after TKR. The Foot Posture Index (FPI) and Arch Index (AI) were measured as well as motion of the tibia, rearfoot and forefoot using a 3D motion analysis system incorporating a multisegment foot model. RESULTS: There were no significant changes in FPI or AI following TKR, however gait analysis revealed significant increases in tibial external rotation (-18.7 ± 7.0° vs -22.5 ± 8.7°, p=0.002), tibial transverse plane range of motion (-9.1 ± 4.6° vs -11.4 ± 6.1°, p=0.0028) and rearfoot range of motion in the frontal plane (8.6 ± 2.6° vs 10.4 ± 2.7°, p=0.002), and a decrease in rearfoot transverse plane range of motion (8.7 ± 5.3° vs 5.9 ± 4.1°, p=0.038) following the procedure. CONCLUSIONS: TKR produces no change in static foot posture, but results in significant changes in rearfoot kinematics during gait. These findings suggest that rearfoot motion compensates for changes in the alignment of the knee, highlighting the ability of the foot to accommodate for proximal skeletal malalignment.

Lower limb proprioception deficits persist following knee replacement surgery despite improvements in knee extension strength.

PURPOSE: Knee pain and disability can persist following knee replacement surgery which may place patients at increased risk of falls. This study investigated the falls risk and the occurrence of falls of people with knee osteoarthritis (OA) before and at 12 months following knee replacement surgery. METHOD: Thirty-five patients with knee OA were tested prior to undergoing knee replacement surgery and at 12 months following surgery using the short form Physiological Profile Assessment, which incorporates tests of vision, lower limb proprioception, knee extension strength, reaction time and postural sway. Physical activity, number of falls, fear of falling, pain, disability and health-related quality of life were also assessed. RESULTS: No significant differences were found between the number of falls pre- and post-surgery (n.s.), with 48.5 and 40% reporting at least one fall in the 12 months before and following the surgery, respectively. Improvements in knee strength, reaction time and fear of falling were evident following surgery, with no improvement in lower limb proprioception. Self-reported pain, function and stiffness were significantly improved, but health-related quality of life deteriorated following the surgery. CONCLUSION: The number of falls experienced following knee replacement surgery remained relatively high, which may be attributed to the persistence of impaired lower limb proprioception. Although knee replacement surgery improves function and alleviates pain, people who undergo this procedure may need to engage in rehabilitation following the surgery to reduce the risk of falling. LEVEL OF EVIDENCE: Therapeutic study investigating the result of treatment on patient outcomes, Level IV.

Knee biomechanics early after knee replacement surgery predict abnormal gait patterns 12 months postoperatively.

An abnormal flexor moment pattern is often evident following total knee replacement (TKR) surgery. We investigated whether such a pattern at 12 months post-surgery could be predicted using biomechanical gait measures assessed before surgery and at 4 months post-surgery. Thirty two TKR patients were evaluated and classified as normal (biphasic pattern) or abnormal (flexor moment pattern) at each time point. Biomechanical parameters collected before surgery and at 4 months post-surgery were then explored for their ability to predict gait patterns at 12 months post-surgery. The gait pattern at 4 months was significantly associated with the 12 month post-surgery gait pattern, with over half of those with a flexor moment pattern at 4 months retaining this pattern at 12 months. Discriminant function analysis indicated that peak knee flexion during early stance, peak knee extension, and peak knee extension moment at 4 months post-surgery were independent predictors of the gait pattern at 12 months. Thus, an abnormal knee flexor moment pattern at 12 months post-surgery can be predicted by biomechanical analysis 4 months after surgery. Therefore, interventions aimed at improving active extension may need to be implemented early after surgery to restore a normal gait pattern.

Association between skeletal muscle inflammatory markers and walking pattern in people with knee osteoarthritis.

OBJECTIVE: Patients with knee osteoarthritis (OA) are characterized by increased muscle inflammation and altered gait. We investigated the association between proinflammatory mediators in the vastus lateralis and physical function and gait in patients with knee OA. METHODS: Nineteen patients with knee OA underwent gait analysis, assessment of self-reported pain and physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), and a muscle biopsy that was taken during their knee replacement surgery. Muscle was analyzed for cellular protein inflammatory mediators, interleukin-6, monocyte chemotactic protein 1 (MCP-1), p65 NF-κB, signal transducer and activator of transcription 3 (STAT-3), and JNK-1. Sagittal plane knee function, including early stance knee range of motion (ROM) and knee sagittal plane impulse, was measured using a motion analysis system. Pearson's correlation was used to assess relationships between selected variables. RESULTS: Significant positive correlations were found between MCP-1 and self-perceived stiffness, physical function, and the total WOMAC score (P < 0.05). MCP-1 was also negatively correlated with early stance knee ROM (r = -0.52, P = 0.023). Reduced velocity was associated with elevated levels of p65 NF-κB and STAT-3 (P < 0.05). Knee sagittal plane impulse was negatively correlated with JNK-1 (P = 0.02), indicating reduction in knee impulse with an increased level of JNK-1. CONCLUSION: Increased levels of several proinflammatory mediators were correlated with altered knee function during walking as well as greater physical disability and slower gait velocity. Identification of the cellular and molecular mechanisms associated with muscle inflammation is important to better understand the underlying mechanism responsible for altered gait and function in patients with knee OA.

Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis.

OBJECTIVE: Increased inflammation and pain are inseparable parts of knee osteoarthritis (OA) that may lead to disuse of the affected limb. The aim of this study was to examine the effects of knee OA on inflammation- and atrophy-related genes and proteins in the vastus lateralis muscle of patients with knee OA. METHODS: Nineteen patients with knee OA and 14 asymptomatic control subjects matched for age and body mass index underwent strength measurements and a muscle biopsy. Muscle was analyzed for the total cellular protein of inflammatory kinases (p65 NF-κB, JNK1/2, STAT-3, and suppressor of cytokine signaling 3 [SOCS-3]) and inflammatory intracellular molecules (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], tumor necrosis factor α [TNFα], IL-1ß, and atrogin-1). RESULTS: Knee OA resulted in greater levels of IL-6 protein (34%; P = 0.002). The levels of inflammatory kinases, including STAT-3 (187%; P = 0.002), p65 NF-κB (156%; P = 0.002), and JNK1 (179%; P = 0.027), were also elevated. Furthermore, elevated expression of gene transcripts encoding MCP-1 (28%; P = 0.023), TNFα (85%; P < 0.001), and SOCS-3 (38%; P = 0.055) was observed in patients with knee OA compared with control subjects. Patients with knee OA had reduced muscle strength compared with control subjects (mean ± SEM 84.7 ± 8.7 versus 143.1 ± 20.8 Nm; P = 0.005). Negative correlations were observed between muscle strength and MCP-1 protein abundance (r = -0.37 [P = 0.042]) and the gene expression of TNFα and atrogin-1 messenger RNA (r = -0.46 [P = 0.012] and r = -0.36 [P = 0.040], respectively). CONCLUSION: Gene expression and the protein abundance of numerous muscle markers of inflammation and atrophy were elevated in patients with knee OA, and the increase in muscle inflammation was associated with a reduction in muscle strength. Given the role inflammation markers may play in muscle strength and atrophy, further studies are needed to investigate the effect of exercise intervention on skeletal muscle inflammation.

Physiological risk factors for falls in people with knee osteoarthritis before and early after knee replacement surgery.

PURPOSE: Knee osteoarthritis (OA) is a major cause of disability and a risk factor for falls in older people. The purpose of this study was to assess the falls risk of people with knee OA before surgery and at 4 months following surgery and to compare this to a control group. METHODS: Thirty-five patients with knee OA prior to undergoing knee replacement surgery and 27 asymptomatic age-matched controls participated in the study. The surgical group were tested prior to their surgery and at 4 months post-surgery. The short form of the Physiological Profile Assessment was used to assess falls risk and included tests of vision, lower limb proprioception, knee extension strength, reaction time and postural sway. Physical activity, quality of life, fear of falls and disability before and after surgery were also documented. RESULTS: At least one fall in the previous 12 months was reported for 48% of the surgical group compared with 30% of the control group. Following the surgery, there was a reduction in fear of falling and pain, and improvements in function for the surgical group. However, compared to the control group, the surgical group exhibited a greater fear of falling and reduced lower limb proprioception and knee extension strength both pre- and post-surgery. CONCLUSION: People who undergo knee replacement surgery may be at increased risk of falls both prior to and 4 months following their surgery, primarily due to deficits in knee extension strength and lower limb proprioception. Therefore, interventions to reduce the risk of falls should be implemented early after the surgery.