Preparation of the Femoral Bone Cavity for Cementless Stems: Broaching vs Compaction. A Five-Year Randomized Radiostereometric Analysis and Dual Energy X-Ray Absorption Study

Background

Short-term experimental and animal studies have confirmed superior fixation of cementless implants inserted with compaction compared to broaching of the cancellous bone.

Remote Ischemic Conditioning on Recipients of Deceased Renal Transplants Does Not Improve Early Graft Function: A Multicenter Randomized,Controlled Clinical Trial

Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia–reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham‐RIC. RIC consisted of 4 × 5‐min thigh occlusion by an inflatable tourniquet each followed by 5‐min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham‐RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham‐RIC‐treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98–151] vs. 112 h [95% CI 91–139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719.     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Preoperative Systemic Bone Quality Does Not Affect Tibial Component Migration in Knee Arthroplasty: A 2-Year Radiostereometric Analysis of a Hundred Consecutive Patients

BackgroundBone quality and other preoperative predictive factors may affect implant migration and the survival of knee arthroplasty.MethodsIn a prospective cohort of 100 consecutive patients (65 women) at a mean age of 67.7 years (range 39-87 years), we investigated preoperative predictors of postoperative tibial component migration in cemented and cementless total knee arthroplasties or cemented unicompartmental knee arthroplasty. Predictors consisted of Knee Injury and Osteoarthritis Outcome Score (KOOS) and Oxford Knee Score, questionnaires, bone turnover markers of CTX and P1NP, systemic bone mineral density (BMD), and knee osteoarthritis (OA) grade. Tibial component migration was measured with radiostereometry postoperative, at 1 and 2 years of follow-up.ResultsBetween 1 and 2 years, 19 tibial components migrated continuously (maximum total point motion [MTPM] > 0.2 mm). In general, there was no difference in age, body mass index, BMD, KOOSs, or OA grade between patients with continuous tibial migration compared to patients without continuous migration (P > .11). However, cementless tibial components with continuous migration had a lower KOOS pain score (more pain), lower vitamin D, and a higher bone turnover (CTX) value than patients without continuous migration. There was no association between the BMD and MTPM at 1-year follow-up regardless of prothesis type (P > .17). Patients with osteoporosis and normal BMD had similar mean tibial component MTPM at 2 years (3 prostheses combined; P = .34).ConclusionMigration of tibial components inserted with or without bone cement was not affected by the preoperative bone quality in terms of systemic BMD, bone turnover markers, and OA grade in the knee.     

IL‐10‐specific autoantibodies predict major adverse cardiovascular events in kidney transplanted patients ‐ a retrospective cohort study

End‐stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine‐specific autoantibodies (c‐aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high‐sensitivity C‐reactive protein (hsCRP) and c‐aAbs specific for interleukin (IL)‐1α, tumor necrosis factor (TNF)‐α, IL‐6, and IL‐10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow‐up of 4.9 years (range 1.2–8.2 years). Systemic inflammation was associated with all‐cause mortality in simple and multiple Cox regression analyses. IL‐10‐specific c‐aAbs were associated with MACE after transplantation, suggesting that IL‐10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF‐α‐specific c‐aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro‐inflammatory activity before transplantation is a pathological driver of MACE and all‐cause mortality after transplantation. This information adds to pretransplantation risk estimation in renal transplant candidates.     

Bone Mineral Density Measurements Around Osseointegrated Implants: A Precision Study and Validation of Scan Protocol for Transfemoral Amputees

Visual evaluation of bone changes around an osseointegration (OI) implant in femoral amputees examined on plain radiographs shows that periprosthetic bone resorption takes place during the first years after OI surgery, but the bone mineral density (BMD) change has not been previously quantified by dual-energy X-ray absorptiometry (DXA). Precision is vital when monitoring BMD changes around implants, and thus the aim of this study was to evaluate the precision and feasibility of a scan protocol for BMD measurements in proximity of OI implants. The proximal part of 2 human cadaveric femoral bones (specimens A and B) with OI implants were mounted in a positioning jig and DXA scans were repeated 5 times in increments of 5° from neutral (0°) to 20° flexion and rotation. BMD changes as a result of change in leg position were evaluated. Repeated patient examinations (n?=?20) were conducted in a clinical setting and the precision error was calculated for each of 7 periprosthetic custom-made regions of interest (ROIs). The precision of cadaveric BMD measurements in neutral position was <3.3%. Even 5° flexion or rotation in femur position caused significant changes in average BMD (p?<0.04). Depending on ROI, the percentage of coefficient of variation (%CV) and average BMD was?<6% at 10° flexion and rotation. At 20° flexion, %CV increased up to 12.7% and average BMD increased up to 9.9%. The clinical short-term precision root mean square standard deviation ranged from 0.031?g/cm² to 0.047?g/cm² and %CV ranged from 3.12% to 6.57% depending on ROI. Simulated hip flexion or rotation of the femur affected periprosthetic BMD measurements around OI implants in cadaveric femoral bones, which stresses the importance of a reproducible set-up during DXA scans to reduce measurement errors caused by variation in leg position. Adherence to the scan protocol with a relaxed position of the residual limb resulted in an acceptable short-term precision below 6.6%.     

Expression of hypoxia‐inducible factor‐1α and hepatocyte growth factor in development of fibrosis in the transplanted kidney

Late renal graft loss is associated with interstitial fibrosis. Hypoxia‐inducible factor‐1α (HIF‐1α) is thought to facilitate fibrosis through interaction with TGF‐β1, while hepatocyte growth factor (HGF) may act antifibrotic in the kidney allograft. The aim of this study was to investigate the expression of HIF‐1α and HGF in protocol biopsies as possible prognostic biomarkers for renal fibrosis. Thirty‐nine renal transplant recipients were included in the study. Protocol biopsies performed 1 and 2 years after transplantation were used for immunohistochemistry analysis. The correlation between HIF‐1α/HGF and the Banff score was analysed. In addition, progression in renal fibrosis and graft survival among recipients with high or low expression of HIF‐1α/HGF after transplantation was compared. There was no significant correlation between fibrosis and the HIF‐1α expression 1 and 2 years after transplantation, but an inverse significant correlation between the HGF expression and the fibrosis score 1 year after transplantation was shown. Even when adjusting for human leucocyte antigen mismatches, there was a significant relationship between fibrosis and HGF expression. Graft survival was not significantly correlated to HIF‐1α or HGF at 1 year, although the trend was towards better graft survival with high HGF. HGF may have antifibrotic effects in human renal transplants. (Central.Denmark.Region.Committee number: 1‐10‐72‐318‐13)     

Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352

The novel anti-ischemic compound, BMS-204352 ((3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one)), strongly activates the voltage-gated K+ channel KCNQ5 in a concentration-dependent manner with an EC50 of 2.4 microM. At 10 microM, BMS-204352 increased the steady state current at -30 mV by 12-fold, in contrast to the 2-fold increase observed for the other KCNQ channels [Schr?der et al., 2001]. Retigabine ((D-23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) induced a smaller, yet qualitatively similar effect on KCNQ5. Furthermore, BMS-204352 (10 microM) did not significantly shift the KCNQ5 activation curves (threshold and potential for half-activation, V1/2), as observed for the other KCNQ channels. In the presence of BMS-204352, the activation and deactivation kinetics of the KCNQ5 currents were slowed as the slow activation time constant increased up to 10-fold. The M-current blockers, linopirdine (DuP 996; 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) and XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), inhibited the activation of the KCNQ5 channel induced by the BMS-204352. Thus, BMS-204352 appears to be an efficacious KCNQ channels activator, and the pharmacological properties of the compound on the KCNQ5 channel seems to be different from what has been obtained on the other KCNQ channels.     

Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro

Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H(2)-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms.