Mid- to late-term follow-up of primary hip and knee arthroplasty: the UK SAFE evidence-based recommendations.

To review the evidence and reach consensus on recommendations for follow-up after total hip and knee arthroplasty. A programme of work was conducted, including: a systematic review of the clinical and cost-effectiveness literature; analysis of routine national datasets to identify pre-, peri-, and postoperative predictors of mid-to-late term revision; prospective data analyses from 560 patients to understand how patients present for revision surgery; qualitative interviews with NHS managers and orthopaedic surgeons; and health economic modelling. Finally, a consensus meeting considered all the work and agreed the final recommendations and research areas. The UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE) recommendations apply to post-primary hip and knee arthroplasty follow-up. The ten-year time point is based on a lack of robust evidence beyond ten years. The term 'complex cases' refers to individual patient and surgical factors that may increase the risk for arthroplasty failure. For Orthopaedic Data Evaluation Panel (ODEP) 10A* minimum implants, it is safe to disinvest in routine follow-up from one to years post-non-complex hip and knee arthroplasty provided there is rapid access to orthopaedic review. For ODEP 10A* minimum implants in complex cases, or non-ODEP 10A* minimum implants, periodic follow-up post-hip and knee arthroplasty may be required from one to ten years. At ten years post-hip and knee arthroplasty, clinical and radiological evaluation is recommended. After ten years post-hip and knee arthroplasty, frequency of further follow-up should be based on the ten-year assessment; ongoing rapid access to orthopaedic review is still required. Complex cases, implants not meeting the ODEP 10A* criteria, and follow-up after revision surgery are not covered by this recommendation.

Association between outpatient follow-up and incidence of revision after knee and hip replacements: a population-based cohort study.

BACKGROUND: Follow-up visits 5 or 7 years after surgery were recommended for people having primary hip or knee replacement. The benefits of this practice to patients and the healthcare system, however, have not yet been specifically examined. The aim of this study was to investigate the association between long-term follow-up outpatient hospital visits and revision rates for patients who undergo primary knee or hip replacement surgery. METHODS: Cohorts were identified for patients undergoing knee or hip replacement surgery using medical records from primary care practices within the UK Clinical Practice Research Datalink (CPRD) GOLD dataset linked to hospital records from the English Hospital Episodes Statistics (HES) data. Two groups of patients were compared in terms of revision and mortality rates: those with at least one long-term (between five and 10 years since primary surgery) follow-up visit at the orthopaedic department ('Follow-up' group), and those without ('No follow-up' group). RESULTS: A total of 9856 (4349 in the Follow-up group) patients with knee replacement and 10,837 (4870 in the Follow-up group) with hip replacement were included in the analysis. For knee replacement, the incidence of revision was 3.6% for those followed-up and 0.6% for those not followed-up. An adjusted regression model confirmed the difference in the hazard ratio (HR) for revision was statistically significant (HR: 5.65 [95% CI 3.62 to 8.81]). Mortality at 4 years was lower for the Follow-up (17%) compared to the No follow-up group (21%), but this difference was not statistically significant (HR: 0.95 [0.84 to 1.07]). For hip replacement, the incidence of revision rates were 3.2 and 1.4% for the follow-up and not follow-up groups, respectively, the difference being statistically significant (HR: 2.34 [1.71 to 3.20]). Mortality was lower for the Follow-up (15%) compared to the No follow-up group (21%), but the difference was not statistically significant (HR: 0.91 [0.81 to 1.02]). CONCLUSION: Patients attending follow-up orthopaedic consultations show a higher risk of revision surgery compared to those who are not followed-up. A cause for this difference could not be identified in this study but a likely explanation is that surgeons play an effective role as ultimate arbitrators when identifying patients to be included in long-term follow-up lists.

UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national datasets tell us about mid-late term revision risk after knee replacement?

OBJECTIVE: To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up. DESIGN: Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs)). PARTICIPANTS: Primary elective KRs aged ≥18 years. EVENT OF INTEREST: Revision surgery ≥5 years (mid-late term) postprimary KR. STATISTICAL METHODS: Cox regression modelling to ascertain risk factors of mid-late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision. RESULTS: NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995-2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0-8.8), with 1055 (0.6%) mid-late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02-18.3), with 352 (2.0%) mid-late term revisions.Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.No implant factors were identified. CONCLUSION: The risk of mid-late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality.

UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national data sets tell us about mid-late term revision risk after hip replacement? Retrospective cohort study.

OBJECTIVE: To identify patients at risk of mid-late term revision of hip replacement to inform targeted follow-up. DESIGN: Analysis of linked national data sets from primary and secondary care (Clinical Practice Research Datalink (CPRD-GOLD); National Joint Registry (NJR); English Hospital Episode Statistics (HES); Patient-Reported Outcome Measures (PROMs)). PARTICIPANTS: Primary elective total hip replacement (THR) aged≥18. EVENT OF INTEREST: Revision surgery≥5 years (mid-late term) after primary THR. STATISTICAL METHODS: Cox regression modelling to ascertain risk factors of mid-late term revision. HR and 95% CI assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision. RESULTS: NJR-HES-PROMs data were available from 2008 to 2011 on 142 275 THR; mean age 70.0 years and 61.9% female. CPRD GOLD-HES data covered 1995-2011 on 17 047 THR; mean age 68.4 years, 61.8% female. Patients had minimum 5 years postprimary surgery to end 2016. In NJR-HES-PROMS data, there were 3582 (2.5%) revisions, median time-to-revision after primary surgery 1.9 years (range 0.01-8.7), with 598 (0.4%) mid-late term revisions; in CPRD GOLD, 982 (5.8%) revisions, median time-to-revision 5.3 years (range 0-20), with 520 (3.1%) mid-late term revisions.Reduced risk of mid-late term revision was associated with older age at primary surgery (HR: 0.96; 95% CI: 0.95 to 0.96); better 6-month postoperative pain/function scores (HR: 0.35; 95% CI: 0.27 to 0.46); use of ceramic-on-ceramic (HR: 0.73; 95% CI: 0.56 to 0.95) or ceramic-on-polyethylene (HR: 0.76; 95% CI: 0.58 to 1.00) bearing surfaces.Increased risk of mid-late term revision was associated with the use of antidepressants (HR: 1.32; 95% CI: 1.09 to 1.59), glucocorticoid injections (HR: 1.33; 95% CI: 1.06 to 1.67) and femoral head size≥44 mm (HR: 2.56; 95% CI: 1.09 to 6.02)No association of gender, obesity or Index of Multiple Deprivation was observed. CONCLUSION: The risk of mid-late term THR is associated with age at primary surgery, 6-month postoperative pain and function and implant factors. Further work is needed to explore the associations with prescription medications observed in our data.

A comparative study of patients presenting for planned and unplanned revision hip or knee arthroplasty.

AIMS: The aim of this study was to conduct a cross-sectional, observational cohort study of patients presenting for revision of a total hip, or total or unicompartmental knee arthroplasty, to understand current routes to revision surgery and explore differences in symptoms, healthcare use, reason for revision, and the revision surgery (surgical time, components, length of stay) between patients having regular follow-up and those without. METHODS: Data were collected from participants and medical records for the 12 months prior to revision. Patients with previous revision, metal-on-metal articulations, or hip hemiarthroplasty were excluded. Participants were retrospectively classified as 'Planned' or 'Unplanned' revision. Multilevel regression and propensity score matching were used to compare the two groups. RESULTS: Data were analyzed from 568 patients, recruited in 38 UK secondary care sites between October 2017 and October 2018 (43.5% male; mean (SD) age 71.86 years (9.93); 305 hips, 263 knees). No significant inclusion differences were identified between the two groups. For hip revision, time to revision > ten years (odds ratio (OR) 3.804, 95% confidence interval (CI) (1.353 to 10.694), p = 0.011), periprosthetic fracture (OR 20.309, 95% CI (4.574 to 90.179), p < 0.001), and dislocation (OR 12.953, 95% CI (4.014 to 41.794), p < 0.001), were associated with unplanned revision. For knee, there were no associations with route to revision. Revision after ten years was more likely for those who were younger at primary surgery, regardless of route to revision. No significant differences in cost outcomes, length of surgery time, and access to a health professional in the year prior to revision were found between the two groups. When periprosthetic fractures, dislocations, and infections were excluded, healthcare use was significantly higher in the unplanned revision group. CONCLUSION: Differences between characteristics for patients presenting for planned and unplanned revision are minimal. Although there was greater healthcare use in those having unplanned revision, it appears unlikely that routine orthopaedic review would have detected many of these issues. It may be safe to disinvest in standard follow-up provided there is rapid access to orthopaedic review. Cite this article: Bone Joint J 2022;104-B(1):59-67.

Pilot study: Is a long-term follow-up service beneficial for patients undergoing revision hip replacement surgery?

PURPOSE: Total hip arthroplasty (THA) is highly successful but some patients will require later revision surgery. This pilot study evaluates the effects of long-term follow-up for patients undergoing revision hip replacement. METHODS: Consecutive patients undergoing aseptic revision of THA were recruited from a large orthopaedic unit to a single centre, observational study. Primary outcomes were changes in patient-reported scores from pre-revision to 12 months post-surgery. Secondary outcomes were costs during hospital stay up to 6 months post-revision. Participants were retrospectively allocated to two groups-those with regular orthopaedic review prior to revision (Planned revision) or those without (Unplanned revision). RESULTS: 52 patients were recruited, 7 were unrevised, one incomplete baseline questionnaires. There were 25 planned and 19 unplanned revisions with no significant differences between groups at baseline. At 12 months, 34 complete data sets were available for analysis, 17 in each group. Change scores were analysed with Mann-Whitney U test; none reached statistical significance. There was a significant difference for length of stay: Planned group 5 days (2-22), Unplanned 11 days (3-86) (Mann-Whitney U test, p = 0.023). No significant differences found for theatre time or component costs. Resource costs post-revision surgery are presented. CONCLUSION: This pilot study indicates that some change in methods would be required for future work. The results show that there may be some financial benefit from providing long-term follow-up of THA but a larger study is needed to explore these findings and to discuss the impact on recommended guidelines.

The use of tissue adhesive as an adjunct to wound closure in knee arthroplasty does not reduce wound ooze.

INTRODUCTION: Persistent wound ooze has been associated with prolonged length of hospital stay and increased risk of infection. Recently, the use of tissue adhesive after hip and knee arthroplasty has been described. We believe that knee arthroplasty wounds exhibit different behavior compared to hip arthroplasty due to the increased wound-margin tension associated with knee flexion. PATIENTS AND METHODS: Forty-three patients undergoing total knee arthroplasty (TKA) by a single surgeon were studied. All wounds were closed using staples with or without tissue adhesive. Post-operatively, the wounds were reviewed daily for ooze. Dressings were changed only if soaked > 50% or if there was persistent wound discharge of more than 2 × 2 cm at 72 h. RESULTS: There were 21 patients in the tissue adhesive (group 1), 22 in the non-tissue adhesive (group 2) with the average age for group 1 of 72.2 years and for group 2 of 69.3 years. The median length of stay for both groups was 4 days (range of 3-7 days for group 1 and 2-6 days for group 2) (P = 0.960). The tissue adhesive group showed a statistically significant reduction in wound ooze on day 1 (P = 0.019); however, the difference was not significant on the following days. The median for the number of dressing changes for group 1 was zero changes and for group 2, one change. This was not statistically significant (P = 0.112). No complications were observed in both groups and there were no reactions to the tissue adhesive. CONCLUSION: The data from this case series suggest that the use of tissue adhesive may reduce wound ooze on day 1 only. The latter is most likely due to significant tensile forces to which the knee arthroplasty wound is subjected in the immediate post-operative rehabilitation. Further, the cost of tissue adhesive is not offset by reduced dressing changes or length of hospital stay.

Setting up an arthroplasty care practitioner-led virtual clinic for follow-up of orthopaedic patients.

This article provides an overview of the set up for an arthroplasty care practitioner (ACP)-led virtual orthopaedic clinic (VOC). Suitable patients attend a local hospital for an X-ray and complete a questionnaire, but do not physically attend a clinic. This has been running successfully in a university teaching hospital and has led to cost savings, a reduction in outpatient waiting times and high levels of patient satisfaction. Similar clinics have the potential to become normal practice across the NHS. This article outlines the steps necessary to implement a successful VOC. The lessons learnt during this exercise may be useful for other ACPs when setting up a VOC.

Systematic review of the clinical effectiveness for long-term follow-up of total hip arthroplasty.

Objectives: Total hip arthroplasty (THA) is highly successful but national registries indicate that average age has lowered and that younger patients are at higher risk of revision. Long-term follow-up of THA was historically recommended to identify aseptically failing THA, minimising the risks associated with extensive changes, but follow-up services are now in decline. A systematic review was conducted to search for evidence of the clinical or cost-effectiveness of hip arthroplasty surveillance. Methods: The study was registered with PROSPERO International Prospective Register of Systematic Reviews and conducted according to PRISMA guidelines; databases included MEDLINE and Embase, and all studies were quality assessed. Original studies (2005 to 2017) reporting follow-up of adults with THA in situ >5 years were included. Researchers extracted quantitative and qualitative data from each study. Results: For eligibility, 4,137 studies were screened: 114 studies were included in the final analysis, representing 22 countries worldwide. Data extracted included study endpoint, patient detail, loss to follow-up, revisions, scores and radiographic analysis. Six themes were derived from inductive content analysis of text: support for long-term follow-up, subgroups requiring follow-up, effect of materials/techniques on THA survival, effect of design, indicators for revision, review process. Main findings-follow-up was specifically recommended to monitor change (eg asymptomatic loosening), when outcomes of joint construct are unknown, and for specific patient subgroups. Outcome scores alone are not enough, and radiographic review should be included. Conclusion: There were no studies directly evaluating the clinical effectiveness of the long-term follow-up of THA but expert opinions from a range of international authors advocated its use for defined subgroups to provide patient-centred care. In the absence of higher level evidence, these opinions, in conjunction with emerging outputs from the national joint registries, should be used to inform services for long-term follow-up of THA.

Towards UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): protocol for an evaluation of the requirements for arthroplasty follow-up, and the production of consensus-based recommendations.

INTRODUCTION: Hip and knee arthroplasties have revolutionised the management of degenerative joint diseases and, due to an ageing population, are becoming increasingly common. Follow-up of joint prostheses is to identify problems in symptomatic or asymptomatic patients due to infection, osteolysis, bone loss or potential periprosthetic fracture, enabling timely intervention to prevent catastrophic failure at a later date. Early revision is usually more straight-forward surgically and less traumatic for the patient. However, routine long-term follow-up is costly and requires considerable clinical time. Therefore, some centres in the UK have curtailed this aspect of primary hip and knee arthroplasty services, doing so without an evidence base that such disinvestment is clinically or cost-effective. METHODS: Given the timeline from joint replacement to revision, conducting a randomised controlled trial (RCT) to determine potential consequences of disinvestment in hip and knee arthroplasty follow-up is not feasible. Furthermore, the low revision rates of modern prostheses, less than 10% at 10 years, would necessitate thousands of patients to adequately power such a study. The huge variation in follow-up practice across the UK also limits the generalisability of an RCT. This study will therefore use a mixed-methods approach to examine the requirements for arthroplasty follow-up and produce evidence-based and consensus-based recommendations as to how, when and on whom follow-up should be conducted. Four interconnected work packages will be completed: (1) a systematic literature review; (2a) analysis of routinely collected National Health Service data from five national data sets to understand when and which patients present for revision surgery; (2b) prospective data regarding how patients currently present for revision surgery; (3) economic modelling to simulate long-term costs and quality-adjusted life years associated with different follow-up care models and (4) a Delphi-consensus process, involving all stakeholders, to develop a policy document which includes a stratification algorithm to determine appropriate follow-up care for an individual patient. ETHICS AND DISSEMINATION: Favourable ethical opinion has been obtained for WP2a (RO-HES) (220520) and WP2B (220316) from the National Research Ethics Committee. Following advice from the Confidentiality Advisory Group (17/CAG/0122), data controllers for the data sets used in WP2a (RO-HES) - NHS Digital and The Phoenix Partnership - confirmed that Section 251 support was not required as no identifiable data was flowing into or out of these parties. Application for approval of WP2a (RO-HES) from the Independent Group Advising on the Release of Data (IGARD) at NHS Digital is in progress (DARS-NIC-147997). Section 251 support (17/CAG/0030) and NHS Digital approval (DARS-NIC-172121-G0Z1H-v0.11) have been obtained for WP2a (NJR-HES-PROMS). ISAC (11_050MnA2R2) approval has been obtained for WP2a (CPRD-HES).

Protocol for follow up of hip arthroplasty in the long term: effect on revision (WHISTLER study).

Total hip arthroplasty (THA) is highly successful for reducing pain and improving function, providing health-related quality of life benefit. Demand for THA is increasing with associated increase in revision hip surgery. Hip arthroplasty surveillance (long-term follow up) can identify asymptomatically failing THA to prepare for revision surgery, reducing potential for complications or complexity of surgery. However, it is unknown whether the surveillance of THA can be shown to improve the patient outcomes or reduce costs around revision surgery. With the current need to reduce unnecessary health consultations and to show the economic advantages of any service, the purpose of this study is to consider the relative effectiveness of hip arthroplasty surveillance on revision hip arthroplasty. This is a single-centre, observational study in which consecutive patients undergoing aseptic revision of THA over 12 months in a large orthopaedic unit will be considered for participation. Primary outcome measures will be change in each of three valid patient-reported scores from pre-operatively to 12 months post-surgery. Secondary outcomes will be the costs of treatment calculated using data obtained from the participants' hospital records and a self-report questionnaire. An exploratory approach will be used to investigate the effect of surveillance on the outcomes of interest. A linear mixed method model will be used to study the change in scores between baseline and 12 months. The economic evaluation will be a cost-utility analysis, which compares the value of alternative interventions by attaching costs to the quality-adjusted life years produced by each intervention.

Nrf2 upregulates ATP binding cassette transporter expression and activity at the blood-brain and blood-spinal cord barriers.

Activation of nuclear factor E2-related factor-2 (Nrf2), a sensor of oxidative stress, is neuroprotective in animal models of cerebral ischemia, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury. We show here that Nrf2 activation with sulforaphane (SFN) in vivo or in vitro increases expression and transport activity of three ATP-driven drug efflux pumps at the blood-brain barrier [P-glycoprotein, ATP binding cassette b1 (Abcb1); multidrug resistance-associated protein-2 (Mrp2), Abcc2; and breast cancer resistance protein (Bcrp), Abcg2]. Dosing rats with SFN increased protein expression of all three transporters in brain capillaries and decreased by 50% brain accumulation of the P-glycoprotein substrate verapamil. Exposing rat or mouse brain capillaries to SFN increased P-glycoprotein, Bcrp, and Mrp2 transport activity and protein expression; SFN increased P-glycoprotein activity in mouse spinal cord capillaries. Inhibiting transcription or translation abolished upregulation of P-glycoprotein activity. No such effects were seen in brain capillaries from Nrf2-null mice, indicating Nrf2 dependence. Nrf2 signaled indirectly to increase transporter activity/expression. The p53 inhibitor pifithrin abolished the SFN-induced increase in transporter activity/expression, and the p53-activator nutlin-3 increased P-glycoprotein activity. SFN did not alter P-glycoprotein transport activity in brain and spinal cord capillaries from p53-null mice. Inhibitors of p38 MAPK and nuclear factor κB (NF-κB) blocked the effects of SFN and nutlin-3 on P-glycoprotein activity. These results implicate Nrf2, p53, and NF-κB in the upregulation of P-glycoprotein, Bcrp, and Mrp2 at blood-CNS barriers. They imply that the barriers are tightened selectively (efflux transporter upregulation) by oxidative stress, providing increased neuroprotection, but also reduced penetration of many therapeutic drugs.

Deep sequencing identification of novel glucocorticoid-responsive miRNAs in apoptotic primary lymphocytes.

Apoptosis of lymphocytes governs the response of the immune system to environmental stress and toxic insult. Signaling through the ubiquitously expressed glucocorticoid receptor, stress-induced glucocorticoid hormones induce apoptosis via mechanisms requiring altered gene expression. Several reports have detailed the changes in gene expression mediating glucocorticoid-induced apoptosis of lymphocytes. However, few studies have examined the role of non-coding miRNAs in this essential physiological process. Previously, using hybridization-based gene expression analysis and deep sequencing of small RNAs, we described the prevalent post-transcriptional repression of annotated miRNAs during glucocorticoid-induced apoptosis of lymphocytes. Here, we describe the development of a customized bioinformatics pipeline that facilitates the deep sequencing-mediated discovery of novel glucocorticoid-responsive miRNAs in apoptotic primary lymphocytes. This analysis identifies the potential presence of over 200 novel glucocorticoid-responsive miRNAs. We have validated the expression of two novel glucocorticoid-responsive miRNAs using small RNA-specific qPCR. Furthermore, through the use of Ingenuity Pathways Analysis (IPA) we determined that the putative targets of these novel validated miRNAs are predicted to regulate cell death processes. These findings identify two and predict the presence of additional novel glucocorticoid-responsive miRNAs in the rat transcriptome, suggesting a potential role for both annotated and novel miRNAs in glucocorticoid-induced apoptosis of lymphocytes.

Empirical support for radiographic review: a follow-up study of total hip arthroplasty.

Routine post surgery surveillance of total hip arthroplasty (THA) is widely recommended to identify asymptomatic failure but inclusion of an x-ray adds to service costs. Evidence is needed to support orthopaedic opinion in order to identify what should be included in surveillance. An investigation was conducted to establish whether an x-ray is needed in addition to patient reported outcome measures. One hundred and fifty-four THA had been assessed at 3 years and were reviewed again at 6 to 9 years (mid-term) when radiographic signs of deterioration commonly appear. Data were explored for associations between radiographic changes and changes in the participants' Oxford Hip Score, age, EuroQol 5-D score or comorbidities. Hierarchical multiple regression analysis showed that the number of radiographic changes could not be predicted by any of the other variables. This supports the inclusion of an x-ray in THA surveillance and suggests that the state of the THA cannot be determined by the use of patient reported outcome measures alone. This has implications for future arthroplasty surveillance.

Glucocorticoids modulate microRNA expression and processing during lymphocyte apoptosis.

Glucocorticoids modulate immune development and function through the induction of lymphocyte apoptosis via mechanisms requiring alterations in gene expression. Recently, short, noncoding, microRNAs have been identified as key regulators of lymphocyte function; however, it is unknown whether glucocorticoids regulate noncoding microRNAs and whether this regulation contributes to lymphocyte apoptosis. We now show by both microarray and deep sequencing analysis that microRNAs are substantially repressed during glucocorticoid-induced apoptosis of primary rat thymocytes. Mechanistic studies revealed that primary microRNA transcripts were not repressed, whereas the expression of the key microRNA processing enzymes: Dicer, Drosha, and DGCR8/Pasha, were significantly reduced at both the mRNA and protein levels during glucocorticoid-induced apoptosis. To delineate the role of Dicer depletion and microRNA repression in apoptosis, we silenced Dicer expression in two human leukemic cell lines and demonstrated that Dicer depletion significantly enhanced glucocorticoid-induced apoptosis in both model systems. Finally, in vitro and in vivo overexpression of the conserved miR-17-92 polycistron, which was repressed significantly by dexamethasone treatment in both our microarray and deep sequencing studies, blunted glucocorticoid-induced apoptosis. These studies provide evidence of altered post-transcriptional microRNA expression and the repression of the microRNA bioprocessing pathway during glucocorticoid-induced apoptosis of lymphocytes, suggesting a role for microRNA processors and specific microRNAs in cell life/death decisions.

Glucocorticoid-induced apoptosis of healthy and malignant lymphocytes.

Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.

Use of morphometry to quantify osteolysis after total hip arthroplasty.

BACKGROUND: Progressive osteolysis threatens the longevity of hip arthroplasties and radiographic review is recommended. Measurement of osteolytic lesions in a clinical setting has not been achieved easily in the past. Other radiologic investigations provide accurate information but cost and risk to the patient prohibit their use in routine review. QUESTIONS/PURPOSES: We developed a simple, reliable tool to be used in hip arthroplasty review to quantify osteolytic changes seen on plain film radiographs. METHODS: A morphometric grid was developed and tested on simulated and actual osteolytic lesions. Four health professionals measured lesions on each of two occasions. Intraclass correlation coefficients (ICC) for interobserver and intraobserver reliabilities were calculated and Bland-Altman plots were constructed for graphic analysis. RESULTS: The ICCs for interobserver reliability on the simulated and actual osteolytic lesions were in the range 0.90 to 0.96. The values for intraobserver (test-retest) reliability were 0.97 to 0.98. The Bland-Altman plots confirmed agreement and in each case, proximity of the mean to zero indicated no significant bias. CONCLUSIONS: The data show a morphometric grid is reliable for measuring osteolytic changes after hip arthroplasty. CLINICAL RELEVANCE: This tool has potential to improve monitoring processes for hip arthroplasty and to be useful in future research studies. Additional work is needed to test for validity and clinical importance of the measurements obtained.