Posterior Bearing Overhang Following Medial and Lateral Mobile Bearing Unicompartmental Knee Replacements

This study explores the extent of bearing overhang following mobile bearing Oxford unicompartmental knee replacement (OUKR) (Oxford Phase 3, Zimmer Biomet). The Oxford components are designed to be fully congruent, however knee movements involve femoral rollback, which may result in bearing overhang at the posterior margin of the tibial implant, with potential implications for; pain, wear, and dislocation. Movement is known to be greater, and therefore posterior overhang more likely to occur, with; lateral compared to medial implants, anterior cruciate ligament deficiency, and at extremes of movement. 24 medial, and 20 domed lateral, OUKRs underwent sagittal plane knee fluoroscopy during step‐up and forward lunge exercises. The bearing position was inferred from the relative position of the femoral and tibial components. Based on the individual component sizes and geometry the extent the posterior part of the bearing which overhung the posterior part of the tibial component was calculated. There was no significant posterior overhang in knees with medial implants. Knees with lateral domed implants exhibited overhang at flexion angles beyond 60°, the magnitude of which increased with increasing flexion angle, reaching a maximum of 50% of the bearing length at 140° (range 0‐140°). This demonstrates a clear difference between the kinematics, and prevalence and extent of posterior bearing overhang between medial and lateral OUKRs

Comparison of outcomes after UKA in patients with and without chondrocalcinosis: a matched cohort study

Purpose: Chondrocalcinosis can be associated with an inflammatory arthritis and aggressive joint destruction. There is uncertainty as to whether chondrocalcinosis represents a contraindication to unicompartmental knee arthroplasty (UKA). This study reports the outcome of a consecutive series of patients with chondrocalcinosis and medial compartment osteoarthritis treated with UKA matched to controls. Methods: Between 1998 and 2008, 88 patients with radiological chondrocalcinosis (R-CCK) and 67 patients with histological chondrocalcinosis (H-CCK) were treated for end-stage medial compartment arthritis with Oxford UKA. One-to-two matching was performed to controls, treated with UKA, but without evidence of chondrocalcinosis. Functional outcome and implant survival were assessed in each group. Results: The mean follow-up was 10 years. The mean Oxford Knee Score (OKS) at final follow-up was 43, 41 and 41 in H-CCK, R-CCK and control groups (change from baseline OKS was 21, 18 and 15, respectively). The change was significantly higher in H-CCK than in control but was not significantly different in R-CCK. Ten-year survival was 96 % in R-CCK, 86 % in H-CCK and 98 % in controls. Although the survival in H-CCK was significantly worse than in control, only one failure was due to disease progression. Conclusion: The presence of R-CCK does not influence functional outcome or survival following UKA. Pre-operative radiological evidence of CCK should not be considered to be a contraindication to UKA. H-CCK is associated with significantly improved clinical outcomes but also a higher revision rate compared with controls. Level of evidence: Case control study, Level III

The interaction of caseload and usage in determining outcomes of unicompartmental knee arthroplasty: A meta-analysis

Background: Outcomes following UKA are variable and influenced by surgical caseload (UKA/year) and usage (percentage of primary knee arthroplasty that are UKA), which relates to indications. This meta-analysis assesses the relative importance of these factors. Methods: MEDLINE (Ovid), Embase (Ovid) and the Web of Science (ISI) were searched for consecutive series of minimally invasive cemented Phase 3 Oxford medial UKA. The primary outcome measure was revision-rate/100 observed component years (%pa). Series were divided into groups according to caseload and usage. Results 46studies, including 12,520 knees, were identified. The annual revision-rate varied from 0%pa to 4.35%pa, mean 1.21%pa (95%CI 0.97-1.47). In series with mean follow-up of ten-years or more the revision-rate was 0.63%pa (95%CI 0.46-0.83), which equates to a ten-year survival of 94% (95%CI 92%-95%). Aseptic loosening, lateral arthritis, bearing dislocation, and unexplained pain were the predominant failure mechanisms with revision for patello-femoral problems and polyethylene wear exceedingly rare (<0.1%). Both increasing caseload (p=0.02) and usage (p<0.001) were associated with decreasing revision-rate. The lowest revision-rates were achieved with a caseload >24 UKA/year (0.88%pa, 95%CI 0.63-1.61) and usage >30% (0.69%pa, 95%CI 0.50-0.90). Usage was more important than caseload: with high-usage (≥20%) the revision-rate was low, whether the caseload was high (>12UKA/year) or low (≤12UKA/year), (0.94%pa (95%CI 0.69-1.23) and 0.85%pa (95%CI 0.65-1.08) respectively); whereas with low-usage (<20%) the revision-rate was high, whether the caseload was high or low (1.58%pa, 95%CI 0.57- 3.05 and 1.76%pa, 95%CI 1.21-2.41). Conclusion: To achieve optimum results with mobile-bearing UKA surgeons, whether high or low-caseload, should adhere to the recommended indications such that ≥20%, or ideally >30% of their knee replacements are UKA. If they do this then they can expect to achieve results similar to those of the long-term series, which all had high-usage (>20%) and an average ten-year survival of 94%

Water induced sediment levitation enhances downslope transport on Mars

On Mars, locally warm surface temperatures (~293 K) occur, leading to the possibility of (transient) liquid water on the surface. However, water exposed to the martian atmosphere will boil, and the sediment transport capacity of such unstable water is not well understood. Here, we present laboratory studies of a newly recognized transport mechanism: “levitation” of saturated sediment bodies on a cushion of vapor released by boiling. Sediment transport where this mechanism is active is about nine times greater than without this effect, reducing the amount of water required to transport comparable sediment volumes by nearly an order of magnitude. Our calculations show that the effect of levitation could persist up to ~48 times longer under reduced martian gravity. Sediment levitation must therefore be considered when evaluating the formation of recent and present-day martian mass wasting features, as much less water may be required to form such features than previously thought

A mammalianized synthetic nitroreductase gene for high-level expression

Background The nitroreductase/5-(azaridin-1-yl)-2,4-dinitrobenzamide (NTR/CB1954) enzyme/prodrug system is considered as a promising candidate for anti-cancer strategies by gene-directed enzyme prodrug therapy (GDEPT) and has recently entered clinical trials. It requires the genetic modification of tumor cells to express the E. coli enzyme nitroreductase that bioactivates the prodrug CB1954 to a powerful cytotoxin. This metabolite causes apoptotic cell death by DNA interstrand crosslinking. Enhancing the enzymatic NTR activity for CB1954 should improve the therapeutical potential of this enzyme-prodrug combination in cancer gene therapy. Methods We performed de novo synthesis of the bacterial nitroreductase gene adapting codon usage to mammalian preferences. The synthetic gene was investigated for its expression efficacy and ability to sensitize mammalian cells to CB1954 using western blotting analysis and cytotoxicity assays. Results In our study, we detected cytoplasmic protein aggregates by expressing GFP-tagged NTR in COS-7 cells, suggesting an impaired translation by divergent codon usage between prokaryotes and eukaryotes. Therefore, we generated a synthetic variant of the nitroreductase gene, called ntro, adapted for high-level expression in mammalian cells. A total of 144 silent base substitutions were made within the bacterial ntr gene to change its codon usage to mammalian preferences. The codon-optimized ntro either tagged to gfp or c-myc showed higher expression levels in mammalian cell lines. Furthermore, the ntro rendered several cell lines ten times more sensitive to the prodrug CB1954 and also resulted in an improved bystander effect. Conclusion Our results show that codon optimization overcomes expression limitations of the bacterial ntr gene in mammalian cells, thereby improving the NTR/CB1954 system at translational level for cancer gene therapy in humans

Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease

Cell-Type Specific Expression of a Dominant Negative PKA Mutation in Mice

We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology