Abstract Background Adverse local tissue reaction formation has been suggested to occur with the Modular Dual Mobility (MDM) acetabular design. Few reports in the literature have evaluated fretting ...and corrosion damage between the acetabular shell and modular metal inserts in this modular system. We evaluated a series of 18 retrieved cobalt chromium MDM inserts for evidence of fretting and corrosion. Methods We assessed the backsides of 18 MDM components for evidence of fretting and corrosion in polar and taper regions based on previously established methods. We collected and assessed 30 similarly designed modular inserts retrieved from metal-on-metal (MoM) total hip arthroplasties as a control. Results No specific pattern of fretting or corrosion was identified on the MDM inserts. Both fretting and corrosion were significantly greater in the MoM cohort than the MDM cohort, driven by higher fretting and corrosion scores in the engaged taper region of the MoM inserts. Conclusion MoM components demonstrated more fretting and corrosion than MDM designs, specifically at the taper region, likely driven by differences in the taper engagement mechanism and geometry among the insert designs. The lack of significant fretting and corrosion observed in the MDM inserts are inconsistent with recent claims that this interface may produce clinically significant metallosis and adverse local tissue reactions.
Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain ...unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Femoral stems with dual-taper modularity were introduced to allow independent control of length, offset, and version. Corrosion and fretting related to micromotion at the neck-stem junction ...are thought to stimulate an adverse local tissue reaction (ALTR). Analysis of 60 consecutively retrieved modular-neck stem implants (Rejuvenate, Stryker) revised primarily for ALTR was done to determine the variables influencing corrosion and fretting patterns at the neck-stem interface. Taper damage evaluation was performed with stereomicrocopic analysis with two observers. Evidence of fretting and corrosion was seen at the neck-stem taper in all implants, including three implants revised for periprosthetic fractures within four weeks of the index surgery indicating that this process starts early. Femoral stems paired with the long overall neck lengths had significantly higher corrosion scores. Correlation of the corrosion severity at particular locations with the length of implantation suggests that the neck-stem junction experiences cyclic cantilever bending in vivo. The positive correlation between the length of implantation and fretting/corrosion scores bodes poorly for patients who still have this implant. Scanning electron microscopy on a subset of specimens was also performed to evaluate the black corrosion material. We strongly urge frequent follow-up exams for every patient with this particular modular hip stem.
Significant research attention has been devoted to examining the relationship between HR practices and firm performance, and research support has assumed HR as the causal variable. Using data from 45 ...business units (with 62 data points), this study examines how measures of HR practices correlate with past, concurrent, and future operational performance measures. The results indicate that correlations with performance measures at all 3 times are both high and invariant, and that controlling for past or concurrent performance virtually eliminates the correlation of HR practices with future performance. Implications are discussed.
Fibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a ...common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21’s mechanisms and therapeutic potential.
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•A human allele in FGF21 is associated with higher alcohol as well as sugar intake•Phenotypes associated with this allele likely mimic those of lower FGF21 function•The human allele in FGF21 is associated with lower total body-fat percentage•The human allele in FGF21 is associated with higher blood pressure and waist-hip ratio
Drugs targeting the hormone FGF21 may have beneficial health effects. Variations in human DNA in the FGF21 gene provide an indication of what those effects may be. Here, we show that variation in the FGF21 gene is associated with higher blood pressure and altered body shape, despite lower total body-fat percentage.
Abstract Background Dual mobility designs were introduced to increase stability and reduce the risk of dislocation, both being common reasons for surgical revision after total hip arthroplasty. The ...in vivo behavior of dual mobility constructs remains unclear, and to our knowledge, no data have been published describing in vivo surface damage to the polyethylene bearing surfaces. Methods We used surface damage assessed on the inner and outer polyethylene bearing surfaces in 33 short-term retrieved dual mobility liners as evidence of relative motion at the 2 bearings. A lever out test was performed to determine the force required for dislocation of the cobalt-chromium femoral head from the polyethylene liner. Results Both bearings showed damage; however, the inner polyethylene bearings had higher damage scores, lower prevalence of remaining machining marks, and higher incidence of concentric wear, all consistent with more motion at the inner polyethylene bearing. The inner polyethylene bearings also had a higher occurrence of embedded titanium debris. The damage sustained in vivo was insufficient to lead to intraprosthetic dislocation in any of the retrieved components. Lever out tests of 12 retrievals had a mean dislocation load of 261 ± 52 N, which was unrelated to the length of implantation. Conclusion Our short-term retrieval data of 33 highly cross-linked polyethylene dual mobility components suggest that although motion occurs at both bearing articulations, the motion of the femoral head against the inner polyethylene bearing dominates. Although damage was not severe enough to lead to intraprosthetic dislocation, failure may occur long term and should be assessed in future studies.
Background
Fretting and corrosion at head-neck junctions of total hip arthroplasties (THAs) have been associated with adverse local tissue reactions in patients with both metal-on-polyethylene (MoP) ...and metal-on-metal (MoM) prostheses. Femoral head size contributes to the severity of fretting and corrosion in large-diameter MoM THAs, but its impact on such damage in MoP THAs remains unknown.
Questions/purposes
(1) Is femoral head size associated with increased fretting or corrosion at the head-neck junction in MoP total hips? (2) Is duration of implantation associated with increased fretting or corrosion?
Methods
The severity of fretting/corrosion on surfaces of head tapers and stem trunnions was visually examined in 154 MoP THAs retrieved as part of 3282 revision surgeries performed at our institution between January 1, 2007, and December 31, 2013. Fretting and corrosion damage were subjectively graded by two independent observers on a 1 to 4 scale, and their relations to head size, alloy combinations, taper/trunnion design, length of implantation (LOI), and location were investigated. Differences in scores never exceeded one grade, and this occurred in only 17% of examined implants. With the available implants, the study provided 88% power to detect differences of 0.5 in fretting or corrosion scores in these analyses.
Results
Fretting and corrosion of the tapers and the trunnions were not affected by head size (p = 0.247, p = 0.471, p = 0.837, and p = 0.868, respectively), although taper/trunnion design affected taper fretting (p = 0.005) and corrosion (p = 0.0031) and trunnion fretting (p = 0.0028). Head taper fretting (observed in 73% of heads) increased with LOI, but head taper corrosion (noted in 93% of heads) was not affected. Trunnion fretting (observed in 86% of stems) was more severe in mixed-alloy combinations and with increased LOI and was more severe proximally. Trunnion corrosion (noted in 72% of stems) was also location-dependent with greater corrosion distally.
Conclusions
Fretting and corrosion are regular occurrences in MoP THAs, but neither damage type was related to femoral head size. Conversely, taper design, LOI, and alloy combination affected the severity of both fretting and corrosion.
Clinical Relevance
Although it has been suggested that trunnion corrosion seen in MoP bearings is a function of larger diameter heads, our data suggest that larger femoral heads may be used for increased damage at the modular junction of MoP THAs.
Dual mobility (DM) liners were introduced to reduce instability in total hip arthroplasty. They were found to allow for motion predominantly at the femoral head and the inner bearing of the ...acetabular liner; however, little is known if this motion is sufficient to alter polyethylene material characteristics. We assessed cross-link (XL) density and oxidation index (OI) measurements of the inner and outer bearing articulations.
Thirty-seven DM liners were collected with a duration of implantation greater than 2 years. Clinical and demographic data were collected from a chart review. A cylinder was cored from the apex of each liner and cut into 4.5 mm long inner and outer diameter segments for XL density swell ratio testing. The OI was measured from sagittal 100 μm microtome slices using Fourier transform infrared spectroscopy. Student’s t-tests were used to determine differences in OI and XL density between the bearings. Spearman’s correlation assessed relationships between patient demographics, OI, and XL density. Duration of implantation for the cohort was a mean of 35 (range, 24-96) months.
The inner and outer bearing had similar median XL densities (0.17 mol/dm3 versus 0.17 mol/dm3, P = .6). The inner bearing had an increased OI when compared to the outer bearing (0.16 versus 0.13, P = .008). The OI was inversely correlated with XL density (r = −0.50, P = .002).
Small differences were found in oxidation between the inner and outer bearing of the DM construct. Failures at an average of 3 years indicate low levels of oxidation, unlikely to impact the mechanical properties of the material.
Abstract Teriparatide, a parathyroid hormone analogue, is a potent anabolic treatment for postmenopausal osteoporosis. Studies have shown that teriparatide induces large increases in biochemical ...markers of bone formation after 1 month of therapy followed by a delayed increase in bone resorption markers. The aims of this study were to (1) describe changes in bone turnover markers during 28 days of treatment with teriparatide; (2) identify the earliest time point by which most subjects showed a biochemical response to teriparatide; (3) identify potential biomarkers of positive bone response; (4) describe changes in bone turnover markers 4 weeks after stopping teriparatide. We recruited 15 osteopenic postmenopausal women, ages 55–69 (mean 62) years. All received 20 μg teriparatide subcutaneously for 28 days. Serum levels of the bone formation markers type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), and the bone resorption markers crosslinked C-telopeptide of type I collagen (Sβ-CTX), crosslinked N-telopeptide of type I collagen (S-NTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were measured on 11 occasions: three times before dosing (baseline) and on days 3, 7, 10, 14, 19, 24 and 28 and at day 56 (i.e., 28 days after stopping teriparatide ). During the first 2 days of teriparatide treatment, PINP levels increased rapidly, by 8.2% (90% confidence interval (CI) 6.9%, 9.5%) and continued to increase until the end of treatment to 110.8%. PICP and OC showed a similar, but less pronounced, pattern. All three markers increased by at least 75% at day 28. A small, transient decrease in bone resorption markers occurred over the same period. Following cessation of treatment, concentrations of bone formation markers decreased to within 20% of baseline values by day 56. In conclusion, the bone formation markers PINP, PICP and OC show a rapid and robust increase in response to teriparatide, which is noticeable during the first week of therapy. PINP is the most responsive marker. These findings have important implications for monitoring patients treated with teriparatide and may also inform the design of studies of new anabolic agents for osteoporosis.
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