The accuracy of intramedullary femoral alignment in total knee replacement in the prescence of ipsilateral hip replacement

Objectives: During total knee replacement (TKR) surgery, the most commonly used method for aligning the distal femur appropriately is via an intramedullary (IM) distal femoral alignment rod. The alignment of the rod itself is reliant on the isthmus which is used to most accurately place the rod in the correct anatomical axis. In the instance of something preventing the rod from entering the isthmus correctly, such as a hip replacement, then the degree of accuracy could be assumed to be even less. Mechanical-anatomical malalignment has been shown to decrease the implant (TKR) survival and so methods of increasing accuracy of alignment relative to the mechanical axis have been developed. At present the most accurate method intraoperatively is computer navigation and several studies have demonstrated improved alignment. An increasing number of patients year on year are having both knee and hip replacements and as the population ages the likelihood of having both a knee and hip replacement will also increase. We propose that the presence of a hip replacement within the isthmus of the femur may further decrease the accuracy of the IM alignment of the femur leading to incorrect implant positioning. Methods: The study was conducted on 10 cadaveric specimens (20 femurs). Computational navigation instrumentation was attached in turn to each femur and the ideal alignment data recorded in a standard fashion by a single operator (principal investigator). A standard entry port was then be made in the femur for the introduction of the IM rod. An IM rod was then inserted with the distal femoral cutting block in the accepted position recorded blindly on the computer navigation (both in terms of varus/valgus alignment to the mechanical axis and the degree of flexion). The process was then repeated at 3 levels to represent primary and revision hip lengths from the greater trochanter (replicating the changes that would occur in the presence of a hip replacement) The process was recorded three times at each level. Results: The resection angles between the cutting surface and the mechanical axis were measured and collected by means of computer navigation system. The results show that the IM alignment had mean Valgus of 0 degrees +/- 0.8 but with a hip replacement in situ this increased to 0.46 degrees +/- 1.49 (range 2.5 varus to 4.5 valgus), with a revision stem 0.825 +/- 1.68 (range 2.5 varus to 4.5 valgus)and long stemmed revision 1.325 +/- 2.09 (range 5 varus to 6.5 valgus). In terms of Flexion IM alignment had a mean flexion of 0.92 +/- 1.7 (range 3 extension to 4 flexion) but with a hip replacement in situ this increased to 1.88 degrees +/- 2.03 (range 2.5 extension to 8.5 flexion), with a revision stem 2.35 +/- 2.2 (range 2.5 extension to 8 flexion) and long stemmed revision 2.75 +/- 2.16(range 3.5 extension to 7 flexion). Conclusion: This Study concludes that the prescence of a hip replacement, in particular long stemmed prosthesis, further reduces the accuracy of IM alignment in the Femur for Total Knee Replacement. Consideration of an alternative method, such as navigation, should be considered insuch situations

Effects of centrally administered etanercept on behaviour, histology and TNF-α expression in mice following a peripheral immune challenge

Background: Peripheral cytokines affect central nervous system (CNS) function, triggering anxiety and cognitive decline. Although peripheral blockade of tumor necrosis factor (TNF-α) by etanercept, has been effective in alleviating rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated effects of central etanercept administration post-peripheral immune challenge, on behaviour and histology. Methods: 12-week-old C57BL/6 mice (n=40) were challenged with either LPS or saline, administered peripherally 24hr before being treated with etanercept or artificial CSF (aCSF), via intracerebroventricular injection. Mice underwent behavioural analyses for locomotion (open field test: OFT), memory (Y maze) and anxiety (elevated zero maze: EZM) 24hr post etanercept/aCSF treatment. Brain tissue was then collected to estimate number of hippocampal microglia and expression of Tnfa. Results: Acute systemic challenge with LPS decreased weight in mice at 24hr, and impaired locomotor activity. LPS significantly increased anxiety-like behaviour (2-way ANOVA: Interaction: P=0.096; Saline/LPS challenge: P=0.0006, aCSF/etanercept treatment: P=0.0008), which was reversed by etanercept and significantly reduced cognition in the Y Maze (Interaction: P=0.037, Saline/LPS challenge: P=0.31, aCSF/etanercept treatment: P=0.80), which was not reversed by etanercept. LPS challenge also increased Tnfa expression in the hippocampus (Interaction: F(1,13)=28.04, P=0.0001, Saline/LPS challenge: P=0.0003, aCSF/etanercept treatment: P=0.021) and etanercept treatment was effective in reducing this Tnfa expression (P=0.001). Etanercept also significantly reduced microglial numbers within the hippocampus, which were increased following LPS administration (2-way ANOVA: Interaction: P= 0.0041; Saline/LPS challenge: P<0.0001, etanercept/aCSF: P=0.08,). Conclusion: A single dose of etanercept was found to be effective in significantly decreasing anxiety, Tnfa expression and microglia numbers 48hr post-peripheral immune challenge. The present study suggests that there is effective cross-talk between peripheral and central immune systems. Additionally behavioural and biological changes caused by LPS challenge which may be mediated by TNF-α related central inflammation, were reversed by etanercept treatment

Introduction to spinal cord injury

[Extract:] The spinal cord is a component of the human central nervous system (CNS), which includes the brain and spinal cord. The brain is complex and has many diverse functions, such as consciousness, thought, imagination, creativity, attention, executive functions, language, emotional experience, learning and memory. Additionally, it modulates and regulates the functions of the organ systems, the endocrine system and motor control

Immune-mediated regulation of Neurotrophins: a role for TNF

Neurogenesis is an important process regulating learning and memory, with neurotrophic factors like Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) essential to neurogenesis in the central nervous system. Recent evidence points to the role of immune mediators, particularly the cytokine tumor necrosis factor alpha (TNF) in the regulation and expression of neurotrophins. TNF signals through two main receptor subtypes - TNF-R1 and TNF-R2, with the TNF-R1 pathway seen as neurodegenerative and the TNF-R2 pathway as neuroproliverative. Previous studies have indicated that TNF regulates the expression of BDNF and NGF; however the exact mechanisms of this have not been clearly elucidated leaving the relative involvement of the TNF-R1 and TNF-R2 signalling pathways unknown. Therefore the aim of this study was to elucidate the mechanisms through which TNF exerts its influence on neurotrophins and how this affects learning and memory. The study used genetically modified 3 month old mice, (n=14 per strain), in TNF-/-, TNF-R1-/- andTNF-R2-/-, as well as wild type control mice on a B.6 background. The mice were subject to a behavioural battery incorporating the Barnes Maze to measure cognition like behaviour and Elevated Zero Maze to assess anxiety. An ELISA was then performed on hippocampal and prefrontal cortex tissue (n=7 per strain) to assess the amount of BDNF and NGF expressed in these areas. Cognitive deficits were seen in TNF-KO, TNF-R1 KO and TNF-R2 KO mice on the Barnes Maze with an increase in time taken to learn the location of the escape box compared to WT mice. Furthermore, increased anxiety was observed in these strains as measured by the Elevated Zero Maze (p<0.001). ELISA data revealed low levels of NGF in TNF-KO and TNF-R2 KO mice, while low levels of BDNF were observed in the TNF-R2 KO mice. In contrast, neither NGF nor BDNF levels were altered in TNF-R1-/- mice. These results indicate that constitutional levels of TNF are required for normal learning and involve signalling via both the TNFR1-/- and TNFR2-/- pathways. The impairment in cognition in TNF KO and TNF-R2 KO mice was accompanied by changes in neurotophin levels indicating this may be a potential mechanism whereby TNF regulates cognition and behaviour. Interestingly signalling via TNF-R1 also impaired cognition, but was not associated with changes in neurotrophins, with further studies needed to determine how this primarily neurodegenerative pathway is necessary for normal learning

Immune-mediated regulation of Neurotrophins: a role for TNF

Neurogenesis is an important process regulating learning and memory, with neurotrophic factors like Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) essential to neurogenesis in the central nervous system. Recent evidence points to the role of immune mediators, particularly the cytokine tumor necrosis factor alpha (TNF) in the regulation and expression of neurotrophins. TNF signals through two main receptor subtypes - TNF-R1 and TNF-R2, with the TNF-R1 pathway seen as neurodegenerative and the TNF-R2 pathway as neuroproliverative. Previous studies have indicated that TNF regulates the expression of BDNF and NGF; however the exact mechanisms of this have not been clearly elucidated leaving the relative involvement of the TNF-R1 and TNF-R2 signalling pathways unknown. Therefore the aim of this study was to elucidate the mechanisms through which TNF exerts its influence on neurotrophins and how this affects learning and memory. The study used genetically modified 3 month old mice, (n=14 per strain), in TNF-/-, TNF-R1-/- andTNF-R2-/-, as well as wild type control mice on a B.6 background. The mice were subject to a behavioural battery incorporating the Barnes Maze to measure cognition like behaviour and Elevated Zero Maze to assess anxiety. An ELISA was then performed on hippocampal and prefrontal cortex tissue (n=7 per strain) to assess the amount of BDNF and NGF expressed in these areas. Cognitive deficits were seen in TNF-KO, TNF-R1 KO and TNF-R2 KO mice on the Barnes Maze with an increase in time taken to learn the location of the escape box compared to WT mice. Furthermore, increased anxiety was observed in these strains as measured by the Elevated Zero Maze (p<0.001). ELISA data revealed low levels of NGF in TNF-KO and TNF-R2 KO mice, while low levels of BDNF were observed in the TNF-R2 KO mice. In contrast, neither NGF nor BDNF levels were altered in TNF-R1-/- mice. These results indicate that constitutional levels of TNF are required for normal learning and involve signalling via both the TNFR1-/- and TNFR2-/- pathways. The impairment in cognition in TNF KO and TNF-R2 KO mice was accompanied by changes in neurotophin levels indicating this may be a potential mechanism whereby TNF regulates cognition and behaviour. Interestingly signalling via TNF-R1 also impaired cognition, but was not associated with changes in neurotrophins, with further studies needed to determine how this primarily neurodegenerative pathway is necessary for normal learning

Effects of centrally administered etanercept on behaviour, histology and TNF-α expression in mice following a peripheral immune challenge

Background: Peripheral cytokines affect central nervous system (CNS) function, triggering anxiety and cognitive decline. Although peripheral blockade of tumor necrosis factor (TNF-α) by etanercept, has been effective in alleviating rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated effects of central etanercept administration post-peripheral immune challenge, on behaviour and histology. \ud \ud Methods: 12-week-old C57BL/6 mice (n=40) were challenged with either LPS or saline, administered peripherally 24hr before being treated with etanercept or artificial CSF (aCSF), via intracerebroventricular injection. Mice underwent behavioural analyses for locomotion (open field test: OFT), memory (Y maze) and anxiety (elevated zero maze: EZM) 24hr post etanercept/aCSF treatment. Brain tissue was then collected to estimate number of hippocampal microglia and expression of Tnfa.\ud \ud Results: Acute systemic challenge with LPS decreased weight in mice at 24hr, and impaired locomotor activity. LPS significantly increased anxiety-like behaviour (2-way ANOVA: Interaction: P=0.096; Saline/LPS challenge: P=0.0006, aCSF/etanercept treatment: P=0.0008), which was reversed by etanercept and significantly reduced cognition in the Y Maze (Interaction: P=0.037, Saline/LPS challenge: P=0.31, aCSF/etanercept treatment: P=0.80), which was not reversed by etanercept. LPS challenge also increased Tnfa expression in the hippocampus (Interaction: F(1,13)=28.04, P=0.0001, Saline/LPS challenge: P=0.0003, aCSF/etanercept treatment: P=0.021) and etanercept treatment was effective in reducing this Tnfa expression (P=0.001). Etanercept also significantly reduced microglial numbers within the hippocampus, which were increased following LPS administration (2-way ANOVA: Interaction: P= 0.0041; Saline/LPS challenge: P<0.0001, etanercept/aCSF: P=0.08,). \ud \ud Conclusion: A single dose of etanercept was found to be effective in significantly decreasing anxiety, Tnfa expression and microglia numbers 48hr post-peripheral immune challenge. The present study suggests that there is effective cross-talk between peripheral and central immune systems. Additionally behavioural and biological changes caused by LPS challenge which may be mediated by TNF-α related central inflammation, were reversed by etanercept treatment

Tumor necrosis factor alpha and its receptors in behaviour and neurobiology of adult mice, in the absence of an immune challenge

Tumor necrosis factor alpha (TNF-α) is a vital component of the immune system and CNS. We previously showed that 3-month-old TNF-α and TNF-α receptor knockout mice had impaired cognition, whilst at 12-months-old mice had better cognition. To extend these findings on possible age-dependent TNF-α effects in the brain, we investigated the behaviour of 6-month-old TNF-α knockout mice and their neurobiological correlates. 6-month-old TNF−/−, TNF-R1−/− and TNF-R2−/− mice were compared to age-matched WT mice and tested for various behaviours. ELISA hippocampal levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) and qPCR mRNA levels of Tnfa, Tnfr1, Tnfr2, Il10 and Il1β were measured. TNF-R1−/− and TNF−/− mice were found to have lesser exploratory behaviour than WT mice, while TNF-R1−/− mice displayed better memory than WT and TNF-R2-/− mice. Both TNF−/− and TNF-R2−/− mice exhibited significantly lower immobility on the depression test than WT mice. Additionally, TNF−/− mice expressed significantly lower levels of BDNF than WT mice in the hippocampus while TNF-R1−/− mice displayed significantly lower BDNF levels compared to both WT and TNF-R2−/− mice. TNF-R2−/− mice also displayed significantly higher levels of NGF compared to TNF-R1−/− mice. These results illustrate that TNF-α and its receptors mediate several behavioural phenotypes. Finally, BDNF and NGF levels appear to be regulated by TNF-α and its receptors even under immunologically unchallenged conditions

Effects of centrally administered etanercept on behavior, microglia, and astrocytes in mice following a peripheral immune challenge

Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF)-α has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated the effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviors and microglia and astrocyte numbers. Twelve-week-old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 h before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioral analyses for locomotion, memory, and anxiety-like behavior 24 h post-etanercept/aCSF treatment, and tissue was collected to estimate the numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behavior, which was significantly improved following treatment with etanercept (two-way ANOVA: Interaction: F(1,30)=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023). For cognition, a significant interaction effect found by two-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared with Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (two-way ANOVA: Interaction: F(1,15)=11.41, P=0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08). Centrally administered etanercept improved anxiety-like behavior but not spatial memory under a peripheral immune challenge and was associated with a decrease in the hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behavior possibly mediated by a reduction of TNF-α-related central inflammation